Elsevier

The Lancet

Volume 377, Issue 9780, 28 May–3 June 2011, Pages 1846-1854
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(11)60545-XGet rights and content

Summary

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.

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide.1, 2, 3 1·5 million people were diagnosed with the disease in 2008 and more than 1·3 million died.1 Non-small-cell lung cancers (NSCLCs) account for more than 85% of all lung cancers;1 about 75% of patients with NSCLC present with advanced-stage (unresectable or metastatic) disease.

Erlotinib is a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor,4, 5 which is approved by the US Food and Drug Administration for treatment of patients with locally advanced or metastatic NSCLC whose disease has not responded to more than one previous chemotherapy regimen.4, 5 A phase 3 study5 showed that second-line or third-line monotherapy with erlotinib improved overall survival in patients with NSCLC.

The recombinant, anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody bevacizumab, combined with paclitaxel and carboplatin, was approved by the US Food and Drug Administration for first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC.6 A phase 3 study showed this combination significantly improved overall survival and progression-free survival in patients with NSCLC compared with carboplatin and paclitaxel alone.7, 8 Another phase 3 trial9 showed that the addition of bevacizumab to cisplatin and gemcitabine improved progression-free survival and objective responses rates for first-line treatment of non-squamous NSCLC; however, overall survival was not improved.

Bevacizumab and erlotinib target different tumour growth pathways (angiogenesis and EGFR activity, respectively) with little overlap in their toxic-effect profiles. These two drugs have potentially complementary mechanisms to control tumour growth.10, 11, 12, 13, 14

The safety and activity of combination erlotinib-bevacizumab were assessed in a phase 1/2 trial15 for patients with relapsed and refractory non-squamous NSCLC. The combination dose was established at 15 mg/kg bevacizumab once every 3 weeks and 150 mg erlotinib once per day. The objective response rate in 34 patients in phase 2 was 20%, disease-control rate was 85%, and median overall survival was 12·6 months.15

In a multicentre phase 2 trial16 of patients with relapsed and refractory non-squamous NSCLC who were randomly allocated to receive erlotinib plus bevacizumab, bevacizumab and chemotherapy, or chemotherapy alone, median overall survival was better in the groups that received bevacizumab (13·7 months for erlotinib plus bevacizumab and 12·6 months for bevacizumab and chemotherapy) than it was with chemotherapy alone (8·6 months); safety data favoured the erlotinib plus bevacizumab group.

In this phase 3 trial, we aimed to further assess the efficacy of bevacizumab in combination with erlotinib compared with erlotinib and placebo in patients with recurrent or refractory advanced-stage NSCLC who had disease progression during or after first-line therapy.

Section snippets

Study design and participants

In our international, double-blind, placebo-controlled phase 3 trial (BeTa), we enrolled patients who presented to 177 study sites in 12 countries with cytologically or histologically confirmed advanced-stage NSCLC that was recurrent or refractory after standard first-line chemotherapy or chemoradiotherapy. Patients were eligible if they were aged 18 years or older and had Eastern Cooperative Oncology Group performance status scores of 2 or lower. Patients with squamous cell carcinoma were

Results

Between June 8, 2005, and April 16, 2008, we enrolled 636 patients at 177 study sites in 12 countries and randomly allocated 319 patients to the bevacizumab group and 317 to the control group (figure 1, table 1). 200 (63%) patients in the bevacizumab group discontinued treatment because of disease progression, compared with 243 (77%) in the control group.

Baseline characteristics were much the same between treatment groups (table 1). 448 (70%) of 636 patients had previously received carboplatin

Discussion

We assessed the efficacy of addition of bevacizumab to erlotinib in patients with recurrent, advanced, or metastatic NSCLC after failure of standard first-line chemotherapy, and showed that addition of bevacizumab to erlotinib did not improve overall survival (figure 2). Bevacizumab added to erlotinib seemed to prolong progression-free survival, objective response rate, and duration of response compared with erlotinib alone; median progression-free survival and objective response rates were

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