ArticlesErlotinib 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
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.
Section snippets
Study design and participants
NEJ026 was a randomised, open-label, multicentre, phase 3 study done in 69 centres across Japan (appendix pp 6–8).
Eligible patients were at least 20 years old and had histologically or cytologically confirmed non-squamous NSCLC, EGFR-positive status (exon 19 deletion or exon 21 Leu858Arg point mutation), stage IIIB–IV disease (defined according to the 7th edition of the General Rule for Clinical and Pathological Record of Lung Cancer [2010]17) or recurrent disease, one or more measurable
Results
Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled and randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). Two patients in the erlotinib plus bevacizumab group withdrew from the study before treatment initiation (one withdrew consent and one withdrew at the physician's discretion) and were excluded from all analyses. Two patients in the erlotinib monotherapy group were randomised in error; one patient had received adjuvant uracil-tegafur
Discussion
To the best of our knowledge, this is the first report of a multicentre phase 3 study to compare the efficacy of bevacizumab and erlotinib combination treatment with that of erlotinib monotherapy in patients with NSCLC. Our preplanned interim analysis showed that the median progression-free survival of patients in the erlotinib plus bevacizumab group was significantly improved compared with that of patients in the erlotinib alone group. The addition of bevacizumab to erlotinib therefore seems
Data sharing
Deidentified participant data will be made available when analyses of all primary and secondary endpoints have been published, following the completion of a data transfer agreement.
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