Cancer Drug News Editor's Blog

Increasing OC rates call for more research

2010-07-28T11:25:00.001+01:00

According to the American Cancer Society, oral cancer (OC) has increased by 21 per cent in the last five years, while new cancers of all types have risen by 8 per cent. Tongue squamous cell carcinoma (TSCC) is one of the most common types of OC and has increased by more than 37 per cent in this period. Although overall cancer deaths decreased during this period, those due to OC increased by 4 per cent and those due to TSCC by 10 per cent. According to Cancer Research UK, while female OC rates have remained significantly lower than male rates, incidence trends have been similar, with an average increase of 3 per cent each year since 1989. It is well documented that this increase in OC is largely due to lifestyle, with smoking and heavy alcohol consumption significantly increasing the risk of an individual developing the disease.

However, new research by scientists at the University of Illinois at Chicago (UIC) may help in the fight against this ever-increasing cancer. According to the researchers, the spread of cancer cells in the tongue may be reduced if a gene that regulates cancer cell migration can be controlled. Dr Xiaofeng Zhou, assistant professor in the UIC Center for Molecular Biology of Oral Diseases, led the study and believes that OC is an under-treated and poorly-understood disease, noting that improvements in patient survival require better understanding of tumour invasion and how the cancer spreads.

The study, which was published in the 1st August issue of the International Journal of Cancer (2010;127:505-512), examined a non-coding gene, called miR-138, and demonstrated that a reduced level of it is associated with enhanced ability of TSCC cells to spread. Previously, the same team reported that reduced miR-138 level is correlated with enhanced metastatic potential in TSCC cells. In the current study, it was demonstrated that miR-138 suppresses TSCC cell migration and invasion by regulating two key genes in the Rho GTPase signalling pathway, RhoC and ROCK2. The scientists believe that miR-138 may serve as a novel therapeutic target for TSCC patients at risk of metastatic disease.

Further, Case Western Reserve University School of Dental Medicine researchers recently discovered a biomarker, called human beta defensin-3, which may serve as an early warning to OC. The defensin is present in all OCs and associated with the early stages of the disease. It is thought that using the biomarker to detect OC holds potential for saving lives when the cancer is most curable.

The increasing prevalence of OC highlights the need for more work like this to be conducted. Research such as that carried out by UIC and Case Western may mean that aggressive tumours can be detected early and targeted therapies can eventually be developed in the fight against this disease.

Alice Rossiter
Editor, Cancer Drug News

Shares tumble as trials fail

2010-06-24T22:11:00.003+01:00

Several Phase II and III trials have recently produced disappointing data, resulting in the failure to meet primary and secondary endpoints. The impact of this can be huge for some of the smaller companies, causing share prices to drop considerably.

Of particular note, Curis, Roche and Genentech's Phase II trial of GDC-0449, a first-in-class Hedgehog pathway inhibitor, tested in combination with Avastin (bevacizumab) and FOLFOX or FOLFIRI chemotherapy in first-line metastatic colorectal cancer (MCRC) patients did not meet its primary endpoint of extending the time from randomisation to disease progression or death when compared to patients who received only the current standard-of-care treatment. As a result, Curis' share price sank by 48 per cent, whereas the company's stock had more than doubled during the past year until this point. Despite these disappointing results in MCRC, Curis remains encouraged that the clinical development of GDC-0449 in other cancers continues to make good progress.

Further disappointment arose for Bayer HealthCare and Onyx Pharmaceuticals, when a final analysis of the Phase III NExUS trial evaluating Nexavar (sorafenib) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) showed that the study did not meet its primary endpoint of improving overall survival (OS) in the first-line setting, although a positive secondary endpoint of progression-free survival (PFS) was observed. The two companies are to further review the findings of this analysis to determine what, if any, impact these data might have on other ongoing clinical trials evaluating the safety and efficacy of sorafenib.

Marshall Edwards (Novogen) recently experienced a similar blow, when a final analysis of the company's Phase III OVATURE trial of orally-administered phenoxodiol in women with recurrent ovarian cancer determined that the study did not show a statistically significant improvement in its primary (PFS) or secondary (OS) endpoints. Following this news, the company's share price dropped by 50 per cent.

Also, in May, GTx reported top-line results of a Phase III trial evaluating toremifene 20mg for the prevention of prostate cancer (PCA) in men with high-grade prostatic intraepithelial neoplasia, which showed that the incidence of PCA was lower in men receiving the drug compared to placebo, but not statistically significantly different (p=0.385). A 10.2 per cent relative risk reduction at three years was observed. Following these results, the company's share price dropped by over 33 per cent. Dr Mitchell S Steiner, CEO of GTx, commented: "We designed the Phase III trial based upon the successful outcome of our Phase IIb clinical trial. Toremifene 20mg did also reduce prostate cancer in our Phase III study, but based on our review of the top-line data, there is not a sufficient reduction in cancers compared to placebo over a three-year period to demonstrate the statistical significance required for this study."

Alice Rossiter
Editor, Cancer Drug News

Potential miRNA drug target identified for mesothelioma

2010-05-28T12:56:00.002+01:00

Although mesothelioma is generally regarded to be a rare cancer, it appears to be getting more common. More than 2,300 people are diagnosed with the disease every year in the UK alone, with approximately five-times as many cases in men as in women. According to Cancer Research UK, the number of cases of mesothelioma in the UK each year is expected to rise dramatically over the next 20 years because of the heavy use of asbestos in industry from the end of the second world war up until the mid-1970s. Mesothelioma in the chest (pleural mesothelioma; PM) is much more common than in the abdomen (peritoneal mesothelioma).

Recent work by Rosetta Genomics and New York University demonstrated the potential of miR-31, an miRNA that has recently been characterised as a suppressor of breast cancer metastases, to be used for the development of new therapies against mesothelioma and other cancers. In the study, published in the 12th May online edition of the Journal of Biological Chemistry (10.1074/jbc.M110.100354), cell lines derived from mesothelioma patients were found not to express miR-31. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion and clonogenicity of mesothelioma cells. The reintroduction of miR-31 suppressed cell cycle and inhibited expression of multiple factors involved in co-operative maintenance of DNA replication and cell cycle progression.

miRNAs, described as the body's master switches, hold significant potential for therapeutic applications, and have been shown to be highly-sensitive and specific biomarkers in recent work. Kenneth A Berlin, President and CEO of Rosetta, commented: "This latest publication is another demonstration of miRNAs' potential role in cancer therapeutics and details the significant impact a single miRNA can have on disease course." Using its diagnostic tests for cancer, and robust and diverse miRNA-based product pipeline, Rosetta plans to continue its research in this field by harnessing the power of miRNAs.

A further development in mesothelioma also occurred in May, as MolMed received clearance from the FDA for the IND application filed to initiate a Phase III trial of its investigational antitumour drug, NGR-hTNF, for the treatment of malignant PM (MPM). The study, NGR015, is a pivotal randomised, double-blind, placebo-controlled, international, multi-centre, Phase III trial, expecting to enrol adult patients affected by MPM with disease progressing after chemotherapy. The main endpoint of the trial is overall survival; secondary endpoints include progression-free survival, disease control rate, safety and patient quality of life. Based on the positive results of a multi-centre, Phase II study, this Phase III trial is optimally designed to investigate the full therapeutic potential of NGR-hTNF in the treatment of MPM. If positive data are yielded from this study, NGR-hTNF may represent a novel treatment option for malignant mesothelioma.

Alice Rossiter
Editor, Cancer Drug News

New findings could advance fight against BC

2010-05-14T12:30:00.001+01:00

Recent findings by scientists could help advance the fight against breast cancer (BC). A team at the University of Kentucky (UoK) Markey Cancer Center has identified a key molecular mechanism in BC that enables tumour cells to metastasise, while a separate study has uncovered five new regions of the genome that increase a woman's risk of developing the disease by between 6 and 16 per cent.

The work conducted by the UoK could lead to new lines of research aimed at developing treatments for metastatic BC (MBC). The research, published in the 13th April online issue of The EMBO Journal (10.1038/emboj.2010.63), focused on the process by which tumour cells stop clinging to other cells and become motile. The increased motility of tumour cells at the initial step of metastasis is similar to epithelial-mesenchymal transition (EMT). In all EMT processes, cells lose the expression of E-cadherin, which functions as a "molecular glue" that attaches cells to one another. The team explained that when E-cadherin is broken down, tumour cells start to migrate and spread throughout the body.

A protein called Snail acts as a master switch in the cell's nucleus to suppress E-cadherin expression and induce EMT in the cell. Agents that can disrupt the interaction of Snail are thought to have great therapeutic potential for treating MBC. Leading on from these findings, the scientists at the UoK are keen to develop drugs that can treat metastatic cancer.

Separately, a study funded by Cancer Research UK (CRUK) and the Wellcome Trust has found five new regions of the genome that increase a woman's risk of developing BC by between 6 and 16 per cent. As more of these low-risk sites are found, scientists believe that it may be possible to create tests for a combination of them that together significantly increase risk, which could ultimately help doctors to make decisions about prevention, diagnosis and treatment for women who are more likely to get BC.

The scientists scanned the entire genetic code of over 4,000 women with BC and a family history of the disease for genetic variations that appeared more often compared to healthy women. They then tested the most promising regions in over 12,000 women with BC and 12,000 women without the disease in an international collaboration. Although the results now take the total number of gene regions linked to the risk of BC to 18, scientists are still unsure which genes are causing this increased risk. Lead author, Professor Doug Easton, director of CRUK's Genetic Epidemiology Unit at the University of Cambridge, commented: "While each of these sites have a small impact on breast cancer risk, by finding more of these genes, we may be able to develop a test that can predict more reliably a woman's risk of developing breast cancer."

Alice Rossiter - Editor, Cancer Drug News

Neutropenia still prevalent despite drug availability

2010-04-21T21:40:00.002+01:00

According to findings from a pan-European patient and nurse survey presented at the 7th Annual European Oncology Nursing Society (EONS) Spring Convention, held from 15th to 16th April, in the Hague, the Netherlands, 30 per cent of patients surveyed experienced an infection as a result of chemotherapy (CT), 45 per cent of which were associated with neutropenia or febrile neutropenia (FN). These results suggest that despite the widespread availability of prophylactic treatments, a significant number of cancer patients continue to be affected by neutropenia and its consequences.

The survey, which was sponsored by Amgen, was conducted by the EONS in nine European countries to explore current perceptions and issues relating to cancer therapy and infection, specifically neutropenia and FN. The survey found that 57 per cent of patients with an infection required hospitalisation, whilst 37 per cent had to have their CT delayed or changed as a result of neutropenia, infection or FN. More than nine out of ten nurses questioned agreed that preventing infections, such as FN, is important to achieve a successful outcome for patients undergoing CT. Kay Leonard, EONS Board Member, commented: "The survey results suggest that the risk of neutropenia and the impact this can have on patients' clinical care and quality of life must be taken even more seriously...it is important to ensure patients are receiving the most effective and appropriate prophylactic therapies as early as possible to help achieve positive treatment outcomes and prevent related complications before they develop."

Treatments are available to prevent and manage CT-induced infections, and significant progress has been made in the development of proactive therapies to help manage side effects of CT. For example, in March, the European Medicines Agency's CHMP adopted a positive opinion recommending the granting of a marketing authorisation for Hospira's Nivestim (filgrastim), a recombinant human G-CSF intended for the treatment of neutropenia. This medicine has been shown to be similar to Amgen's Neupogen (filgrastim), which is already authorised in the EU for the same indication and as one of the company's major products, achieved 2009 sales of US$1,288 million. Further, Sandoz' (Novartis) Zarzio (filgrastim) was launched in the UK last year and has been shown to have an efficacy and safety profile comparable with Neupogen, but is 10 per cent less expensive.

Many recombinant human G-CSFs are available to treat or prevent neutropenia, and therefore reduce associated complications. This is reflected in 54 per cent of nurse survey respondents who confirmed using G-CSFs prophylactically to prevent FN in patients receiving CT. An additional 27 per cent of nurses reported using both G-CSFs and antibiotics, however, 85 per cent of nurse respondents expressed concerns regarding patient compliance to treatment.

Moreover, it was reported by patients in the survey that access to and provision of treatments that prevent infection varies widely across Europe. A significant number of patient respondents did not appear to fully understand their risk of developing FN, which suggests a need for improvement in communication between patients and healthcare providers.

Alice Rossiter
Editor, Cancer Drug News

Skin cancer rates rapidly rising

2010-04-09T10:20:00.003+01:00

In line with its launch of the 2010 SunSmart campaign, Cancer Research UK (CRUK) has revealed that people aged 60 to 79 years of age are now over five-times more likely to be diagnosed with malignant melanoma (MM) than their parents would have been 30 years ago.

Of all ages, this generation has seen the biggest increase in incidence rates of melanoma, rising from seven cases per 100,000 people in the mid-1970s to 36 cases per 100,000 today. This rise shows the impact that a shift in tanning behaviour has had on a whole generation of men and women who would have been in their 20s and 30s in the 1970s, when holidays in the sun became cheap and popular, and sunbeds arrived in the UK.

According to CRUK statistics, the most common kind of skin cancer is non-melanoma skin cancer. More than 75,000 cases are registered each year in the UK, but it is estimated that the actual number is at least 100,000. More than 10,400 cases of MM are diagnosed each year in the UK and more than 2,000 people a year die from the disease.

For men in their 60s and 70s, the rates of melanoma have risen most dramatically; they are over seven-times more likely to be diagnosed with the disease than in the 1970s. For men and women of all ages, melanoma incidence rates have quadrupled since the 1970s. This rise in incidence rates is expected to continue: by 2024, rates in people aged 60 to 79 are predicted to increase by one-third from current statistics. Caroline Cerny, SunSmart manager at CRUK, commented: "The battle against melanoma is far from won. Today, the problem threatens to get worse as teenagers continue to crave a tan on the beach and top it up cheaply on sunbeds."

CRUK also noted that there has been a large increase in the overall death rates. Over a similar period, they have more than doubled from 1.2 per 100,000 in 1971 to 2.6 per 100,000 in the UK in 2007. If melanoma death rates had stayed the same as they were in 1973, approximately 19,000 fewer people would have died from the disease.

Although the incidence rates are predicted to rise, there are currently many promising drugs in development for MM. Of particular note, Pain Therapeutics (PT) recently reported encouraging clinical data with PTI-188, an early-stage drug for MM. Although efficacy was not a primary endpoint, PT and its clinical investigators were encouraged by the number of melanoma tumours that had either stabilised or decreased in size after a single dose of PTI-188. Further, Vical recently completed enrolment of the planned 375 subjects in its multi-national, Phase III trial of Allovectin-7 in patients with MM. Allovectin-7 is a novel gene-based immunotherapeutic with a unique mechanism of action that is fundamentally different from currently-approved treatments and has the potential to be the first new primary treatment approved for MM in nearly 20 years.

Alice Rossiter
Editor, Cancer Drug News

HRT linked to LC risk

2010-03-10T15:29:00.001Z

Women who take hormone replacement therapy (HRT) are at an increased risk of developing lung cancer (LC), new research by the Oregon Health and Science University suggests. As published in the 16th February online edition of the Journal of Clinical Oncology (10.1200/JCO.2009.25.9739), women aged 50 to 76 years who take oestrogen plus progestin (O+P) may have an increased risk of the disease.

According to the researchers, although the risk is duration-dependent, with women taking HRT for ten or more years at greatest risk of developing LC, an acceptable length of HRT has yet to be determined. However, it was noted that while the risk of developing LC for women using O+P for ten years or longer was approximately 50 per cent more than women not using HRT, this risk is small compared to the risk from smoking.

The scientists reviewed data collected from 2000 to 2002, and identified 36,588 peri- and postmenopausal participants aged 50 to 76 years who met their study criteria and followed them for six years. At the end of the observation period, December 2007, 344 of the participants had developed LC. After adjusting for smoking, age and other factors that affect the risk of the disease, the researchers determined that the use of O+P for ten or more years was associated with an increased risk for LC, compared with no use of HRT. They also found that the duration of use was associated with an advanced stage of cancer at diagnosis.

This research is not the first to highlight the risk of HRT use with LC. Scientists from the University of California, Los Angeles Medical Center previously reported that HRT using O+P increases the risk of death from LC. After the eight-year total follow-up from the study, published in the 20th September 2009 online edition of The Lancet (10.1016/S0140-6736(09)61526-9), the researchers found that more women died from LC in the combined HRT group than in the placebo group (73 compared to 40 deaths). In other words, women in the HRT group were 71 per cent more likely to die.

Further, it is not just an increased risk of LC that has been linked with HRT. According to results from a Stanford University study, published in the 5th February 2009 edition of the NEJM (2009;360:573-587), postmenopausal women who take combined O+P menopausal hormone therapy for at least five years double their annual risk of breast cancer. This multi-centre study also found that women on HRT can quickly reduce their risks of cancer simply by stopping the therapy.

Research such as this suggests that postmenopausal women, especially current smokers or long-term past smokers, should carefully consider these risks before initiating or continuing combined O+P use.

Alice Rossiter
Editor, Cancer Drug News

Scientists establish link between deprivation and poor prognosis for BC

2010-03-01T15:33:00.000Z

Deprivation has long been known to play a role in the development of a wide range of diseases, and to a higher risk of recurrence or death for patients diagnosed with a number of cancers. Previously, the effect of material deprivation on cancer survival in England and Wales was measured by Cancer Research UK, and results showed that cancer survival for adults is generally lower among patients in more deprived groups, even after allowance is made for the higher mortality from all causes of death in these groups.

The reasons for survival rates differing between breast cancer (BC) sufferers from poorer areas and more affluent areas has never been fully understood. Now, researchers from the University of Dundee have established a link between deprivation and the p53 gene, which explains why women from poorer backgrounds are less likely to survive BC. The team identified, for the first time, that p53 mutation in BC is associated with socio-economic deprivation, and that this helps account for the poorer prognosis for women from deprived communities.

As detailed in the 26th January online edition of the British Journal of Cancer (10.1038/sj.bjc.6605540), the scientists found that women from deprived backgrounds were more likely to experience a mutation of p53, and that this linked to higher relapse and mortality rates. According to the team, there are two ways that p53 mutations can come about; one is as a result of genetic predisposition and the other is as a result of lifestyle. Smoking, drinking and poor diet can lead to p53 mutations, and are more common in women from lower socio-economic groups, who are also more likely to experience a recurrence of the disease and to die as a result of BC.

The survey looked at a total of 246 women who underwent treatment for BC between 1997 and 2001. Examining frozen tissue, tests were carried out to determine p53 mutation status. Using the patients' postcodes, a deprivation score was attributed to each and examined against the outcome (full recovery, relapse, death). The team found that patients in the lowest socio-economic group were significantly more likely to have a relapse and die compared to those in more affluent categories. They also demonstrated that the worse survival and shorter disease-free interval in BC for the most deprived patients is associated with tumour p53 mutation.

This research demonstrates a strong link between p53 and deprivation, and then between p53 mutation and recurrence and death. The social application of this work would suggest that if deprivation can be targeted, then the deprived population would be less likely to have problems with their p53 gene and go on to develop BC. In reality, this is unlikely to be achieved, however, there has been numerous work surrounding the p53 protein: Cyclacel Pharmaceuticals' seliciclib (CYC202) is a promising anticancer agent that promotes cancer cell death by downregulation of key proteins, such as p53 and Mcl-1, associated with survival of cancer cells; and new research by Dartmouth Medical School has shown that p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.

Alice Rossiter
Editor, Cancer Drug News

Melanoma drugs potentially harmful to some patients

2010-02-17T14:43:00.001Z

It is well known within the scientific community that the BRAF gene is faulty in approximately half of malignant melanomas and many other cancers, making it a suitable drug target. Drugs that block BRAF function in cells are already showing positive results in early clinical trials in melanoma. While the long-term effects of these drugs are not yet known, two new reports have suggested that these drugs may have unintended consequences in patients whose tumours lack mutations in the BRAF gene.

In separate studies, conducted by researchers in the US, from the Memorial Sloan-Kettering Cancer Center, and the UK, by the Institute of Cancer Research (ICR), scientists tested the drugs to better understand how they behave in cells, and found that they spurred the growth of some tumours. These preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors, as they could make their cancers worse.

Based on these studies, it is thought that giving these drugs to patients whose tumours have normal copies of the BRAF gene could accelerate tumour growth. The findings suggest that physicians need to avoid treating patients who do not have certain genetic mutations, as they could potentially cause harm. The drugs primarily target a mutation in the BRAF gene, called V600E. Many, but not all of the patients enrolled in clinical trials of BRAF inhibitors have had this mutation in their tumours. The alteration is present in approximately half of all melanomas and it activates growth-promoting messages from the MAPK signalling pathway.

The new studies focused on tumours that had mutations elsewhere in the pathway. Both groups found that BRAF inhibitors can promote tumour growth in melanoma cells that lack the V600E mutation by activating other elements of the pathway. The researchers proposed several models that could potentially explain how a drug designed to inhibit the pathway could lead to its activation. The US study's first author, Dr Georgia Hatzivassiliou, of Genentech (Roche), noted that the new results, which were published in the 3rd February online edition of Nature (10.1038/nature08833), clearly indicate that the effects of BRAF inhibitors depend on the cellular context of a tumour cell. For instance, both research teams found that the drugs could activate BRAF signalling in melanoma tumours with mutations in the RAS gene, which is part of the BRAF pathway.

As reported by the ICR in the 22nd January issue of Cell (2010;140:209-221), the drugs fuelled rather than blocked the growth of melanoma cells with RAS mutations. Both studies concluded that a central player in the activation of the BRAF pathway was a protein, called CRAF, which is a close relative of BRAF. These findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors and give researchers information about where to look in the signalling pathway.

This work has large implications, with every tumour being different; understanding more surrounding the biology of these tumours may allow scientists to develop better treatment options. Further, the impact of this research will enable physicians to target treatments more precisely to patients who will definitely benefit, and avoid treating those who will not. The financial impact of these findings is at present unknown, however, there are BRAF inhibitors currently in clinical development. Plexxikon's PLX4032 (also known as RG7204), which is in-licensed by Roche, is currently in an open-label, single-arm, Phase II trial, called BRIM2 (B-Raf Inhibitor in Melanoma), in previously-treated metastatic melanoma patients, and recently entered a pivotal Phase III trial, BRIM3, for the same indication.

Alice Rossiter
Editor, Cancer Drug News

Positive data presented at recent LC conference

2010-01-21T10:42:00.002Z

At the recent AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer in Coronado, CA, many positive advances were presented, including a new study, which suggested that retreating non-small cell lung cancer (NSCLC) patients with AstraZeneca's Iressa (gefitinib) could have a beneficial effect, Phase II study results of ASA404 (vadimezan) in patients with either squamous or non-squamous NSCLC and preclinical results showing that Synta Pharmaceuticals' STA-9090 is active against 100 per cent of all NSCLC cell lines tested.

With regard to the gefitinib study, researchers evaluated 15 patients who were retreated with the drug after more than one cycle of chemotherapy for advanced or metastatic NSCLC. Among the six patients who had showed partial response (PR) with initial gefitinib treatment, two patients showed an additional PR and three continued to show stable disease (SD). Among the nine patients who showed SD with the initial gefitinib treatment, two patients showed PR and three showed SD. The overall disease control rate was 66.7 per cent.

Separately, ASA404 showed promise in patients with either squamous or non-squamous NSCLC. These results support ongoing Phase III studies of the drug in NSCLC. Under development by Novartis, which licensed the drug from Antisoma, ASA404 has a unique mechanism of action against a tumour's blood supply. The product has been shown to cause selective disruption of the established tumour vasculature, inhibition of tumour blood flow and tumour necrosis. This unique mechanism of action could provide an option for patients with either squamous or non-squamous NSCLC. Treatment options for patients with advanced-stage NSCLC are limited, particularly for those with squamous histology where some treatments exhibit limited efficacy or serious side effects.

