Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).

Background: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.
Methods: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.
Results: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.
Conclusions: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.
Trial Registration Number: JapicCTI-194782, jRCT2080224706, UMIN000036970.
Competing Interests: Competing interests: HS reports grants from Eisai and lecture fees from Daiichi Sankyo and Eisai to her institution outside the submitted work. JT reports grants from Daiichi Sankyo, Eli Lilly, and FSJD to his institution outside the submitted work; consulting fees, support for attending a meeting, and fees for an advisory board from Daiichi Sankyo; lecture fee from Eli Lilly; and payments for an advisory board from AstraZeneca. YT reports grants from Ono Pharmaceuticals, Taiho, Eli Lilly, Daiichi Sankyo, and MSD. NM reports grants from Chugai, Eli Lilly, AstraZeneca, Daiichi Sankyo, MSD, Eisai, Novartis Pharma, Sanofi, Kyowa-Kirin, and Nippon-Kayaku to his institution outside the submitted work; and lecture fees from Chugai, Pfizer, AstraZeneca, and Eli Lilly. MT reports lecture fees from AstraZeneca, Daiichi Sankyo, Eisai, and Eli Lilly, and MSD. KM reports contracts from MSD, Chugai, Eisai, Daiichi Sankyo, Eli Lilly, and ICON Japan to his institution; lecture fees from Daiichi Sankyo, Chugai, Kyowa-Kirin, and MSD; and fees for an advisory board from Daiichi Sankyo. KA reports grants from Chugai, Eisai, and Takeda Pharmaceutical; lecture fees from AstraZeneca, Daiichi Sankyo, Taiho, Pfizer, Novartis Pharma, Eli Lilly, and Chugai. HI reports grants from Chugai, Eli Lilly, Nihon Kayaku, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, MSD, Sanofi, Novartis, Bayer, and Boehringer Ingelheim to his institution outside submitted work; consulting fees from Chugai, Kyowa Kirin, AstraZeneca, Eli Lilly, Pfizer, and Daiichi Sankyo; and lecture fees from Chugai, AstraZeneca, Eli Lilly, Pfizer, Taiho, Daiichi Sankyo, Eisai, and Kyowa Kirin. TM reports grants from Sysmex, Eisai, MSD, Pfizer, Novartis Pharma, Sanofi, Chugai, AstraZeneca, and Ono Pharmaceuticals outside submitted work; lecture fees from Eisai, Pfizer, Novartis Pharma, Chugai, Eli Lilly, AstraZeneca, Kyowa-Kirin, and Taiho. KIY reports lecture fees from Chugai and Bristol Myers Squibb outside the submitted work. CKI reports research funding from Otsuka Pharmaceutical and Eli Lilly outside the submitted work; lecture fees from Taiho. HK reports grants from Chugai, Taiho, and Mochida Pharmaceutical; lecture fees from AstraZeneca, Daiichi Sankyo, Taiho, Pfizer, and Novartis. KEY reports a grant from Boehringer Ingelheim; lecture fees from Chugai, Eli Lilly, AstraZeneca, Pfizer, and Boehringer Ingelheim. TT reports lecture fees from Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Celltrion Healthcare. All other authors declare no competing interests.
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