Abstract OT2-04-07: Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial)
Authors: Masuda Jun , Tsurutani Junji , Masuda Norikazu , Futamura Manabu , Matsumoto Koji , Aogi Kenjiro , Takahashi Masato , Iwata Hiroji , Iwasa Tsutomu , Mukohara Toru , Yoshimura Kenichi , Ueno Takayuki , Takano Toshimi 
Published: March 2020

Abstract
Background: In this year, anti-programmed death-ligand 1 (PD-L1) antibody has been approved for PD-L1-positive metastatic triple-negative breast cancer by the U.S. Food and Drug Administration. The synergistic effect of the combination of anti-PD-L1 antibody, CDK4/6 inhibitor and endocrine therapy (ET) has been anticipated based on various preclinical data. A Phase Ib study (JPCE, NCT02779751) of abemaciclib plus pembrolizumab demonstrated manageable safety and promising anti-tumor activity in patients with HR-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib and ET (letrozole [LET] or fulvestrant [FUL]) as a first or second-line treatment in patients with HR+, HER2- MBC. Trial Design: This is a multicenter, multi-cohort, nonrandomized, open-label Phase II study to evaluate the efficacy and safety of nivolumab in combination with abemaciclib and ET (LET or FUL) in patients with HR+, HER2- MBC. Since there is no safety data of the combination of nivolumab, abemaciclib and ET, we evaluate safety and tolerability of the combination therapy in the first 6 patients with predefined dose-limiting toxicities. Patients will receive nivolumab 240 mg/body on day 1, 15, abemaciclib 150mg twice daily, and either LET 2.5mg once daily (LET cohort) or FUL 500mg on day1, day15 (FUL cohort) every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Pre- or perimenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligibility Criteria: Key eligibility criteria for the LET cohort are: postmenopausal HR+, HER2- MBC with ECOG PS≤1, measurable disease, no prior systemic therapy. ET in the adjuvant setting is permitted if the patient has a disease-free interval &gt; 12 months from the completion of ET. Key eligibility criteria for the FUL cohort are: HR+, HER2- MBC with ECOG PS≤1, measurable disease, no more than one ET or any prior chemotherapy for MBC. Patients are required to have a disease that progressed while receiving adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for MBC. Specific Aims: The primary endpoint is the objective response rate (ORR) and key secondary endpoints include progression-free survival, overall survival, and the safety of the protocol treatment. Statistical Design: The threshold and expected ORR of LET cohort are 55% and 75%, respectively, and 16 patients are needed to ensure a statistical power of 80% (α=0.20). The threshold and expected ORR of FUL cohort are 45% and 60%, respectively, and 32 patients are needed to ensure a statistical power of 80% (α=0.20). Target Accrual: A total of 53 patients (LET cohort: 18, FUL cohort: 35) will be enrolled and duration of enrollment will be 1 year and 4 months. This trial opened to accrual in June 2019. Clinical trial information: JapicCTI-194782. Contact Information: Jun Masuda, Toranomon Hospital, Tokyo, Japan, masu-j@toranomon.gr.jp
Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-07.