This was a randomized, open-label, phase 3 trial of nivolumab plus ipilimumab followed by nivolumab monotherapy versus sunitinib monotherapy. Randomization (in a 1:1 ratio) was performed with a block size of 4 with stratification according to IMDC risk score (0 vs. 1 or 2 vs. 3 to 6) and geographic region (United States vs. Canada and Europe vs. the rest of the world).
Nivolumab and ipilimumab were administered intravenously at a dose of 3 mg per kilogram over a period of 60 minutes and 1 mg per kilogram over a period of 30 minutes, respectively, every 3 weeks for four doses (induction phase), followed by nivolumab monotherapy at a dose of 3 mg per kilogram every 2 weeks (maintenance phase). Sunitinib was administered at a dose of 50 mg orally once daily for 4 weeks of each 6-week cycle. No dose reductions were allowed for nivolumab or ipilimumab. Dose delays for adverse events were permitted in both groups. Patients treated with nivolumab plus ipilimumab had to discontinue both nivolumab and ipilimumab if they had a treatment-related adverse event during the induction phase that required discontinuation, and they could not continue on to nivolumab maintenance therapy. Detailed discontinuation criteria are shown in theSupplementary Appendix , available with the full text of this article at NEJM.org .
A November 2017 protocol amendment, after the primary end point had been met, permitted crossover from the sunitinib group to the nivolumab-plus-ipilimumab group. Nivolumab, ipilimumab, and sunitinib were provided by the sponsors, except when sunitinib was procured as a local commercial product in certain countries.
Nivolumab and ipilimumab were administered intravenously at a dose of 3 mg per kilogram over a period of 60 minutes and 1 mg per kilogram over a period of 30 minutes, respectively, every 3 weeks for four doses (induction phase), followed by nivolumab monotherapy at a dose of 3 mg per kilogram every 2 weeks (maintenance phase). Sunitinib was administered at a dose of 50 mg orally once daily for 4 weeks of each 6-week cycle. No dose reductions were allowed for nivolumab or ipilimumab. Dose delays for adverse events were permitted in both groups. Patients treated with nivolumab plus ipilimumab had to discontinue both nivolumab and ipilimumab if they had a treatment-related adverse event during the induction phase that required discontinuation, and they could not continue on to nivolumab maintenance therapy. Detailed discontinuation criteria are shown in the
A November 2017 protocol amendment, after the primary end point had been met, permitted crossover from the sunitinib group to the nivolumab-plus-ipilimumab group. Nivolumab, ipilimumab, and sunitinib were provided by the sponsors, except when sunitinib was procured as a local commercial product in certain countries.