Further, preclinical results showed that STA-9090, a potent, synthetic inhibitor of heat shock protein 90, demonstrated potent activity against 100 per cent of all NSCLC cell lines tested, including those with EGFr, HER2 or KRAS mutations, including the EGFr T790 mutation that is present in approximately 50 per cent of cases of erlotinib or gefitinib resistance. Synta is currently enrolling patients in a single-arm, open-label, single-agent, Phase II study of STA-9090 in patients with Stage IIIb or IV NSCLC, with patient cohorts defined by the genetic profile of their tumours.

STA-9090 potently inhibited cell proliferation in 24 out of 24 human NSCLC lines tested, irrespective of EGFr, HER2 or KRAS mutational status. In vivo, STA-9090 stopped tumour growth in both erlotinib-sensitive and -resistant NSCLC xenograft models. In addition, in a HER2-positive adenosquamous LC study, three out of four animals treated with STA-9090 experienced partial responses, as measured by MRI. Dr Vojo Vukovic, Chief Medical Officer of Synta, stated: "taken together, the in vitro and in vivo results presented at this conference demonstrate the potency, broad activity and safety profile of STA-9090, both as a single agent and in combination with taxanes in NSCLC."

Alice Rossiter
Editor, Cancer Drug News

Advances in skin cancer R&D

2010-01-13T11:38:00.001Z

The last week has seen notable advances in the field of skin cancer research and development, including the initiation of Plexxikon's pivotal Phase III trial of PLX4032 in patients with metastatic melanoma (MM), detailed results of Biofrontera's Phase III comparative study of BF-200 ALA for the treatment of actinic keratosis (AK) and a new study from Stanford University suggesting that an anti-inflammatory prescription drug can reduce the risk of a common skin cancer in humans.

Enrolment has been initiated and the first patient has been dosed in the pivotal Phase III trial of PLX4032, a novel, oral and highly-targeted drug that is designed to inhibit the BRAF cancer-causing mutation that occurs in approximately 50 per cent of melanomas. The randomised, controlled trial, called BRIM3 (BRAF Inhibitor in Melanoma), in previously-untreated patients is part of the planned registration programme for PLX4032. With some tumour shrinkage in nearly all mutation-positive melanoma patients, and 70 per cent of patients achieving at least 30 per cent tumour shrinkage in the company's most recent clinical study, PLX4032 has shown meaningful antitumour activity. BRIM3 is expected to enrol approximately 700 previously-untreated melanoma patients who will be randomised 1:1 with PLX4032 960mg twice daily or dacarbazine.

Separately, detailed results of Biofrontera's Phase III comparative study have confirmed the superiority of BF-200 ALA over Photocure's Metvix (methylaminolevulinate) for the treatment of AK. Patients were treated by photodynamic therapy, combining one of the test compounds or a placebo with a brief red light illumination. With different types of red light sources, BF-200 ALA on average erased all lesions in 78 per cent of the patients, whereas the registered comparator, methylaminolevulinate, only reached a complete healing rate of 64 per cent, and the placebo group of 17 per cent.

Further, according to researchers at Stanford University School of Medicine, a widely-available anti-inflammatory prescription drug can reduce the risk of a common skin cancer in humans. The scientists believe that although oral administration of celecoxib is associated with an increased risk of myocardial infarction and stroke in some people, it is possible that topical application could have a safer, protective effect for people prone to developing basal cell carcinomas (BCCs). The investigators dovetailed studies in mice with a randomised, double-blind, Phase II trial to reach their conclusions.

The researchers enrolled 60 people with a genetic predisposition to BCC in a three-year trial. Approximately half of the patients received celecoxib 200mg twice daily in a tablet format, while the others received a placebo. All patients were monitored at three-month intervals at one of four study sites for the development of new BCCs or the growth of previously-identified cancers. They found that, although both groups continued to develop new cancers during the study, oral celecoxib treatment decreased the growth of skin tumours by approximately 50 per cent, as compared to placebo, in participants who entered the trial with 15 or fewer BCCs. Celecoxib treatment also reduced the overall tumour burden in this group of patients.

Alice Rossiter
Editor, Cancer Drug News

Scientists battle cancer drug resistance

2009-12-02T14:21:00.002Z

A main cause of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Much research is already under way to investigate ways of reducing or preventing chemotherapy (CT) resistance. Now, scientists from Kingston University, London, the UK, have begun a three-year study to analyse why cancer patients become resistant to treatments designed to fight the disease. The team has been awarded £99,000 to investigate why some tumours are sensitive and respond to treatments, and why other tumours do not. The study, funded by cancer charity, BRIGHT (Better Research into Gastrointestinal Cancer Health and Treatment), will look at existing treatments for colorectal cancer (CRC).

Experts from Kingston's Faculty of Science will work with specialists at Royal Surrey County Hospital to examine tumour specimens from CRC patients. They aim to identify signs or markers that could indicate how patients respond to treatment with anticancer drugs. The scientists will also investigate whether cancer stem cells (SCs) play an important role in the progression of CRC, and could be responsible for the poor response or development of resistance to treatment with anticancer drugs.

The study could help local health authorities to target drugs more effectively and spare those who will receive no significant benefit from treatment with what are often expensive drugs. The researchers want to investigate why it is that after several cycles of CT, resistance to the CT agents occurs. Ultimately, the team hopes that the results of the investigation will improve survival among cancer patients. It should also help scientists to develop new drugs to target those patients who do not respond well to medication currently available.

Further research in the field of resistance to cancer therapy could come from a new exclusive licence between Clarient and Minerva Biotechnologies. Minerva has granted Clarient the exclusive right to develop and commercialise a test that identifies the MUC1* protein, a biomarker researchers believe may be implicated in the spread of many cancers, including breast cancer. Early research has demonstrated that MUC1* may play a role in developing resistance to cancer drugs, which means that if scientists can block MUC1*, patients may be able to overcome resistance to a drug and, once again, be offered that therapy.

The MUC1 story has garnered a great deal of attention recently with Minerva's discovery that MUC1 is in an altered form, called MUC1*, on embryonic SCs and cancer cells. This is the first direct evidence that cancer cells grow by hijacking a normal SC mechanism that usually exists in a dormant state on healthy adult cells. Minerva has compelling evidence that cancer cells that grow resistant to anticancer drugs do so by producing more MUC1*. A recent study by Minerva outlined how the blocking of MUC1* can reverse an acquired resistance to cancer drugs, increasing the therapeutic choices for certain solid tumours.

Alice Rossiter - Editor, Cancer Drug News

Various positive data disclosed at AACR-NCI-EORTC meeting

2009-11-25T15:21:00.002Z

Scientists, pharmaceutical companies and industry experts from around the world recently gathered at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held from 15th to 19th November, in Boston, MA, where much encouraging data were presented regarding a wide range of cancer indications. Of particular note, positive data were reported from studies in metastatic melanoma, lymphoma, and head and neck cancer.

Initial data from an ongoing Phase IIa study of Myriad Pharmaceuticals' Azixa (MPC-6827), a microtubule destabilising agent in Stage IV melanoma patients, demonstrated encouraging durations of response. The combination of Azixa at all concentrations with fixed-dose temozolomide, including the previously-determined single-agent maximum tolerated dose of Azixa, was safe and well tolerated. Ten patients achieved stable disease (SD) and two achieved confirmed partial responses (PRs). One patient had SD for four months before achieving a PR for an additional eight months. A second patient had SD for two months before achieving a PR for an additional four months.

Further, data from a Phase I study demonstrated that TopoTarget's belinostat (PXD101) in combination with Velcade (bortezomib) is well tolerated in patients with advanced solid tumours or lymphoma. A total of 22 were evaluable for toxicity and received a total of 58 treatment cycles. At the highest dose level, dose-limiting toxicity included Grade 4 thrombocytopenia and fatigue. Most adverse events (AEs) have been mild to moderate and four patients have maintained SD for four to six cycles of therapy.

Professor Peter Buhl Jensen, CEO of TopoTarget, commented: "we now know that full doses of belinostat can be given with full Velcade doses. This promising combination can now be tested in larger populations...belinostat may become an important treatment alone or may be part of an effective combination treatment as the safety profile of belinostat allows it to be combined in full dose with conventional and novel therapies like Velcade."

Separately, updated results from a Phase I/II trial (REO 011) of Oncolytics Biotech's Reolysin combined with carboplatin and paclitaxel (CP) for patients with advanced cancer, with a focus on H&N cancer, demonstrated that Reolysin was well tolerated when administered intravenously in combination with CP. Of 19 evaluable patients with H&N cancer, mostly squamous cell carcinoma of the H&N refractory to prior platinum-based chemotherapy for recurrent/metastatic disease, eight experienced PRs and six had SD. The total clinical benefit rate observed in H&N cancer patients in the trial was 74 per cent. Of four patients with malignant melanoma on the trial, one experienced a PR and one had SD.

Alice Rossiter - Cancer Drug News Editor

New direction needed for PC research

2009-11-11T15:50:00.003Z

The current focus on individualised care in many different cancer indications has left pancreatic cancer (PC) behind. Patients diagnosed with this disease live no longer today than those diagnosed two decades ago, despite numerous amounts of clinical trials. Whilst there have been great advances in other cancers, with patients benefiting from targeted drugs such as Gleevec (imatinib) and Herceptin (trastuzumab), PC still remains aggressive as ever.

Published in the 26th October online edition of the Journal of Clinical Oncology (10.1200/JCO.2009.21.9022), an expert panel convened by the National Cancer Institute has issued a consensus report that discusses many aspects of developing and testing treatments in this disease, and charts a course for the next five years. The authors of the report have stressed that the recommendations be strongly considered in any clinical trial being planned for PC.

A recommendation is to design pilot studies that test potential treatments in smaller groups before proceeding to larger trials, which have previously yielded disappointing results. Decisions about which molecular targets and potential drugs to pursue will be made based on scientific evidence that will include preclinical and animal studies that better represent PC in humans.

As the report notes, a better understanding of the complex signalling pathways in pancreatic tumours and the role of the local tumour environment are needed. More sophisticated modelling systems and repositories of high-quality biological samples that can be shared among preclinical researchers are also essential. Published in the same issue the Journal of Clinical Oncology (10.1200/JCO.2009.24.2446), a study provides an example of the kinds of trials many in the field hope to avoid in the future. As has been the pattern for these studies, patients saw little or no benefit from the experimental treatment, in this case, a combination of gemcitabine and capecitabine, as compared with gemcitabine alone.

Scientists involved in clinical trials for PC are aware of the limited success, and have already begun to adopt new ideas about developing and testing treatments. Dr Philip A Philip, the report's senior author, commented: "we have to be more thoughtful and innovative in bringing forward new targeted therapies and treatment combinations." The hope is that the new strategy will ensure that resources and patient time are spent on the most promising treatments.

Separately, in findings that could help researchers focus their drug-development efforts, Massachusetts Institute of Technology cancer biologists have identified a subpopulation of cells that can give rise to PC. In mouse models, they also found that tumours can form in other, more mature pancreatic cell types, but only when they are injured or inflamed, suggesting that PC can arise from different types of cells depending on the circumstances. In future studies, the MIT researchers plan to use their mouse models to follow the molecular events that take place during PC development, and identify potential targets for drug treatments and protein markers for early diagnosis. These new mouse models could also help researchers test potential PC treatments.

Alice Rossiter - Cancer Drug News Editor

2,000 UK women denied BC treatment

2009-10-28T15:08:00.000Z

Patients suffering from an aggressive form of breast cancer (BC) are being failed by the NHS and deprived of more treatment options as the National Institute for Health and Clinical Excellence (NICE) rejects GlaxoSmithKline's oral Tyverb (lapatinib) in combination with capecitabine for the treatment of ErbB2-positive BC.

BC is now the most common cancer in the UK. In 2006, >45,500 women were diagnosed with the disease; that is approximately 125 women a day, and in the last ten years, incidence rates in the UK have increased by 6 per cent. As an oral treatment, lapatinib gives patients suffering from ErbB2-positive BC the freedom to spend precious additional months with friends and family without the restrictive ties of regular hospital visits.

The decision to deny NHS patients access to treatment with lapatinib follows the request in July by NICE's Appeal Panel that the Appraisal Committee should reconsider lapatinib under the Institute's end of life (EOL) supplementary guidance. The EOL guidance was specifically developed to help small numbers of patients who have only a few months to live, gain access to important new medicines. GSK submitted additional data demonstrating that lapatinib met all three of the EOL criteria.

NICE recognised that lapatinib met the EOL criteria, acknowledging that additional data submitted by GSK demonstrated that the drug could offer a significant extension to life, but it felt lapatinib was still not a cost-effective use of NHS resources. This decision has been made despite GSK offering the Tyverb patient access programme, which allows NHS patients in the UK free access to lapatinib for the first three months of treatment.

GSK proposed the patient access programme in the UK when NICE indicated early on in its review that it did not consider lapatinib to be cost effective in treating this patient population. The company will continue to honour the access programme for NHS trusts in the UK. A total of 26 trusts have already enrolled in this programme, reflecting the clinical demand for lapatinib and recognising the potential cost effectiveness for the NHS. Simon Jose, General Manager of GSK UK commented: "it is disappointing that, despite acknowledging Tyverb meets these criteria and GSK offering to bear the cost of lapatinib for up to 12 weeks, NICE is still proposing to reject lapatinib. We will continue to offer our patient access programme to individual NHS Trusts to ensure patients have access to Tyverb."

This decision will result in 2,000 UK women a year being denied access to lapatinib on the NHS. These are women for whom there are very few other treatment options available to them at this stage of their disease. By comparison, lapatinib is funded in 18 other European countries for the treatment of women whose advanced BC has returned despite treatment with standard chemotherapy regimes, including intravenous Herceptin (trastuzumab).

Alice Rossiter - Cancer Drug News Editor

Cancer proven to pass from mother to baby

2009-10-22T16:02:00.001+01:00

A rare case of a mother and her infant developing the exact same cancer has allowed an international team of researchers from the Institute of Cancer Research (ICR), to solve a puzzle that has perplexed scientists and clinicians for a century. The scientists, with funding from Leukaemia Research, investigated a situation in which leukaemic cells appeared to have defied accepted theories of biology and spread through the womb from a Japanese woman to her daughter.

Approximately 30 previously-known cases of a mother and infant appearing to share the same cancer had already raised suspicions that such spread was possible. However, there was no genetic evidence to support this theory, and investigators did not know how it could occur as the baby's immune system should have recognised and destroyed any invasive cancer cells that were of maternal, and therefore foreign, origin. In a study, published in the 12th October online edition of PNAS (10.1073/pnas.0904658106), the scientists used advanced genetic fingerprinting to prove for the first time that the infant's leukaemic cells were unquestionably of maternal origin.

The researchers found that both patients' leukaemic cells carried the identical mutated cancer gene, Bcr-Abl1, but the infant had not inherited this gene. This meant that the child could not have developed this type of leukaemia in isolation. To investigate how the cells could have crossed the placental barrier and survived in the offspring, the scientists looked for evidence of some form of immunological acceptance or tolerance of the foreign cells by the foetus. They examined the genes of the cancer cells in the infant and found some DNA missing in the region that controls expression of the major histocompatibility locus. This was significant because HLA molecules primarily distinguish one individual, and his or her cells, from another, so the absence of these molecules on the cancer cells meant that the infant's immune system would not have recognised that they were foreign.

It appears that in this and, the scientists presume, other cases, the maternal cancer cells did cross the placenta into the developing foetus and succeeded in implanting because they were invisible to the immune system. Dr David Grant, Scientific Director at Leukaemia Research, commented: "the important message from this fascinating piece of research is that leukaemia cells can be destroyed by the immune system. Harnessing the power of the immune system to first cure and then protect patients from leukaemia is one of our priority areas of research."

According to Professor Peter Johnson, Cancer Research UK's Chief Clinician, this finding provides further evidence that cancers are generated more often than first thought. A large part of cancer research is on cancer immunity; scientists have known for quite some time that people with deficient immune systems, perhaps because of HIV or immunosuppression after organ transplants, are much more prone to certain types of cancer. The real challenge for researchers now is to work out how to invigorate the immune system so it recognises cancer cells.

Alice Rossiter
Cancer Drug News Editor

Vaccination and testing for HPV could eradicate CC

2009-10-15T12:38:00.002+01:00

According to a cervical cancer (CC) screening expert, Professor Jack Cuzick, from Cancer Research UK, the disease could be eradicated within the next 50 years if countries implement national screening programmes based on the detection of the human papillomavirus (HPV). Cuzick told the recent joint 15th ECCO and 34th ESMO Congress that while the current HPV vaccines protect against two cancer-causing strains of the HPV virus, soon there would be vaccines available that protect against nine types. If vaccination were to be combined with HPV screening, which is much more sensitive than the currently used Pap smear test, then eventually the cancer would disappear in those countries that had successfully implemented national programmes. However, this would require political will and effort at both national and European levels.

The current vaccine holds the promise of eradicating approximately 70 to 75 per cent of CC (caused by HPV types 16 and 18), and there appears to be some additional cross protection amongst types that are closely related to 16 or 18, in particular 31, 45 and a part of 33. There are new vaccines being planned that will vaccinate against nine types; if they are successful, there should be no need to screen women that have been vaccinated at all.

The Pap test relies on subjective assessments by people examining the cells in the smear with a microscope and therefore is open to human error. Cuzick believes that such errors will increase as the proportions of smears with affected cells decline due to increasing numbers of women having been vaccinated. In contrast, the HPV test is almost completely automated, is designed to detect the virus in the smear rather than relying on visual examination and therefore is much less likely to be affected by human error. Cuzick commented: "there's overwhelming evidence that HPV screening is more effective than the Pap smear test, which misses about a third to a half of all high-grade lesions". However, Cuzick warned that the EU and national governments should take the initiative in discussions on implementing screening and vaccination programmes, rather than leaving it to pharmaceutical companies to lead the debate.

During the last fortnight, much data have been reported in relation to CC drug and vaccine trials. Of particular note, results from the PATRICIA (PApilloma TRIal Cervical cancer In young Adults or HPV 008) study showed that GlaxoSmithKline's Cervarix is highly effective at protecting against the two most common CC-causing HPV types, 16 and 18. Furthermore, Cervarix demonstrated efficacy against cervical intraepithelial neoplasia 2+ lesions associated with 12 additional HPV types beyond 16 and 18, including HPV 31, 33 and 45.

In addition, Phase I trial results of ADXS11-001 have shown 36-month survival in three of the 13 evaluable patients treated with Advaxis' therapeutic cancer vaccine, which treats women who have already developed CC as a result of HPV infection, indicating the possibility of persistent immune protection. Further, interim safety and immunogenicity data from a Phase I trial of Inovio Biomedical's VGX-3100 showed that the therapeutic CC vaccine was generally safe and well tolerated, plus it achieved significant cellular and humoral immune responses at the lowest dose administered. VGX-3100 is a DNA vaccine targeting the E6 and E7 proteins of HPV types 16 and 18.

Alice Rossiter - Cancer Drug News Editor

HBV vaccine reduces HCC cases in young

2009-09-29T11:26:00.001+01:00

A 20-year follow-up study has revealed a dramatic drop in liver cancer cases among six- to 19-year-olds who were vaccinated for hepatitis B (HBV) at birth. In July 1984, a universal vaccination programme was initiated among newborn children in Taiwan to prevent HBV infection, which can predispose to the development of hepatocellular carcinoma (HCC).

HCC is responsible for approximately 90 per cent of the primary malignant liver tumours in adults. It is the sixth most common cancer in the world and the third leading cause of cancer-related deaths globally. More than 600,000 cases are diagnosed worldwide each year (>400,000 in China, South Korea, Japan and Taiwan, 54,000 in the EU and 15,000 in the US) and the incidence is increasing. In 2002, approximately 600,000 people died of HCC, including approximately 370,000 in China, South Korea and Japan, 57,000 in the EU and 13,000 in the US.

For the study, which was published in the 16th September online edition of the Journal of the National Cancer Institute (10.1093/jnci/djp288), scientists from the National Taiwan University Department of Pediatrics collected data on 1,958 patients with HCC who were aged six to 29 years at diagnosis in Taiwan between 1983 and 2004 from two national HCC registries. Age- and sex-specific incidence among vaccinated and unvaccinated birth cohorts were analysed by using Poisson regression models. All statistical tests were two-sided. Records of 64 HCC patients and 5,524,435 HBV vaccinees who were born after the initiation of the vaccination programme were compared for HBV immunisation characteristics during infancy and prenatal maternal HBV surface antigen (HBsAg) and e antigen (HBeAg) serostatus.

Results showed that HCC incidence was statistically significantly lower among children aged six to 19 years in the vaccinated cohort compared with the unvaccinated birth cohorts (64 HCCs among vaccinees in 37,709,304 person-years vs 444 cancers in unvaccinated subjects in 78,496,406 person-years, showing an age- and sex-adjusted relative risk of 0.31, p<0.001, for persons vaccinated at birth).

The risk of developing HCC for vaccinated cohorts was statistically significantly associated with: incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine, odds ratio [OR]=4.32, 95% CI, 2.34 to 7.91); prenatal maternal HBsAg seropositivity (OR=29.50, 95% CI, 13.98 to 62.60); and prenatal maternal HBeAg seropositivity (with administration of HBV immunoglobulin at birth, OR=5.13, 95% CI, 2.24 to 11.71; and without it, OR=9.43, 95% CI, 3.54 to 25.11).

These data suggest that the effectiveness of the universal HBV immunisation programme to prevent HCC has extended beyond childhood and into young adulthood over the past two decades. With regard to the National Institute for Health and Clinical Excellence (NICE) recently refusing Bayer HealthCare/Onyx Pharmaceuticals' Nexavar (sorafenib) for the treatment of patients in England and Wales with HCC, despite being the only systemic treatment option that could potentially extend the survival of patients with the disease, it seems that currently, prevention is better than the cure.

Alice Rossiter
Cancer Drug News Editor

MDS patients failed by NHS

2009-09-17T15:23:00.002+01:00

Adding weight to a previous editorial published in Cancer Drug News (see Issue No. 377 - "Is NICE depriving UK patients' options?"), the results of a new survey, launched by the UK MDS Patient Support Group, have shown that almost one-fifth (18 per cent) of patients suffering from myelodysplastic syndromes (MDS) could have lived for longer if they had been able to access treatments that are currently not approved by the UK's National Institute for Health and Clinical Excellence (NICE) for treatment on the NHS. According to current estimates, just fewer than 2,000 new cases of MDS are diagnosed in the UK each year.

The survey of 100 haematologists from England, Wales and Scotland revealed that 56 per cent of blood cancer (BC) experts believe that less priority is given to rarer cancers versus other common cancers. The majority of BC experts (89 per cent) surveyed have faced situations where they have been unable to provide treatments for their BC patients that could have potentially extended their patients' survival as these treatments were not readily available on the NHS or not yet approved by NICE.

David Hall, Chairman of MDS UK Patient Support Group, commented: "these results are alarming and distressing. Denying any patient access to life-extending, blood cancer drugs is immoral and contradicts the very principles upon which the NHS was founded. These new treatments have been thoroughly tested and their efficacy demonstrated. It is ironic that the perceived constraints to availability in the UK seem to be based exclusively on inadequate finance."

The MDS UK Patient Support Group has called upon the Department of Health to re-address this inequality by making proven treatments available to all patients whose life span may otherwise be unnecessarily curtailed. These results have highlighted the gaps in access to treatments that can prolong and improve the lives of patients living with MDS and other BCs. Despite significant advances in the treatment of MDS, the majority of patients cannot get access to and, in some cases, are not even informed about new life-extending drugs until they have been appraised and approved by NICE. The impact of waiting even a month for treatment for MDS can result in a life or death situation.

