Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.

Background: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life.
Methods: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed.
Findings: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47).
Interpretation: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression.
Funding: Chugai Pharmaceutical.
Competing Interests: Declaration of interests TF reports personal fees from Chugai Pharmaceutical, during the conduct of the study, and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. HS reports grants from Chugai Pharmaceutical, AstraZeneca, and MSD, outside the submitted work, and personal fees from Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Novartis Pharma, outside the submitted work. NF reports personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Novartis, Taiho, Kyowa Kirin, MSD, and Pfizer, outside the submitted work. SS reports personal fees from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Hakko Kirin, and Yakult Honsha, outside the submitted work. SI reports grants from Ono Pharmaceutical, and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squibb, Eli Lilly Japan, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. OY reports personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, and Eli Lilly Japan, outside the submitted work. MO reports grants from Chugai Pharmaceutical, during the conduct of the study. MS reports grants and personal fees from Chugai Pharmaceutical, during the conduct of the study. KA reports personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, Astra Zeneca, MSD Oncology, and Bristol-Myers Squibb, outside the submitted work. YTsub reports personal fees from Chugai Pharmaceuticals, AstraZeneca, and Daiichi Sankyo, outside the submitted work. YF reports personal fees from Eli Lilly, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb, outside the submitted work. SW reports grants from AstraZeneca and Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, and Daiichi Sankyo, outside the submitted work. KH reports grants from Taiho Pharmaceutical, Ono Pharma, and MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharma, Boehringer Ingelheim, Novartis, Kyorin Pharmaceutical, and Bristol-Myers Squibb, outside the submitted work, and has a patent EGFR mutation test licensed to LSI Medience. SM reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Pfizer Japan, Taiho Pharmaceutical, and Ono Pharmaceutical, outside the submitted work. KK reports personal fees from AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Boehringer Ingelheim, and Taiho Pharmaceutical, outside the submitted work. MMa reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study, and personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, and Eli Lilly, outside the submitted work. All other authors declare no competing interests
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