Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial

Abstract

Background: Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial.

Methods: In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728.

Findings: Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group.

Interpretation: Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC.

Funding: Genentech.

Figure 1. Trial profile

*This patient was analysed as part of the bevacizumab group for safety analyses. †This patient was analysed as part of the control group for safety analyses.

Figure 2. Kaplan-Meier curves for overall survival

Overall survival is shown for assessable patients randomly allocated to erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group). Thep value for overall survival is based on a stratified log-rank test; stratification factors were Eastern Cooperative Oncology Group performance status, smoking history, and sex.

Figure 3. Forest plot for subpopulations of patients defined by demographics and baseline characteristics, including biomarker expression

Dashed line shows hazard ratio for the overall population. Overall survival hazard ratios were estimated by use of an unstratified Cox model. FISH=fluorescence in-situ hybridisation. NA=not assessable. NR=not reached. ECOG=Eastern Cooperative Oncology Group. NSCLC=non-small-cell lung cancer. EGFR=epidermal growth factor receptor.

Figure 4. Kaplan-Meier curves for progression-free survival

Progression-free survival is shown for assessable patients in the bevacizumab group (randomly allocated to erlotinib plus bevacizumab) and control group (randomly allocated to erlotinib plus placebo). Because of the prespecified use of fixed sequence testing to control the overall type I error rate, which required that the primary endpoint (overall survival) be significant before statistical testing of key secondary endpoints, progression-free survival results could not be defined as significant.