Hilary Jackson, Cancer Research UK's policy manager, noted that: "where NICE has not provided advice on a particular drug, it is up to Primary Care Trusts (PCTs) to decide which they will fund...without NICE approval, we need a fair approach to ensure that doctors, patients and the PCTs themselves are clear about how funding decisions will be made."

It seems concerning that patients are not getting access to drugs that could extend their lives, which have been thoroughly investigated and their efficacy shown, and, in some cases, are available in comparable countries.

Alice Rossiter
Cancer Drug News Editor

Is NICE depriving UK patients' options?

2009-09-01T15:04:00.001+01:00

During the past week, the UK's National Institute for Health and Clinical Excellence (NICE) has issued mixed recommendations on the use of drugs for the treatment of renal cell carcinoma (RCC) and metastatic colorectal cancer (MCRC).

NICE has not recommended Genentech's (Roche) Avastin (bevacizumab), Bayer HealthCare/Onyx Pharmaceuticals' Nexavar (sorafenib) and Wyeth Pharmaceuticals' Torisel (temsirolimus) as first-line treatment options for advanced and/or metastatic RCC. In addition, Nexavar and Pfizer's Sutent (sunitinib) are not recommended for second-line treatment, although both are licensed in the EU for this therapy. According to NICE, the evidence to support the use of the first- and second-line treatments is not strong enough to justify using NHS funds, which could be used for other cancer treatment programmes or in other treatment areas.

In response to this NICE decision, Roche is considering all options. The Appraisal Committee accepted that Avastin in combination with interferon has a similar clinical and cost-effectiveness profile to the already-approved Sutent, but turned it down because it has a licence in other indications, despite the fact that these indications are not currently routinely reimbursed on the NHS.

John Melville, General Manager of Roche UK, commented: "this decision is entirely illogical and neither addresses the needs of patients with renal cancer, nor advances the innovation agenda. Avastin demonstrates the same value to the NHS as sunitinib and this guidance goes against the spirit of end-of-life criteria, which were devised for this very setting."

On a positive note, NICE has recommended the use of Merck Serono's (Merck KGaA) Erbitux (cetuximab) in combination with FOLFOX for the first-line treatment of MCRC, but only when all of the following criteria are met: (a) the primary colorectal tumour has been resected or is potentially operable; (b) the metastatic disease is confined to the liver and is unresectable; (c) the patient is fit enough to undergo surgery to resect the primary colorectal tumour and to undergo liver surgery if the metastases become resectable after treatment with Erbitux; and (d) the manufacturer rebates 16 per cent of the amount of Erbitux used on a per patient basis.

Further, NICE recommended that patients who meet the above criteria should receive treatment with Erbitux for no more than 16 weeks. After this period, treatment with Erbitux should stop and the patient should be assessed for resection of liver metastases. It was also recommended that people with MCRC with metastatic disease confined to the liver who receive Erbitux should have their treatment managed only by multidisciplinary teams that involve highly-specialised liver surgical services. The Appraisal Committee concluded that under the specific circumstances outlined in the guidance, the cost of Erbitux in relation to how well it works is an effective use of NHS resources.

Although the NICE guidance on the use of Erbitux means many MCRC patients will have a new treatment opinion, the decision not to recommend Avastin, Nexavar or Torisel as a first-line therapy for RCC will reduce treatment options for UK patients who are fighting this disease, yet is available for the same indication in comparable countries.

Alice Rossiter - Cancer Drug News Editor

New study reinforces Gardasil's safety

2009-08-26T15:03:00.003+01:00

An analysis of the adverse events (AEs) reported following distribution of Merck & Co's quadrivalent human papillomavirus (qHPV) recombinant vaccine, Gardasil, since 2006, has indicated that AE rates were consistent with prelicensing data and expected background rates of other vaccines, with the exception of a higher proportion of reports of fainting and blood clots.

Gardasil is the world's first cervical cancer vaccine, which can also help to prevent vulvar and vaginal cancers and genital warts caused by HPV types 6, 11, 16 and 18. In June 2006, the FDA licensed Gardasil for females aged nine to 26 years to prevent infection with genital HPV. Shortly after that, the Advisory Committee on Immunization Practices recommended routine vaccination of females aged 11 to 12 years with three doses of qHPV and catch-up vaccination for females aged 13 to 26 years.

In the new study, published in the 19th August issue of JAMA (2009;302:750-757), the researchers analysed reports of AEs following qHPV immunisation received by the Vaccine Adverse Event Reporting System (VAERS) from 1st June 2006 until 31st December 2008. Additional analyses were performed for some AEs following immunisations (AEFIs) in prelicensure trials, those of unusual severity or those that had received public attention.

During the study period, VAERS received 12,424 reports of AEFIs following receipt of qHPV, an overall reporting rate of 53.9 reports per 100,000 vaccine doses distributed. Of the 8,247 reports that included onset interval, 4,393 (40 per cent) occurred on the day of vaccination. Among 9,396 reports (77 per cent) with dose information, 5,772 (61 per cent) followed the first dose, 2,380 (25 per cent) followed the second dose and 1,183 (13 per cent) followed the third dose of qHPV.

Among the 12,424 AEFI reports, 772 (6.2 per cent) were serious, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were: 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders and Guillain-Barré syndrome; and 0.1 for anaphylaxis and death. Analysis indicated a disproportional reporting of fainting and blood clot events.

The VAERS database that was the primary source for the study is one of the many mechanisms used to assess the safety of vaccines. Merck also monitors vaccine safety by conducting comprehensive analyses of AEs reported to the company and shares these analyses with the Centers for Disease Control and Prevention (CDC), the FDA, and regulatory and medical authorities around the world to support their efforts. After carefully reviewing all of the information available to Merck about reported AEs, including the findings in the discussed study, the company continues to be confident in the safety profile of Gardasil. While no vaccine or medicine is completely without risk, leading health organisations throughout the world, including the CDC and EMEA, have reviewed the available safety and efficacy information about Gardasil and continue to recommend its use.

Richard M Haupt, head of the Gardasil clinical programme commented: "we will continue our practice of effectively communicating the safety profile of Gardasil, it's a responsibility Merck takes very seriously...Parents should understand the extensive data supporting the safety profile of this vaccine, and we encourage them to look to CDC and FDA, and to the advice of their own physicians, to make an informed choice about something as important as a vaccine to help prevent cervical cancer".

Alice Rossiter Cancer Drug News Editor

Nanobees take the sting out of cancer

2009-08-12T09:00:00.001+01:00

Researchers at Washington University School of Medicine in St Louis have harnessed the toxin in bee venom to kill tumour cells by attaching the major component of the venom to nano-sized spheres that they call nanobees. In mice, nanobees delivered the bee toxin, melittin, to tumours, while protecting other tissues from the toxin's destructive effects. The tumours were shown to stop growing or shrank.

Melittin is a small protein, or peptide, which is strongly attracted to cell membranes, where it can form pores that break up cells and kill them. Professor Samuel Wickline, a specialist in nanomedicine at Washington University who led the research, explained: "the nanobees fly in, land on the surface of cells and deposit their cargo of melittin, which rapidly merges with the target cells." The investigators have shown that the bee toxin is taken into the cells where it pokes holes in their internal structures.

As detailed in the 10th August online edition of the Journal of Clinical Investigation (10.1172/JCI38842), the scientists tested nanobees in two kinds of mice with cancerous tumours. One mouse breed was implanted with human breast cancer (BC) cells and the other with melanoma tumours. After four to five injections of the melittin-carrying nanoparticles over several days, growth of the BC tumours slowed by nearly 25 per cent, and the size of the melanoma tumours decreased by 88 per cent compared to untreated tumours.

The researchers indicated that the nanobees gathered in these solid tumours because they often have leaky blood vessels and tend to retain material. Scientists call this the "enhanced permeability and retention effect of tumours", and it explains how certain drugs concentrate in tumour tissue much more than they do in normal tissues. Further, the researchers developed a more specific method for ensuring that nanobees target tumours and not healthy tissue, by loading them with additional components. When they added a targeting agent that was attracted to growing blood vessels around tumours, the nanobees were guided to precancerous skin lesions that were rapidly increasing their blood supply. Injections of targeted nanobees reduced the extent of proliferation of precancerous skin cells in the mice by 80 per cent.

The flexibility of nanobees and other nanoparticles made by the group suggests that they could be readily adapted to fit medical situations as needed. The ability to attach imaging agents to nanoparticles means that they can give a visible indication of how much medication reaches tumours and how they respond. Potentially, it is thought that these could be formulated for a particular patient. Overall, the results suggest that nanobees could not only lessen the growth and size of established cancerous tumours, but also act at early stages to prevent cancer from developing.

Alice Rossiter - Cancer Drug News Editor

Mixed developments in Europe

2009-07-28T15:26:00.002+01:00

The past week has seen a mixture of positive and negative developments in Europe and the UK for chronic lymphocytic leukaemia (CLL), hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC).

Of particular interest, the UK's National Institute for Health and Clinical Excellence (NICE) has issued a recommendation for the use of Roche's MabThera (rituximab) in CLL. NICE's final guidance recommends rituximab in combination with fludarabine and cyclophosphamide chemotherapy (CT) as an option for previously-untreated patients with CLL. Professor John Gribben, Consultant Haematologist and Medical Oncologist, Barts and The London NHS Trust, commented: "the ability to add rituximab to chemotherapy is a major advance in the way we can treat CLL. Where previously our goal was just to improve symptoms, for the first time we now have a treatment combination that is capable of producing much higher remission rates and more durable responses."

Further, the EMEA's CHMP has issued a positive recommendation for the use of MabThera in patients with relapsed or refractory CLL. Physicians will soon be able to prescribe MabThera in combination with CT to patients in Europe who have been treated for the disease, but whose cancer has returned or have not appropriately responded to therapy.

Separately, the anticipated decision from NICE on the Final Appraisal Determination for Bayer HealthCare/Onyx Pharmaceuticals' Nexavar (sorafenib), for the treatment of advanced HCC, has been delayed to allow consideration of the patient access scheme, Bayer Schering Pharma has agreed with the Department of Health. The company hopes that NICE will take this opportunity to evaluate and fully understand the benefit of its proposed patient access scheme, and to listen to leading healthcare professionals in the field who were unanimous in their condemnation of the initial negative proposal.

Finally, the CHMP has adopted a negative opinion for the use of Erbitux (cetuximab) in combination with platinum-based CT for the treatment of patients with EGFr-expressing, advanced or metastatic NSCLC. Merck KGaA is evaluating potential appeal options requesting that the CHMP re-examines data demonstrating clinically-relevant benefits to patients. This has come as a huge blow to Merck, with its shares plummeting 12 per cent following the decision.

Alice Rossiter - Cancer Drug News Editor

Progress made in identifying genetic causes of melanoma

2009-07-21T10:55:00.002+01:00

Researchers have identified various genes that cause melanoma and also novel epigenetic markers of the disease that may herald new treatments for patients.

Two studies, published online in Nature Genetics (10.1038/ng.410 and 10.1038/ng.411), and conducted by investigators at Queensland Institute of Medical Research in Australia, King's College London and the University of Leeds, have revealed novel genes implicated in the development of melanoma. One study found that specific changes in two genes, MTAP and PLA2G6, were found to make people more susceptible to developing nevi. In a further 4,000 people, the researchers went on to show that these genes increased the risk of developing melanoma; specifically, those who carry one of the two SNPs have a 25 per cent increased chance of developing melanoma, while for individuals carrying both variants, the risk is doubled.

The second study identified five loci with genotyped or imputed SNPs reaching very high significance. The analysis showed that the genes, MC1R and TYR, are associated with pigmentation, freckling and cutaneous sun sensitivity.

Separately, researchers from Yale University have mapped chemical modifications of DNA in the melanoma genome, finding new markers that will help to develop more effective treatment strategies to fight this disease. In this work, published online in Genome Research (10.1101/gr.091447.109), scientists found 76 promoters with altered methylation patterns in melanomas, most of these showing increased methylation compared to normal. The team focused on five genes in particular, three of which had not been implicated in melanoma until now. The scientists are hopeful that these epigenetic markers may provide a better method for determining the aggressiveness of the disease and for setting a course of treatment.

The incidence of melanoma has been increasing over the past decades. Currently, approximately 132,000 melanoma skin cancers occur globally each year and around 48,000 people worldwide die of melanoma annually. One in every three cancers diagnosed is a skin cancer and, according to Skin Cancer Foundation Statistics, one in every five Americans will develop skin cancer in their lifetime. Melanoma is diagnosed in more than 50,000 new patients in the US annually.

While the rate of incidences continues to rise, survival rate has not improved and the race is on to find the genetic and cellular changes driving melanoma and to devise new means of detection and treatment.

Alice Rossiter - Cancer Drug News Editor

CSCs set to improve cancer treatment

2009-07-02T12:56:00.003+01:00

Research into cancer treatment is currently focusing on cancer stem cells (CSCs), which are responsible for some instances of the disease. Indeed, a University of Rochester Medical Center researcher has resolved the controversy and promise around a dangerous subtype of CSCs, which seem capable of resisting many modern treatments. The research, published in the 26th June edition of Science (2009;324:1670-1673), proposes that this subpopulation of malignant cells may one day provide an important avenue for controlling cancer, especially if new treatments that target the CSC are developed and combined with traditional chemotherapy and/or radiation.

Research from the past ten years suggests that because CSCs may be the root of cancer, they might also provide a new opportunity for a treatment. A group of collaborators, for example, are testing a new drug compound based on the feverfew plant that demonstrates great potential in the laboratory for causing leukaemia CSCs to self destruct.

Further, it was recently reported that researchers at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, on a quest to find lung cancer (LC) SCs, have developed a unique model to allow further investigation into the cells that many believe may be at the root of all LCs. Since CSCs are known to possess unique properties and a predisposition to metastasise, the study's lead author proposed to extract candidate CSCs directly from clinical specimens based on the markers they express and then validate these cells functionally. As detailed in PLoS ONE (10.1371/journal.pone.0005884), in an effort to find LC SCs, the team collected specimens from patients with malignant pleural effusions, and created a microenvironment in which the tumour cells would remain heterogeneous and enable researchers to more easily identify candidate CSCs.

Separately, a study from the University of Michigan (UM) Comprehensive Cancer Center recently indicated that a gene well known to stop or suppress cancer plays a role in CSCs. The researchers found that several pathways linked to the gene, PTEN, also affected the growth of breast cancer SCs. Further, by using a drug that interferes with that pathway, the scientists produced an up to 90 per cent decrease in the number of CSCs within a tumour. As detailed in PLoS Biology (10.1371/journal.pbio.1000121), the UM researchers deleted PTEN in tumours grown in cell cultures and mice, and found an increase in the number of SCs. They also looked at pathways associated with PTEN and reported that the pathway, PI3-K/Akt, regulated the CSC population by activating another SC pathway, Wnt, which is also implicated in multiple cancer types. Thus, new and recent developments seem to reiterate the important role of CSC research in future treatment.

Alice Rossiter
Cancer Drug News - Editor

CRC rates on the rise

2009-06-24T09:46:00.001+01:00

The incidence of colorectal cancer (CRC) is increasing in many countries around the world, according to a new study by the American Cancer Society. The study's authors believe the rise is due to the uptake of so-called 'western' diets and lifestyles, such as high red meat consumption and low levels of exercise. Previous studies have documented significant variations in CRC incidence rates and trends, regionally and across countries. However, no study has examined the worldwide pattern using the most recently updated incidence data from the International Agency for Research on Cancer (IARC).

Scientists reviewed data from 51 cancer registries around the world using databases created by the IARC in order to analyse rates of CRC from 1983 to 1987 through to 1998 to 2002. They found that CRC incidence rates statistically significantly increased for both men and women in 27 of the 51 cancer registries, although the increases were more prominent among men. Of particular note were Slovakia, Slovenia and the Czech Republic in the EU, and Japan, Kuwait and Israel in Asia. In Slovenia, CRC incidence increased by 70 per cent among men and 28 per cent among women, and in Miyagi, Japan, rates in men and women rose by 92 and 47 per cent, respectively.

The researchers, whose findings are published in the June edition of Cancer Epidemiology Biomarkers and Prevention (CEBP; 2009;18:1688-1694), also found that there were substantial variations in CRC incidences between different regional and ethnic groups in some countries, including Japan, Israel and Singapore. The only country where CRC rates statistically significantly declined in both sexes was the US, but the US had a very high rate of CRC to start with. In contrast, economically transitioning countries, such as eastern European nations, most parts of Asia and some South American countries, saw large rises in CRC rates. The study authors believe that this may reflect the increasing adoption of western lifestyles and behaviours in these countries.

Further, a separate study, also published in the same edition of CEBP (2009;18:1695-1698), has focused on the CRC incidence rates among young men and women in the US. The recent, accelerated decline in CRC incidence rates has largely been attributed to an increase in screening among adults aged 50 years and older. Scientists used data to report on CRC incidence trends from 1992 through 2005 among adults under the age of 50 years, for whom screening is not recommended for persons at average risk, by sex, race/ethnicity, age, stage at diagnosis and anatomic subsite.

Overall, incidence rates of CRC per 100,000 young individuals (ages 20 to 49 years) increased 1.5 and 1.6 per cent per year in men and women, respectively, from 1992 to 2005. Among non-Hispanic whites, rates increased for both men and women in each ten-year age grouping (20 to 29, 30 to 39 and 40 to 49 years) and for every stage of diagnosis. In contrast to the overall decreasing trend in CRC incidence in the US, rates are increasing among men and women under the age of 50 years. Further studies are necessary to elucidate causes for this trend, and identify potential prevention and early detection strategies.

Alice Rossiter - Cancer Drug News Editor

J&J reveals two new compounds during R&D review

2009-06-19T14:21:00.003+01:00

With an estimated 75 million cancer sufferers in the world by 2030 and the slow pace of drug development, Johnson & Johnson has recently reviewed its growth strategies and research and development pipeline in oncology with the aim of becoming a leader in cancer therapy within the next five years. The company is continuing to advance its pipeline of new compounds, while also exploring line extensions for existing drugs to fuel its long-term growth and address unmet medical needs in cancer.

Promising compounds in early development include CNTO 328, an anti-interleukin-6 monoclonal antibody, and CNTO 888, a first-in-class anti-CCL2 antibody. CNTO 328 is in development for Castleman's disease (Phase I), multiple myeloma (first-, second- and third-line MM; Phase II), hormone-refractory prostate cancer (Phase II) and supportive care. Clinical responses and disease stabilisation have been observed in MM patients treated with the compound, which has been shown to be safe, well tolerated and biologically active by inducing a rapid and profound normalisation of C-reactive peptides (CRP) in various tumours. J&J plans the filing of CNTO 328 for Castleman’s disease between 2011 and 2013. CNTO 888 is in Phase I development in prostate and ovarian cancer.

Major line extensions include Velcade (bortezomib), developed in partnership with Millennium: The Takeda Oncology Company, in mantle cell lymphoma and non-Hodgkin's lymphoma (NHL). Velcade is already approved in 89 countries, with 61 approvals for front-line MM. A Phase III trial in NHL is under way and Phase II studies, in synergy with Rituxan (rituximab), are producing positive data.

Further, Doxil (doxorubicin liposome injection) is being extended to breast cancer (BC). Already approved in the US for AIDS-related Kaposi's sarcoma, recurrent ovarian cancer (OC) and MM (in combination with Velcade), J&J has submitted an sNDA for the treatment of relapsed BC in combination with Taxotere.

Separately, J&J has filed Yondelis (trabectedin) with the FDA, which was developed in partnership with PharmaMar (Zeltia), for relapsed OC in combination with doxorubicin. Nine trials recently reported provided new data about trabectedin and according to an analysis of data from a Phase III trial, OVA-301, the combination of trabectedin with Doxil/Caelyx results in superior efficacy in patients with relapsed OC with no added decrement to overall health status.

Alice Rossiter - CDN Editor

Highlights from ASCO

2009-06-10T12:28:00.004+01:00

The 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held from 29th May to 2nd June, in Orlando, FL. Whilst a previous editorial published in Cancer Drug News (see Issue No. 364 - "Looking ahead to ASCO") noted that the 4,000 study abstracts for this year's meeting had drawn a mainly disappointing response, there were numerous encouraging results reported. Of particular note were positive Phase III data with Roche's Herceptin (trastuzumab) in aggressive gastric cancer (GC), Phase II results with AstraZeneca's olaparib in breast (BC) and ovarian cancer (OC), and final results from a Phase II trial of OncoGenex Pharmaceuticals' OGX-011 in prostate cancer (PCA).

Specifically, trastuzumab showed unprecedented survival in aggressive GC. Data from the international, Phase III ToGA study demonstrated that adding the drug to standard chemotherapy increases average survival by 26 per cent in patients with HER2-positive advanced and inoperable GC compared to chemotherapy alone. This combination is also particularly beneficial to GC patients whose tumours express higher levels of HER2, increasing their median survival to 16 months. Trastuzumab is already well established as the foundation of care for patients with HER2-positive BC and now, based on the ToGA results, Roche is to seek regulatory approvals for its use in HER2-positive advanced GC.

Separately, olaparib showed potential to make significant impact on outcomes of patients with BRCA-deficient BC and OC. Phase II data for the novel, oral poly (ADP-ribose) polymerase (PARP) inhibitor demonstrated that it is effective and well tolerated in women carrying the BRCA1 or BRCA2 gene mutation with BC or advanced OC. PARP inhibition is being explored as a new therapeutic approach in cancers with impaired DNA repair pathways, one example of which is cancers with BRCA deficiency. Indeed, both studies were selected for inclusion in the 'Best of ASCO' scientific programme.

Finally, it was reported that OGX-011 provides survival benefit to PCA patients. OncoGenex presented final results from a Phase II trial, with analyses indicating a survival benefit in PCA patients treated with the compound in combination with docetaxel compared to docetaxel alone. Patients treated with OGX-011 had a rate of death 51 per cent lower than those treated with docetaxel alone. Scott Cormack, President and CEO of OncoGenex, noted that a 39 per cent reduction in death, consistent with the previously-disclosed preliminary analysis, would be a significant advancement for treatment in this patient population, adding: "the multivariate analysis shows an even greater reduction in death rate than our preliminary data and increases our confidence that we are seeing a real and meaningful survival benefit for patients treated with OGX-011...these data clearly justify advancing to Phase III development, and we expect these data will be key in our partnering discussions for future clinical development and potential commercialisation."

Alice Rossiter - Cancer Drug News Editor

Early collaboration: a sign of the times?

2009-06-04T12:18:00.003+01:00

Touted as a first-of-its-kind deal, Merck & Co and AstraZeneca have teamed up to research a novel combination anticancer regimen composed of two investigational compounds, MK-2206 and AZD6244 (ARRY-886). The collaboration, which is unusual as it involves two drugs so far from approval, will investigate the agents in a Phase I safety and tolerability trial.

Most combination regimens are investigated once the compounds have either progressed to late-stage development or are already commercially available. This new agreement breaks from that mould as the companies appear to have overcome many of the sticking points that have previously prevented this type of interaction between big pharma. The reason that few development agreements between large companies are signed is that they are extremely complicated. Issues concerning control, valuation and overlap with other projects all present hurdles. Then there is the question of working with your competitor, something that is not encouraged.

But it appears that this deal was struck not because the companies were actively seeking such collaboration, rather a chance encounter at an airport in November 2007 led to it happening. Reports suggest that two scientists, one from Merck and the other from AstraZeneca, got talking at airport security about their respective programmes and the rationale for combining them.

Merck's MK-2206 is the most advanced AKT inhibitor in development. AKT acts downstream of PI3K in the PI3K/PTEN/AKT signalling pathway. AstraZeneca's AZD6244 targets MEK, which plays an important role in a parallel signalling pathway. Laboratory evidence has suggested that the two compounds given in combination could have a much more potent affect against tumours than each agent separately. Even though AstraZencea was also working on its own AKT inhibitor and Merck was developing a drug to block MEK, the companies determined that collaborating would offer a quicker route to market.

