Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial

BACKGROUND: Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase III study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC (E1505). The primary endpoint was overall survival. METHODS: Adult patients (≥ 18 years old) with ECOG performance status 0 or 1 with completely resected stage IB (≥4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6–12 weeks of surgery and stratified by chemotherapy regimen, stage, histology, and sex. Minimum mediastinal lymph node sampling at specified levels was required (level 7 and 4 for right-sided tumors or level 7 and 5 and/or 6 for left-sided tumors). Normal laboratory values within two weeks of randomisation were required for enrollment. Chemotherapy, which was selected for each patient prior to randomisation, consisted of four, 3-week (21-day) cycles of cisplatin (75 mg/m(2) in all regimens) with either vinorelbine 30 mg/m(2) days 1 and 8; docetaxel 75 mg/m(2) day 1; OR gemcitabine 1200 mg/m(2) days 1 and 8; OR, starting in 2009 with an amendment, pemetrexed 500 mg/m(2) day 1 along with B12 and folic acid supplementation. Patients were randomised 1:1 to Arm A (chemotherapy) or Arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for one year. Randomisation to treatment arm was performed centrally and determined using permuted blocks within strata with dynamic balancing on institution. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0·025-level test. The primary endpoint was overall survival, which was defined as the time from randomisation to death from any cause, and patients who were thought to be alive at the time of final analysis were censored at the last date of contact with analysis done based on intention to treat. This is final analysis of the primary endpoint of overall survival of E1505 (NCT00324805). FINDINGS: From July 2007 to September 2013, 1501 patients were enrolled, of whom 26% (N=383) had stage IB, 44% (N=636) stage II, and 30% (N=439) stage IIIA) with 28% (N=422) squamous cell histology. Cisplatin-based chemotherapy regimens utilized were vinorelbine 25% (N=377), docetaxel 23% (N=343), gemcitabine 19% (N=283), and pemetrexed 33% (N=497). At a median follow-up time of 50·3 months (IQR 32.9–68.0), estimated OS hazard ratio (B/A) was 0·99 (95% CI: 0·82–1·19, p=0·90). The median OS on Arm A has not been reached and is 85.8 months (95% CI 74.9-NA) on Arm B. Statistically significantly increased grade 3–5 toxicities of note (all attributions) included: overall worst grade (ie all grade 3/4/5 toxicities) (67%(N=496) versus 83%(N=610)); hypertension (8%(N=60) versus 30%(N=219)), and neutropenia (33%(N=241) versus 37%(N=275)) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm (N=15 on arm A and N=19 on arm B). INTERPRETATION: The addition of bevacizumab to adjuvant chemotherapy failed to improve overall survival for patients with surgically resected early stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for resected NSCLC patients. FUNDING: This study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by the National Cancer Institute of the National Institutes of Health.