ATLAS meets primary endpoint

The Phase III ATLAS (AVF3671g) study investigating Tarceva (erlotinib) in combination with Avastin (bevacizumab) as maintenance therapy following initial treatment with bevacizumab plus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) has met its primary endpoint. The trial was stopped early on the recommendation of an independent Data Safety Monitoring Board after a preplanned interim analysis showed that combining erlotinib and bevacizumab significantly extended the time patients lived without their disease advancing, as defined by progression-free survival (PFS), compared to bevacizumab plus placebo. A preliminary safety analysis showed adverse events were consistent with previous erlotinib and bevacizumab studies, as well as trials evaluating the two medicines together, and no new safety signals were observed.

The global, multi-centre, randomised, double-blind, placebo-controlled study enrolled 1,157 patients with locally-advanced, recurrent or metastatic NSCLC. In order to evaluate patients who are often excluded from bevacizumab-based trials, patients with treated brain metastases, tumours of squamous cell histology that were not centrally located in the lung and those taking blood-thinning medications were eligible for this trial. Subjects were initially treated with four cycles of bevacizumab in combination with the investigators' choice of platinum-based CT regimens (carboplatin+gemcitabine, carboplatin+paclitaxel, carboplatin+docetaxel, cisplatin+vinorelbine, cisplatin+docetaxel or cisplatin+gemcitabine). If their cancer did not progress and they did not experience significant toxicity, patients were then randomised (n=768) to receive maintenance therapy with bevacizumab+erlotinib or bevacizumab+placebo until disease progression.

The study's primary endpoint of PFS, as determined by investigators, was defined as the length of time from randomisation to disease progression or death from any cause. PFS assessment began from the start of the maintenance phase of the study after initial treatment with four cycles of bevacizumab and CT. Secondary endpoints included overall survival (OS), incidence of all adverse events and selected Grade 3 or greater adverse events and incidence of treatment discontinuation for reasons other than disease progression.

An earlier study, called BeTa Lung, which evaluated bevacizumab in combination with erlotinib in patients with advanced NSCLC whose disease had progressed following platinum-based CT, failed to meet its primary endpoint of improving OS compared to erlotinib in combination with placebo. However, there was clear evidence of clinical activity, with improvements in the secondary endpoints of PFS and response rate when bevacizumab was added to erlotinib compared to erlotinib alone. An additional trial, called SATURN, showed that erlotinib delayed disease progression when given as a single agent immediately following treatment with CT, compared to placebo. In ATLAS, patients were initially treated with bevacizumab plus CT followed by the addition of erlotinib to bevacizumab in the maintenance phase. Genentech plans to discuss these data with the FDA to determine next steps.

Avastin is currently approved as first-line treatment in combination with carboplatin and paclitaxel for patients with locally-advanced, non-squamous NSCLC, based on a 25 per cent improvement in OS compared to CT alone (hazard ratio=0.80). Tarceva is currently approved as a treatment for patients with advanced NSCLC who have progressed following treatment with at least one prior CT regimen, based on a 37 per cent improvement in OS compared to placebo (hazard ratio=0.73). OSI Pharmaceuticals markets Tarceva through partnerships with Genentech in the US and Roche throughout the rest of the world. Avastin is jointly marketed by Genentech and Roche.

Matthew Dennis - Editor, Cancer Drug News