Scientists battle cancer drug resistance

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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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

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

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?

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

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

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?

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

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

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

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

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