Abstract P3-09-07: A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 trial)
Authors: Takada Masahiro , Yoshimura Michio , Kawaguchi Kosuke , Kotake Takeshi , Uozumi Ryuji , Kataoka Masako , Koyama Takahiko , Kato Hironori , Yoshibayashi Hiroshi , Suwa Hirofumi , Tsuji Wakako , Yamashiro Hiroyasu , Kataoka Tatsuki , Ishiguro Hiroshi , Tokumasu Reitaro , Honda Maya , Yamashita Rikiya , Yonezawa Atsushi , Himoto Yuki , Onishi Natsuko , Parida Laxmi , Morita Satoshi , Toi Masakazu 
Published: March 2020

Abstract
BACKGROUND: In metastatic breast cancer, Overall Response Rate (ORR) for checkpoint inhibitor monotherapy has been limited. Since Radiation Therapy (RT) stimulates anti-cancer immune responses, we evaluated safety and efficacy of a combinatorial therapy of RT with Nivolumab (a Programmed cell death protein 1 (PD-1) inhibitor) on HER2-negative metastatic breast cancer patients in a multicenter and non-randomized phase Ib/II study. PATIENTS AND METHODS: Patients with HER2-negative breast cancer, measurable metastasis (RECIST1.1) and at least one bone metastasis requiring radiation therapy were enrolled. The patients were divided into two cohorts, A and B. Cohort A constitutes estrogen and/or progesterone receptor-positive breast cancer patients that had 1 or 2 lines of endocrine therapy for the metastatic disease. Cohort B constitutes triple negative breast cancer patients that had two or more lines of chemotherapy for metastatic disease and anthracycline and taxane treatment for any disease setting. Single fraction RT of 8 Gy was delivered on day 0. Patients received 3 mg/kg Nivolumab intravenously every 2 weeks from day 1 until the disease progressed. Combined use of endocrine therapy of the physician’s choice was allowed in Cohort A. Primary endpoints were safety and ORR (RECIST1.1) in phase Ib and phase II, respectively. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR) and Progression-Free Survival (PFS). For translational research, we integrated time series multi-omics data that are correlated with Tumor Immune Microenvironment (TIME) to identify novel drug sensitivity-associated signatures using machine learning method. The multi-omics data included data from RNAseq, DNAseq, mass cytometry (CyTOF), multiple cytokines, human leukocyte antigen, radiomics, drug concentrations, tuberculin reaction using Peripheral Blood Mononuclear Cells (PBMCs), serum, plasma, imaging and Formalin-Fixed Paraffin-Embedded (FFPE) samples. RESULTS: 31 patients were enrolled from Jan 2017 to Nov 2018 and 29 patients (18 in Cohort A and 11 in Cohort B) were included in the full analysis set. While seven patients in Cohort A had received 1 or 2 lines of chemotherapy earlier for the metastatic disease, eight patients in Cohort B received three or more lines of chemotherapy. Dose limiting toxicities were not observed in phase Ib. In Cohort A, the ORR was 11.1% (90% with a Confidence Interval (CI) of 3.7-28.6). The best overall responses were: Partial Response (PR) in 2 patients (11.1%), Stable Disease (SD) in 11 patients (61.1%) and Progressive Disease (PD) in 5 patients (27.8%). In Cohort B, ORR was 0% as none of the patients responded to the treatment. The best overall responses were: SD in 4 patients (36.4%), PD in 6 patients (54.5%) and one patient (9.1%) was not evaluated (NE). While the DCR for Cohorts A and B were 72.2% (90% CI: 52.9-85.8) and 36.4% (90% CI: 17.5-60.6), respectively, the median PFS were 4 months (95% CI: 2.1-5.5 months) and 2 months (95% CI: 1.2-4.0 months), respectively. Common toxicities were mild; including 3 patients in Cohort A (16.7%) and 2 patients in Cohort B (18.2%) that experienced grade 3 or 4 toxicity. There were no deaths due to adverse effects. Furthermore, our integrated analysis identified novel candidates for drug sensitivity-associated signatures. CONCLUSIONS: The combination of RT and Nivolumab had a manageable safety profile and demonstrated clinically significant disease control outside the RT fields. Periodic abscopal response data and multi-omics data are also presented. (UMIN: UMIN000026046; ClinicalTrials.gov: NCT03430479).
Citation Format: Masahiro Takada, Michio Yoshimura, Kosuke Kawaguchi, Takeshi Kotake, Ryuji Uozumi, Masako Kataoka, Takahiko Koyama, Hironori Kato, Hiroshi Yoshibayashi, Hirofumi Suwa, Wakako Tsuji, Hiroyasu Yamashiro, Tatsuki Kataoka, Hiroshi Ishiguro, Reitaro Tokumasu, Maya Honda, Rikiya Yamashita, Atsushi Yonezawa, Yuki Himoto, Natsuko Onishi, Laxmi Parida, Satoshi Morita, Masakazu Toi. A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 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 P3-09-07.