Local control of RCC pancreatic metastases is obtained by angiogenesis inhibitors.

BACKGROUND Metastatic clear-cell renal cell carcinoma (m-ccRCC) with pancreatic and/or thyroid metastases (PM/TM) is sensitive to vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Optimal first-line therapy for these patients (VEGFR-TKI-monotherapy, immune checkpoint inhibitor (ICPI) combinations (ipilimumab/nivolumab) or ICPI/VEGFR-TKI-combinations) remains unknown. MATERIALS AND METHODS We studied (A) the specific impact of axitinib and/or pembrolizumab dose reductions and treatment interruptions on response in patients treated with axitinib/pembrolizumab, (B) tumor shrinkage in individual PM upon VEGFR-TKIs and ICPIs, (C) the optimal first-line therapy in m-ccRCC patients with PM/TM in terms of tumor shrinkage, response rate (RR), time-to-progression (TTP) and cancer-specific-survival (CSS) and (D) explored molecular features of PM. RESULTS We describe 5 cases of m-ccRCC patients with PM, treated with first-line axitinib/pembrolizumab, in whom tumor response was clearly linked to axitinib administration and dose rather than pembrolizumab. In 119 individual PM, tumor shrinkage was the highest with ICPI/VEGFR-TKI-combinations followed by VEGFR-TKIs-monotherapy and lowest with ICPIs without VEGFR-TKIs (p < 0.0001). In 40 patients with PM/TM, median maximal tumor shrinkage was -54%, -39% and 0%, respectively (p = 0.04). RR was 83% with ICPI/VEGFR-TKI-combinations, 69% with VEGFR-TKI-monotherapy and 22% with ipilimumab/nivolumab (p = 0.01). Median TTP was not reached, 19 and 27 months, respectively (p = 0.07). Median CSS was not similarly impacted by first-line therapy. PM displayed high AXL-expression and higher infiltration by M2-like anti-inflammatory macrophages compared to other metastatic sites. CONCLUSION In m-ccRCC patients with PM/TM, first-line therapy with VEGFR-TKIs or ICPI/VEGFR-TKI-combinations leads to improved RR and tumor shrinkage, compared to ipilimumab/nivolumab, but not to CSS benefit in the current analysis. PM displayed high AXL-expression and higher infiltration by M2-like anti-inflammatory macrophages compared to other metastatic sites.