Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial

Summary

Background

Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis.

Methods

In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB–IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069.

Findings

Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0–15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2–21·0) compared with 13·3 months (11·1–15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417–0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3–4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred.

Interpretation

The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting.

Funding

Chugai Pharmaceutical.

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients with lung cancer are diagnosed at an advanced stage and prognosis remains poor despite the development of novel therapeutic strategies.1, 2 In 2004, pivotal trials established EGFR tyrosine kinase inhibitor (TKI) therapy as standard of care for patients with EGFR-positive lung cancer.3, 4, 5, 6 Until 2018, only three first-line EGFR TKIs were clinically available: gefitinib, erlotinib, and afatinib.7, 8 Although 60–80% of patients with EGFR-positive tumours had responses following treatment with these drugs, median progression-free survival remains poor (around 1 year) as a result of acquired therapeutic resistance.3, 4, 5, 6, 7, 8

To improve progression-free survival, combination treatments with first-generation or second-generation TKIs have been evaluated in multiple clinical trials.9, 10 Bevacizumab is a VEGF monoclonal antibody, which inhibits angiogenesis to suppress tumour growth by restricting oxygen and nutrient supply to tumours. In the BeTa lung phase 3 study, 11, 12, 13, 14 the combination of bevacizumab and erlotinib was compared with erlotinib monotherapy to evaluate activity in patients with non-small-cell lung cancer (NSCLC) who were not stratified by EGFR mutation status. Although no substantial differences in overall survival were identified between the groups, subgroups analyses suggested that patients with EGFR-positive NSCLC responded better to combination therapy than did patients with EGFR-negative disease. On the basis of the results of the BeTa lung study, the JO25567 phase 2 trial was done.11, 15, 16 Chemotherapy-naive patients with non-squamous NSCLC harbouring common EGFR mutations were randomly assigned to receive erlotinib plus bevacizumab or erlotinib monotherapy. Median progression-free survival was significantly improved in the erlotinib plus bevacizumab group compared with the erlotinib monotherapy group (16·0 months [95% CI 13·9–18·1] vs 9·7 months [5·7–11·1], hazard ratio [HR] 0·54 [95% CI 0·36–0·79]) and had an acceptable toxicity profile. However, the results of the phase 2 JO25567 study cannot be considered entirely conclusive since the study was inadequately powered to assess overall survival. We therefore did this phase 3 trial to compare erlotinib plus bevacizumab combination therapy with erlotinib monotherapy for the treatment of patients with EGFR-positive non-squamous NSCLC.