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Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in
Song-Yang Wu1,2, Ying Xu1,2, Li Chen1,2
1Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Background:
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
Methods:
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
Results:
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
Conclusion:
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
Trial Registration:
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
Insights
Identifying immunomodulatory triple-negative breast cancer (TNBC) patients using CD8 and PD-L1 positivity improves immunotherapy outcomes. A combination regimen of famitinib, camrelizumab, and chemotherapy showed high efficacy and safety in advanced TNBC.
Area of Science:
- Oncology
- Immunotherapy
- Breast Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) show efficacy in triple-negative breast cancer (TNBC), but only benefit a subset of patients.
- There is a critical need to identify patient subpopulations responsive to immunotherapy and explore combination strategies for TNBC.
- Investigating novel patient selection methods and actionable targets is crucial for optimizing TNBC immunotherapy.
Purpose of the Study:
- To identify patient subpopulations in TNBC likely to benefit from immunotherapy.
- To explore actionable targets for combination regimens in TNBC immunotherapy.
- To assess the clinical value of a novel patient selection method and combination therapy in advanced TNBC.
Main Methods:
- Exploratory analyses in the FUSCC cohort to characterize patient selection criteria and targets for TNBC immunotherapy.
- In vivo investigation followed by a phase 2 clinical trial (FUTURE-C-Plus) of a combination regimen.
- Collection of clinicopathological and next-generation sequencing data to identify biomarkers for patient outcomes.
Main Results:
- CD8-positivity identified an immunomodulatory TNBC subpopulation with higher potential to benefit from immunotherapy.
- Angiogenesis was identified as an actionable target to enhance checkpoint blockade efficacy.
- The triplet regimen (famitinib, camrelizumab, chemotherapy) in 48 advanced TNBC patients yielded an 81.3% objective response rate and 13.6-month median progression-free survival, with no treatment-related deaths. Patients with CD8- and/or PD-L1-positive tumors showed better outcomes. PKD1 somatic mutation correlated with worse survival.
Conclusions:
- The study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC.
- Combining CD8, PD-L1 status, and somatic mutation data can guide clinical decision-making and treatment strategies for TNBC.
- This approach holds potential for improving patient selection and treatment outcomes in TNBC immunotherapy.
