UK chooses Cervarix over Gardasil

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

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

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

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

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

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

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