So, how will the partnership progress? The companies have agreed to jointly fund a Phase I trial, after which they will consider further clinical development. If the two companies wish to eventually develop a fixed-dose combination then they may have to expand their relationship to possibly include multiple compounds or entire pathways. It could be that an initial goal would be to have each company move a drug through development to market with an approved label supporting use of the other agent in combination. Indeed, if this deal works, then it may pave the way for future similar collaborations.

Sadly, this will be my last issue as Editor of Cancer Drug News as I am moving on to pursue new challenges within the pharma news industry. I hope that you have found the service a valuable information source and I am sure that the new Editor, Alice Rossiter, will continue to uphold the standards of coverage that you as a reader are used to.

Matthew Dennis - Editor, Cancer Drug News

Looking ahead to ASCO

2009-05-28T09:33:00.003+01:00

As the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) looms, there is just time to look at the data and presentations that will be making the biggest impact. The 4,000 study abstracts for this years Meeting, to be held from 29th May to 2nd June, in Orlando, FL, have now been published, and have drawn a mainly disappointing response. However, there are some biotech companies that will be worth keeping an eye on.

One such company with positive results to present is OncoGenex Pharmaceuticals, whose investigational prostate cancer (PCA) drug, OGX-011, has produced promising Phase II results. Some analysts have commented that the data could be significantly better than Dendreon’s Provenge (sipuleucel-T). At the time results were submitted to ASCO, the preliminary median overall survival in patients with advanced PCA who were treated with OGX-011 plus docetaxel was 27.5 months compared to 16.9 months for patients treated with docetaxel alone. Final survival data as of April for this trial will be presented during the Meeting.

Another company to report encouraging results will be Exelixis, from a Phase II study of XL184 in patients with progressive glioblastoma multiforme. The drug is being co-developed with Bristol-Myers Squibb. In the trial, XL184 was shown to shrink brain tumours in some patients, according to interim results. At four weeks, 26 patients have been assessed. Ten of them (38 per cent) had tumour shrinkage of at least 50 per cent, including one patient who had a 100 per cent reduction in tumour size. Nine patients had tumour measurement changes ranging from 24 to -49 per cent and seven had at least a 25 per cent increase in tumour burden. Of 17 patients who had not received prior anti-angiogenic treatment, nine had at least a 50 per cent reduction in tumour burden.

OSI Pharmaceuticals will also create a lot of attention at the Meeting. The company will present data from two Phase III studies looking at the use of its drug Tarceva (erlotinib) as front-line maintenance therapy in patients with non-small cell lung cancer. OSI hopes that the data from the two studies, called SATURN and ATLAS (AVF3671g), will convince physicians to use the drug, which is co-marketed with Roche, more in the maintenance setting. However, results showed only a small gain over placebo in the time before disease progressed for certain lung cancer patients, leaving many onlookers less than impressed with the data.

Apart from these presentations, there seems little to get excited about. Roche will present data on the use of adjuvant Avastin (bevacizumab) in colon cancer, but the company has already disclosed the study's failure to produce a significant survival benefit. Results of that trial, known as C08, along with around 30 late-breaking studies will be unveiled at the Meeting, which will hopefully hold more surprises than the published abstracts.

Matthew Dennis - Editor, Cancer Drug News

RCC: targeted therapies increase survival

2009-05-21T10:06:00.002+01:00

The arrival of targeted therapies has dramatically improved outcomes for patients with renal cell carcinoma (RCC). With approvals of Bayer/Onyx Pharmaceuticals' Nexavar (sorafenib), Pfizer's Sutent (sunitinib), Novartis' Afinitor (everolimus) and Wyeth's Torisel (temsirolimus), doctors now have a anumber of agents to choose from to treat patients.

However, due to the fact that in subjects with advanced RCC, who are receiving therapy, their disease will ultimately progress, physicians must choose from the drugs available to best extend survival whilst preserving quality of life. This requires consideration of the overall treatment plan from the outset, so that when selecting which agent to start treatment with, the doctor must contemplate effective options for subsequent therapy.

Current retrospective data suggest that there is no cross-resistance between tyrosine kinase inhibitors (TKIs), which means that they can be effectively used in sequence. These data also hint to a preferred treatment sequence, where patients treated with sorafenib prior to sunitinib may experience longer periods of progression-free survival compared with those receiving sunitinib then sorafenib. Furthermore, Phase III evidence indicates that the mTOR inhibitor, everolimus, retains full efficacy in patients who have already been treated with both sorafenib and sunitinib. Therefore an optimal sequence, based on currently available evidence, might be two TKIs followed by an mTOR inhibitor.

Further to this, results from a Phase III study have shown that treatment with sunitinib achieved a median overall survival (OS) greater than two years in patients with metastatic RCC. The data support the recent publication of final guidance from the UK's National Institute for Health and Clinical Excellence (NICE), which recommends the use of sunitinib for the first-line treatment of advanced RCC.

The results, published in the online edition of the Journal of Clinical Oncology, also support a recent recommendation made by a group of oncologists in the UK to use sunitinib as a first-line treatment for metastatic RCC.

The trial data showed that the median OS for patients who received sunitinib versus interferon (IFN) alpha was 26.4 versus 21.8 months, respectively (p=0.051). However, an exploratory analysis of patients who received only one line of treatment (ie, no subsequent treatments after stopping their sunitinib or IFN alpha therapies) showed that sunitinib almost doubled the median OS compared to IFN alpha (28.1 vs 14.1 months; hazard ratio=0.647; p=0.003). This is a reflection of clinical practice in the UK where generally patients are only funded for one line of treatment at most.

According to Pfizer, before NICE guidance only one-third of primary care trusts (PCTs) were funding sunitinib to some extent. Since the guidelines were published, 90 per cent of PCTs have committed to full funding of sunitinib in accordance with NICE guidance. In 2007, Pfizer cut the price of sunitinib by 5 per cent and committed to providing one cycle/course of the treatment free of charge to every eligible patient in the UK, in an effort to increase patient access. This move amounts to an average saving of between 19 and 29 per cent per patient for the cost of treatment, depending upon the type and stage of their tumour. The average annual cost for a patient taking sunitinib is £24,168.

Matthew Dennis - Editor, Cancer Drug News

Cervarix on top in head-to-head, but how meaningful?

2009-05-12T14:21:00.002+01:00

The first comparative study of the two licensed human papillomavirus (HPV) vaccines, Cervarix and Gardasil (HPV types 6, 11, 16, 18 recombinant vaccine), has shown that the former generated a significantly higher immune response as measured by neutralising antibodies (Abs) and memory B-cells.

Although GlaxoSmithKline has touted these results as highly positive, others have hit back claiming that the trial is meaningless as it did not look at which vaccine was more effective at preventing actual cases of cervical cancer or precancerous lesions. This would require a longer and larger trial, which GSK has said it has no plans to conduct. Instead, the company hopes that the head-to-head study will boost the profile of Cervarix, which is yet to be launched in the US and is trailing Sanofi Pasteur MSD's (sanofi-aventis and Merck & Co joint venture) Gardasil in global markets.

Meanwhile, recent data on Gardasil have shown that the vaccine offers protection from certain HPV strains for up to 9.5 years; previously, data only showed its effects for five years. In another study, Gardasil reduced the number of abnormal Pap tests and cervical procedures. However, with Gardasil's US sales falling and Cervarix not even on the market yet in that territory, can the comparative trial data make a difference in revenues for GSK?

Gardasil, which was first to market, and launched in the US and Europe in 2006, generated sales of US$1.4 billion in 2008, while Cervarix brought in just US$231 million. Cervarix is still awaiting US marketing approval, and has only been adopted as the vaccine in national immunisation programmes for two European countries, the UK and the Netherlands. The FDA refused to approve Cervarix until GSK provided more clinical information, but the company expects approval to come later this year.

So what of the new comparative data? The presence of Abs is a first indication of the body's ability to protect itself against disease, but this does not necessarily mean Cervarix could prevent more infections than Gardasil. The study showed that Cervarix provided significantly higher neutralising Ab levels than Gardasil: more than two-times higher for HPV type 16 and more than six-times higher for HPV 18. For both virus strains, Cervarix also induced 2.7-times more memory B-cells, another important element of the immune system.

According to GSK, the study "offers the first evidence that these two vaccines do not generate the same immune response against HPV types 16 and 18, the two most common cancer-causing virus types". Its competitor was dismissive of the data, with Bennett Lee, Medical Director for Gardasil at Sanofi Pasteur MSD commenting: "We see no clinical relevance in the results of this study ... and we don't see the point of doing such a comparison. If you want to compare vaccines, you compare clinical efficacy". However, the final word will come from doctors and patients when, and if, Cervarix is licensed in the US later this year.

Matthew Dennis - Editor, Cancer Drug News

Iressa set to make it at second asking

2009-04-30T12:23:00.003+01:00

The EMEA's CHMP has issued a positive opinion supporting the approval of AstraZeneca's targeted oral anticancer drug, Iressa (gefitinib), for the treatment of non-small cell lung cancer (NSCLC). Specifically, the CHMP has recommended approval of Iressa for adults with locally-advanced or metastatic NSCLC with activating mutations of EGFr-tyrosine kinase, in all lines of therapy. However, AstraZeneca will be required to conduct a follow-up measure study to generate further data in a Caucasian NSCLC patient population. The company is in discussion with the CHMP to finalise the study design and endpoints.

The opinion was based on a submission package including two pivotal Phase III studies, IPASS (IRESSA Pan-ASia Study) and INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere). The IPASS trial exceeded its primary objective, demonstrating superior progression-free survival (PFS), greater objective response rate (ORR), improved tolerability and significant quality-of-life benefits for Iressa, compared to carboplatin+paclitaxel doublet chemotherapy (CT) in clinically-selected first-line patients in Asia. However, the treatment effect was not constant over time, with the probability of being progression-free in favour of carboplatin+paclitaxel in the first six months and in favour of Iressa in the following 16 months. This was likely due to the different effect of Iressa in subgroups defined by EGFr tumour mutation status. PFS was significantly longer for Iressa than doublet CT in patients with EGFr mutation-positive tumours, and significantly longer for doublet CT than Iressa in patients with EGFr mutation-negative tumours.

The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality-of-life benefits for Iressa, compared to standard CT (docetaxel) in the pretreated setting. Preplanned subgroup analyses showed a significant improvement in PFS and ORR for Iressa over docetaxel in patients with EGFr mutation-positive tumours.

In 2005, AstraZeneca withdrew its EU marketing authorisation application for Iressa following data from the Phase III ISEL (IRESSA Survival Evaluation in Lung cancer) study in pretreated patients not eligible for further CT. ISEL did not meet its primary objective of a statistically significant improvement in OS for Iressa compared to placebo, but did confirm a number of important clinical benefits, including tumour shrinkage and a significant improvement in time-to-treatment failure. The refractory nature of the ISEL population is the most likely explanation for the magnitude of the survival improvement with Iressa, compared to placebo, not reaching statistical significance.

But what sort of a comeback will Iressa be making? Only a day after the CHMP decision, Roche announced that it is collaborating on a trial to investigate Tarceva (erlotinib) in LC patients with genetic mutations in EGFr. The results from the EURTAC trial, if positive, will support a submission by Roche to the EMEA to seek an additional new indication for use of Tarceva, putting it in direct competition with Iressa. Tarceva is already approved, and unlike Iressa, has been shown to benefit all patients, whether or not they have a mutated version of EGFr. Based on this, it looks likely that Iressa will become a niche product. However, a launched product is better for AstraZeneca than one sat on the shelf.

Matthew Dennis - Editor, Cancer Drug News

Provenge finally meets expectations

2009-04-22T14:56:00.001+01:00

Dendreon's pivotal Phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment; also known as D9902B) study of Provenge (sipuleucel-T) in men with advanced prostate cancer (PCA) has met its primary endpoint of improving overall survival (OS) compared to placebo. The magnitude of the survival difference observed in the intent-to-treat population resulted in the study successfully achieving the prespecified level of statistical significance defined by its design. The safety profile of Provenge appeared to be consistent with prior studies.

The 512-patient, randomised, placebo-controlled study enrolled men with metastatic androgen-independent PCA and was conducted under a Special Protocol Assessment (SPA) agreement with the FDA. Because the data meet the criteria and specifications outlined in the SPA, Dendreon intends to file an amendment to its existing BLA in the fourth quarter of this year. News of the success triggered a huge jump in the company's share price. After closing on 13th April at US$7.30, the stock rose to a high of US$22.10 on 14th April, a 202 per cent increase.

It is expected that Dendreon will form an international partnership in the third quarter of the year to commercialise the vaccine, although the company will likely market Provenge alone in the US. Some analysts predict that once approved, Provenge could reach peak annual sales of US$2 billion. The vaccine is expected to achieve rapid uptake based on the survival benefit and good safety profile alone.

Detailed results from the trial will be presented during a plenary session at the American Urological Association Annual Meeting, to be held from 25th to 30th April, in Chicago, IL. Provenge may represent the first in a new class of active cellular immunotherapies specifically designed to engage the patient's own immune system against cancer.

Although the success of the trial has been heralded as a breakthrough for therapeutic cancer vaccines, it has also reignited debate about the FDA’s strict guidelines for drug approvals, and especially for innovative medicines. Two years age, the Agency decided not to approve Provenge despite an endorsement by one of its Advisory Committees, which recommended that there was substantial evidence supporting the efficacy and safety of the vaccine. In making its recommendations, the Advisory Committee was asked if the submitted data established that Provenge was reasonably safe and whether there was substantial evidence that the product was efficacious. The Advisory Committee voted 17 to 0 in favour of the safety of Provenge and 13 to 4 in favour of the efficacy question.

However, the FDA went against the Advisory Committee and requested additional clinical data in support of the efficacy claim contained in the submission. Now that the results are available from the IMPACT study, the FDA will be under increasing pressure to approve the vaccine, especially as the conditions in the SPA that the Agency agreed with Dendreon look to have been met. What could now stand in the way of approval? Possibly, quality control regarding the manufacture of the vaccine.

Matthew Dennis - Editor, Cancer Drug News

GSK looks to expand use of lapatinib; to appeal NICE decision

2009-04-08T15:47:00.004+01:00

GlaxoSmithKline has simultaneously submitted regulatory applications in the EU and US to expand the use of Tyverb/Tykerb (lapatinib) to include the first-line treatment of breast cancer (BC). The variation to the EU marketing authorisation and the sNDA were submitted, respectively, to the EMEA and to the FDA for the combination of lapatinib plus an aromatase inhibitor for use in patients with hormone-sensitive, metastatic BC.

The submissions are based on results from the recent EGF30008 study, which evaluated lapatinib plus Novartis' aromatase inhibitor, Femara (letrozole), in women with hormone receptor-positive metastatic BC that may or may not overexpress the HER2-positive receptor. Results from the study showed that women experienced a 5.2 month increase in median progression-free survival when treated with lapatinib+letrozole, compared to those treated with letrozole alone. Results from the intent-to-treat group showed that lapatinib+letrozole provided an additional 1.1 month before disease progression, compared to letrozole treatment alone.

Lapatinib, in combination with capecitabine, is currently authorised in 74 countries. In March 2007, the FDA approved lapatinib in combination with capecitabine for the treatment of patients with advanced or metastatic BC whose tumours overexpress HER2/ErbB2 and who have received prior therapy, including an anthracycline, a taxane and Herceptin (trastuzumab). In June 2008, the EC granted a conditional marketing authorisation for lapatinib in all 27 EU member states.

According to Espicom Business Intelligence, sales of lapatinib in BC could reach US$1,732 million by 2014; however, longer-term sales will be partially impacted by the launch of other targeted therapies, such as Roche’s pertuzumab, which is anticipated to be launched in 2012. Even if the drug is approved for first-line treatment, it may still not reach patients in some countries. GSK has recently stated that it is to appeal the UK's National Institute for Health and Clinical Excellence (NICE) decision in March to recommend against funding lapatinib, in combination with capecitabine, for women with advanced BC. If successful, the appeal will enable the NHS to offer a similar level of access to lapatinib as other EU countries where it has been granted funding, which incclude Slovenia, Slovakia, France, Spain, Germany, Italy and Ireland.

Although NICE acknowledged that lapatinib is an effective treatment for eligible women, it was rejected on the grounds that it was not a cost-effective use of NHS resources. This decision was reached despite GSK offering a patient access programme whereby the cost of up to 12 weeks' treatment would be paid by the company. GSK's analysis suggests that the cost-effectiveness of lapatinib in the context of the patient access programme (sensitive to the proportion of trastuzumab used in clinical practice) demonstrated a cost per QALY gain for lapatinib of just over £16,000 versus the usual care given to these patients, which includes standard chemotherapy and trastuzumab regimens.

Matthew Dennis - Editor, Cancer Drug News

Caution raised over integrin inhibitors

2009-03-25T11:36:00.001Z

When designing drugs to target and treat cancer, the last thing that you want to happen is for the agents to actually promote tumour growth. But this is what a study by scientists from the UK has found is the case when low doses of an experimental angiogenesis inhibitor were given to mouse models. However, there is hope that turning the findings on their head will help in the development of new ways to make these drugs as effective as possible. In the future, it may be feasible to combine these inhibitors with other drugs to maximise their effectiveness for patients.

Angiogenesis inhibitors are designed to block the supply of blood to the tumour to prevent it from growing. Some of these have proven successful in the clinic and gone on to be widely used, such as Avastin (bevacizumab) and Sutent (sunitinib), while others, such as those that inhibit the v3 and v5 integrins, have entered clinical trials but have generally been unsuccessful.

One such agent under development that targets integrins is cilengitide, which is thought to work by targeting the tumour and its vasculature. The agent is currently being investigated in a Phase III trial for the treatment of glioblastoma multiforme (GBM), as well as a number of Phase II studies in several indications, including advanced non-small cell lung cancer and squamous cell carcinoma of the head and neck. Now, scientists from the Institute of Cancer, Queen Mary's University London, the Institute of Cancer Research and the Beatson Institute for Cancer Research have found evidence to suggest that low doses of cilengitide in laboratory studies can have the opposite effect to what was expected and promote cancer growth.

The work, which was published in the 22nd March online edition of Nature Medicine (10.1038/nm.1941), showed that low concentrations of the drug promoted VEGF-mediated angiogenesis by altering v3 integrin and VEGFr-2 trafficking, thereby promoting endothelial cell migration to VEGF. The study found that while higher concentrations of cilengitide can block angiogenesis, lower concentrations can actually stimulate the supply of blood to the tumour and can promote its growth. These results may explain why initial results from early-stage clinical trials have not been as promising as hoped.

Cilengitide is being developed by Merck Serono (Merck KGaA), which in response to the Nature Medicine article issued a statement citing previous findings in numerous preclinical models of the drug in vitro and in vivo that diverge from the latest results. The company also countered with the fact that cilengitide has been studied in more than 750 patients in various long-term settings supporting its current development. Notably, the clinical data for cilengitide in the treatment of GBM, both as a single agent and in combination, have been encouraging. However, all current Merck Serono studies are investigating cilengitide in combination treatment (either radiotherapy and chemotherapy or chemotherapy and another targeted therapy), so there may be some truth in the fact that this class of drugs will not have utility as single agents. Only time will tell.

Matthew Dennis - Editor, Cancer Drug News

Dendreon surges on Provenge hope

2009-03-18T16:21:00.002Z

Shares in Dendreon have increased dramatically over the past few days, possibly as the result of investors trying to cash in before the company releases final results from its make-or-break IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment; also known as D9902B) study. The trial is designed to assess the safety and efficacy of the investigational active cellular immunotherapy, Provenge (sipuleucel-T), in men with metastatic androgen-independent prostate cancer (PCA). Dendreon’s shares closed at US$4.05 on 13th March, up 46 per cent on the closing price on 11th March of US$2.77.

The latest price increase was likely triggered by the release of Dendreon’s fourth quarter and 2008 year-end financial results on 12th March, confirming that it anticipates the IMPACT study to continue to its final analysis, which is expected to be completed by the end of April. Favourable blinded, interim results from the trial were previously reported in October 2008, when the independent Data Monitoring Committee (IDMC), which is overseeing the trial, recorded a 20 per cent reduction in the risk of death in the Provenge arm relative to placebo (hazard ratio=0.80; 95% CI, 0.610 to 1.051). The IDMC observed no safety concerns and recommended that the study continues as planned. However, at that time the company only announced that the final analysis was anticipated in the middle of 2009.

At the final analysis, if the study demonstrates approximately a 22 per cent reduction in the risk of death, based on 304 events, the company would expect the trial to meet its primary endpoint of overall survival (OS). Should the prespecified criterion for statistical significance be achieved, Dendreon would anticipate amending its BLA based on these interim results. The initial BLA filing was based primarily on an improvement in OS observed in the Phase III D9901 trial. Following an FDA Advisory Committee vote that there was substantial evidence of efficacy of Provenge and that it was reasonably safe, the Agency requested additional clinical data to support the proposed efficacy claim. The FDA has since indicated that either a positive interim or final analysis for OS from the IMPACT trial would be sufficient to address the request for additional information to support the proposed efficacy claim.

Sipuleucel-T contains mature, autologous antigen presenting cells (APCs) that are obtained from the patient via a standard procedure approximately two days before each scheduled infusion. The patient's APCs are then transported to a Dendreon manufacturing facility where they are co-cultured with a recombinant fusion protein containing prostatic acid phosphatase. The activated, antigen-loaded APCs (now sipuleucel-T) are then delivered to the physician's office for infusion into the patient. Sipuleucel-T is then infused into the patient, where it can potentially stimulate a T-cell response against PCA cells. Well, that is the theory anyway, and investors buying up Dendreon’s shares will hope that is also the case in the IMPACT study. They will also have their fingers crossed that the company can hit the heady heights of April 2007, when its shares reached US$23.58.

Matthew Dennis - Editor, Cancer Drug News

Merck to pay US$41.1 billion for Schering-Plough

2009-03-13T12:08:00.001Z

A definitive merger agreement has been unanimously approved by the Boards of Directors under which Merck & Co and Schering-Plough will combine, under the name Merck, in a stock and cash transaction. Under the terms of the agreement, Schering-Plough shareholders will receive 0.5767 shares and US$10.50 in cash for each share of Schering-Plough. Each Merck share will automatically become a share of the combined company.

Based on the closing price of Merck stock on 6th March, the consideration to be received by Schering-Plough shareholders is valued at US$23.61 per share, or US$41.1 billion in the aggregate. This price represents a premium to Schering-Plough shareholders of approximately 34 per cent based on the closing price of Schering-Plough stock on 6th March. The consideration also represents a premium of approximately 44 per cent based on the average closing price of the two stocks over the last 30 trading days.

Upon closing of the transaction, Merck shareholders are expected to own approximately 68 per cent of the combined company and Schering-Plough shareholders are expected to own approximately 32 per cent. Merck anticipates that the transaction will be modestly accretive to non-GAAP EPS in the first full year following completion and significantly accretive thereafter.

The combination significantly broadens Merck's portfolio of medicines driven, in part, by the addition of valuable products with long periods of exclusivity. By leveraging the combined company's expanded product offerings, Merck expects to benefit from additional revenue growth opportunities. For example, the combined company will have expanded opportunities for life-cycle management through the introduction of potential new combinations and formulations of existing products. In addition, Merck and Schering-Plough together have high-potential early-, mid- and late-stage pipeline candidates. The transaction will double the number of potential medicines Merck has in Phase III development, bringing the total to 18. The combined company will have a more diverse portfolio across important therapeutic areas, including oncology.

