Sunitinib (VEGFR TKI) Response in mccRCC Tracks with Pro-inflammatory TME; DSP Signature Predicts Benefit

Sunitinib is an oral VEGFR/PDGFR/KIT tyrosine kinase inhibitor; in this Phase 2 single-arm trial in metastatic clear cell RCC treated peri-cytoreductive nephrectomy (NCT00715442), 46 patients underwent spatial whole-transcriptome digital spatial profiling (DSP) across tumor, myeloid, endothelial, and CD8+ T-cell compartments. With long follow-up (median 9.8 years), median time-to-progression was 8.2 months and median OS was 36.3 months—broadly in the historical first-line sunitinib range for PFS (8–11 months) and OS (26 months), noting this trial reports TTP rather than PFS and reflects an older pre–IO/TKI era. Grade 3–4 sunitinib toxicities included hand–foot syndrome, fatigue, and hematologic AEs; responders showed enriched pro-inflammatory/immunostimulatory programs, while non-responders had immunosuppressive programs including higher PD-L1 in myeloid cells, exhausted CD8 signatures, and pro-angiogenic VEGF-dependent/independent resistance pathways; a DSP-derived gene signature reportedly predicted response in an external cohort.