A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC)

Abstract

LBA8002 Background: B when added to chemotherapy, and E alone, each lead to improved survival in the treatment of patients (pts) with NSCLC (Sandler et al, NEJM 2006, 355:2542–2550; Shepherd et al, NEJM 2005, 353:123–132). Pre-clinical and clinical data (Herbst, J Clin Oncol 2007, 25: 4743–4750) suggest that the combination of B and E may improve the efficacy of NSCLC treatment. This potential was demonstrated in the BETA (B in combination with E compared with E alone for treatment of advanced NSCLC after failure of standard first-line chemotherapy) trial, a phase III trial in which progression free survival (PFS) was improved for patients treated with B + E (Hainsworth, Thoracic Oncol 2008, 3(11) Supp. 4:S302). Methods: The ATLAS study was designed to evaluate B + E (150 mg daily) versus B alone, following B + platin-containing doublet chemotherapy, in pts with stage IIIb/IV NSCLC. Enrolled pts were B-eligible, including pts with treated brain metastases, and pts anticoagulated with low molecular weight heparin(s). Pts with peripheral and/or extra-thoracic squamous tumors were also eligible. Pts received 4 cycles of B (15 mg/kg every 3 weeks) with chemotherapy. Pts who had not experienced disease progression (DP) or significant toxicity were then randomized to receive B + E or B + placebo (P). The primary objective of ATLAS was to compare PFS in pts receiving B + E versus B + placebo. Secondary objectives included the assessment of safety, and overall survival. A data safety monitoring committee (DSMC) monitored safety and efficacy. Results: 1,160 patients were enrolled and 768 randomized from May 2005 to May 2008. The DSMC recommended stopping the trial at the second planned interim efficacy analysis, because it met the primary endpoint. The median PFS after randomization was 4.8 mos for (B + E) vs. 3.7 mos for (B + P), HR= 0.722 (95% CI: 0.592–0.881), p = 0.0012. The safety profile for B + E was consistent with known profiles for B and E. Conclusions: E added to B treatment after chemotherapy with B significantly improves the PFS of patients treated in the first-line setting for locally advanced, recurrent, or metastatic NSCLC. [Table: see text]

EGFR Tyrosine Kinase Inhibitors and Monoclonal Antibodies: Clinical Trial Review

“…ATLAS was a randomized, double-blind, placebocontrolled phase IIIb trial that compared bevacizumab alone with or without erlotinib after completion of platinum-containing doublet chemotherapy plus bevacizumab [43]. The trial was closed after the second planned interim analysis, when the endpoint of PFS was achieved.…”

Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor

“…However, the addition of bevacizumab to cisplatin/gemcitabine chemotherapy did not improve OS [26]. Trials investigating the use of bevacizumab as maintenance therapy are currently underway [27,28].…”

Impact of biomarkers on non-small cell lung cancer treatment

“…At least two different phase III studies have explored the use of erlotinib in this setting [74,75]. In the SATURN trial, 889 advanced NSCLC patients with no disease progression after 4 cycles of standard platinum-based chemotherapy were randomized to erlotinib or placebo until progression or unacceptable toxicity [74].…”

“…The study met its primary endpoint of improved progression-free survival for erlotinib (HR 0.71, p<.0001), an advantage that translated into a significantly prolonged overall survival (11.0 versus 12.0 months, HR 0.81, p=0.0088) [76]. In the ATLAS trial, bevacizumab plus erlotinib were compared with bevacizumab alone in 768 patients with advanced NSCLC with no evidence of progression after first-line platinum-based chemotherapy plus bevacizumab [75]. Again, the trial met the primary endpoint of improved progression-free survival in the combination arm (4.8 versus 3.7 months, HR 0.72, p= 0.0012), confirming the activity of this regimen formerly tested in the BETA study [77].…”

“…These observations emerged also for erlotinib, particularly when considering data from the BR.21 study [67], and from the TALENT [63] and TRIBUTE [66] trials of chemotherapy with or without erlotinib, where never-smoking status resulted as an independent predictive factor for survival for subjects in the erlotinib arm. The SATURN and ATLAS trials of erlotinib as maintenance treatment reinforced the idea that clinical patient selection might be an effective strategy to be pursued [74,75], although a progression-free survival benefit with erlotinib, even of limited magnitude, was observed in the majority of subgroups regardless of clinical features predictive for an EGFR TKI benefit.…”