Discussion
pembrolizumab, hypoxia, toxicities, reduced primary tumour, tumour
HYPOXIA, INFILTRATION, TUMOUR
In this study, 17 patients with locally advanced ccRCC received neoadjuvant treatment with sitravatinib plus nivolumab, and proceeded to nephrectomy with curative intent. Although the ORR of 11.8% did not meet the prespecified target of 30%, likely due to the short duration of neoadjuvant treatment, median DFS was not reached at data cut-off and the 24-month DFS probability was 88% (95% CI, 61–97). This result is comparable to the 24-month DFS probability of 77.3% (95% CI 72.8–81.1) observed in the KEYNOTE-564 phase 3 trial following a 12-month course of adjuvant pembrolizumab in patients with ccRCCIn Phase 2 trials in both locally advanced and metastatic ccRCC, neoadjuvant therapy has been associated with reduced primary tumour burden prior to surgeryResults from correlative assessments support modulation of the tumour microenvironment by sitravatinib via hypoxia and immunomodulation pathways; this modulation was further enriched with the combination of sitravatinib and nivolumab. Gene expression analyses showed that the angiogenesis biomarkers Increased CD8+ T cell infiltration and correspondingly low CD4/CD8 T cell ratio are associated with poor prognosis in ccRCCGSEA analysis showed that the In conclusion, this Phase 2 study demonstrated that short-term neoadjuvant sitravatinib plus nivolumab does not substantially increase ORR but may modulate the immune microenvironment and yield high DFS probabilities in locally advanced ccRCC. Despite the presence of qualifying toxicities leading to dose de-escalation after the first 7 patients enrolled, all patients regardless of starting dose of sitravatinib were able to safely proceed to surgery. Biomarker findings were consistent with the mechanism of action of sitravatinib, demonstrating that angiogenesis inhibition and anti-tumoural immunomodulation were the key pathways that were upregulated with sitravatinib and further augmented with combination treatment. These data demonstrate an immune response with sitravatinib that is supportive of its action in favourably modulating the TME.