LUX-Lung 8 trial: new data
Phase III data from Boehringer Ingelheim’s LUX-Lung 8 trial was presented recently at the European Society for Medical Oncology (ESMO) 2014 Congress held in Madrid, Spain. This is the first study to directly compare the efficacy of two different targeted agents in patients with advanced squamous cell carcinoma (SCC) of the lung. It demonstrated superior progression-free survival (PFS: length of time before the tumour starts to progress) of afatinib compared to erlotinib.

Afatinib, an irreversible ErbB Family Blocker, showed significant improvement across several measures of efficacy, in particular for the primary endpoint of PFS compared to erlotinib in patients after failure of first-line chemotherapy. 

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, with SCC representing approximately 30% of NSCLC cases.
LUX-Lung 8 demonstrated that afatinib significantly reduced the risk of disease progression by 18% when compared to erlotinib, and delayed tumour growth (PFS by independent review: 2.4 versus 1.9 months). In addition, afatinib showed an improvement in the secondary endpoint of disease control rate (DCR: the percentage of patients who achieved complete response, partial response or stable disease, 46% versus 37%). The objective response rate (ORR: the percentage of patients who achieved a partial or complete response to therapy) was numerically higher with afatinib compared to erlotinib (5% versus 3%).

Favourable trends were noted in delaying the worsening of lung cancer symptoms and global health status/quality of life. The proportion of patients reporting improvement in cough and global health status/quality of life, respectively, was significantly higher with afatinib versus erlotinib. Results of overall survival (OS: length of time patients live for), the key secondary endpoint, are not yet mature, and will therefore be assessed at a later stage in the trial and reported at a future medical congress.

Co-lead investigator Glen D. Goss, Director of Clinical and Translational Research, The Ottawa Hospital Cancer Center, University of Ottawa, Canada, commented: “The results of LUX-Lung 8 demonstrate the progression-free survival benefit for afatinib over erlotinib in advanced squamous cell carcinoma of the lung, a disease with poor prognosis for which there are currently limited treatment options.”

The overall rate of severe (≥ grade 3) and serious adverse events was comparable between both therapies. Incidence of severe adverse events was 50.2% in patients treated with afatinib compared to 49.1% with erlotinib. A higher incidence of ≥ grade 3 diarrhoea and stomatitis were observed in patients treated with afatinib compared to erlotinib (≥ grade 3 diarrhoea: 9% versus 2%; stomatitis: 3% versus 0%), while there was a higher incidence of ≥ grade 3 rash/acne observed with erlotinib compared to afatinib (9% versus. 6%). 

New data for metastatic colorectal cancer
Important new data from two trials evaluating different treatment approaches in metastatic colorectal cancer provide reassurance for clinicians that current treatment choices are valid, and confirm that molecular characterisation of such tumours is vital.

The latest results of the phase III, randomised FIRE-3 and CALGB/SWOG 80405 trials were presented at the ESMO 2014 Congress. The trials evaluated different approaches to first line treatment in colorectal cancer patients with normal or ‘wild type’ versions of the RAS gene.
Specifically, they compared adding either the epidermal growth factor receptor (EGFR)-blocker cetuximab or the anti-vascular endothelial growth factor (VEGF) inhibitor bevacizumab to combination chemotherapy.

Professor Dirk Arnold, director of the Department of Medical Oncology, Klinik für Tumorbiologie in Freiburg, Germany, said: “Surprisingly, the smaller FIRE-3 trial showed a clear overall survival gain by adding the anti-EGFR antibody cetuximab to FOLFIRI chemotherapy for the patients with RAS wild type tumours, but overall survival was a secondary endpoint. RECIST response rate, their primary endpoint, and progression free survival (PFS) did not show any difference.”

The FIRE-3 study authors suggest that improvements in tumour burden reduction, measured in parameters such as ‘early tumour shrinkage’ and ‘depth of response’ (which refers to the relative decrease in tumour shrinkage compared to the initial tumour diameter) may help explain the improvements in overall survival.

Arnold added: “However, the results of the larger CALGB trial, which failed to show an overall survival difference with cetuximab versus bevacizumab, raise questions about this theory,” 

The findings also suggest that more biomarkers are needed beyond expanded RAS testing, to determine the best treatment strategy in metastatic colorectal cancer.

Commenting on the likely response of the clinical and research community to the findings, Arnold said: “The results confirm that both treatment strategies are an option, as we have not yet found the ultimate predictive biomarker for selection of the optimal treatment in metastatic colorectal cancer—and we also need to consider other additional factors when choosing the most appropriate treatment for a particular patient.”

Professor Fortunato Ciardiello from Second University of Naples, Italy, ESMO President-Elect, commented: “These types of studies contribute to our concept of ‘precision medicine’, in the search for the best treatment for patients with advanced colorectal cancer. RAS testing should be considered mandatory before initiating first line treatment for all patients with metastatic colorectal cancer.”

