Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Abstract

BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options

“…Recently, therapy options with cabozantinib or immune checkpoint inhibitors such as nivolumab alone or in combination with ipilimumab have shown an OS advantage in 2nd and 1st line therapy of ccRCC versus sorafenib [8] or sunitib [9]. Checkpoint inhibitors might be a new and very interesting option for metastatic nccRCC for which the therapeutic options are limited.…”

Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

“…4 Nivolumab was identified as improving overall survival (OS), in contrast to everolimus (hazard ratio [HR], 0.73; P = .002). 5 In patients with intermediate-risk or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the median OS in the combination IO arm was not reached (NR) versus 26.0 months in the sunitinib arm (HR, 0.63; P<.001). 5 In patients with intermediate-risk or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the median OS in the combination IO arm was not reached (NR) versus 26.0 months in the sunitinib arm (HR, 0.63; P<.001).…”

Adjuvant therapy in renal cell carcinoma

“…39,40 ADJUVANT TRIALS WITH IMMUNE CHECKPOINT INHIBITORS The immune system can recognize mutated proteins called neoantigens, which are expressed on the surface of tumor cells to mount an antitumor response. 42 The ability of ICIs to maintain antitumor efficacy even after their discontinuation generated interest in evaluating ICIs in the adjuvant setting. PD-1 and PDL-1 checkpoint inhibitors selectively block the interaction between the PD-1 expressed on T cells and the PD L-1 expressed on tumor cells and may restore effective antitumor immunity (Fig.…”

“…However, with further prospective validation, these genomic signatures may be used to identify high-risk patients for inclusion in future clinical trials ( Table 2). In an external validation cohort of more than 600 patients, the continuous recurrence score (median, 37; interquartile range, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] was associated significantly with recurrence-free interval (hazard ratio [HR], 3.91 [95% CI, 2.63-5.79] for a 25-unit increase in score; P < .0001). In an external validation cohort of more than 600 patients, the continuous recurrence score (median, 37; interquartile range, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] was associated significantly with recurrence-free interval (hazard ratio [HR], 3.91 [95% CI, 2.63-5.79] for a 25-unit increase in score; P < .0001).…”