PMID- 37709297
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20230922
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 11
IP  - 9
DP  - 2023 Sep
TI  - 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).
LID - 10.1136/jitc-2023-007126 [doi]
LID - e007126
AB  - 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.
CI  - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Masuda, Jun
AU  - Masuda J
AD  - Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese 
      Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
AD  - Department of Medical Oncology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
FAU - Sakai, Hitomi
AU  - Sakai H
AUID- ORCID: 0000-0001-8396-9121
AD  - Advanced Cancer Translational Research Institute, Showa University, Shinagawa-ku, 
      Tokyo, Japan sakai-h@med.showa-u.ac.jp.
AD  - Department of Medical Oncology, Kindai University Faculty of Medicine, 
      Osaka-Sayama, Osaka, Japan.
FAU - Tsurutani, Junji
AU  - Tsurutani J
AD  - Advanced Cancer Translational Research Institute, Showa University, Shinagawa-ku, 
      Tokyo, Japan.
FAU - Tanabe, Yuko
AU  - Tanabe Y
AD  - Department of Medical Oncology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
FAU - Masuda, Norikazu
AU  - Masuda N
AD  - Department of Breast and Endocrine Surgery, Nagoya University Graduate School of 
      Medicine, Nagoya, Aichi, Japan.
AD  - Department of Surgery, Breast Oncology, National Hospital Organization Osaka 
      National Hospital, Osaka, Japan.
FAU - Iwasa, Tsutomu
AU  - Iwasa T
AD  - Department of Medical Oncology, Kindai University Faculty of Medicine, 
      Osaka-Sayama, Osaka, Japan.
FAU - Takahashi, Masato
AU  - Takahashi M
AD  - Department of Breast Surgery, National Hospital Organization Hokkaido Cancer 
      Center, Sapporo, Hokkaido, Japan.
AD  - Department of Breast Surgery, Hokkaido University Hospital, Sapporo, Hokkaido, 
      Japan.
FAU - Futamura, Manabu
AU  - Futamura M
AD  - Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 
      Gifu, Japan.
FAU - Matsumoto, Koji
AU  - Matsumoto K
AD  - Department of Medical Oncology, Hyogo Cancer Center, Akashi, Hyogo, Japan.
FAU - Aogi, Kenjiro
AU  - Aogi K
AD  - Department of Breast Surgery, National Hospital Organization Shikoku Cancer 
      Center, Matsuyama, Ehime, Japan.
FAU - Iwata, Hiroji
AU  - Iwata H
AD  - Department of Breast Oncology, Aichi Cancer Center, Nagoya, Aichi, Japan.
FAU - Hosonaga, Mari
AU  - Hosonaga M
AD  - Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese 
      Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
FAU - Mukohara, Toru
AU  - Mukohara T
AD  - Department of Medical Oncology, National Cancer Center-Hospital East, Kashiwa, 
      Chiba, Japan.
FAU - Yoshimura, Kiyoshi
AU  - Yoshimura K
AD  - Department of Clinical Immuno-oncology, Clinical Research Institute for Clinical 
      Pharmacology and Therapeutics, Showa University, Shinagawa-ku, Tokyo, Japan.
FAU - Imamura, Chiyo K
AU  - Imamura CK
AD  - Advanced Cancer Translational Research Institute, Showa University, Shinagawa-ku, 
      Tokyo, Japan.
FAU - Miura, Sakiko
AU  - Miura S
AD  - Department of Pathology, Showa University, Shinagawa-ku, Tokyo, Japan.
FAU - Yamochi, Toshiko
AU  - Yamochi T
AD  - Department of Pathology, Showa University, Shinagawa-ku, Tokyo, Japan.
FAU - Kawabata, Hidetaka
AU  - Kawabata H
AD  - Department of Breast and Endocrine Surgery, Toranomon Hospital, Minato-ku, Tokyo, 
      Japan.
FAU - Yasojima, Hiroyuki
AU  - Yasojima H
AD  - Department of Surgery, Breast Oncology, National Hospital Organization Osaka 
      National Hospital, Osaka, Japan.
FAU - Tomioka, Nobumoto
AU  - Tomioka N
AD  - Department of Breast Surgery, National Hospital Organization Hokkaido Cancer 
      Center, Sapporo, Hokkaido, Japan.
FAU - Yoshimura, Kenichi
AU  - Yoshimura K
AD  - Medical Center for Translational and Clinical Research, Hiroshima University 
      Hospital, Hiroshima, Japan.
FAU - Takano, Toshimi
AU  - Takano T
AUID- ORCID: 0000-0002-8417-5291
AD  - Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese 
      Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
AD  - Department of Medical Oncology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
LA  - eng
SI  - UMIN-CTR/UMIN000036970
SI  - JapicCTI/JapicCTI-194782
PT  - Clinical Trial, Phase II
PT  - Journal Article
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 60UAB198HK (abemaciclib)
RN  - 31YO63LBSN (Nivolumab)
RN  - 0 (Aminopyridines)
RN  - 0 (Benzimidazoles)
RN  - 7LKK855W8I (Letrozole)
RN  - 0 (Antibodies)
SB  - IM
MH  - Humans
MH  - Female
MH  - *Breast Neoplasms/drug therapy
MH  - Nivolumab/therapeutic use
MH  - Aminopyridines/therapeutic use
MH  - Benzimidazoles/therapeutic use
MH  - Letrozole
MH  - Antibodies
PMC - PMC10503337
OTO - NOTNLM
OT  - breast neoplasms
OT  - clinical trials, phase III as topic
OT  - immune checkpoint inhibitors
OT  - immunotherapy
COIS- 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.
EDAT- 2023/09/15 00:42
MHDA- 2023/09/18 12:42
PMCR- 2023/09/13
CRDT- 2023/09/14 20:32
PHST- 2023/08/08 00:00 [accepted]
PHST- 2023/09/18 12:42 [medline]
PHST- 2023/09/15 00:42 [pubmed]
PHST- 2023/09/14 20:32 [entrez]
PHST- 2023/09/13 00:00 [pmc-release]
AID - jitc-2023-007126 [pii]
AID - 10.1136/jitc-2023-007126 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2023 Sep;11(9):e007126. doi: 10.1136/jitc-2023-007126.