Treatment of Advanced Renal-Cell Carcinoma.

To the Editor: In their article on the CheckMate 025 trial, Motzer and colleagues (Nov. 5 issue)1 report that nivolumab, as compared with everolimus, prolonged survival among patients with previously treated advanced renal-cell carcinoma. This trial opens the era of checkpoint inhibitors in renal-cell carcinoma and could help determine the most effective treatment sequence. Sunitinib and pazopanib are multitargeted tyrosine kinase inhibitors and first-line options that have similar efficacy.2 However, with nivolumab as second-line treatment, they may not be equivalent. Indeed, the mechanism of efficacy of tyrosine kinase inhibitors in renal-cell carcinoma is still largely unknown and may not rely only on the action on endothelial cells through the inhibition of vascular endothelial growth factor receptor. Sunitinib was shown to have direct antitumor effects and to exacerbate intratumoral heterogeneity in renalcell carcinoma,3 results that may be interesting since immunotherapies may work best in tumors with a high mutational burden.4 Furthermore, sunitinib has an immune effect that could have a positive or negative influence on the efficacy of nivolumab.5 Those effects could change the guidelines for the choice of first-line treatment. We wonder whether the authors would discuss the efficacy of nivolumab as a second-line treatment after the failure of sunitinib or pazopanib.