Abstract PS12-10: Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR+, HER2- metastatic breast cancer: WJOG11418B NEWFLAME trial
Authors: Masuda Jun , Tsurutani Junji , Masuda Norikazu , Tanabe Yuko , Iwasa Tsutomu , Takahashi Masato , Futamura Manabu , Matsumoto Koji , Aogi Kenjiro , Iwata Hiroji , Hosonaga Mari , Mukohara Toru , Yoshimura Kenichi , Takano Toshimi 
Published: February 2021

Abstract
Background: Currently, the standard immunotherapy treatment for anti-programmed death-ligand 1 (PD-L1)-positive triple-negative breast cancer is a combination of PD-L1 antibody and nab-paclitaxel. PD-1/PD-L1 antibody was investigated as a treatment for hormone receptor positive (HR+) breast cancer; however, the efficacy of single agents is poor. In pre-clinical studies, anti-PD-1/PD-L1 antibody, CDK4/6 inhibitors, and endocrine therapy (ET) have synergistic effects. We initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib, and ET (fulvestrant [FUL] or letrozole [LET]) as a first- or second-line treatment for patients (pts) with HR+, human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). Methods: This multicenter, multi-cohort, nonrandomized, open-label phase II study evaluated the efficacy and safety of nivolumab, abemaciclib, and ET (FUL or LET) in pts with HR+, HER2- MBC. Key eligibility criteria for the FUL cohort were: HR+, HER2- MBC with ECOG PS ≤ 1; measurable disease; no more than one ET; no prior chemotherapy for MBC; and had exhibited disease progression while receiving ET, adjuvant ET, or ≤ 12 months after adjuvant ET. Key eligibility criteria for the LET cohort were: postmenopausal HR+, HER2- MBC with ECOG PS ≤ 1; measurable disease; and no prior systemic therapy. ET as an adjuvant was permitted if the patient had a disease-free interval &gt; 12 months after the completion of ET. Patients received 240 mg nivolumab on days 1 and 15, 150 mg abemaciclib twice daily, and either 500 mg FUL on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg LET once daily (LET cohort) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Key secondary endpoints included toxicity, disease control rate (DCR: CR+PR+SD), progression-free survival (PFS), and the overall survival (OS). The threshold and expected ORR of the FUL cohort were 45% and 60%, respectively; and 32 pts would ensure a statistical power of 80% (α = 0.20). The threshold and expected ORR of the LET cohort were 55% and 75%, respectively; and 16 pts would ensure a statistical power of 80% (α = 0.20). Results: Between June and December 2019, 17 pts were enrolled (FUL cohort: n = 12, LET cohort: n = 5). One patient in the FUL cohort was excluded due to prior treatment history. Enrollment was closed and combination treatment was discontinued mid-study due to safety concerns. All pts had ≥ 1 adverse event (AE). AEs ≥ Grade 3 were observed in 91.7% and 100% of pts in the FUL and LET cohorts, respectively. Immune-related AEs ≥ Grade 3 were observed in 66.7% and 60.0% of pts in the FUL and LET cohorts, respectively. The most frequent AEs ≥ Grade 3 were elevated liver function tests (LFT; FUL cohort: 50.0%, LET cohort: 60.0%). Immune-related (elevated LFT) AEs ≥ Grade 3 were observed in 50.0% and 40.0% of pts in the FUL and LET cohorts, respectively. Severe AEs (SAEs) were observed in 50.0% and 60.0% of pts in the FUL and LET cohorts, respectively. One treatment-related patient death occurred in the LET cohort due to interstitial lung disease (ILD). ORR was 54.5% (6/11) and 20% (1/5) in the FUL and LET cohorts, respectively. DCR was 90.9% (10/11) in the FUL cohort and 80.0% (4/5) in the LET cohort. Due to the discontinuation, PFS and OS were undetermined. Conclusions: Although nivolumab + abemaciclib + FUL appeared to have activity, our findings do not support further investigation of this combination therapy due to toxicity. Toxicity profiles vary with CDK4/6 inhibitors; therefore, a different inhibitor may improve tolerability. Results of the ongoing nivolumab, palbociclib, and ET trial are awaited (CheckMate 7A8, NCT04075604). Clinical trial information: JapicCTI-194782.
Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kenichi Yoshimura, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR+, HER2- metastatic breast cancer: WJOG11418B NEWFLAME trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-10.