Abstract PS3-01: Tislelizumab plus sitravatinib and nab-paclitaxel in patients with untreated locally recurrent or metastatic triple negative breast cancer (TNBC): updated efficacy and safety results

Abstract Background: The PD-(L)1 inhibitor-chemotherapy combination has established efficacy as first-line treatment for PD-L1 positive metastatic TNBC, but novel treatment regimens are still needed to improve the clinical outcomes for the whole population of TNBC in the first-line setting. Emerging evidence indicates that the combination of anti-angiogenic therapies and PD-(L)1 blockade may act synergistically, thereby potentiating enhanced antitumor activity. Sitravatinib (Sitra) is a spectrum-selective tyrosine kinase inhibitor that could potently inhibit split kinase receptors and TAM receptors. SPARK study was a multi-cohort, two-stage design, phase II trial (NCT04734262) to evaluate the efficacy and safety of tislelizumab (Tisle) plus Sitra, with or without nab-paclitaxel (nab-P), for locally recurrent or metastatic TNBC. We previously reported that the triplet combination of Tisle, Sitra and nab-P (cohort C) yielded encouraging anti-tumor activity in the first-line treatment setting (Lei Fan, et al. Cancer Res (2024) 84 (9_Supplement): PO1-06-12). Here, we report the updated results of this cohort. Methods: Eligible patients with untreated locally recurrent or metastatic TNBC were enrolled in the Tisle+Sitra+nab-P cohort to receive Tisle (200 mg, iv, day 1, Q3W) plus Sitra (70 mg, po, qd) and nab-P (100mg/m2, iv, days 1 and 8, Q3W) until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints were DCR, PFS, DOR, 1-year OS rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were required in stage 1 (n=18) to continue the study, and >19 responders were needed by the end of study (N=35) to demonstrate superiority with Tisle+Sitra+nab-P (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). The stage 1 criterion was met to complete the full enrollment. Results: Between September 9, 2022, and June 2, 2023, a total of 37 patients were enrolled, with a median age of 49 years. 15 (40.5%) patients had CD8+ disease defined as CD8 IHC staining ≥10%, 20 (54.1%) had CD8- disease, and the CD8 status was unavailable in 2 patients. After a median follow-up of 14.7 months (range: 2.8-20.1) (data cut-off: May 31, 2024), the Tisle+Sitra+nab-P cohort met its primary endpoint with 26 out of the first 35 efficacy-evaluable patients achieving objective response per RECIST v1.1. In the total of 37 efficacy-evaluable patients, the confirmed ORR was 75.7% (28/37; 95% CI: 58.8%-88.2%), including 7 CRs and 21 PRs. DCR was 97.3% (95% CI: 85.8%-99.9%). As of the data cut-off date, the median PFS was 10.3 months (95% CI 7.9-14.0). The median PFS was 12.9 months in patients with CD8+ disease, and 8.7 months in patients with CD8- disease. The median OS was not reached; 1-year OS rate was 90.5% (95% CI: 73.3%-96.9%). TRAEs occurred in 36 (97.3%) patients, of which 15 (40.5%) experienced grade ≥3 TRAEs. SAEs were reported in 11 (29.7%) patients. No new safety concerns were detected. Conclusions: The triplet combination of Tisle, Sitra, and nab-P demonstrated clinically meaningful ORR and PFS with acceptable safety profile as first-line treatment for patients with untreated locally recurrent or metastatic TNBC. Notably, patients with CD8+ expression achieved impressive PFS, indicating that CD8 status might be a biomarker for efficacy prediction. Continued follow-up is being conducted to assess long-term survival and safety. Citation Format: Xiyu Liu, Ying Xu, Xiuzhi Zhu, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Songyang Wu, Han Wang, Shen Zhao, Yi Xiao, Li Chen, Min He, Wei Zhu, Zhigang Zhuang, Fengyi Hou, Ayong Cao, Genhong Di, Jiong Wu, Keda Yu, Guangyu Liu, Xin Hu, , Yizhou Jiang, Zhonghua Wang, Lei Fan, Zhiming Shao. Tislelizumab plus sitravatinib and nab-paclitaxel in patients with untreated locally recurrent or metastatic triple negative breast cancer (TNBC): updated efficacy and safety results [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS3-01.