As reported in The Lancet Oncology by Robert J. Motzer, MD, and colleagues, extended follow-up of the phase III CheckMate 214 trial has shown a maintained survival benefit for first-line nivolumab/ipilimumab vs sunitinib in patients with previously untreated intermediate- or poor-risk advanced renal cell carcinoma (RCC). Benefits were also observed in the entire study population, and no new safety signals were observed.

Robert J. Motzer, MD

Study Details

The open-label trial included 1,096 patients from 175 sites in 28 countries with advanced or metastatic RCC with a clear-cell component. Patients were randomly assigned to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses followed by nivolumab (3 mg/kg) every 2 weeks (n = 550) or sunitinib (50 mg once daily) for 4 weeks in 6-week cycles (n = 546). Among these patients, 425 vs 422 had intermediate- or poor-risk disease (as defined by the International Metastatic Renal Cell Carcinoma Database Consortium) and 125 vs 124 had favorable-risk disease.

The primary endpoints were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective response per IRRC using Response Evaluation Criteria in Solid Tumors, version 1.1, in intermediate-risk or poor-risk patients.

In the previously reported primary analysis, performed at a prespecified interim analysis with a minimum follow-up of 17.5 months, nivolumab/ipilimumab was associated with significantly improved overall survival (median = not reached vs 26.0 months, hazard ratio [HR] = 0.63, P < .001) and objective response rate (42% vs 27%, P < .001), with a numeric benefit in progression-free survival that did not meet the designated α level (P < .009) for statistical significance (median = 11.6 vs 8.4 months, HR = 0.82, P = .03).

Findings in Extended Analysis

The current extended analysis occurred at a minimum follow-up of 30 months and median follow-up of 32.4 months, with a data cutoff in August 2018. Among patients with intermediate- or poor-risk disease, median overall survival was not reached in the arm treated with nivolumab/ipilimumab (95% confidence interval [CI] = 35.6 months–not estimable) vs 26.6 months (95% CI = 22.1–33.4 months) in the arm treated with sunitinib (HR = 0.66, P < .0001).

Median progression-free survival was 8.2 vs 8.3 months (HR = 0.77, P = .0014); the progression-free survival curves for the two treatment groups began to separate after approximately 9 months, with estimated 30-month progression-free survival being 28% vs 18%. Objective response rates were 42% vs 29% (P = .0001). Overall survival at 30 months was 60% vs 47%.

In the intent-to-treat population, median overall survival was not reached (95% CI = not estimable) vs 37.9 months (95% CI = 32.2 months–not estimable; HR = 0.71, P = .0003). Investigator-assessed median progression-free survival was 9.7 vs 9.7 months (HR = 0.85, P = .027); the progression-free survival curves for the two groups began to separate after 12 months, with estimated 30-month progression-free survival being 28% vs 18%. Investigator-assessed objective response rates were 41% vs 34% (P = .015). Overall survival at 30 months was 64% vs 56%.

Among favorable-risk patients, median overall survival was not reached in either group (HR= 1.22, P = .44); overall survival at 30 months was 80% vs 85%. Investigator-assessed median progression-free survival was 13.9 vs 19.9 months (HR = 1.23, P = .19), with 30-month rates of 29% vs 35%. Objective response rates were 39% vs 50% (P = .14).

In the intent-to-treat population, 264 patients in the nivolumab/ipilimumab group (48%) and 334 patients in the sunitinib group (61%) received subsequent systemic therapies. In the nivolumab/ipilimumab group, the most common were sunitinib (22% of patients), pazopanib (17%), axitinib (16%), and cabozantinib (11%). In the sunitinib group, the most common were nivolumab (35%), axitinib (21%), sunitinib (12%), and everolimus (11%).

Adverse Events

No new safety signals for study treatments were identified during extended follow-up. Among all patients, treatment-related grade 3 or 4 adverse events occurred in 47% of patients treated with nivolumab/ipilimumab vs 64% of patients treated with sunitinib; the most common were increased lipase (10%), increased amylase (6%), and increased alanine aminotransferase (5%) in the nivolumab/ipilimumab group and hypertension (17%), fatigue (10%), and palmar-plantar erythrodysesthesia (9%) in the sunitinib group.

Treatment-related adverse events led to study drug discontinuation in 22% vs 12% of patients. Potentially immune-related adverse events of any grade occurred in 81% vs 83% of patients within 30 days of the last dose of study drug. Among patients in the nivolumab/ipilimumab group, 29% received ≥ 40 mg of prednisone or equivalent daily for potentially immune-related adverse events, with 19% receiving treatment for  2 weeks or more and 10% for 30 days or more.

No additional treatment-related deaths were observed since the primary analysis. Death was considered treatment-related in eight patients in the nivolumab/ipilimumab group and four patients in the sunitinib group.

The investigators concluded, “The results suggest that the superior efficacy of nivolumab/ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab/ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.”

Robert J. Motzer, MD, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol-Myers Squibb and ONO Pharmaceutical. For full disclosures of the study authors, visit thelancet.com.