Spatial transcriptomics tumor microenvironment determinants of tyrosine kinase inhibitor response in renal cell carcinoma: results from a phase 2 clinical trial.
Elshad Hasanov, Mostafa I H Ali, Shriya Deshmukh et al.
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In 30 seconds
This phase 2 clinical trial examined whether spatially resolved tumor gene-expression patterns were associated with sunitinib response in 46 patients with metastatic clear cell renal cell carcinoma. Median time-to-progression was 8.2 months (95% CI: 6.1-19.3), and overall survival was 36.3 months (95% CI: 19.7-70.5). Responders had more pro-inflammatory and immunostimulatory tumor-microenvironment programs; non-responders showed immunosuppressive features, including elevated myeloid-cell PD-L1 and exhausted CD8+ T-cell signatures. Spatial-profiling models performed well in an external sunitinib-treated cohort, but less well with avelumab plus axitinib, suggesting treatment-context specificity.
Key findings
- Among 46 trial patients, median time-to-progression was 8.2 months (95% CI: 6.1-19.3) and overall survival was 36.3 months (95% CI: 19.7-70.5).
- Responders showed pro-inflammatory and immunostimulatory programs, whereas non-responders had immunosuppressive programs, elevated myeloid-cell PD-L1, and exhausted CD8+ T-cell signatures.
- Spatial profiling identified potential resistance mechanisms involving SPP1-associated myeloid programs and VEGF-dependent and independent angiogenic pathways.
- Models performed well in an external sunitinib-treated cohort but less well in the avelumab-plus-axitinib cohort.
Why it matters
The findings link distinct tumor-microenvironment states with sunitinib response and suggest that immune regulation and angiogenic signaling may help explain treatment heterogeneity in metastatic ccRCC. The weaker model performance in a different treatment cohort also underscores that biomarker performance may depend on the therapy being evaluated, rather than generalizing across regimens.
What to keep in mind
The trial included 46 patients, and the abstract does not report prospective validation of the spatial biomarkers as treatment-selection tools.