Schering-Plough's current oncology products, which include Caelyx (pegylated liposomal doxorubicin), Intron A (interferon alpha-2b recombinant for injection)/PegIntron (peginterferon alpha-2b) and Temodar/Temodal (temozolomide) Capsules, will enable Merck to expand its presence in this area and provide the necessary foundation to take advantage of the combined company's promising pipeline. Merck also expects to benefit from a solid portfolio of women's health products, which includes the cervical cancer vaccine, Gardasil (human papillomavirus quadrivalent types 6, 11, 16 and 18 vaccine, recombinant).

The transaction is subject to approval by Merck and Schering-Plough shareholders, and the satisfaction of customary closing conditions and regulatory approvals, including expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Act, as well as clearance by the EC under the EC Merger Regulation and certain other foreign jurisdictions. Merck and Schering-Plough expect to complete the transaction in the fourth quarter of 2009, by which time there may well have been more such acquisitions, with Bristol-Myers Squibb being the current favourite target.

Matthew Dennis - Editor, Cancer Drug News

Synta suspends SYMMETRY study

2009-03-13T11:59:00.004Z

Based on an analysis by an independent Data Monitoring Committee (DMC), Synta Pharmaceuticals has suspended the Phase III SYMMETRY (Synta Metastatic Melanoma Elesclomol Trial) trial, which was comparing elesclomol (STA-4783) in combination with paclitaxel to paclitaxel alone in chemotherapy-naïve patients with Stage IV metastatic melanoma. Following the suspension, shares in Synta fell from US$6.39 at the end of 26th February to close on 27th February at US$1.36, a decrease in value of nearly 79 per cent.

The decision was based on the results of an analysis by the DMC, which identified safety concerns, including an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol+paclitaxel) compared to the control arm of paclitaxel alone. The final analysis of the primary endpoint (progression-free survival) as assessed by independent reviewers has not been carried out yet. Elesclomol is an apoptosis stimulator, which acts by inducing oxidative stress in cancer cells by rapidly producing reactive oxygen species. Response to this oxidative stress leads to apoptosis.

Based on these findings, Synta has also revealed that additional ongoing studies with elesclomol, including a study of elesclomol in combination with docetaxel in hormone-refractory metastatic prostate cancer and a monotherapy dose-escalation study, will be suspended pending further analysis of the results of the SYMMETRY trial. Synta is contacting investigators regarding appropriate patient notification and care. The company is also in discussions with its collaborator, GlaxoSmithKline, about the future development of elesclomol. However, it looks likely that GSK will terminate the collaboration.

Such a huge setback could spell the end for Synta, especially in the current economic climate. However, the company has stated that it has both the resources and a diverse pipeline of novel drug candidates in the oncology and anti-inflammatory areas that will allow it to continue operating. The company has recently received two milestone payments that should help its current cash position. These include an up-front payment of US$16 million from Roche for the development of the Synta CRACM (calcium release-activated calcium modulator) programme for the treatment of inflammatory and autoimmune diseases, as well as committed research funding of US$9 million over the next two years. The second payment of US$10 million was received from GSK after Synta achieved a milestone related to the development of elesclomol.

Synta's pipeline includes: STA-9090, a novel heat shock protein 90 inhibitor that is currently in two Phase I studies in solid tumours; STA-5326 (apilimod mesylate), an oral interleukin (IL)-12/IL-23 inhibitor currently in a Phase IIa study in rheumatoid arthritis; STA-9584, a vascular disrupting agent for cancer in preclinical development; and additional programmes in the research and preclinical development stages. Synta shareholders will hope that these programmes prove more successful than elesclomol.

Matthew Dennis - Editor, Cancer Drug News

NICE and SMC tighten purse strings

2009-02-19T11:08:00.002Z

The UK's National Institute for Health and Clinical Excellence (NICE) has issued its final appraisal document recommending the use of Pfizer's Sutent (sunitinib) as a first-line treatment for patients with metastatic renal cell carcinoma (RCC). However, sunitinib is the only one of four drugs being appraised that has been preliminarily cleared for use on the NHS, once again raising the question of drug access in the UK compared to the rest of Europe.

NICE is also currently appraising the use of Roche/Genentech's Avastin (bevacizumab), Bayer/Onyx Pharmaceuticals' Nexavar (sorafenib) and Wyeth's Torisel (temsirolimus) for the treatment of advanced and/or metastatic RCC. Following the independent advisory Committee meeting on 14th January, NICE has decided to split this appraisal in two in order to get guidance out to the NHS as quickly as possible. In the first appraisal, sunitinib is recommended as a first-line treatment option in advanced and/or metastatic RCC for patients who are suitable for immunotherapy with an ECOG performance status of 0 or 1. Sunitinib demonstrated a significant improvement in progression-free survival versus interferon alpha. The median survival of patients treated with sunitinib exceeded two years. In September 2008, NICE had issued an appraisal consultation document that advised against the use of all four medicines for the treatment of advanced and/or metastatic RCC. The latest announcement reverses NICE's previous recommendation regarding the coverage of sunitinib, making it the only one of the four medicines under review, that is so far recommended for coverage.

Sunitinib, an oral multi-kinase inhibitor, was first approved in January 2006 for advanced RCC. The drug works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer. Pfizer has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of sunitinib is free to the NHS.

In the second appraisal, bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for advanced and/or metastatic RCC. In addition, the two drugs also licensed for second-line treatment of advanced or metastatic RCC, sorafenib and sunitinib, are not recommended for this indication. Guidance on bevacizumab, sorafenib and temsirolimus for first-line treatment and sorafenib and sunitinib for the second-line treatment of RCC is available for public consultation via NICE until 4th March.

In a statement from Wyeth, the company commented that it believes that denying patients access to the benefits of temsirolimus in extending life-expectancy compared to standard existing therapy is a devastating and cruel blow to patients and their families. Temsirolimus, despite being found to be clinically effective, has been deemed not to be cost-effective in the current assessment.

Similarly disappointing news was announced in Scotland, as the Scottish Medicines Consortium (SMC) published its guidance on the use of GSK's Tyverb (lapatinib) and Eli Lilly's Alimta (pemetrexed), ruling that in both cases the manufacturer did not present a sufficiently robust economic case to gain acceptance. Lapatinib is approved in Europe, in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer, while pemetrexed is indicated, in combination with cisplatin, for the first-line treatment of patients with locally-advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Despite clinical evidence that the two drugs can extend patients' lives by around two months and six weeks, respectively, the price that this comes at is still not seen as cost-effective.

Matthew Dennis - Editor, Cancer Drug News

ATLAS meets primary endpoint

2009-02-04T12:16:00.003Z

The Phase III ATLAS (AVF3671g) study investigating Tarceva (erlotinib) in combination with Avastin (bevacizumab) as maintenance therapy following initial treatment with bevacizumab plus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) has met its primary endpoint. The trial was stopped early on the recommendation of an independent Data Safety Monitoring Board after a preplanned interim analysis showed that combining erlotinib and bevacizumab significantly extended the time patients lived without their disease advancing, as defined by progression-free survival (PFS), compared to bevacizumab plus placebo. A preliminary safety analysis showed adverse events were consistent with previous erlotinib and bevacizumab studies, as well as trials evaluating the two medicines together, and no new safety signals were observed.

The global, multi-centre, randomised, double-blind, placebo-controlled study enrolled 1,157 patients with locally-advanced, recurrent or metastatic NSCLC. In order to evaluate patients who are often excluded from bevacizumab-based trials, patients with treated brain metastases, tumours of squamous cell histology that were not centrally located in the lung and those taking blood-thinning medications were eligible for this trial. Subjects were initially treated with four cycles of bevacizumab in combination with the investigators' choice of platinum-based CT regimens (carboplatin+gemcitabine, carboplatin+paclitaxel, carboplatin+docetaxel, cisplatin+vinorelbine, cisplatin+docetaxel or cisplatin+gemcitabine). If their cancer did not progress and they did not experience significant toxicity, patients were then randomised (n=768) to receive maintenance therapy with bevacizumab+erlotinib or bevacizumab+placebo until disease progression.

The study's primary endpoint of PFS, as determined by investigators, was defined as the length of time from randomisation to disease progression or death from any cause. PFS assessment began from the start of the maintenance phase of the study after initial treatment with four cycles of bevacizumab and CT. Secondary endpoints included overall survival (OS), incidence of all adverse events and selected Grade 3 or greater adverse events and incidence of treatment discontinuation for reasons other than disease progression.

An earlier study, called BeTa Lung, which evaluated bevacizumab in combination with erlotinib in patients with advanced NSCLC whose disease had progressed following platinum-based CT, failed to meet its primary endpoint of improving OS compared to erlotinib in combination with placebo. However, there was clear evidence of clinical activity, with improvements in the secondary endpoints of PFS and response rate when bevacizumab was added to erlotinib compared to erlotinib alone. An additional trial, called SATURN, showed that erlotinib delayed disease progression when given as a single agent immediately following treatment with CT, compared to placebo. In ATLAS, patients were initially treated with bevacizumab plus CT followed by the addition of erlotinib to bevacizumab in the maintenance phase. Genentech plans to discuss these data with the FDA to determine next steps.

Avastin is currently approved as first-line treatment in combination with carboplatin and paclitaxel for patients with locally-advanced, non-squamous NSCLC, based on a 25 per cent improvement in OS compared to CT alone (hazard ratio=0.80). Tarceva is currently approved as a treatment for patients with advanced NSCLC who have progressed following treatment with at least one prior CT regimen, based on a 37 per cent improvement in OS compared to placebo (hazard ratio=0.73). OSI Pharmaceuticals markets Tarceva through partnerships with Genentech in the US and Roche throughout the rest of the world. Avastin is jointly marketed by Genentech and Roche.

Matthew Dennis - Editor, Cancer Drug News

Pfizer to benefit from Wyeth acquisition

2009-02-04T12:11:00.002Z

A definitive merger agreement has been entered into under which Pfizer will acquire Wyeth in a cash-and-stock transaction, currently valued at US$50.19 per share, or a total of approximately US$68 billion. The Boards of Directors of both companies have approved the combination, which will create one of the most diversified companies in the global healthcare industry.

Under the terms of the transaction, each outstanding share of Wyeth common stock will be converted into the right to receive US$33.00 in cash and 0.985 of a share of Pfizer common stock, subject to the terms of the merger agreement. Based on the closing price of Pfizer stock as of 23rd January, the stock component is valued at US$17.19 per share. The transaction provides immediate value to Wyeth shareholders through the cash component, as well as continued participation in the future prospects expected to result from the combination through their ownership of approximately 16 per cent of Pfizer’s shares. The transaction will be financed through a combination of cash, debt and stock. A consortium of banks has provided commitments for a total of US$22.5 billion in debt. Pfizer and Wyeth expect the transaction to close at the end of the third quarter or during the fourth quarter 2009.

The new company will be an industry leader in human, animal and consumer health. With the combined biopharmaceuticals business, it will lead in primary and specialty care as well as in small and large molecules. Its geographic presence in most of the world’s developed and developing countries will be unrivalled. Wyeth already has a leadership position in growth areas, such as vaccines, nutritionals and biologics. But what will Pfizer be getting for its money?

In the oncology area, Wyeth currently markets the following products: Torisel (temsirolimus) for the treatment of advanced renal cell carcinoma, and also filed in the EU for mantle cell lymphoma; Neumega (oprelvekin) for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with non-myeloid malignancies who are at high risk of severe thrombocytopenia; Mylotarg (gemtuzumab ozogamicin) for the treatment of patients with CD33+ acute myeloid leukaemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy; and Relistor (methylnaltrexone) subcutaneous injection for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. These will be combined with Pfizer's marketed products, which include Camptosar (irinotecan) for colorectal cancer; Sutent (sunitinib) for gastrointestinal stromal tumours and renal cell carcinoma; and Aromasin (exemestane) for breast cancer.

But what about future products? Wyeth's R&D pipeline includes the following oncology compounds: bosutinib, in Phase III for chronic myelogenous leukaemia and Phase II for breast cancer combination therapy; inotuzumab ozogamicin in Phase III for follicular non-Hodgkin's lymphoma (NHL) and Phase II for diffuse large B-cell lymphoma/NHL; and neratinib (HKI-272), which is in late-stage trials for breast cancer. Although Pfizer has many novel drugs in Phase I and II development, its current Phase III pipeline mainly consists of new indications for sunitinib. The main benefit to come from the acquisition of Wyeth will be Pfizer's increased exposure to areas of the oncology market that it does not currently serve, such as haematological cancers and supportive products.

Matthew Dennis - Editor, Cancer Drug News

Europe: drug access still unequal

2009-01-20T15:14:00.003Z

Four years on from the original study, an update to the Karolinska Report has found that European patients still face unequal access to cancer treatment, depending on where they live. These inequalities and gaps in survival are particularly noticeable when comparing Eastern Europe with Northern and Western Europe. The report by Dr Nils Wilking, a clinical oncologist at the Karolinska Institutet, and Dr Bengt Jönsson, Professor of Health Economics at the Stockholm School of Economics, which is based on findings from the 27 EU countries (excluding Cyprus and Malta), Iceland, Norway and Switzerland, updates and improves on two earlier reports by the same authors in 2005 and 2007. The most recent report was supported by an unrestricted grant from the European Federation of Pharmaceutical Industries and Associations.

The report reveals that whereas cancer incidence is increasing, cancer mortality is decreasing, indicating the positive impact of screening programmes and improvements in treatments. "New treatments have made it possible to target diseases more effectively. For cancer patients, these newer therapies mean an improved quality of life, with less time spent in hospital and the chance to return to their day-to-day activities earlier," stated Wilking.

However the report highlights wide gaps in Europe in relative survival rates. For example, in Sweden 60.3 per cent of men and 61.7 per cent of women diagnosed with cancer survive compared to only 37.7 per cent of men and 49.3 per cent of women in the Czech Republic. EUROCARE 4 data also shows that for a similar incidence, cancer patients in Sweden have greater chances of survival than those in the UK. Healthcare systems in Europe are spending more on cancer, but this expenditure remains lower than the relative burden of cancer in comparison to other diseases.

Patients in Austria, France and Switzerland have the broadest access to newer cancer treatments while Poland, the Czech Republic and the UK continue to lag behind. Jönsson emphasised: "The inequalities, highlighted in our original report in 2005, still remain. For patients and society this is a real concern, as expectations are that all patients in Europe should have equal opportunity to access these treatments, particularly when evidence shows that access to cancer treatment is linked to an improvement in outcome".

The report authors urged policy-makers to take action and proposed new policies to improve treatment access for patients in Europe:

adapt healthcare budgets generally and hospital budgets specifically to incorporate the introduction of new cancer drugs;
introduce separate funding for cancer drugs, with or without requirements of an additional gathering of data;
expedite (regulatory and economic) review times for innovative cancer drugs; and
promote a European collaborative approach to collecting available scientific information for Health Technology Assessments (HTAs).

The number of cancer drugs has increased substantially over the last ten to 15 years, and it is likely that a further increase in the number of agents will be seen over the next five years. It is expected that the number of cancer drugs approved during 2007 and 2012 will be 50. With this influx of new technology and growing patient awareness of treatment options, already stretched healthcare budgets will come under increasing pressure to deliver. How HTAs play a part in this will be a major point of discussion.

Matthew Dennis - Editor, Cancer Drug News

Why bladder cancer is deadlier in some

2009-01-16T11:54:00.002Z

Bladder cancer (BC) is much more likely to be deadly for women and African-Americans, but the reasons long believed to explain the phenomenon account for only part of the differences for such patients compared to their white and male counterparts. These findings, published in the 1st January issue of Cancer (2009;115:68-74), raise a question for doctors and patients: if age, tumour type and stage of the disease upon diagnosis do not account for the increased lethality of the disease in women and African-Americans, then what does?

It is a big question facing researchers in this area where the disease is more lethal in those patients who are less likely to get it. Men are more than three-times as likely as women to develop the disease, and white people are nearly twice as likely to get the disease as African-Americans. Yet, once the disease is present, it is far deadlier in women and African-Americans.

In the new study, scientists at the University of Rochester Medical Center have shown for the first time that the factors traditionally thought to be responsible for the differing course are responsible for only about one-third of the difference between white men and women, and up to two-thirds of the difference between African-Americans and their white counterparts.

To perform the study, researchers analysed the records of 101,249 patients who were diagnosed with BC from 1990 to 2003 as part of the SEER (Surveillance, Epidemiology, and End Results) programme. The team found that in the first year after diagnosis, women were anywhere from approximately 80 to 114 per cent more likely to die from the disease than their male counterparts. That increase was slightly lower in year two, when women were around 52 to 55 per cent more likely to die.

When it came to race, the researchers found that African-Americans were approximately 73 to 103 per cent more likely than their white counterparts to die from the disease within the first two years after diagnosis, and around 40 to 117 per cent more likely to die three or four years after diagnosis. The investigators then examined the data to try to uncover the reasons behind these differences. The team found that the factors traditionally thought to be responsible accounted for only approximately 30 per cent of the difference between the genders among white people, and around 50 to 70 per cent of the differences between the races and genders among African-Americans.

The study's authors speculate about other factors that might be responsible for the differences, though they say that further study is necessary to know for sure. Some of the other issues that might play a role include the choice of treatment, differences among tumours that were not taken into account in the study and access to healthcare. The authors believe that poorer access to healthcare is a clear cause of the higher mortality rates for African-Americans. When it comes to gender, some of the differences are likely to be caused by factors that are not currently understood, such as hormonal differences. But a factor that is known to play a key role is people's reaction when they see blood in their urine. Men are more likely than women to notice blood in their urine, to think it is abnormal, and to report it to doctors and even then, when it is reported, doctors are 65 per cent more likely to refer men than women to urologists.

Matthew Dennis - Editor, Cancer Drug News

2009: the year ahead

2009-01-07T14:12:00.001Z

One of the major events scheduled for 2009 is the finalisation of Roche's acquisition of Genentech. Having been initially outlined in July 2008, when Roche proposed to acquire the outstanding publicly-held interest in Genentech for US$89.00 per share in cash, or a total payment of approximately US$43.7 billion, the deal has since stalled. After considering the offer, Genentech concluded that Roche's proposal significantly undervalued the company.

At the time, the offer represented a one-day premium of 8.8 per cent to Genentech's closing price of US$81.82 on 18th July and a one-month premium of 19.0 per cent to Genentech's closing price of US$74.76 on 20th June. However, many analysts predicted that the move undervalued the company and saw Genentech's refusal coming, pricing the company higher at between US$100.00 and US$120.00 per share. Genentech shares have recently been trading between US$81.00 and US$84.00.

With both companies refusing to move, the current situation could ultimately work in either's favour. With Roche drawing out the process, it may be possible to extract a lower price for Genentech's remaining shares. However, it looks more likely that a delay will benefit Genentech shareholders as final results from the NSABP C-08 study of Avastin (bevacizumab) plus chemotherapy in adjuvant early-stage colorectal cancer are expected in the first half of 2009. Following an interim analysis in October 2008, the independent Data Monitoring Committee overseeing the trial recommended that the study continued as planned. Investors are watching the study closely since it may open up a major new market for Avastin and the news may strengthen Genentech's position when negotiating a higher bid from Roche. Additional results are expected from studies investigating Avastin in breast cancer and Rituxan (rituximab) as a potential lupus treatment, possibly further strengthening Genentech's case.

With the current financial climate set to continue into 2009, there are sure to be more companies adopting cost saving programmes and re-aligning their activities to focus on drugs that offer near-term value. It is expected that the development of many early-stage drug candidates will be put on hold or discontinued as companies look to streamline and reduce cash expenditure. As was seen in 2008, funding will still be a big hurdle for biotech companies, with many expected to merge and consolidate or disappear altogether.

Access to new drugs looks set to remain an issue. However, in the UK, the National Institute for Health and Clinical Excellence (NICE) has just issued new guidelines, which should improve access to life-extending drugs for people dying from cancer. NICE appraisal committees will now follow the new guidelines, which were drawn up following a public consultation, when reviewing treatments that may extend the lives of patients who are terminally ill.

The guidelines cover drugs that would normally be deemed too expensive for standard NHS use and which are licensed for a terminal illness affecting a small number of patients with less than two years to live. The drugs will have to meet set criteria in order to be approved for NHS use, including being shown to extend life by at least three months compared with standard NHS treatment. Experts estimate that some 10,000 cancer patients a year in the UK could benefit from the move. However, how these guidelines are put into practice over the next 12 months will give more of an indication of real impact.

Matthew Dennis - Editor, Cancer Drug News

Losers of 2008

2009-01-07T13:58:00.007Z

As the year begins, it provides an opportunity to reflect on the past 12 months and to highlight those companies and drugs that have not fared so well. Starting off the year badly, as a knock-on effect from 2007, was Novacea, which in April received notification from Schering-Plough of its termination of the collaboration agreement relating to the development of Asentar (DN-101). In 2007, the companies halted the Phase III ASCENT-2 trial of Asentar for the treatment of patients with androgen-independent prostate cancer (PCA), due to an imbalance of deaths between the two treatment arms. The companies then suspended enrolment in other ongoing trials involving the drug. There was a glimmer of hope for Novacea later in the year as it entered into a merger agreement with Transcept Pharmaceuticals, however Asentar was offered no such lifeline and there are no plans to resurrect it.

As with previous years, cancer vaccines promised much in 2008, but again failed to deliver. Favrille's Phase III registration trial for Specifid (mitumprotimut-T) administered following Rituxan (rituximab) in patients with follicular B-cell non-Hodgkin's lymphoma failed to show a statistically significant improvement in the primary endpoint of time-to-progression. Due to the results, Favrille is discontinuing development of the vaccine and is currently evaluating steps to conserve cash and recognise value on its assets, which include a reverse merger with MyMedicalRecords.com. Cell Genesys also suffered as the company, along with Takeda and its wholly-owned subsidiary, Millennium Pharmaceuticals, suspended further development of GVAX immunotherapy for PCA. In October, Cell Genesys terminated the Phase III VITAL-1 trial of GVAX in patients with asymptomatic, metastatic hormone-refractory PCA following an analysis, which indicated that the trial had a <30 class="blsp-spelling-error" id="SPELLING_ERROR_24">Genesys to implement a substantial restructuring plan, which will include the loss of around 80 per cent of its employees.

Other drugs to fail in Phase III included Taiho Pharmaceutical's S-1 in advanced gastric cancer, which caused sanofi-aventis to return its development and commercialisation rights to the oral anticancer agent, as well as Progen Pharmaceuticals' PI-88 in hepatocellular carcinoma, for which the company cited reduced commercial opportunities. A further surprise came when the FDA notified Introgen Therapeutics that its BLA for Advexin (contusugene ladenovec), the company's targeted p53 tumour suppressor gene therapy for the treatment of recurrent, refractory squamous cell carcinoma of the head and neck (SCCHN), was not sufficiently complete and would not be filed at this time. Introgen intends to appeal this refuse to file decision and is reviewing the various options available to it. The decision came as a surprise, as earlier in August, the EMEA accepted for review Gendux Molecular's (Introgen) MAA for Advexin for the treatment of recurrent, refractory SCCHN.

But perhaps the biggest loser of the year was Bristol-Myers Squibb, which lost out to Eli Lilly in the race to takeover ImClone Systems. However, BMS did receive approximately US$1 billion in cash following the acquisition, an amount that in the current financial climate is perhaps as valuable.

Matthew Dennis - Editor, Cancer Drug News

Winners of 2008

2008-12-18T16:34:00.003Z

As the year draws to a close, there is just time to reflect on the past 12 months and to highlight those companies and drugs that have triumphed and failed. With only seven major new drug approvals in the US and Europe, compared to 11 in 2007, it would seem that the pharmaceutical industry and regulators are suffering from the knock-on effects of the current financial climate, where prudence is now key.

