Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were need in stage 1 (n=18) for the study to continue, and >19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-12.