Sitravatinib plus tislelizumab in locally recurrent or metastatic triple-negative breast cancer: a multi-cohort, single-arm, phase II clinical trial (SPARK Trial)

While immunotherapy-chemotherapy combinations are approved for programmed death-ligand 1 (PD-L1)-positive advanced triple-negative breast cancer (TNBC), the therapeutic potential of sitravatinib-enhanced immunotherapy remains unexplored. This multi-cohort, single-arm study enrolled 67 patients with locally recurrent/metastatic TNBC. Cohorts A (n = 21) and B (n = 40) received sitravatinib 70 mg or 100 mg once daily plus tislelizumab, with 38/67 participants having ≥ 1 prior systemic therapy. The primary endpoint was confirmed objective response rate (ORR); secondary endpoints included median progression-free survival (PFS) and safety. Multi-omics analyses including single-cell sequencing and genomic profiling were performed on tumor samples to identify biomarkers linked to treatment response. Confirmed ORR was 38.1% (8/21) in Cohort A and 50.0% (20/40) in Cohort B. Median PFS was 8.2 months (Cohort A) and 5.4 months (Cohort B). Notably, 95.3% (41/43) of previously treated patients had PD-L1 combined positive score (CPS) < 10. No grade 4/5 treatment-related adverse events occurred. Biomarker analysis revealed Th17 cell infiltration and TYRO3/AXL/MERTK (TAM) pathway activation correlated with response, while FAM47C mutations and LSM1+ cancer-associated fibroblasts were enriched in non-responders. Post-treatment TP53 mutation clearance and increased CD8+ T cell proportions predicted improved outcomes. Sitravatinib plus tislelizumab demonstrates promising efficacy and safety as a chemo-free regimen for metastatic TNBC, including PD-L1-negative tumors. Biomarkers such as Th17 cell infiltration, TAM signaling, and TP53 mutation dynamics may guide patient selection. These findings support further validation of this combination in PD-L1-negative TNBC and highlight the role of multi-omics in optimizing immunotherapy strategies. ClinicalTrials.gov, NCT04734262.