The year got off to a good start, when in January the EC granted marketing approval to Abraxis BioScience's Abraxane (paclitaxel protein-bound particles for injectable suspension; albumin-bound) for the treatment of metastatic breast cancer in patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. The first US approval came in the form of Cephalon's Treanda (bendamustine) for Injection, for the treatment of patients with chronic lymphocytic leukaemia (CLL) in March. Later in the year, the FDA also approved bendamustine for the treatment of patients with indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In October, the EC granted a full marketing authorisation, in the form of a positive Commission Decision, for EpiCept's Ceplene (histamine dihydrochloride) for the remission maintenance and prevention of relapse in adult patients with acute myeloid leukaemia in first remission.

The major winners of 2008 were definitely in the field of supportive care for cancer. In January, the EC and FDA approved Merck & Co's fosaprepitant dimeglumine (MK-0517) for Injection, an intravenous therapy for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV). Available as Emend in the US and Ivemend in the EU, the drug was approved for use in combination with other anti-emetic medicines for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately- and highly-emetogenic cancer CT. A further approval came in September, as the FDA approved ProStrakan's Sancuso (granisetron), a novel, patent-protected transdermal patch for the prevention of CINV; the product was launched in the US in November.

Another approval to support cancer patients came in April when the EC granted marketing authorisation to Cephalon's Effentora, a buccal tablet formulation of fentanyl, for the treatment of breakthrough cancer pain in adult patients who are already receiving maintenance opioid therapy for chronic pain. More good news came as both the FDA and EC approved Progenics Pharmaceuticals/Wyeth Pharmaceuticals' Relistor (methylnaltrexone injection), in April and July, respectively, for subcutaneous use for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. In what could be the final approval of the year, in December, the FDA granted marketing authorisation to Genzyme's Mozobil (plerixafor injection), a drug intended to be used in combination with G-CSF to mobilise haematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with NHL and multiple myeloma. Hopefully 2009 will be a more fruitful year.

Matthew Dennis - Editor, Cancer Drug News

Cancer to lead death toll in 2010?

2008-12-18T16:30:00.004Z

Despite the fact that cancer incidence and death rates for men and women in the developed world continue to decline, cancer is projected to become the leading cause of death worldwide in the year 2010, and low- and middle-income countries will feel the impact of higher cancer incidence and death rates more sharply than industrialised countries.

To coincide with the International Agency for Research on Cancer releasing the new edition of the World Cancer Report, in the US, the nation's leading cancer organisations joined forces at an event called Conquering Cancer: A Global Effort, to focus attention on the growing global cancer burden and discuss efforts needed to address the problem. The American Cancer Society, the Lance Armstrong Foundation and Susan G. Komen for the Cure discussed how each organisation is addressing the global cancer problem and together issued a call to action for the incoming US presidential administration and Congress.

According to the report, the burden of cancer doubled globally between 1975 and 2000. It is estimated that it will double again by 2020 and nearly triple by 2030. This translates to far greater numbers of people living with and dying from the disease. The report estimates that there were some 12 million new cancer diagnoses worldwide in 2008, and more than 7 million people will die from the disease.

The projected numbers for the year 2030 are 20 to 26 million new diagnoses and 13 to 17 million deaths. The growing cancer burden includes global increases of incidence of approximately 1 per cent each year, with larger increases in China, Russia and India. Reasons for the increased rates include adoption of Western habits in less developed countries, such as tobacco use and higher-fat diets, and demographic changes, including a projected population increase of 38 per cent in less developed countries between 2008 and 2030. In addition to increases in cancer incidence and death rates, the report identifies challenges in cancer care, especially in Africa, where pain management and palliative care are very limited because any use of narcotics is prohibited by law in several countries.

The call to action steps issued by the three organisations include: 1) making vaccines that prevent cancer-causing infections more widely available to low-income nations, including efforts to make the human papillomavirus vaccine accessible and affordable; 2) committing to a comprehensive tobacco control approach in the US, which includes taking measures proven effective in reducing smoking rates and having Congress grant the FDA authority to regulate tobacco; 3) ratifying immediately the Framework Convention on Tobacco Control, the first ever global public health treaty that sets forth comprehensive measures to reduce health and economic impacts of tobacco; 4) supporting efforts of non-governmental organisations to build advocacy and resources, empower survivors and reduce suffering in low- to middle-income countries by working with governments, medical professionals and the corporate sector to enable individuals to adopt healthier behaviours; 5) promoting culturally-sensitive risk reduction and education campaigns by leveraging US efforts to help build capacity of non-governmental organisations in other countries; and 6) investing in cancer research and expanding access to prevention and early detection measures in the US, with a specific focus on increasing federal funding of medical research.

Matthew Dennis - Editor, Cancer Drug News

More teens needed for trials

2008-12-03T15:01:00.002Z

A new UK study has highlighted the small number of teenagers who are enrolled in clinical trials for cancer, despite the benefits of being involved. Inclusion in studies has been shown to improve cancer survival, because it provides access to new drugs, better quality of care through frequent monitoring and access to a wider group of specialists. The results of the work have been published in the 1st December online edition of the British Journal of Cancer (10.1038/sj.bjc.6604751).

Scientists from University College London analysed enrolment in Phase III trials from April 2005 to March 2007 involving teenagers and young adults (TYA), as well as children. All of the young patients involved in trials had been diagnosed with leukaemia, lymphoma, brain and central nervous system, bone sarcomas or male germ cell tumours. The researchers found that only 25.2 per cent of 15 to 19-year-olds and 13.1 per cent of 20 to 24-year-olds were enrolled in clinical trials, compared with 43.2 per cent of ten to 14-year-olds. Rates increased among ten to 14-year-olds and 15 to 19-year-olds during April 2006 to March 2007 compared with the previous 12 months, but fell among 20 to 24-year-olds.

The investigators noted that there were four trials available for patients with CNS tumours, yet no over-16s were enrolled in these trials. They also observed that over-15s were much less likely to take part in clinical trials in England than children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. However, other possible influences, such as difficulties associated with the consent of TYA require further evaluation.

Study leader Dr Lorna Fern, who co-ordinates research into TYA with cancer at the National Cancer Research Institute has said that the US and Australia had also reported a similar trend. Young people are constantly falling through the gap between paediatric and adult cancer specialists and there are not enough trials for the types of cancers that affect them. This is an important study that can be used as the base on which progress is measured in the UK. Before now, it was not known how many young people with cancer were recruited onto clinical trials. It is hoped that in the future, closer dialogue between those involved in planning and running trials for children and for adults will improve trial availability and recruitment.

Amending the age eligibility criteria is one possible solution, although it may not completely address the problem of recruiting TYA. In the EURAMOS-1 trial (an international osteosarcoma trial), a fall off in recruitment has been seen beyond the age of 15, despite an age eligibility criteria which spans the whole paediatric and TYA population. Average accrual to EURAMOS-1 in England, Scotland and Wales has demonstrated a decline in accrual from 42.7 per cent for patients aged ten to 14 years, 38.3 per cent for those aged 15 to 19, and 15.7 per cent of patients aged 20 to 24 from 2005 to 2008.

It is feared that significant improvements in outcomes from cancer for TYA will remain elusive without a coalition of forces including funders, policy makers, biologists, clinicians and patients.

Matthew Dennis - Editor, Cancer Drug News

Last chance for Iressa?

2008-11-27T14:37:00.003Z

Results from the Phase III INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study, published in the 22nd November edition of The Lancet (2008;372:1809-1818), have shown that patients with pretreated advanced non-small cell lung cancer (NSCLC) who received the oral anticancer drug, Iressa (gefitinib), had comparable survival to those treated with intravenous docetaxel. In addition, gefitinib had a more favourable tolerability profile than docetaxel and significantly more gefitinib-treated patients had an improvement in quality of life.

These results follow previous disappointing data for the drug in the ISEL (IRESSA Survival Evaluation in Lung cancer) study, where gefitinib failed to demonstrate a survival advantage versus placebo in NSCLC patients. This led to a severe restriction on the use of the drug in the US and also to AstraZeneca withdrawing its MAA in Europe. As such, gefitinib is not currently licensed in the EU, however on 2nd May, AstraZeneca submitted an MAA to the EMEA seeking approval as a treatment for locally-advanced or metastatic NSCLC patients pretreated with platinum chemotherapy (CT). The application is based on data from the INTEREST study and is the first time a targeted therapy, an EGFr tyrosine kinase inhibitor, has proven non-inferiority for overall survival (OS) relative to CT in patients with pretreated advanced NSCLC.

The INTEREST study was a randomised, open-label, parallel-group trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally-advanced or metastatic recurrent NSCLC who had previously received platinum-based CT. Patients were randomly assigned to receive gefitinib (250mg/day; n=733) or docetaxel (75mg/m2; n=733). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFr-gene-copy number in the intention-to-treat population.

In the study, 1,433 patients were analysed per protocol (723 in the gefitinib group and 710 in the docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 vs 576 events; hazard ratio [HR]=1.02; 96% CI, 0.905 to 1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFr-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR=1.09; 95% CI, 0.78 to 1.51; p=0.62; median survival 8.4 vs 7.5 months).

Will these new data signal a resurrection for the drug? With such mixed results for gefitinib, it is hard to imagine doctors altering their prescribing habits on the basis of the INTEREST data alone, especially when there are many of other options available for treating LC patients. Tarceva (erlotinib), another EGFr inhibitor, is available, as is Avastin (bevacizumab), with more on the horizon, including Erbitux (cetuximab). One thing that could save gefitinb is the use of pharmacogenomics and a test to predict which patients would be suitable for treatment with the drug. However, this is an expensive and time-consuming undertaking, one that AstraZeneca may not see as financially rewarding or competitive as there are already EGFr inhibitors available, such as cetuximab and Vectibix (panitumumab), that are marketed alongside companion diagnostics. As such, INTEREST could be gefitinib’s final chance of success.

Matthew Dennis - Editor, Cancer Drug News

Targeted drugs reduce attrition rates

2008-11-20T10:58:00.002Z

The results of a new study published in the 14th November online edition of Nature Reviews Drug Discovery (10.1038/nrd2758) suggest that advances in drug development have led to an increase in the number of drugs reaching cancer patients. Scientists from Cancer Research Technology (CRT; Cancer Research UK [CRUK]) obtained data on 974 cancer drugs in clinical development, and calculated that there was a probability that 18 per cent of those entering the clinic would make it to market. Previously it was estimated that in some studies only 5 per cent of cancer drugs in the pipeline become standard treatments for the disease.

The data search was limited to agents which entered Phase I trials after January 1995 and before September 2007, of which 137 are the molecularly-targeted drug class, kinase inhibitors. The research showed that kinase inhibitors were almost three-times more likely to reach patients than other types of anticancer drug. The investigators believe that a better understanding of the basic biology of cancer has enabled the development of this type of new drug, which includes Herceptin (trastuzumab) for breast cancer and Glivec/Gleevec (imatinib) for leukaemia.

The study highlights the fact that understanding more about the basic biology of cancer is making a real difference to the success rate of new anticancer drug development. Additionally, improved drug-discovery processes and advances in medicinal chemistry have also contributed to better success rates of drugs in development. Furthermore, better understanding of a patient's genetic make-up and how they will respond to certain drugs has led to improvements in clinical trial design.As drug development continues to advance, minimising the number of drugs which fail to make it to market will remain key as the cost of discovery and development of those drugs which do not reach market is borne by those that do. The true cost of a drug reaching the market has recently been estimated to be US$0.8 billion to US$1.0 billion.

According to one of the study authors, Professor Herbie Newell, Director of Translational Research at CRUK: "We strongly believe that both industry and academia must improve the availability of data related to failed as well as successful drug development programmes. The sharing of such information can only be beneficial for clinical, scientific and commercial reasons, and will help measure our progress as well as pinpoint areas for improvement."

Historically, the oncology pipeline has been largely made up of small-molecule cytotoxic drugs, which have a low therapeutic index and can fail in clinical trials due to toxicity or efficacy reasons. The recent explosion of information coming from work into understanding the molecular basis of cancer has led to an increase of drugs targeting specific pathways, drugs that are specifically designed to treat cancer, rather than randomly killing proliferating cells. As more information becomes available and newer drugs that are better targeted move into the pipeline, the attrition rate for cancer drugs may reach levels seen with other therapy areas, such as cardiovascular disease where 20 per cent of agents in development reach the market.

Matthew Dennis - Editor, Cancer Drug News

MethylGene cuts staff

2008-11-05T12:38:00.001Z

Celgene has terminated its licensing agreement with MethylGene for oncology histone deacetylase (HDAC) inhibitors, including MGCD0103. As a result, MethylGene will reacquire all rights to MGCD0103 and other HDAC and sirtuin inhibitors in territories licensed to Celgene including North America and the EU. As part of the termination provisions, Celgene will continue to support MGCD0103 for a period of 90 days to ensure a smooth transition. As a results of this, MethylGene will implement a strategic initiative to focus its resources on the clinical development of its proprietary pipeline.

In August, the FDA placed a partial clinical hold on MGCD0103 studies as a result of the voluntary suspension of enrolment of new patients into trials evaluating the drug following observations of pericarditis or pericardial effusion in 19 subjects out of approximately 400 patients treated. Under the partial clinical hold, patients currently enrolled in MGCD0103 trials who are confirmed to have no signs or symptoms of pericarditis or pericardial effusion may continue in their respective studies. MethylGene believes that regaining exclusive rights to MGCD0103 will allow it to accelerate submissions to the FDA aimed at lifting the partial clinical hold.

The termination of the agreement does not affect MethylGene's relationship with Taiho Pharmaceutical for Japan and certain other Asian countries. Celgene acquired the rights to MGCD0103 through its March 2008 acquisition of Pharmion. MethylGene now owns the worldwide rights to three compounds, MGCD0103 (with the exception of certain Asian territories), MGCD265 and MGCD290, all of which are at various stages of clinical development.

MethylGene also announced that after a review of the company's current research, development and business activities, it will focus on advancing its clinical pipeline, which represents the most attractive, near-term value-generating opportunities. Accordingly, the company will begin a process to discontinue its discovery research activities, including a phased workforce reduction. The first phase of the reduction will occur over the next two months with additional reductions planned during 2009 as funded discovery research with Celgene for sirtuin inhibitors for cancer and with Otsuka Pharmaceutical for kinase inhibitors for ocular diseases are concluded. It is expected that approximately half of the company's current staff of 109 full-time employees will be affected by the transition when completed as planned.

With the implementation of this initiative, it is estimated that MethylGene will have sufficient resources to carry out currently-planned development and operational activities into approximately the third quarter of 2010. These plans include the continuing development of MGCD265 into Phase II trials, MGCD290 through Phase I studies and pursuing the removal of the partial clinical hold on MGCD0103. MethylGene will evaluate progressing MGCD290 into Phase II trials after reviewing Phase I data and evaluating potential partnerships and/or additional funding requirements. The company will also evaluate the status of MGCD0103 once the compound is released from partial clinical hold.

Matthew Dennis - Editor, Cancer Drug News

GVAX: development halted

2008-10-21T15:48:00.003+01:00

Cell Genesys has decided to terminate the Phase III VITAL-1 (Vaccine ImmunoTherapy with Allogeneic Prostate Cancer Cell Lines) trial of GVAX immunotherapy in patients with asymptomatic, metastatic hormone-refractory prostate cancer (HRPCA) following an independent Data Monitoring Committee (IDMC) analysis, which indicated that the trial had a <30 per cent chance of meeting its predefined primary endpoint of an improvement in survival. In August, the company halted VITAL-2, the second Phase III trial investigating GVAX in PCA, after a recommendation from the IDMC following the observation of an imbalance in deaths between the two treatment arms.

Following the termination of VITAL-2, Cell Genesys requested the IDMC conduct a futility analysis of the VITAL-1 trial, which was fully enrolled in 2007 with 626 patients and compared GVAX to Taxotere (docetaxel) plus prednisone. The latest news hit the company's stock price hard, with shares falling by 73 per cent from a close of US$0.61 on 15th October to open at US$0.16 on 16th October.

In view of these terminations, Cell Genesys is to place on hold the further development of GVAX for PCA pending a review of the programme with its collaborator, Takeda Pharmaceutical. As a result, Cell Genesys will reduce its staff of 290 by approximately 75 per cent by the end of 2008, with further reductions anticipated in the first half of 2009 as additional activities are phased out. As of 30th September, the company had approximately US$150 million in cash and currently estimates that the year-end cash will be approximately US$128 million. Personnel-related restructuring charges of approximately US$12.8 million are expected to be incurred in the fourth quarter of 2008.

Cell Genesys has also reported results of a preliminary analysis of the VITAL-2 trial. In contrast to VITAL-1, the VITAL-2 study was conducted in patients with symptomatic, metastatic HRPCA and compared the combination of GVAX+docetaxel to docetaxel+prednisone as a control. At the time that this study was terminated, the IDMC reported an imbalance in deaths between the two treatment arms that was observed during a routine safety monitoring meeting of the committee. More specifically, of 114 deaths at the time of the IDMC review, 67 occurred in the GVAX+docetaxel treatment arm and 47 in the docetaxel+prednisone control arm.

A total of 408 patients had been enrolled in the study up to that point in time. The company has now conducted an initial analysis of the incomplete trial data set that was reviewed by the IDMC in August. The analysis has revealed no apparent imbalance in patient baseline characteristics with respect to both demographic and disease prognostic factors. In addition, no significant toxicities in the GVAX+docetaxel therapy arm were observed that could explain the imbalance in deaths and in fact, the vast majority of deaths in both treatment arms were reported as due to progression of PCA. Of note, fewer treatment cycles with docetaxel were administered to patients in the GVAX+docetaxel arm compared to the control arm, a difference which was statistically significant.

In a conference call, the company's Chief Executive Officer, Stephen Sherwin, stated that Cell Genesys has since found no evidence that the GVAX regimen carried toxic effects that could explain the additional deaths. "We don't have all the answers," he commented, although cancer sufferers, shareholders and employees will wish that he at least had some.

Matthew Dennis - Editor, Cancer Drug News

NICE set to block Tyverb's use on NHS

2008-10-14T16:52:00.002+01:00

A draft recommendation by the UK's National Institute for Health and Clinical Excellence (NICE) in a second technology appraisal consultation document (ACD) has indicated that GlaxoSmithKline's Tyverb (lapatinib; known as Tykerb in the US and certain other markets) should not be used in the NHS, except in clinical trials. The oral drug is currently approved in the EU in combination with Xeloda (capecitabine) for the treatment of women with ErbB2 (HER2)-positive advanced breast cancer (BC), whose disease has stopped responding to Herceptin (trastuzumab). The draft guidance comes despite GSK proposing a patient access programme (PAP), where it would bear the cost of the drug for the first 12 weeks of treatment.

Lapatinib, in combination with capecitabine, is the only treatment option that is licensed for use in patients with this aggressive form of advanced BC, who have limited treatment options remaining if their cancer has continued to grow despite treatment with standard chemotherapies and trastuzumab for advanced disease. In a pivotal trial that led to its EU licence, lapatinib+capecitabine significantly increased the time-to-progression (TTP) for patients with ErbB2-positive BC compared with capecitabine alone. In its draft guidance, NICE acknowledged that lapatinib is a clinically-effective option and noted that lapatinib+capecitabine was associated with improved TTP and progression-free survival.

In recognition that the first ACD from NICE did not consider lapatinib to be cost effective in treating this patient population, GSK proposed a PAP, where the company would bear the cost of lapatinib for all eligible patients, for up to the first 12 weeks of treatment. The NHS would commence payment only for those patients who continue to receive clinical benefit beyond 12 weeks. Criteria for continuation of therapy beyond 12 weeks would be determined by the individual person's clinician, based on reduction in lesion size, presence of stable disease or improvement in other response criteria such as symptoms. This programme was designed to provide access to all eligible patients and deliver cost-effectiveness at a threshold that should have been acceptable to NICE.

The cost effectiveness of lapatinib+capecitabine was supported by a comparison to trastuzumab-containing regimens and capecitabine alone, representing the established treatment regimens in NHS clinical practice. Whilst NICE accepted that trastuzumab is widely used following progression of the disease, the Committee suggested that it was unlikely to be cost effective, and therefore did not accept trastuzumab as a valid comparator. According to GSK, the way in which the decision was made makes it very difficult to ever demonstrate the cost effectiveness of lapatinib in this patient population, even in light of the proposed PAP.

Following the ACD, GSK will continue to work with NICE to demonstrate the cost effectiveness of lapatinib in all eligible patients by seeking to validate trastuzumab as a legitimate comparator. The next meeting will be held on 19th November, however, it looks as though NICE will stick with its current draft guidance and recommend against funding lapatinib on the NHS.

Matthew Dennis - Editor, Cancer Drug News

Market jitters affecting takeovers?

2008-10-14T16:46:00.002+01:00

As the world financial crisis deepens, the potential takeover deals involving Genentech and Roche, as well as ImClone Systems and Bristol-Myers Squibb, continue to play out. The current market situation could have an impact on the first takeover, although the second looks more likely to proceed smoothly.

For the first time since Roche made its bid to acquire Genentech in July for US$89.00 per share, the latter's shares have dropped below the offer price, ending on 29th September at US$85.30. The uncertainty now surrounding the bid has fuelled speculation that an improved offer may not be made. When Roche proposed the deal, the cost of borrowing was not as high as it in the current climate. Now there are concerns that Roche would have trouble financing the deal, which currently stands at US$43.7 billion, given the current credit market conditions. However, many analysts believe Roche's strong balance sheet and predictable cash flow will still allow it to secure funding for the deal.

The current situation could ultimately work in Roche's favour as the company may choose to draw out the process in order to extract the lowest possible price for Genentech's remaining shares. It may be that many Genentech shareholders would also prefer to wait, given that interim results are expected in November from a key clinical trial looking at the use of Avastin (bevacizumab) in colon cancer patients who have had tumours surgically removed; final results of the 2,700-patient study are due in 2009.

As for BMS' takeover offer for ImClone, which currently stands at US$62.00 per share in cash, Carl Icahn, ImClone's Chairman of the Board, recently commented that the "hostile tender of US$62, at this time, seems absurd". ImClone reportedly has an offer from another large pharmaceutical company of US$70.00 per share, also in cash, subject to due diligence, which was scheduled to be finished on 28th September. ImClone is expecting that a solid offer from this company will be made or a formal rejection, in which case the suitor will be identified, by the end of business on 1st October. Both of these offers, BMS' valued at US$4.7 billion and the other at US$6.1 billion, do not rely on either company raising funds so should not be affected by recent financial developments.

But to add to the uncertainty, Merck KGaA has entered the fray. Although the company has said that it will not bid for ImClone on its own, it has stated that it may consider taking part in a potential approach for the company. Could it join forces with rumoured suitors, such as Eli Lilly and Pfizer, which has coincidentally said recently that it will focus its early-stage research and development programmes on high growth areas, including cancer?

Matthew Dennis - Editor, Cancer Drug News

Bidding war to start for ImClone?

2008-09-16T16:50:00.003+01:00

ImClone Systems' Chairman of the Board, Carl Icahn, has stated that the Special Committee of ImClone's Board of Directors has informed Bristol-Myers Squibb that following the Special Committee's review and discussion, and based upon the advice it received from its advisors, the Special Committee has determined that the unsolicited offer that ImClone received from BMS to acquire ImClone for US$60 per share in cash is inadequate.

Icahn also disclosed that he has had several conversations with the Chief Executive Officer of a large pharmaceutical company. As a result of such conversations, the pharmaceutical company has submitted a proposal, subject to due diligence, but not subject to financing, to acquire ImClone for US$70 per share in cash. Names being bandied about for the unknown bidder include Merck KGaA, Pfizer and GlaxoSmithKline, as well as AstraZeneca and sanofi-aventis. The Special Committee has determined, subject to the execution of a confidentiality agreement, to allow this company to conduct due diligence for a two-week period, subject to extension by mutual consent. No determination has been made as to whether US$70 per share would be adequate.

