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Background <p>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.</p> Methods <p>This multi-cohort, single-arm study enrolled 67 patients with locally recurrent/metastatic TNBC. Cohorts A (<i>n</i> = 21) and B (<i>n</i> = 40) received sitravatinib 70&#xa0;mg or 100&#xa0;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.</p> Results <p>Confirmed ORR was 38.1% (8/21) in Cohort A and 50.0% (20/40) in Cohort B. Median PFS was 8.2&#xa0;months (Cohort A) and 5.4&#xa0;months (Cohort B). Notably, 95.3% (41/43) of previously treated patients had PD-L1 combined positive score (CPS) &lt; 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 <i>FAM47C</i> mutations and LSM1<sup>+</sup> cancer-associated fibroblasts were enriched in non-responders. Post-treatment <i>TP53</i> mutation clearance and increased CD8<sup>+</sup> T cell proportions predicted improved outcomes.</p> Conclusions <p>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 <i>TP53</i> 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.</p> Trial registration <p>ClinicalTrials.gov, NCT04734262.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Xi-Yu Liu,
  • Xin-Yi Sui,
  • Ying Xu,
  • Fan Yang,
  • Song-Yang Wu,
  • Xiu-Zhi Zhu,
  • Ke Zuo,
  • Shuo-Wen Cao,
  • Xi Jin,
  • Li Chen,
  • Lin-Xiaoxi Ma,
  • Wen-Juan Zhang,
  • Fu-Gui Ye,
  • Fei-Lin Qu,
  • Ding Ma,
  • Yi Xiao,
  • Gen-Hong Di,
  • Guang-Yu Liu,
  • Ke-Da Yu,
  • Jiong Wu,
  • Xin Hu,
  • Yi-Zhou Jiang,
  • Zhong-Hua Wang,
  • Zhi-Ming Shao,
  • Lei Fan

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov, NCT04734262.