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
Mené au Japon sur 228 patients atteints d'un cancer du poumon non à petites cellules de stade avancé ou métastatique et présentant une mutation EGFR, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et l'intérêt, du point de vue de la qualité de vie, de l'ajout du bévacizumab à l'erlotinib
Background : Bevacizumab is a promising candidate for combination treatment with epidermal growthfactor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomesfor patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, aphase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolongedprogression-free survival compared with erlotinib alone in these patients. In furtheranalyses, 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 hospitalsand 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 previouslyreceived systemic chemotherapy, and were randomly assigned (1:1) by a computer-generatedrandomisation sequence and minimisation to receive either 150 mg oral erlotinib oncedaily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinibonce daily, until disease progression or intolerable toxicity. Randomisation was stratifiedaccording to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, andstudy personnel (including those assessing outcomes) were unmasked to treatment allocation.We report the secondary outcomes of overall survival and quality of life (the periodfrom enrolment to confirmation of a minimally important difference on the EuropeanOrganisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTCQLQ]-C30), and the exploratory outcome of time from enrolment to progressive diseaseduring second-line treatment or death. Overall survival and the exploratory outcomewere analysed in the modified intention-to-treat population, which comprised all randomlyassigned patients who received at least one dose of the study drug and had responseevaluations. Quality of life was analysed in patients in the modified intention-to-treatpopulation who had completed the quality of life questionnaires. The trial is registeredwith the University Hospital Medical Information Network Clinical Trials Registry,UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currentlyclosed. Findings : Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients whoreceived bevacizumab–erlotinib and 112 who received erlotinib only were included inthe modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a medianfollow-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 23·9months (IQR 14·2–39·1), the median time from enrolment to progressive disease duringsecond-line treatment or death was 28·6 months (95% CI 22·1–35·9) in the bevacizumab–erlotinibgroup 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 differenceon the EORTC QLQ-C30 was 6·0 months (95% CI 5·2–11·3) in the bevacizumab–erlotinibgroup 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 withmetastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Whythe 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 seenbecause overall survival was influenced by treatment regimens used after disease progression.