In response to this disclosure, BMS sent a letter to Icahn stating its disappointment that the offer had been rejected without discussing its merits with BMS and its advisors. BMS also noted that, in contrast to the competing offer, it has made a formal written offer that has been approved by its Board of Directors, is not subject to due diligence and has been fully disclosed to ImClone's stockholders.

BMS currently holds the exclusive long-term marketing rights in the US to Erbitux (cetuximab) and related compounds, including IMC-11F8. BMS stated that it has no intention of agreeing to any modifications to these rights. Additionally, ImClone should understand that BMS’ offer is for the entire company, and any potential restructuring of ImClone could severely jeopardise its value and deprive stockholders of the benefits of the BMS offer.

BMS continues to look forward to engaging directly with ImClone and its financial and legal advisors to discuss the merits of its all-cash offer to acquire the approximately 83 per cent of the company that BMS does not already own. In reply, ImClone submitted a letter to BMS in which it stated that with regard to the assertion concerning rights to IMC-11F8 (which, if ultimately approved for sale, may have a significant competitive effect on Erbitux), ImClone disagrees that BMS' rights are clear and does not waive any rights that ImClone may have with regard thereto. If BMS wishes to make another offer that it believes ImClone would not find inadequate, it is free to do so. Upon receipt of that offer, ImClone will respond appropriately. However, BMS' Chief Financial Officer Jean-Marc Huet has stated that the company is willing to "walk away" from the deal if needed.

Exactly what belongs to whom in the BMS-ImClone partnership will be a key question of interest as ImClone's new mystery bidder conducts its due diligence over the next few weeks. It seems likely that Merck KGaA may be the interested party because it partners with ImClone in selling Erbitux in some countries outside North America and has touted the drug's prospects of being approved for other types of cancer. Perhaps the bidding will now start in earnest?

Matthew Dennis - Editor, Cancer Drug News

Telomerase finally gives up its structure

2008-09-16T16:48:00.004+01:00

In a landmark study, researchers from the Wistar Institute have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all cancers. It is hoped that this achievement will open the door to the creation of new, broadly-effective cancer drugs, as well as anti-ageing therapies. The results of the work have been published in the 31st August online edition of Nature (10.1038/nature07283).

Scientists have been searching for over ten years to develop drugs that shut down telomerase, which is considered the best target for the development of new cancer treatments, but they have been hampered in large part by a lack of knowledge of the enzyme's structure. The new findings should help investigators in their efforts to design effective telomerase inhibitors. According to lead study author, Dr Emmanuel Skordalakes, assistant professor in Wistar's Gene Expression and Regulation Program: "Telomerase is an ideal target for chemotherapy because it is active in almost all human tumours, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects."

In humans, telomerase adds multiple repeats of a short DNA sequence to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during cell division. When telomerase is dormant, telomeres shorten each time a cell divides, eventually leading to genetic instability and cell death. The enzyme is active in cells that multiply frequently, such as embryonic stem cells, but is switched off almost entirely in normal adult cells. Cancer cells, however, often regain the ability to activate telomerase, which has been implicated in 90 per cent of human tumours. The enzyme permits cells to replicate indefinitely and achieve the cellular immortality that is the hallmark of cancer.

Telomerase is a complex structure made up of multiple protein domains and a stretch of RNA, which contains the template the enzyme uses to synthesise telomeres. In 2007, the researchers solved the structure of a key segment of the molecule, the TRBD domain, where RNA binding occurs. However, the complexity of telomerase has proved a roadblock to determining the enzyme's overall architecture, as has the ability to obtain sufficient quantities of the enzyme.

By screening a wide variety of organisms, including protozoa and insects, the scientists discovered that a gene from the red flour beetle could produce telomerase in copious amounts, and a stable form. The researchers used X-ray crystallography, to determine the 3D structure of the enzyme's active region, the catalytic component called telomerase reverse transcriptase protein (TERT). The work revealed surprising features, including the fact that the molecule's three domains are organised into a doughnut shape, an unexpected configuration. Knowledge of the structure allowed the researchers to create a model of the enzyme's function. Looking forward, the scientists plan to further study TERT and search for new telomerase inhibitors that could become cancer therapies, as well as looking at modifying existing drugs. Now telomerase has finally given up its structure, the hard work really starts.

Matthew Dennis - Editor, Cancer Drug News

Price may prohibit HPV vaccination in developing world

2008-09-16T16:43:00.002+01:00

As vaccinations against human papillomavirus (HPV) begin for girls in another western country, this time in Scotland, questions remain about how best to utilise this technology in other world regions. As discussed at the World Cancer Congress, which was held from 27th to 31st August, in Geneva, Switzerland, the development of highly-effective vaccines against HPV and promising new screening tests provide an unprecedented opportunity to tackle the disease in poor countries, where pap smear screening has largely failed because it is too expensive and too complicated to implement.

At present, approximately 80 per cent of cervical cancer (CC) deaths occur in developing countries, and estimates predict that if current trends continue, these regions will face a 75 per cent increase in the number of cases in the next two decades. Presented at the Congress was the first broad analysis of the cost-effectiveness of introducing HPV vaccination and new screening methods into the hardest hit regions of the world, which include Asia-Pacific, Latin America and the Caribbean. The benefits varied, depending on the size and make-up of the population and the burden of CC in each country.

It was determined that in the Asia-Pacific region, which accounts for more than half of the world's CC cases, vaccination would be cost-effective, even in the poorest countries, if the cost per vaccinated girl was between US$10 and US$25. For Latin America and the Caribbean, the cost per vaccinated girl, including delivery and logistics costs, would have to be less than US$25 to be cost-effective for all countries. In the most developed populations in the region, vaccination would be cost-saving if the cost per vaccinated girl is between US$25 and US$60, and cost-effective at higher prices.

According to Professor Francesc Xavier Bosch of the Catalan Institute of Oncology: "Efforts are needed now to adapt the current price of the vaccines so they meet what individual countries can afford; the solution may be tiered pricing according to gross national income per capita and according to the scale of country effort. Currently the vaccine's price in the private sector is approximately US$120 per dose, or US$360 per vaccinated girl. Many countries will need subsidies for some time."

The price of the vaccine and the support for massive vaccination campaigns is one of the biggest barriers for the moment, but several other challenges lay ahead. Those include generating the political support for an intervention whose pay-off is two or more decades away, cultural acceptability of the vaccine and monitoring the circulating virus. Uncertainties that may affect the success of vaccination programmes include the duration of protection and whether booster shots might be needed, and whether the vaccines will be as effective in girls whose immune systems are suppressed by either malnutrition or other chronic infections, such as HIV or malaria.

For the near future, in developing countries, both vaccination and screening will be needed. However, in the beginning, many countries may have to continue to focus on screening alone until the vaccine becomes more affordable.

Matthew Dennis - Editor, Cancer Drug News

Draft NICE guidance denies RCC drugs

2008-08-13T15:57:00.003+01:00

The UK's National Institute for Health and Clinical Excellence (NICE) has issued preliminary recommendations for the treatment of renal cell carcinoma (RCC), concluding that Roche/Genentech's Avastin (bevacizumab), Bayer/Onyx Pharmaceuticals' Nexavar (sorafenib), Pfizer's Sutent (sunitinib) and Wyeth Pharmaceuticals' Torisel (temsirolimus) are not recommended as treatment options for advanced and/or metastatic disease. Although the drugs were shown to be clinically effective and extend life for RCC patients, they were deemed to not be a cost-effective use of NHS resources. NICE is expected to issue final guidance in January 2009.

Following the decision, Cancer Research UK (CRUK) has called for NICE to alter the way that it appraises the value of drugs for rare diseases, such as metastatic RCC, where clinical benefit is proven but evidence is limited due to the small number of available patients. Professor Peter Johnson, CRUK's chief clinician, stated: "We are disappointed at NICE's view that although these drugs are clinically effective, their high price means that they are not considered to be value for money for the NHS. These drugs have shown a small but definite improvement in an illness where there are few alternative treatments. If this decision stands it will be very frustrating for cancer patients and their clinicians."

The charity put forward that possible solutions include looking at the way that pharmaceutical companies are charging the NHS for drugs, and whether appropriate allowances are being made by NICE to compensate for the lack of large-scale trials in these areas. However, it turns out that proposals were submitted by two of the manufacturers relating to drug acquisition costs. But these were not considered by the Department of Health as they had not been agreed before the appraisal.

The preliminary guidance raises questions as to how NICE evaluates cancer drugs, particularly for cancers that only affect a relatively small number of people. The gold-standard method of testing whether a treatment works and is safe is through the use of clinical trials. The larger the number of patients enrolled in a study, and the longer it lasts, the more sure researchers can be about its results. This works for diseases that affect large numbers of people, such as breast and lung cancer, but only around 2,000 people every year are diagnosed with metastatic RCC. Further, only one in ten people diagnosed with this stage of the disease is alive five years later. This means that for relatively rare diseases like this, it can take a long time to conduct large enough studies to gather the evidence needed to gain approval from regulatory agencies.

Even if these studies do demonstrate benefit, as those for the four drugs did, there is still the cost-effectiveness hurdle to overcome. When NICE analysed the data from the trials with its models, it found that the drugs were expensive (around £20,000 to £35,000 per patient per year) compared to the benefit they brought patients. However, concerns have also been raised about these models, which are designed to examine giving drugs to large numbers of people. Are they equally valid for looking at relatively uncommon diseases, such as metastatic RCC? Hopefully NICE will be able to answer these questions when its final guidance is published.

Matthew Dennis - Editor, Cancer Drug News

BMS moves to buy ImClone

2008-08-13T15:48:00.004+01:00

Bristol-Myers Squibb has proposed to enter into an agreement to acquire ImClone Systems for US$60.00 per share in cash, or a total payment of approximately US$4.5 billion. BMS currently owns approximately 17 per cent of all outstanding shares of ImClone. BMS' all-cash offer, which is not conditioned on the receipt of financing or on the conduct of due diligence, represents a premium of approximately 30 per cent over ImClone's closing stock price on 30th July, a premium of approximately40 per cent over the average closing price of ImClone's stock during the most recent one-month period and a premium in excess of 40 per cent for the average closing stock prices of ImClone stock during each of the most recent three- and 12-month periods.

James M Cornelius, BMS' Chairman and Chief Executive Officer, stated that the transaction represents an evolutionary development in the companies' seven-year-long relationship. BMS is the natural partner for ImClone as it possesses the knowledge base and resources to advance the company's growth over the long-term, not only with respect toErbitux (cetuximab), which the companies jointly commercialise, but also in terms of developing ImClone's pipeline assets.

ImClone's Board of Directors has formed a committee to study the acquisition offer and to retain advisors to assist it in determining the appropriate course of action. However, the Board's preliminary view is that the offer substantially undervalues the company. ImClone pointed out that its Board has been discussing the possibility of separating the company into its Erbitux and its pipeline businesses in order to maximise the value of the company.

Chairman of ImClone's Board, Carl C Icahn, has stated that he was disturbed that one of the directors on the ImClone Board who is the BMS designee was privy to the information discussed at previous meetings concerning the potential separation of ImClone into two separate components and how this restructuring might enhance stockholder value. Accordingly, the Board is reviewing whether BMS had access to confidential information concerning ImClone and its pipeline. Additionally, Icahn pointed out that ImClone has a pipeline antibody, IMC-11F8, under development which, if ultimately approved for sale, might have a significant competitive effect on Erbitux and that BMS may have no rights to market that product under its agreements with the company.

If BMS gained control of all the Erbitux revenues it would fill a long-term hole caused by the loss of patent protection, starting in 2012 and 2013,surrounding the company's heart disease drug, Plavix (clopidogrel),and antihypertensive, Avapro (irbesartan). Erbitux is indicated for use in the treatment of patients with metastatic colorectal cancer and in the treatment of squamous cell carcinoma of the head and neck. Under the agreement between BMS and ImClone, which expires in September2018, ImClone receives a distribution fee based on a flat rate of 39 per cent of Erbitux net sales in North America. This agreement was amended in July 2007 to provide for additional development funding for certain indications.

Merck KGaA is also a partner in the co-development and co-commercialisation of Erbitux in Japan and other markets outside of the US. As such, it could perhaps emerge as the most likely competitor for ImClone. It would make sense for Merck to protect its investment in the drug, since it was the company's own clinical trial that finally persuaded the FDA to approve Erbitux, and a new Merck trial has shown it to be efective in fighting lung cancer as well.

Matthew Dennis - Editor, Cancer Drug News

Review confirms Gardasil's safety; predicted sales hit

2008-08-13T15:39:00.003+01:00

Based on the review of available information, the FDA and the Centers for Disease Control and Prevention (CDC) have reaffirmed that Gardasil (quadrivalent human papillomavirus [HPV] types 6, 11, 16, 18 recombinant vaccine) continues to be safe and effective, and its benefits continue to outweigh its risks.

To date, the manufacturer, Merck & Co has distributed over 16 million doses of Gardasil in the US and as of 30th June, there have been 9,749 reports of adverse events following vaccination. Of these, 94 per cent were classified as reports of non-serious events, and 6 per cent as serious events. The non-serious events include syncope, pain at the injection site, headache, nausea and fever.

However, concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of 30th June, 20 deaths had been reported, although there was not a common pattern that would suggest they were caused by the vaccine. According to the review, in cases where autopsy, death certificate and medical records were available, the cause of death was explained by factors other than the vaccine.

Guillain-Barré syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. The FDA and CDC have reviewed the reports and, to date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. Thromboembolic disorders have also been reported in people who have received Gardasil. Most of these individuals had risk factors for blood clots, such as use of oral contraceptives, which are known to increase the risk of clotting. Thromboembolic disorders as well as other medical events are being studied through the Vaccine Safety Datalink Project in previously-planned, controlled studies. Merck has also committed to conduct a large post-marketing study to further assess the vaccine's safety.

The vaccine is one of Merck's flagship products but its sales have been under pressure. The company has recently predicted 2008 Gardasil sales of between US$1.4 billion and US$1.6 billion, down from prior estimates of US$1.9 billion to US$2.1 billion. The lower forecast is due, in part, to Merck's failure earlier in the year to receive US approval to market the vaccine to older women aged 27 to 45 years, as well as to extend its indication to include HPV types not included in the vaccine.

Gardasil is approved in the US for use in girls and women aged nine through 26 years to prevents infection with the types of HPV that cause most cases of cervical cancer and genital warts. The CDC's Advisory Committee on Immunization Practices recommended routine three-dose vaccination of girls aged 11 and 12 years. The vaccine is also recommended for girls and women aged 13 through 26 years who have not yet been vaccinated or who have not received all three doses.

Gardasil is marketed by sanofi pasteur MSD (sanofi-aventis’ joint venture [JV] with Merck) in EU countries covered by the JV and several other European countries. In the remaining European countries, located in Central and Eastern Europe, the vaccine is marketed by Merck Sharp & Dohme under the tradename, Silgard.

Matthew Dennis - Editor, Cancer Drug News

Roche looks to buy Genentech

2008-08-13T15:34:00.002+01:00

Roche has proposed to acquire the outstanding publicly-held interest in Genentech for US$89.00 per share in cash, or a total payment of approximately US$43.7 billion to equity holders of Genentech other than Roche. Roche acquired a majority stake in Genentech in 1990 and currently owns 55.9 per cent of all outstanding shares.

The offer represents a one-day premium of 8.8 per cent to Genentech's closing price of US$81.82 on 18th July and a one-month premium of 19.0 per cent to Genentech's closing price of US$74.76 on 20th June. However, many analysts predict that the move undervalues the company and Genentech will refuse the initial offer, pricing the company higher at between US$100.00 and US$120.00 per share.

If the deal does go through then it would be the biggest in the sector since Pfizer paid US$57 billion for Pharmacia five years ago. The pharmaceutical sector is witnessing a spate of acquisitions of biotech companies as groups search for new drugs, especially in oncology, to offset the decline in their product pipelines.

Under the proposed acquisition, Genentech will operate as an independent research and early development centre within Roche from its existing campus in South San Francisco, CA, retaining its expertise and approach to discovering and progressing new molecules. The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilisation between the companies, leading to enhanced overall innovation within the Group. Roche's recently-adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi and delivery technologies, as well as licensing activities, continues to provide a stimulating environment for the creation of medically-differentiated medicines.

Roche's Pharma commercial operations in the US will be moved from Nutley to Genentech's site in South San Francisco, CA. The existing US sales organisations of both companies will be maintained, resulting in a very strong presence in several specialty areas. The combined entity will be the seventh largest US pharmaceuticals company in terms of market share. It will generate more than US$15 billion in annual revenues and will employ around 17,500 pharma employees in the US alone, including a combined sales force of approximately 3,000 people. Including diagnostics, the Roche Group will employ around 25,000 people in the US.

With various clinical trial results expected in the next 18 months, analysts expect that Genentech's share price could soar on the back of positive data. Genentech's Avastin (bevacizumab) is in clinical testing as a secondary treatment for colon and breast cancer, and Rituxan (rituximab) is being investigated as a possible lupus treatment. Some experts believe that positive outcomes could bring Genentech an additional US$5 billion in peak sales for Avastin alone. The ultimate goal, however, would be to pair Genentech's therapeutics with Roche’s diagnostics to inform physicians which patients can benefit from specific treatments. The move looks like a smart one for both parties.

Matthew Dennis - Editor, Cancer Drug News

TroVax hits problems in TRIST

2008-07-21T11:13:00.002+01:00

Following its fourth interim review of the TRIST (TroVax Renal Immunotherapy Survival Trial) study, the independent Data Safety Monitoring Board (DSMB) has advised that TroVax administered according to the protocol will not meet the predefined primary efficacy endpoint. The Phase III study is investigating the vaccine in locally-advanced or metastatic clear cell renal carcinoma (RCC) and has a primary endpoint of overall survival in the TroVax-treated versus the placebo group. TroVax is Oxford BioMedica's (OBM) novel therapeutic cancer vaccine, which is being developed in collaboration with sanofi-aventis.

The DSMB has recommended that the study continues because there is important scientific merit and more to be learned by additional follow-up of all patients, but further vaccinations are discontinued; OBM has implemented the recommendation. In addition, the company intends to amend the statistical plan of the study to determine whether patient outcome is dependent on the number of TroVax doses administered. The news hit the former’s share price hard, as its stock fell from a close of 18.5p on 10th July, to open at 7p on 11th July, before closing the day at 7.5p, a 59 per cent drop.

The companies will discuss the proposed TRIST protocol amendments with regulatory authorities. With these amendments, a focus of the ongoing TRIST study will be to explore the number of doses that provide optimal benefit. In particular, it may be that the optimal benefit-to-risk ratio is delivered without the requirement for as many vaccinations as specified in the original TRIST study protocol. It is unlikely that the TRIST study alone will support registration of TroVax in RCC, although the trial may ultimately demonstrate a survival advantage for TroVax, and the results may form part of a regulatory submission alongside an additional confirmatory trial.

The randomised, placebo-controlled TRIST study was initiated in November 2006 and completed recruitment of 733 patients in March 2008 at more than 100 sites in the US, EU and Eastern Europe. It is designed to evaluate TroVax in combination with standard-of-care in locally-advanced or metastatic clear cell RCC. The original trial protocol, which was the subject of a Special Protocol Assessment by the FDA, allowed for patients to receive up to 13 immunisations over 73 weeks.

TroVax targets the tumour antigen 5T4, which is broadly distributed throughout a wide range of solid tumours. The product consists of a modified vaccinia Ankara vector, which delivers the gene for 5T4 and stimulates a patient's body to produce an anti-5T4 immune response. This immune response destroys tumour cells carrying the 5T4 antigen.

OBM and sanofi-aventis will evaluate the available data and the implications on the development plan for TroVax, including the planned Phase III trials in colorectal cancer (CRC). The Oncology Clinical Trials Office, part of the Clinical Pharmacology Department of the University of Oxford, has stated that the DSMB's recommendations in relation to the TRIST study "does not impact on our enthusiasm to progress the QUASAR V TroVax study" in adjuvant CRC. But it remains to be seen what the companies' stance on future trials is.

Matthew Dennis - Editor, Cancer Drug News

Europe moves in right direction

2008-07-10T12:43:00.005+01:00

The first research to examine recent trends in European cancer incidence, mortality and survival together has shown that cancer prevention and management in Europe is moving in the right direction. However, the work reveals that variations between countries in policies for mass screening, access to healthcare and treatment are reflected in the different cancer rates. The research, consisting of ten papers, has been published in a special July edition of the European Journal of Cancer and coincides with the start of work by the EC to draw up a new EU Cancer Action Plan.

In one study (2008;44:1345-1389), scientists from the Erasmus Medical Centre obtained data on incidence, mortality and five-year survival from the mid-1990s to the mid-2000s from cancer registries in 21 European countries, and used it to analyse trends. The researchers found that generally in the more prosperous countries of Northern and Western Europe the trend was downwards for cancer incidence; the exceptions were for obesity-related cancers, such as colorectal and postmenopausal breast cancer (BC), and for tobacco-related cancers in women, such as lung cancer.

Incidence and mortality from tobacco-related cancer decreased for men in Northern, Western and Southern Europe, they increased for both sexes in Central Europe and for women nearly everywhere in Europe. With the exception of smoking-related cancers, mortality trends generally in most cancers were moving downwards for the majority of Europe.

Survival rates for most cancers generally improved. The investigators state that this is due to better access to specialised diagnostics, staging and treatment. For instance, although the incidence of BC continues to rise in most countries, deaths are declining and survival is improving. The rising incidence and survival rates are partly influenced by the presence of organised BC screening programmes and even opportunistic screening that increases the detection of smaller and less aggressive tumours. Survival and mortality is also influenced by improved staging and treatment, such as the use of tamoxifen in postmenopausal patients and chemotherapy in premenopausal patients.

The impact of mass screening is investigated in greater depth in another paper (2008;44:1404-1413), and in a further paper (2008;44:1425-1437), on the potential ways of closing the gap between Central and Eastern Europe through changes in lifestyles, which could reduce the incidence of some cancers. Another report (2008;44:1451-1456), by scientists from the Institute of Public Health of the Republic of Slovenia, outlines some of the issues for Europe, including the identification of five groups of key stakeholders: patients, health policy, reimbursement and financing agencies, research and finally, pharmaceutical and medical technology industries. Four key resources are identified as the most relevant to successful cancer management: human resources, physical resources, knowledge resources and social resources.

The paper concludes that Europe must focus on four types of interventions: primary prevention and health promotion; secondary prevention with proven screening programmes; more equitable access to optimal treatment and integration of all cancer care services; and sustained and consistent support for advanced independent research. All of those involved in the oncology field will hope that the EC listens to its experts and outlines a plan that will tackle these important issues.

Matthew Dennis - Editor, Cancer Drug News

Advexin moves closer to market

2008-07-04T08:17:00.004+01:00

Introgen Therapeutics has submitted a BLA to the FDA, while simultaneously Gendux Molecular (Introgen) has submitted an MAA to the EMEA, both seeking marketing approval for Advexin (INGN 201), the company's targeted p53 tumour suppressor gene therapy, to treat recurrent, refractory head and neck cancer. INGN 201 represents the first in a new class of tumour suppressor cancer therapy and is the first of its kind to be submitted for regulatory approval in the US and Europe. Introgen has requested priority review from the FDA for INGN 201, meaning that the treatment could be on the market in early 2009. The news buoyed Introgen's share price as it rose nearly 16 per cent, from a close of US$1.51 on 27th June, to start 30th June at US$1.75.

INGN 201 therapy harnesses the body's natural tumour suppression mechanisms to fight cancer, without the toxicities associated with conventional cancer treatments. Abnormalities in protective tumour suppressor p53 pathways are associated with the majority of all solid cancers. Designed to restore patients' ability to fight cancer, INGN 201 delivers large doses of the normal p53 gene to target abnormal p53 function present in tumour cells, which triggers natural tumour suppression mechanisms in cancer without harming normal cells.

