FLEX study of first-line Erbitux and platinum chemotherapy could change treatment options for advanced NSCLC
SummaryOf patients with lung cancer, 80 per cent have non-small cell lung cancer (NSCLC) and of those, 40 per cent are not diagnosed until their disease is advanced and has spread to other organ sites. Current targeted treatment has improved survival but is not suitable for all. Now a new trial, FLEX, shows adding the targeted therapy Erbitux (cetuximab) to chemotherapy increases survival for all types of NSCLC.
The search for treatments to improve survival has been intensive. At least 15 phase III trials involving more than 12,000 patients have evaluated new agents alongside chemotherapy but have drawn a blank. None has been able to show an improvement in overall survival when added to chemotherapy other than the targeted monoclonal antibody therapy bevacizumab (Avastin) and more recently, cetuximab (Erbitux). Bevacizumab was the first to demonstrate a survival advantage. This is an anti-angiogenesis agent which shrinks tumours by targeting the vascular endothelial growth factor (VEGF), depriving them of a blood supply. The treatment is already licensed for use in combination with carboplatin/paclitaxel chemotherapy after the ECOG 4599 trial of 878 patients (excluding those with squamous cell carcinomas) showed that, when compared to chemotherapy alone, it could improve median survival by 2 months (12.3 vs 10.3 months).
Unfortunately, serious side effects are a risk of bevacizumab treatment in around 40 per cent of patients for whom it is considered unsuitable. These are people with squamous cell cancers and older, sicker patients who face increased risks of pulmonary haemorrhage and other complications.
Now there is at last the prospect of new treatment options with broader applications for NSCLC following presentation of a clinical trial which may lead to availability of another biologic agent, cetuximab, acting via a different mechanism. Cetuximab targets tumours expressing the epidermal growth factor receptor (EGFR), blocking their growth, and is already licensed for the treatment of metastatic colorectal cancer and for head and neck cancers.
FLEX shows cetuximaab significantly increased survival
Data from the randomised phase III FLEX (First-line in Lung cancer with ErbituX) trial presented in June 2008 at the annual meeting of the American Society of Clinical Oncology (ASCO) have shown that patients with advanced NSCLC, treated first-line with a combination of cetuximab (Erbitux), cisplatin and vinorelbine, live significantly longer than patients treated with the platinum-based chemotherapy alone. An overall survival difference of 1.2 months (11.3 vs 10.1 months) favoured the addition of cetuximab to chemotherapy (p=0.04).
Results of the 1125-patient study were presented in the ASCO 2008 Plenary Session by Professor Robert Pirker, Program Director for Lung Cancer at the Medical University of Vienna, Austria, on behalf of investigators from 166 centres in 30 countries worldwide. “The FLEX results show cetuximab added to a platinum-based chemotherapy has set a new standard for first-line treatment of patients with advanced NSCLC,” he told the meeting. “This is the first trial of a front-line targeted therapy to include patients with squamous cell carcinomas, and patients who have a particularly poor prognosis.”
The trial recruited previously-untreated patients with wet IIIB/IV NSCLC whose tumours expressed the EGFR and who were without brain metastases. Patients with ECOG Performance Status (PS) 0, I and 2, and with any histological subtype of NSCLC were included. Of these 60 per cent were PS 1 and 17 per cent PS 2. Just over one third (34 per cent) had squamous cell carcinomas, 47 per cent had adenocarcinomas and the remainder had other large cell cancers. Of 1688 patients screened, 85 per cent showed tumours testing positive for EGFR by immunohistochemistry and 1125 entered the study. Most patients (94 per cent) had Stage IV disease, The majority were Caucasian (84 per cent) and male (70 per cent). Patients ranged between ages 18 and 83 with a median age of 59.
The chemotherapy treatment schedule was cisplatin 80mg/m2 day 1, and vinorelbine 25 (30)mg/m2 days 1,8, every 3 weeks for up to 6 cycles. Patients randomised to cetuximab received the standard loading dose of 400mg/m2 then 250mg/m2 weekly until disease progressed or they experienced intolerable toxicity. Median treatment duration was 14 weeks for chemotherapy and 18 weeks for cetuximab. Of patients randomised to chemo plus cetuximab, 80 per cent continued cetuximab as maintenance therapy.
The primary endpoint of FLEX was overall survival with secondary endpoints of response rate, progression-free survival, disease control, quality of life, and safety. Response rates were 36 and 29 per cent p=0.01 favouring cetuximab plus chemo, progression-free survival was 4.8 months in each group and time to treatment failure was 4.2 and 3.7 months respectively (p=0.01). Benefits were seen across all histological sub-types, and occurred irrespective of PS, gender, age, smoking status and tumour stage, said Professor Pirker.
On safety, Professor Pirker said the main cetuximab-related adverse event, as expected, was an acne-like rash which is a prognostic marker of response and which was amenable to treatment. There was no significant difference between treatment-related deaths (3 per cent in the cetuximab + chemo group and 2 per cent in the chemotherapy only group).
Discussing the study in Plenary Session, Professor Thomas Lynch of Harvard Medical School noted response rate and overall survival benefit were significantly improved by adding cetuximab to platinum-based chemotherapy. “This results in a clinically meaningful benefit for a broad population of patients with advanced NSCLC,” he commented.
On ethnic differences in survival, he said they underscored the need for better understanding of population genomics. Asian patients are likely to have higher rates of EGFR mutation which would explain their better prognosis, he said. Asian patients had a better overall survival rate compared to Caucasians but they showed different characteristics and numbers were too small to draw meaningful conclusions, said Professor Pirker.
Patient selection by molecular biomarkers predictive of response was becoming increasingly important on grounds of cost, Professor Lynch suggested. Restricting treatment to patients most likely to respond would boost median survival. Increasing this by 2.5 months compared to chemotherapy alone would improve the cost benefit ratio of cetuximab. The study was right to include only patients with EGFR positive tumours, he added. In future patients’ tumours might be screened to detect whether they also expressed wild type or mutant K-RAS genes, and for EGFR gene amplification detected by fluorescence in situ hybridisation (FISH). In one phase II study of lung cancer (SWOG 0342) both progression-free survival (6 vs 3 months) and overall survival (16 vs 8 months) were doubled among a small subset of patients with EGFR FISH-positive tumours treated with cetuximab and chemotherapy Tumours with wild-type KRAS genes are more likely to respond well to cetuximab than those with mutant KRAS, according to retrospective data from the CRYSTAL and OPUS trials in colorectal cancer, also presented at this year’s ASCO meeting. The same may apply in lung cancer. A further analysis of FLEX, comparing outcomes in patients with and without tumour KRAS mutant and wild type biomarkers is under way, said Professor Pirker.
Pirker R et al. FLEX: a randomised, multicentre, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer. Abstract 3 Late-Breaking Abstracts ASCO 2008, to be published in a supplement to the June 20 issue of Journal of Clinical Oncology.