Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

By R. Motzer, N. Tannir, D. McDermott, O. A. Frontera, B. Melichar, T. Choueiri, E. Plimack, P. Barthélémy, C. Porta, S. George and 22 more. New England Journal of Medicine, 2018

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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.)

Subfields: Oncology, Pulmonary and Respiratory Medicine

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Charles Swanton

Citations in the corpus

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, background): “Recently, a large phase III study demonstrated that the combination of nivolumab and ipilimumab was superior to sunitinib in intermediate- and poor-risk patients, but not in good-risk patients [28].”
Renal cell carcinoma (2017, background): “Recently, a large phase III study demonstrated that the combination of nivolumab and ipilimumab was superior to sunitinib in intermediate- and poor-risk patients, but not in good-risk patients [28].”
Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence (2020, background): “In another trial, CheckMate-214, a phase 3 study, a combination of nivolumab and ipilimumab was compared against sunitinib (standard of therapy) for untreated intermediate- or poor-risk advanced RCC patients based on a better response rate and overall survival (OS) with the combination regimen; the ”
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic (2018, background): “advanced melanoma, non-small cell lung cancer (NSCLC), urothelial cancer (UC), renal cell carcinoma (RCC), and other cancer types [1-8].”
European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. (2019, background): “However, due to a paradigm change in first-line treatment for intermediate- and poor-risk patients shown in the CheckMate 214 study [62], the role and sequence of CN in the era of immunotherapy need to be reinvestigated.”