According to Dr Jack Roth, inventor of Advexin and professor at the University of Texas MD Anderson Cancer Center: "This is an important milestone in the clinical application of gene therapy for cancer patients. With the use of p53 biomarkers, Advexin will provide more effective and less toxic treatment for head and neck cancer patients who have limited treatment options."

The submissions are based on pivotal Phase II and III trials evaluating survival, tumour response and safety in patients with recurrent, refractory end-stage, squamous cell carcinoma of the H&N. These studies incorporated common diagnostic tests to identify patients most likely to benefit from INGN 201 based upon pretreatment tissue analyses to determine p53 profile status.

The Phase III trial achieved the study's objectives and demonstrated clinical benefit of INGN 201 in comparison to the control drug, methotrexate. The patients most likely to benefit from INGN 201 treatment with increased tumour responses and survival were identified by prespecified p53 biomarker profiles. Overall, the study results demonstrated that INGN 201 addresses an unmet medical need and the combination of biomarker testing and treatment has the potential to provide recurrent H&N cancer patients with an effective therapy that is less toxic than standard chemotherapies.

INGN 201 is Advexin’s lead product candidate, approval of which may open the door for the company’s other gene therapy drugs. Indeed, INGN 201 is being investigated in Phase II trials for breast, non-small cell lung and oesophageal cancer, as well as earlier-stage studies in prostate, ovarian, bladder, brain and bronchoalveolar cancer. However, it is unclear whether regulatory bodies will even approve INGN 201. The FDA has faced considerable scrutiny in recent years for approving drugs that have turned out to produce dangerous side effects, and it has become more cautious as a result. How the Agency along with the EMEA will view the first in a new class of drugs remains to be seen.

Matthew Dennis - Editor, Cancer Drug News

UK chooses Cervarix over Gardasil

2008-06-19T10:00:00.010+01:00

The Department of Health (DoH), UK, has awarded the contract to provide the vaccine against human papillomavirus (HPV) to GlaxoSmithKline for its product, Cervarix. The contract is to supply the vaccine that protects against cervical cancer (CC) and precancerous cell changes in the cervix caused by HPV. The vaccine will guard against the two HPV strains that cause 70 per cent of cases of CC, types 16 and 18. The vaccine will be made available to girls aged 12 to 13 years from September, while a year later it will also be administered to girls up to 18 years of age in a two-year, catch-up programme.

GSK's CC vaccine is approved in 64 countries worldwide, but this was the first major national tender for which the company had bid. According to Eddie Gray, President of Pharmaceuticals Europe for GSK: "This is great news for girls and women across the UK and reflects the growing confidence in Cervarix, which provides cervical cancer protection with a strong and sustained immune response."

The UK's Joint Committee on Vaccination and Immunisation, which provides independent expert advice to ministers on vaccination, examined a wide range of evidence before recommending in June 2007 that an HPV vaccination programme be routinely introduced for 12 to 13 year old girls. However, this left the DoH to choose between Cervarix and its competitor, sanofi pasteur MSD's (sanofi-aventis and Merck & Co joint venture) Gardasil (quadrivalent HPV types 6, 11, 16, 18, recombinant vaccine), which are both licensed in the EU.

An adjudication was carried out to examine the vaccines offered against a wide range of criteria, such as their scientific qualities and cost effectiveness. The criteria used for the adjudication had been shared in advance with the companies which tendered. Following this process, the DoH selected Cervarix, going against the decision of many EU countries who have opted for Gardasil and the wider protection it offers. Commenting on this, Dr Nicholas Kitchin, UK Medical Director, sanofi pasteur MSD, stated: "We regret that school girls in the UK, unlike most of their peers in Western Europe, the USA, Australia, New Zealand and Canada, will not benefit from the unmatched cervical cancer protection and additional benefits provided by the world's leading HPV vaccine, Gardasil."

Cervarix uses GSK's proprietary AS04 adjuvant as its main differentiating point, which may enhance the immunogenicity of the vaccine, therefore potentially reducing the need for booster shots. However, the long-term efficacy of the two vaccines is believed to be similar.

The key reason for the DoH choosing Cervarix is likely to be price. With a list price for a full course of Gardasil as high as US$375 per person in the US, HPV vaccine costs are a key issue. Although the cost of Cervarix is commercially confidential, it can presently be administered through private clinics at a cost of £130.00 per injection (the immunisation course consists of three injections). GSK may have offered a heavily discounted price, relative to Gardasil, making the DoH’s decision easier. Another factor that must not be forgotten is the fact that GSK is, after all, a British company.

Matthew Dennis - Editor, Cancer Drug News

Ten years of rituximab

2008-06-17T21:12:00.003+01:00

As MabThera (rituximab) reaches ten years of market availability in Europe for the treatment of non-Hodgkin's lymphoma (NHL), what does the future hold for the monoclonal antibody (MAb)?

Approved in June 1998 by the EC, although launched earlier in the US (where it is known as Rituxan), rituximab (formerly IDEC-C2B8) was the first anticancer MAb, heralding an influx of the molecules into treatment regimens for multiple tumour types. Originally discovered by IDEC (now Biogen Idec) and jointly developed along with Genentech, Roche and Zenyaku Kogyo, the MAb targets the CD20 protein that is expressed on over 95 per cent of B-cell lymphomas. It was the first MAb therapy to demonstrate a clinically-significant antitumour response, which finally provided proof of principle that these molecules could be efficacious, as well as specific and less toxic. Such a combination of attributes has seen rituximab realise significant revenue, with sales of US$2,252 million in 2006 and US$2,515 million in 2007.

Rituximab was initially approved to treat only a specific subset of patients with NHL. Over the years, the MAb has gained approval to treat additional types of NHL and has become a front-line therapy when used in combination with various chemotherapy regimens. But what about the future of the MAb? Ongoing clinical studies are investigating the long-term use of rituximab as a maintenance therapy to prevent relapse in patients with follicular lymphoma. These trials have shown that maintenance therapy prolongs the duration of remission and that the MAb can be safely administered for up to two years. Additionally, rituximab is in Phase III trials for relapsed and first-line chronic lymphocytic leukaemia. Rituximab has also been approved in areas outside of oncology, such as for the treatment of rheumatoid arthritis, and is being investigated as a therapy for lupus, multiple sclerosis and platelet disorders.

Sales of rituximab look set to remain at a steady level for the next five years, however, in April 2007, Dr Reddy's Laboratories launched Reditux, its brand of rituximab, in India. Reditux, for the treatment of NHL, is priced at around half the originator’s price. Dr Reddy's also announced plans to market Reditux in other markets, including the US, when the product's patent expires in 2015.

The success of rituximab has paved the way for the development and approval of additional anticancer MAbs, treating tumour types such as colorectal, breast, lung, and head and neck cancer. Rituximab has not only altered the way that NHL is treated, but it has significantly changed the approach to cancer drug development. MAb therapies are now an essential part of cancer treatment regimens and clinical trials. Future challenges will involve how to best incorporate new MAb therapies with current treatments, including new forms of immunotherapy. Despite the threat of future biosimilar competition, there is clearly life still left in the original MAb.

Matthew Dennis - Editor, Cancer Drug News

Studies link oral disease and cancer

2008-06-01T19:20:00.007+01:00

According to results from two recent studies, periodontal disease and tooth loss are associated with an increased risk of certain malignancies, including those involving the kidney, pancreas, oesophagus, head and neck, and lung. The reason for the associations are unclear, but could be due to the fact that periodontal disease is either a marker for a cancer-susceptible immune system or has a direct carcinogenic effect. The scientists speculate that bacterial infection and inflammation resulting from poor oral care that leads to tooth loss could also be driving development of these cancers.

In the first study, published in the 6th May online issue of The Lancet Oncology (10.1016/S1470-2045(08)70106-2), researchers from Imperial College, London and the Harvard School of Public Health analysed data from the HPFS (Health Professionals Follow-up Study), a survey of male health professionals in the US that was initiated in 1986. The subjects completed general questionnaires at baseline and then every two years, as well as dietary questionnaires every four years.

During a median follow-up period of 17.7 years, 5,720 incident cancer cases were documented among 48,375 participants. The most common malignancies were colorectal, melanoma, lung, bladder and advanced prostate. After accounting for smoking, diet and other known risk factors, a history of periodontal disease was linked to an increased risk of cancer, with a hazard ratio (HR) of 1.14. In terms of specific malignancies, the HRs were 1.36 for lung cancer (LC), 1.49 for kidney cancer, 1.54 for pancreatic cancer and 1.30 for haematologic cancers.

Among never-smokers, periodontal disease was linked to total and haematologic cancer, but not to LC. Thus, the overall link between periodontal disease and LC probably resulted from residual confounding due to smoking. According to the study authors, given the systemic effects of periodontal disease and the potential involvement of the immune system, as a marker of susceptibility or through changes in immune surveillance, further research on the role of periodontal disease in cancer, especially haematological cancers, is warranted.

In the other study, published in the May edition of Cancer Epidemiology Biomarkers & Prevention (2008;17:1222-1227), researchers from Aichi Cancer Center in Nagoya and Nagoya University School of Medicine measured rates of 14 different cancers and rates of tooth loss in 5,240 cancer patients in Japan, and compared those rates among 10,480 matched cancer-free participants. The investigators specifically found that people with tooth loss were 136 per cent more likely to develop oesophageal cancer (OC), had a 68 per cent increased risk of developing H&N cancer and a 54 per cent greater chance of developing LC. The scientists also found that the rate of cancer increased proportionally to the number of teeth a patient had lost. These increased risks were seen after researchers took into account a patient’s history of smoking and alcohol use.

The researchers noted that age and gender affected the associations between tooth loss and cancer risk. For H&N and OCs, there were clear associations between tooth loss and cancer risk in women and patients younger than 70 years old, but a less clear link in men and older patients. The investigators commented that while widespread inflammation could explain the link between tooth loss and cancer risk, tooth loss in the cancer patients may simply reflect unhealthy behaviours that contribute to cancer risk. Furthermore, people who have lost teeth may not be able to eat a healthy diet, and diet is also a factor in cancer development.

Matthew Dennis - Editor, Cancer Drug News

Targeted combination effective against metastatic BC

2008-05-21T14:40:00.004+01:00

GlaxoSmithKline has reported positive data from the first randomised, multi-centre, open-label Phase III trial of the combination of two targeted agents, Tykerb (known as Tyverb in Europe; lapatinib) and Herceptin (trastuzumab), in women with HER2-positive metastatic breast cancer (BC).

In the study, 296 patients with HER2 (ErbB2)-positive BC who had documented progression on trastuzumab treatment in the metastatic setting were eligible to be randomised to receive lapatinib (1,000mg) plus trastuzumab (2mg/kg weekly after 4mg/kg loading dose) or lapatinib alone (1,500mg). Patients were heavily pretreated and had received a median of six prior anticancer regimens. Patients had received a median of three prior lines of trastuzumab. The primary endpoint of the study was progression-free survival (PFS), and secondary endpoints included clinical benefit rate, response rate and overall survival. If patients progressed on the lapatinib monotherapy arm after four weeks of therapy, they could cross over to receive the combination of lapatinib+trastuzumab.

Despite receiving multiple prior lines of anticancer therapy, patients who received lapatinib plus trastuzumab in this study experienced:

a statistically significant increase in median PFS versus lapatinib alone (12 vs 8.1 weeks);
a 27 per cent reduction in the risk of disease progression (hazard ratio [HR]=0.73; p=0.008);
a response rate of 10.3 versus 6.9 per cent;
double the overall clinical benefit rate versus lapatinib alone (24.7 vs 12.4 per cent; p=0.01); and
a trend in improved overall survival (HR=0.75; p=0.106).
The study also demonstrated the activity of lapatinib as a single agent in this patient population, with patients on this arm achieving a median PFS of 8.1 weeks and an overall clinical benefit rate of 12.4 per cent.

Adverse events were similar in both arms, with Grade 1/2 diarrhoea significantly higher in the lapatinib+trastuzumab arm (53 vs 41 per cent; p=0.03). Two patients in the combination arm and one patient in the lapatinib monotherapy arm experienced symptomatic decreases in left ventricle ejection fracture (LVEF); one patient in the lapatinib+trastuzumab arm died due to a pulmonary thromboembolism with progressive malignant pleural effusions; two patients with LVEF decrease later recovered. Isolated cases of asymptomatic transient decreases in LVEF were noted in both treatment arms.

Both treatments target the HER2 protein but work in different ways. Trastuzumab attaches to the outside of the HER2 protein, while lapatinib enters the cell to block signals from the HER2 protein for the cancer to grow. The clinical synergy of lapatinib and trastuzumab confirms previous observational findings in preclinical studies and previously reported data from a Phase I study. These latest findings confirm the rationale for further research of this combination in earlier lines of therapy in the metastatic setting and in early-stage disease. Additional analysis is under way to explore the benefit that lapatinib plus trastuzumab can offer to less heavily-pretreated patients.

Matthew Dennis - Editor, Cancer Drug News

Pharmexa pins hopes on Telovac

2008-05-16T09:24:00.004+01:00

Pharmexa has decided to stop further patient enrolment in its PrimoVax Phase III trial of GV1001 for pancreatic cancer (PC) after a preliminary analysis showed no survival benefit for the vaccine. The decision does not affect the company's other Phase III trial, Telovac, which is currently recruiting patients at sites in the UK.

PrimoVax was designed to investigate the use of GV1001, a peptide vaccine targeting telomerase, administered before chemotherapy in 520 patients with non-resectable PC. The study had enrolled approximately 360 subjects and was being conducted at 77 hospitals in ten European countries, as well as Australia and the US. The trial had a primary endpoint of survival, while secondary endpoints included time-to-progression and safety.

The patients in the PrimoVax trial were randomly divided into two equally sized groups: half received standard treatment with gemcitabine and half received GV1001. If the condition of the patients in the second group deteriorated, treatment with gemcitabine was added. Preliminary data based on the deaths of 174 patients showed that the survival was no better in the GV1001 group compared to the group that received gemcitabine treatment. The final conclusions with respect to survival and all secondary endpoints must await the further follow-up of patients and full analyses of the data.

The PrimoVax trial was designed as a continuation of a previous Phase I/II study with GV1001, which showed that monotherapy treatment with the vaccine significantly prolonged patient survival, compared to the effect previously seen with gemcitabine. However the Phase III results suggest that the vaccine is not best utilised in this setting.

According to Pharmexa's Chief Executive Officer, Jakob Schmidt: "It has been an open question from the start whether GV1001 should be administered before chemotherapy, as in the PrimoVax trial, or during or after chemotherapy as in the Telovac trial. We now know that giving it first does not improve overall survival in non-resectable PC patients. The focus going forward will be to show that GV1001 has a role in combination with chemotherapy and we have therefore decided to continue our support of the Telovac trial."

In contrast to the PrimoVax study, Telovac is investigating combination gemcitabine and capecitabine therapy with concurrent and sequential chemo-immunotherapy using GV1001 in patients with locally-advanced or metastatic PC. It is hoped that these two different treatment schedules will provide information as to the best time to administer the vaccine. In addition, Pharmexa is not wholly shouldering the responsibility for the trial. The study is being supported by the UK National Cancer Research Institute (NCRI) and the Pancreas Cancer Sub-Group of the NCRI, and is funded by Cancer Research UK through the Liverpool Cancer Trials Unit. Pharmexa pays for vaccine for the study and a part of the costs related to monitoring and data collection.

Early immunomonitoring data in the Telovac trial has demonstrated the immunostimulation of the vaccine, supporting the choice of scheduling and confirming the notion that immune therapies will be maximally effective when combined with treatments that cause apoptosis, such as chemotherapy. Pharmexa will be hoping that this is the case, now that its eggs concerning GV1001 are firmly in one basket.

Matthew Dennis - Editor, Cancer Drug News

Gender survival differences linked to EGFr variants

2008-05-16T09:20:00.004+01:00

A study by researchers at the University of Southern California (USC) and Keck School of Medicine has found evidence that supports gender-related differences in the development and survival of metastatic colorectal cancer (CRC). The study, which was published in the 15th April edition of Cancer Research (2008;68:3037-3042), found that specific gene variants in EGFr linked to the development of CRC resulted in opposite survival outcomes for men and women.

Germline variations in EGFr DNA have been linked with poor prognosis in CRC, however, when researchers looked at EGFr as a prognostic factor, they found that it had opposite implications for men and women. The scientists expected to find that high expression would correlate with a poor prognosis and faster growth of the cancer. What they found, however, was that men followed the expected trend, while women's response was the opposite.

In the study, researchers analysed 318 patients (177 men and 141 women) with metastatic CRC that were treated at the USC/Norris Comprehensive Cancer Center and the LAC+USC Medical Center between 1992 and 2003. The team studied two independent functional polymorphisms of EGFr, one at codon 497 in the extracellular domain of the EGFr gene and the other related to dinucleotide repeats within intron 1. All the patients were exposed to similar chemotherapy treatments. When genomic DNA samples were analysed, the investigators found that women who had specific gene variants linked with high expression of EGFr had higher overall survival (OS) rates, while men with the same variants had lower survival.

Specifically, median OS in men with the Arg/Arg variant of the 497 polymorphism was 10.3 months, while for those with a Lys allele it was 13.7 months. Among women, the corresponding figures were 16.0 and 14.0 months. For the intron polymorphism, a repeat length <20>20. The corresponding survival rates for women were 17.6 and 14.1 months.

According to Dr Heinz-Josef Lenz, Professor of Medicine at the Keck School of Medicine: "This is the first report to show that the prognostic value of EGFr depends on gender. This may suggest that, in the future, molecular markers should be evaluated differently in women and men and that treatment decisions may depend on gender and not only on molecular or clinical findings."

As to mechanisms that might explain these differences, the researchers point out that the colon expresses both oestrogen receptor beta and androgen receptor, and that EGFr interacts with both. Therefore, EGFr may have molecular intermediates that interact in a gender-specific way to effect EGFr pathway activation. Previous research has shown a protective effect of female hormones in CRC survival. The new findings indicate that hormone receptors are important in signal pathways related to the survival of patients. Research will now need to be performed to determine whether men and women respond differently to certain cancer therapies. This may lead to targeted chemotherapy that is tailored to get the best response from male and female patients.

Matthew Dennis - Editor, Cancer Drug News

CT causes delayed CNS damage

2008-05-02T10:42:00.012+01:00

Although the lack of specificity of chemotherapy (CT) has always been a limiting factor in its use, patients' brains were thought to be offered some protection by the blood-brain barrier. However, it is becoming increasingly recognised that many CT agents can affect brain function by both direct and indirect methods.

Now, research published in the 22nd April edition of the Journal of Biology (2008;7:12) has demonstrated that treatment with a single CT agent, 5-FU, by itself is sufficient to cause a syndrome of delayed degeneration in the central nervous system (CNS). The drug is a widely used CT agent that is administered, alone or in combination with other agents, in the treatment of cancers of the colon, rectum, breast, stomach, pancreas, ovaries and bladder.

Surprisingly, little is known about the side effects of CT on the CNS, despite the obvious clinical importance. Until now, researchers have not fully understood the underlying biology, including whether these effects require: exposure to multiple CT agents; CT agents plus the body's own response to cancer; blood-brain barrier damage; or inflammation.

In the new work, Professor Mark Noble and colleagues from the University of Rochester Stem Cell and Regenerative Medicine Institute and Harvard Medical School discovered that short-term systemic administration of 5-FU to mice caused both acute CNS damage and a syndrome of progressively worsening delayed damage. This damage was not self-repairing, and instead became worse over time. In addition, the scientists demonstrated that treatment with CT also had delayed effects on the speed with which information is transferred from the ear to the brain.

Noble commented: "Multiple clinical reports have identified neurotoxicity as a complication of treatment regimens in which chemotherapeutic agents such as 5-fluorouracil are components. As treatments with chemotherapeutic agents will clearly remain the standard of care for cancer patients for many years to come, the need to better understand such damage is great."

One key finding of the study was that clinically-relevant concentrations of 5-FU were toxic not only for dividing cells of the CNS but also for the cells that produce the insulating myelin sheaths, called non-dividing oligodendrocytes. The delayed damage the researchers measured was to the myelinated tracts of the CNS and associated with extensive myelin pathology. The findings regarding the speed of ear-to-brain information transfer may offer a non-invasive means of analysing myelin damage associated with cancer treatment.

The research provides the first demonstration that delayed CNS damage can be induced by a single CT agent and also generates the first animal model of such damage. These studies further demonstrate that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage. Previous studies have linked various CT agents, including methotrexate, cyclophosphamide, adriamycin and cisplatin, with impaired cognitive function, although results have been variable. This new work is consistent with the clinical syndrome that is commonly observed in patients and will hopefully guide future studies into the mechanisms of acute and delayed injury to the brain from clinically-relevant exposure to CT agents.

Matthew Dennis - Editor, Cancer Drug, News

HPV linked to lung cancer

2008-05-01T20:05:00.007+01:00

Although the link between viruses and cancer has long been established, it is only recently with the introduction of vaccines against human papillomavirus (HPV) that in-roads have been made into exploiting this connection for preventative purposes. Now it seems that more cancers may have a viral link, in particular to HPV, raising the possibility that these tumours could be prevented by vaccination.

Scientists from the University of Louisville presented data at the 1st European Lung Cancer Conference, held from 23rd to 26th April, in Geneva, Switzerland, suggesting that HPV may contribute to the development of non-small cell lung cancer (NSCLC). The researchers examined 23 NSCLC samples from patients in Kentucky and found six tested positive for the presence of HPV, the virus that causes many cases of cervical cancer (CC), and is also known to be carcinogenic or co-carcinogenic in anogenital, oropharyngeal and oesophageal cancer. One sample was later shown to be CC that had metastasised to the lungs.

Of the remaining five virus-positive samples, two were found to be HPV type 16, two were HPV type 11 and one was HPV type 22. According to the study authors, the fact that five out of 22 NSCLC samples were HPV-positive supports the assumption that the virus contributes to the development of the disease. All the patients in this study were also smokers, leading the researchers to hypothesise that HPV has a role as a co-carcinogen, which increases the risk of cancer in a smoking population. Of particular interest to the investigators was the fact that the virus was present in the lung tumours themselves, but not in the surrounding tissue, lending credence to the suspicion that a causal relationship exists between the virus and NSCLC.

At present, the scientists do not have any evidence that non-smokers have an increased risk for NSCLC. However, one area of possible future scientific inquiry could be to sample NSCLCs from non-smokers to see if they have HPV. Although it could be an aetiology in non-smokers, the investigators suspect that it causes a higher risk in smokers to develop NSCLC.

Lead study author, Dr Arash Rezazadeh, a fellow of medical oncology and haematology at the University of Louisville, stated: "In terms of HPV, our finding is pretty controversial. And this is just the beginning of the road. There is much more work to be done. But it's important to know that being infected with this virus does appear to increase lung cancer risk."

The availability of a vaccine to prevent infection with HPV is being discussed widely in the US and many other countries, but almost exclusively in relation to its utility as a way to prevent CC, which occurs only in women. The possibility that HPV could be implicated in NSCLC raises the question of whether the vaccination should be used to prevent the disease and whether men should also be vaccinated; this is something that needs to be tested. Further studies are planned to look for signs of HPV infection in the respiratory tract of NSCLC patients and to explore the possibility for using HPV infection as a screening indicator for the disease. e that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage. Previous studies have linked various CT agents, including methotrexate, cyclophosphamide, adriamycin and cisplatin, with impaired cognitive function, although results have been variable. This new work is consistent with the clinical syndrome that is commonly observed in patients and will hopefully guide future studies into the mechanisms of acute and delayed injury to the brain from clinically-relevant exposure to CT agents.

Matthew Dennis - Editor, Cancer Drug News