Promising results for advanced melanoma drug
The combinational treatment of cobimetinib with Zelboraf® (vemurafenib), the first personalised medicine to extend life in the first-line setting for over 30 years, in patients with advanced melanoma (BRAFV600 mutation-positive) can prevent disease progression (progression-free survival; PFS) by 9.9 months compared to 6.2 months following treatment of vemurafenib alone.

This is according to results presented at the ESMO Congress. They show that patients treated with cobimetinib in combination with vemurafenib reduces the risk of their disease worsening by half (49). In addition, the study found that the objective response rate (tumour response to treatment) was higher in the combination compared to vemurafenib alone (68% versus 45%). This expands on the wealth of data for vemurafenib, which was launched in 2012 as the first BRAF inhibitor proven to extend overall survival in this patient population by over one year.

Dr James Larkin, Consultant Medical Oncologist at The Royal Marsden and Lead Investigator for the trial, said: “We are delighted to have been able to further explore the treatment options for patients with advanced melanoma. This data could represent a significant step forward in the treatment of this disease. The data shows that the combination of vemurafenib with cobimetinib prolongs progression-free survival significantly in comparison with vemurafenib alone. Not only that but it also shows that the side effects are generally manageable, which is incredibly important for our patients. Vemurafenib has been hailed as one of the biggest breakthrough treatments for malignant melanoma in the past 30 years and in just three years we have been able to make major strides in improving on its effectiveness as a treatment for patients. This latest trial is helping to cement The Royal Marsden as a global leader in this field of research.”

The findings presented at ESMO are the results of CoBRIM, an international randomised, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of cobimetinib in combination with vemurafenib, compared to vemurafenib alone. This study included patients from nine English trial centres out of 11 based in the UK. In addition, the latest data follows further evidence stemming from the open-label, Phase 1b study (BRIM7), which initially showed that the combination of cobimetinib and vemurafenib can be safely co-administered and had demonstrated anti-tumour activity. 

The safety profile of the CoBRIM study was also consistent with the BRIM7 study. The most common adverse events observed in the combination arm compared to vemurafenib alone included diarrhoea (57% versus 28%), nausea (39% versus 24%), photosensitivity (28% versus 16%), liver lab abnormalities (increased alanine aminotransferase [24% versus 18%], increased aspartate aminotransferase [22% versus 13%]), increase in creatine phosphokinase (an enzyme released by muscles, 30% versus 3%) and vomiting (21% versus 12%).
There has been a significant rise in melanoma cases in recent years. It is estimated that 13,300 people developed the condition in the UK in 2011, equating to 37 people every day, compared to 1,800 in 1975. Advances in treatment have meant that more than eight in 10 people with melanoma survive for five years or longer following their diagnosis. However, latest statistics tell us that approximately 2,000 malignant melanoma patients die every year, making continued research and development in this therapy area essential.

Cervical cancer experimental drug shows improvement in survival
For patients with cervical cancer that has recurred after treatment or has spread elsewhere in the body, adding the experimental drug cediranib to standard chemotherapy improves tumour shrinkage and adds a modest improvement in progression-free survival, researchers reported at the ESMO 2014 Congress.

In Europe, about 70% of patients with cervical cancer are cured by either surgery or chemo-radiotherapy. Those patients with recurrent or secondary cancer have a very poor outlook. Only about 20–30% have tumour shrinkage after conventional chemotherapy and survival is usually less than one year.

In the phase II CIRCCa trial, researchers compared two groups of patients with relapsed or metastatic cervical cancer given conventional chemotherapy with carboplatin and paclitaxel plus either cediranib (34 patients) or an identical looking placebo tablet (35 patients).
Dr Paul Symonds, of the Department Cancer Studies and Molecular Medicine at the University of Leicester, said: “Cervical cancers with a well-developed blood supply can have a particularly bad outcome. The experimental drug cediranib blocks the cell surface receptor VEGF, which stimulates the growth of new blood vessels to feed the growth of tumours.”

In the study, patients who received cediranib in addition to chemotherapy had greater tumour shrinkage than those treated by chemotherapy plus placebo (66% versus 42%). There was also a modest but statistically significant increase in median progression-free survival (35 versus 30 weeks). There was no statistically significant difference in median overall survival.

One month into treatment, VEGF receptor 2 levels in blood were more likely to be reduced in cediranib group (median change in log10 VEGFR-2 from baseline 0.036 versus 0.067).

Side-effects, particularly raised blood pressure and diarrhoea were increased in patients taking cediranib and were treated with standard medication.

The researchers are now conducting an individual patient analysis to correlate response to chemotherapy with the fall in VEGFR receptor levels in the blood. They are also looking at other tumour biomarkers that may have been reduced by cediranib.

Commenting on the study, Dr Andres Poveda, Head of the Gynecological Oncology Clinic at Fundación Instituto Valenciano de Oncología, Valencia, Spain, who was not involved in the research, said the CIRCCa study is the second recent trial to show the benefit of adding an antiangiogenic drug to chemotherapy in cervical cancer.

“The impact on progression-free survival is important, and other trial objectives were reached, such as response rate,” Poveda said.