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

HPV linked to lung cancer

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

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

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

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

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

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

Matthew Dennis - Editor, Cancer Drug News