This was a multicenter, randomized, open-label, phase 3 trial comparing avelumab plus axitinib with sunitinib. Randomization (in a 1:1 ratio) was stratified according to ECOG performance-status score (0 vs. 1) and geographic region (United States vs. Canada and Western Europe vs. the rest of the world).
Avelumab was administered at a dose of 10 mg per kilogram of body weight as a 1-hour intravenous infusion every 2 weeks. An antihistamine and acetaminophen were administered approximately 30 to 60 minutes before each infusion. Axitinib was administered orally at a starting dose of 5 mg twice daily on a continuous dosing schedule. Sunitinib was administered at a dose of 50 mg orally once daily for 4 weeks of a 6-week cycle. Dose escalations and reductions of axitinib and dose reductions of sunitinib are described in the protocol (available at NEJM. org).17 ,18 Dose reductions of avelumab were not permitted, but subsequent infusions could be omitted in response to persisting toxic effects. The original primary objective was to show the superiority of avelumab plus axitinib over sunitinib in prolonging progression-free survival among patients with advanced renal-cell carcinoma, irrespective of PD-L1 expression. A June 2017 protocol amendment, while data were still masked, was based on new data from a single-group phase 1b trial14 (link) and two trials of immune checkpoint inhibitors that showed an overall survival benefit among patients with renal-cell carcinoma.5 (link),6 (link) This amendment changed the primary objective of the trial to show the superiority of avelumab plus axitinib over sunitinib with respect to either progression-free or overall survival among patients with PD-L1–positive tumors.
Avelumab was administered at a dose of 10 mg per kilogram of body weight as a 1-hour intravenous infusion every 2 weeks. An antihistamine and acetaminophen were administered approximately 30 to 60 minutes before each infusion. Axitinib was administered orally at a starting dose of 5 mg twice daily on a continuous dosing schedule. Sunitinib was administered at a dose of 50 mg orally once daily for 4 weeks of a 6-week cycle. Dose escalations and reductions of axitinib and dose reductions of sunitinib are described in the protocol (available at NEJM. org).17 ,18 Dose reductions of avelumab were not permitted, but subsequent infusions could be omitted in response to persisting toxic effects. The original primary objective was to show the superiority of avelumab plus axitinib over sunitinib in prolonging progression-free survival among patients with advanced renal-cell carcinoma, irrespective of PD-L1 expression. A June 2017 protocol amendment, while data were still masked, was based on new data from a single-group phase 1b trial14 (link) and two trials of immune checkpoint inhibitors that showed an overall survival benefit among patients with renal-cell carcinoma.5 (link),6 (link) This amendment changed the primary objective of the trial to show the superiority of avelumab plus axitinib over sunitinib with respect to either progression-free or overall survival among patients with PD-L1–positive tumors.
