Phase 2 Study of Nivolumab Plus Bevacizumab Plus Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer

Background: Programmed cell death-1 inhibitors have been developed for various cancer types. Potential synergistic effects of nivolumab, bevacizumab, and paclitaxel (triple therapy) were observed in preclinical models, but triple therapy has not been evaluated for metastatic breast cancer (mBC) in clinical trials. Methods: This investigator-initiated, phase 2, multicentre, single-arm study (WJOG9917B) was performed to evaluate the efficacy and safety of triple therapy in the first-line setting for patients with human epidermal growth factor receptor 2 (HER2)-negative mBC. Treatment was continued until disease progression or intolerable toxicity. The primary endpoint was the percentage of patients with a centrally assessed objective response. Key secondary endpoints included disease control, progression-free survival (PFS), overall survival (OS), and toxicities. This study was registered on the UMIN registry (ID: UMIN000030242). Findings: Between February 2018 and October 2018, 57 females with HER2-negative mBC patients were enrolled. An objective response was seen in 39 of 56 patients (70%, 95% confidence interval [CI] 55·9%–81·2%), which met the primary endpoint. Disease control was achieved in 55 patients (98%, 95% CI 90·4%–100%). The median PFS was 14·8 months (95% CI, 11·0 to not reached), with a median follow-up of 13·9 months. The estimated OS at 12 months was 88% (95% CI 76·4%–94·0%). Median OS was not reached. Adverse drug reactions of grade 3 or 4 occurred in 33 of 57 patients (58%). There were no treatment-related deaths. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3 or 4 events in eight patients (14%). Interpretation: Nivolumab, bevacizumab, and paclitaxel as first-line triple therapy showed promising efficacy and manageable toxicity in patients with HER2-negative mBC. Registration: This study was registered on the UMIN registry (ID: UMIN000030242). Funding: Ono Pharmaceutical Company. Declaration of Interests: Y. Ozaki reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from Chugai outside the submitted work. J. Tsurutani reports research funds from Ono Pharmaceutical in relation to this work; grants from Daiichi Sankyo, Kyowa Kirin, Chugai, Pfizer, Eisai, Nippon Kayaku, and Eli Lilly; consulting fees from Asahi Kasei; lecture fees from Eisai, Chugai, Taiho, Daiichi Sankyo, Eli Lilly, Pfizer, Nippon Kayaku, Novartis, and AstraZeneca, support for attending meetings from Eisai and Daiichi Sankyo; and participation on advisory boards for Daiichi Sankyo, Eisai, AstraZeneca, and Eli Lilly outside the submitted work. T. Mukohara reports research funds from Ono Pharmaceutical in relation to this work; and grants from Daiichi Sankyo, Sysmex, MSD, Pfizer, Eisai, Chugai, Novartis, Sanofi, Seagen, and AstraZeneca; lecture fees from Eisai, Novartis, Chugai, Eli Lilly, AstraZeneca, and Kyowa Kirin outside the submitted work. T. Iwasa reports research funds from Ono Pharmaceutical in relation to this work. M. Takahashi reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from AstraZeneca, Eli Lilly, Eisai, and Pfizer outside the submitted work. Y. Tanabe reports grants provided to the institution from Ono Pharmaceutical, outside of the submitted work. H. Kawabata reports research funds from Ono Pharmaceutical in relation to this work; and research funds from MSD, Daiichi Sankyo, Novartis, Taiho, and Chugai outside the submitted work. N. Masuda reports research funds from Ono Pharmaceutical in relation to this work; grants from Chugai and Eisai; personal fees, honoraria, and research funding provided to the institution from Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, Takeda, Kyowa Kirin, Novartis, and Daiichi Sankyo; and research funding provided to the institution from MSD, Nippon Kayaku, and Sanofi outside of the submitted work. M. Futamura reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from Chugai, Taiho, Takeda, Novartis, and Eisai outside the submitted work. H. Minami reports research funds from Ono Pharmaceutical in relation to this work; grants from Ono Pharmaceutical, Asahi Kasei Pharma, Astellas, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Chugai, Daiichi Sankyo, Sumitomo Dainippon, Eisai, Kyowa Kirin, Merck Serono, MSD, Nippon Shinyaku, Sanofi, Takeda, CSL Behring, Nippon Kayaku, Shionogi, Taiho, Eli Lilly, Novartis, and Mitsubishi Tanabe; personal fees and funding for clinical trials from Ono Pharmaceutical, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, MSD, Pfizer, Taiho, and Novartis; personal fees from Celgene, Sumitomo Dainippon, Eisai, Janssen, Kyowa Kirin, Merck Serono, Otsuka, Sanofi, Takeda, Genomic Health, AbbVie, and Eli Lilly; and funding for clinical trials from AstraZeneca and Amgen outside the submitted work. K. Matsumoto reports research funds from Ono Pharmaceutical in relation to this work; grants from MSD, Chugai, Icon Japan, Eisai, Ono Pharmaceutical, AstraZeneca, and Novartis; and personal fees from MSD, Chugai, Eisai, Ono Pharmaceutical, AstraZeneca, Novartis, Eli Lilly, AbbVie, Kyowa Kirin, Centurion, and Taiho outside the submitted work. K. Yoshimura reports research funds from Ono Pharmaceutical in relation to this work; and personal fees and lecture fees from AstraZeneca, Eisai, Otsuka, Nippon Kayaku, Eli Lilly, Novartis, Boehringer Ingelheim, and Chugai outside the submitted work. S. Kitano reports research funds from Ono Pharmaceutical in relation to this work; joint research funds/contract research expenses for clinical trials from Ono Pharmaceutical, Boehringer Ingelheim, and Chugai; joint research funds from Daiichi Sankyo, Eisai, Astellas, Gilead Sciences, Takara Bio, and PACT Pharma; contract research expenses for clinical trials from Regeneron and MSD; and grants from the Japan Agency for Medical Research and Development (AMED) and Japan Society for the Promotion of Science (JSPS); consulting fees from Immunity Research; lecture fees and participation on advisory boards for Ono Pharmaceutical, AstraZeneca, Chugai, Pfizer, Boehringer Ingelheim, Novartis, Daiichi Sankyo, MSD, Sumitomo Dainippon, Eisai, Bristol-Myers Squibb, Regeneron, and GSK; lecture fees from Sanofi, Taiho, and Ayumi Pharmaceutical; participation on advisory boards for Rakuten Medical; and comment fees from Pharmaceuticals and Medical Devices Agency (PMDA) outside the submitted work. T. Takano reports research funds from Ono Pharmaceutical in relation to this work; grants provided to the institution from Chugai, Daiichi Sankyo, Ono Pharmaceutical, MSD, and Eisai; and lecture fees from Chugai, Daiichi Sankyo, Eisai, Kyowa Kirin, Pfizer, Eli Lilly, and Celltrion Healthcare outside the submitted work. Ethics Approval Statement: This trial was conducted according to Good Clinical Practice and the Declaration of Helsinki, and was approved by institutional review boards at all participating sites.