Abstract OT1-05-02: Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial
Authors: Li Huihui , Tan Qiaorui , Sun Shujuan , Zhou Dongdong , Yu Bo , Su Mu , Li Baojiang , Fang Shu , Qiang Ling , Ren Guohua , Bu Bing , Yin Sha , Man Xiaochu , Qiu Pengfei , Wang Xinzhao , Li Chao , Cao Fangli , Shao Qian , Han Dali , Song Lihua , Fan Bingjie , Zhang Baoxuan , Xu Liang , Zhao Xianguang , Liao Yuqian , Xie Xuemei , Liu Lanping 
Published: March 2023

Abstract
Background: Anti-PD-1 antibody combined with antiangiogenic drugs have demonstrated antitumor activity in advanced triple negative breast cancer (TNBC). Anlotinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has synergistic effect with anti-PD-1 antibody. Preclinical studies showed that metronomic chemotherapy inhibited angiogenesis and enhanced immunotherapy efficacy in TNBC via modulation of tumor immune microenvironment. We hereby conducted a single-arm, multicenter, phase II trial to investigate the efficacy and safety of sintilimab (anti-PD-1 antibody) in combination with anlotinib plus metronomic chemotherapy as a potential novel therapeutic strategy in advanced TNBC and explore potential biomarkers. Methods: Forty-three cases were planning to be included in this trial. The eligible patients who had received no more than two lines of chemotherapy for metastatic disease were enrolled and received sintilimab (200 mg iv q3w) in combination with anlotinib (12 mg po d1-14 q3w) plus capecitabine (500 mg po, tid) or vinorelbine (40 mg po, tiw) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR) and secondary endpoints are disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Blood samples collected at different time points of the baseline, first and second cycle post-treatment, and disease progression were used for next-generation sequencing of ctDNA containing 654 tumor-related genes. Results: As of July 2022, a total of 32 patients were enrolled, and 29 patients were evaluable for efficacy. 2 patients (6.9%) achieved complete response (CR). 6 patients (20.7%) achieved partial response (PR). The ORR is 27.6% (8/29) and DCR is 79.3% (23/29). The median PFS was not reached. The most common grade 1 or 2 adverse events (AEs) include elevated thyroid stimulating hormone (37.0%, 10/27), hand-foot syndrome (18.5%, 5/27), elevated aspartate aminotransferase (14.8%, 4/27), elevated bilirubin (11.1%, 3/27) and hypertension (11.1%, 3/27). Grade 3 AEs include elevated bilirubin (3.7%, 1/27) and hypertension (3.7%, 1/27). No grade 4 or 5 AEs occurred. By analyzing ctDNA mutations of blood samples in 10 patients at baseline, we found that genes with high mutation frequency were HLA-DRB5 (8/10, 80%), TP53 (7/10, 70%), HLA-DRB1 (5/10, 50%) and PIK3CA (4/10, 40%). Among these 10 patients, 2, 3 and 5 patients achieved PR, SD and PD, respectively. The number of gene mutations in patients with PD was higher than that in patients with PR or SD at baseline. This indicate that mutations in ctDNA may be associated with poor efficacy in advanced TNBC. But this still needs further verification. Dynamic analysis of gene mutations at different time points showed that the amplification of HLA-DRB5 or the elimination of KMT2D, RELN and TP53 occurred in patients with PR and SD, but not in patients with PD. Conclusions: Sintilimab in combination with anlotinib plus metronomic chemotherapy has shown favorable efficacy and acceptable safety profile in patients with advanced TNBC. The clinical significance of ctDNA dynamic monitoring needs further validation. Clinical trial information: ChiCTR2100044725
Citation Format: Huihui Li, Qiaorui Tan, Shujuan Sun, Dongdong Zhou, Bo Yu, Mu Su, Baojiang Li, Shu Fang, Ling Qiang, Guohua Ren, Bing Bu, Sha Yin, Xiaochu Man, Pengfei Qiu, Xinzhao Wang, Chao Li, Fangli Cao, Qian Shao, Dali Han, Lihua Song, Bingjie Fan, Baoxuan Zhang, Liang Xu, Xianguang Zhao, Yuqian Liao, Xuemei Xie, Lanping Liu. Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial [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 OT1-05-02.