First Line Treatment with Erlotinib Plus Bevacizumab or with Erlotinib Alone in Patients with Advanced Non-Squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations (NEJ026): An Open-Label, Randomized, Multicenter, Phase 3 Study

Abstract

Background: Resistance to first- or second-generation TKI monotherapy, the standard treatment for EGFR mutation-positive NSCLC, develops in less than a year. A phase II study comparing combination therapy of erlotinib and bevacizumab (BE) with erlotinib (E) monotherapy demonstrated the higher efficacy and safety of BE in patients. To validate these results, we have conducted a phase III study. Methods: The NEJ026 study was an open-label, randomized phase III clinical study. The patients with EGFR mutation-positive NSCLC were randomly allocated to a BE combination therapy or E monotherapy arm. In both arms, patients were orally administered 150 mg/day of erlotinib. In the BE arm, patients were additionally intravenously administered 15 mg/kg of bevacizumab every 21 days. The primary endpoint was progression-free survival (PFS). Interim analysis for evaluating efficacy was planned for when 67% of final events were attained. Findings: Between Jun 3, 2015 to Aug 31, 2016, 228 patients were enrolled. Preplanned interim analysis was performed on Sep 21, 2017. Median PFS for patients in the BE arm was 16·9 months (95% CI, 14·2-21·0), which was significantly superior to the value of 13·3 months (95% CI, 11·1-15·3) for patients in the E monotherapy arm. The response rates were 72·3% (95%CI 63·1-80·4) in the BE arm and 66·1% (95%CI 56·5-74·7) in the E arm. The rate of hypertension (45·5% vs 8·8%), proteinuria (32·1% vs 2·6%), and hemorrhage (25·9% vs 2·6%) significantly increased in the BE arm, but remained manageable. There were no treatment-related deaths. Interpretation: The results of this phase III study confirm that BE combination therapy can be a new standard treatment for patients with EGFR mutation-positive NSCLC. Clinical Trial Number: The trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; 000017069). Funding Statement: This study was funded by Chugai Pharmaceutical. The funding source gave its approval at the conception of this study and was involved in the provision of information; however, it was not involved in preparation of the protocol, analysis, and interpretation of the results. Declaration of Interests: HS reports grants from Chugai Pharmaceutical, AstraZeneca, and MSD, personal fees from Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, outside the submitted work. TF reports personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. NF has nothing to disclose. KW has nothing to disclose. SS reports personal fees from Chugai Pharma, AstraZeneca, Nippon Boehringer Ingelheim, MSD, Taiho Pharmaceutical, Pfizer, Eli Lilly and Company, and Novartis, non-financial support from Kyowa Hakko Kirin, Bristol-Myers Squibb, Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squib, Eli Lilly Japan, Taiho Pharmaceutical, and DAIICHI SANKYO COMPANY, outside the submitted work. NT has nothing to disclose. OY has nothing to disclose. MO reports and Research grants and clinical trial fee to my research at Hiroshima University was provided from Chugai Pharma. IN has nothing to disclose. KA has received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Chugai Pharmaceutical. Yukari T has nothing to disclose. YF reports personal fees from Chugai Pharmaceutical, and AstraZeneca, outside the submitted work. NM has nothing to disclose. GA has nothing to disclose. SW reports personal fees from AstraZeneca, Chugai Pharma, Bristol-Myers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, and Taiho Pharmaceutical, outside the submitted work. MasakiM has nothing to disclose. KH reports personal fees from Chugai pharmaceuticals, during the conduct of the study; In addition, KH has a patent EGFR mutation detection method with royalties paid to LSI medience. TN reports grants from Chugai Pharmaceutical, during the conduct of the study. SM reports grants from North East Japan Study Group, during the conduct of the study; personal fees from Chugai Pharmaceutical, outside the submitted work. KK reports grants from Chugai Pharmaceutical, during the conduct of the study. MakotoMD reports personal fees from Chugai Pharmaceutical., during the conduct of the study; grants and personal fees from Boehringer Ingelheim, AstraZeneca, personal fees from Eli Lilly, outside the submitte Ethics Approval Statement: The study was conducted in compliance with the Helsinki Declaration and GCP Guidelines. Moreover, the study protocol was reviewed and approved by the central institutional review board (IRB). Although the primary endpoint was met and the independent data monitoring committee recommended that the study be ceased, we decided to continue our investigation to attain secondary and exploratory endpoints. The JO25567 study, however, was not designed to detect OS-related benefits and the OS analysis was additionally performed just for half of patients with consent. Therefore, a combined analysis of OS data from the NEJ026 and JO25567 studies was considered. To resolve any ethical issues with our approach, this study was continued after we notified all investigators of the results of our interim analysis and obtained permission for the addition of bevacizumab to the treatment regimen of patients in the E monotherapy arm.