Abstract P1-12-08: Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer: WJOG11418BTR NEWFLAME_TR

Background Previously, we reported the clinical outcomes of the combination of anti-PD-1 Ab, cyclin-dependent kinase 4/6 inhibitors, and endocrine therapy (ET) in patients with ER positive/HER2 negative advanced breast cancer in SABCS2020; biomarker analysis has been performed to provide insight into the hepatotoxicy frequently observed in the study. Methods Subjects received 240 mg nivolumab IV on days 1 and 15, 150 mg abemaciclib PO twice daily, and either 500 mg fulvestrant (FUL) on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg letrozole (LET) once daily (LET cohort). The primary endpoint was objective response rate and secondary endpoints included toxicity evaluated in the CTCAE along with an exploratory endpoint as related to the biomarker analysis. Archival tumor tissues were collected before study entry and blood and stool samples were collected at baseline and on cycle3 day1. Tumor tissues were subjected to IHC analysis and RNA sequencing followed by subtyping using NGS. High throughput cytokine analysis using ELISA-based assay were performed with serum samples and cell sorting analysis of PBMC was performed with FACS. Results From June 2019 to December 2019, 17 subjects were enrolled (FUL cohort [n = 12], LET cohort [n = 5]). The study was prematurely closed due to safety concerns such as hepatotoxicity and interstitial lung disease. AEs ≥ Grade 3 were observed in 91.7% and 100% of patients 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%). Serum cytokine analysis from the subjects with severe hepatotoxicity indicated cytokine storm with elevations of sCD30/TNFRSF8, IL-11, -34, Pentraxin-3, sTNF-R1, -R2, TSLP, which was supported by the findings of reduction of effector regulatory T cells in PBMC. IHC study in liver biopsy from three subjects with the toxicity revealed infiltration of CD8+ T cells and FOXP3+ T reg into the liver, suggesting the immune related liver injury upon the treatment with nivolumab and abemaciclib. HLA typing was performed in the 17 patients but no association between HLA type and ILD or hepatotoxicity were observed. Conclusions The frequent and severe immune related hepatotoxicity induced by the combination of anti-DD-1 and CDK 4/6 inhibitors might have been an immune-boosting therapy as suggested in the preclinical studies. This study was supported by the Ono Pharmaceutical Co., LTD. The registration number of the study is UMIN000036970. Citation Format: Junji Tsurutani, Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K. Imamura, Sakiko Miura, Toshiko Yamochi, Kenichi Yoshimura, Toshimi Takano, Hidetaka Kawabata. Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer: WJOG11418BTR NEWFLAME_TR [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-08.