Robert J. Motzer, MD
As reported in The Lancet Oncology by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues, extended follow-up of the phase III CheckMate 214 trial has shown maintained survival benefit of first-line nivolumab/ipilimumab vs sunitinib among patients with previously untreated intermediate- or poor- risk advanced renal cell carcinoma.1 Benefits were also observed in the entire study population, and no new safety signals were observed.
Study Details
In the open-label trial, 1,096 patients from 175 sites in 28 countries with advanced or metastatic disease with a clear cell component were randomly assigned to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 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 International Metastatic Renal Cell Carcinoma Database Consortium intermediate- or poor-risk disease and 125 vs 124 had favorable-risk disease. The primary endpoints were overall survival, progression-free survival per independent radiology review committee, and objective response per independent radiology review committee using Response Evaluation Criteria in Solid Tumors version 1.1 in intermediate-risk or poor-risk patients.
In the previously reported (primary) analysis,2 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 months, hazard ratio [HR] = 0.63, P < .001) and the 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 analysis1 occurred at a minimum follow-up of 30 months and a median follow-up of 32.4 months, with data cutoff in August 2018.
Among patients with intermediate- or poor-risk disease, median overall survival was not reached in the nivolumab/ipilimumab group (95% confidence interval [CI] = 35.6 months to not estimable) vs 26.6 months (95% CI = 22.1–33.4 months) in the sunitinib group (HR = 0.66, P < .0001), and the objective response rate was 42% vs 29% (P = .0001). Overall survival rate at 30 months was 60% vs 47%. 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%.
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 to not estimable; HR = 0.71, P = .0003), and the investigator-assessed objective response rate was 41% vs 34% (P = .015). Overall survival rate at 30 months was 64% vs 56%. 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%.
Nivolumab Plus Ipilimumab vs Sunitinib
- With extended follow-up, overall survival remained significantly improved with nivolumab/ipilimumab vs sunitinib in patients with intermediate- or poor-risk renal cell carcinoma.
- Extended follow-up suggests a late benefit of nivolumab/ipilimumab in progression-free survival.
Among favorable-risk patients, median overall survival was not reached in either group (HR= 1.22, P = .44); overall survival rate 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%. The objective response rate was 39% vs 50% (P = .14).
In the intention-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 therapies were sunitinib (120, 22%), pazopanib (95, 17%), axitinib (86, 16%), and cabozantinib (61, 11%). In the sunitinib group, the most common therapies were nivolumab (192, 35%), axitinib (117, 21%), sunitinib (65, 12%), and everolimus (60, 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 adverse events were increased lipase (10%), increased amylase (6%), and increased alanine aminotransferase (ALT, 5%) in the nivolumab/ipilimumab group and hypertension (17%), fatigue (10%), and palmar-plantar erythrodysesthesia (9%) in the sunitinib group. More grade 3 or 4 treatment-related adverse events occurred during combination treatment vs nivolumab maintenance in the nivolumab/ipilimumab group. Treatment-related adverse events led to study drug discontinuation in 22% vs 12% of patients, with the most common causes in the nivolumab/ipilimumab group being increased ALT (3%), diarrhea (3%), and increased aspartate aminotransferase, and the most common causes in the sunitinib group being fatigue (1%), increased ALT (1%), diarrhea (1%), pancreatitis (1%), and thrombocytopenia (1%).
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 at least 40 mg of prednisone or its equivalent daily for potentially immune-related adverse events, with 19% receiving treatment for at least 2 weeks and 10% for at least 30 days.
No additional treatment-related deaths were observed since the primary analysis. Death was considered related to treatment in eight patients in the nivolumab/ipilimumab group (due to pneumonitis, pneumonia and aplastic anemia, immune-mediated bronchitis, lower gastrointestinal hemorrhage, hemophagocytic syndrome, sudden death, liver toxic effects, and lung infection) and four patients in the sunitinib group (due to cardiac arrest in two patients, heart failure, and multiple organ failure).
The investigators concluded: “The results suggest that the superior efficacy of nivolumab plus 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 plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.”
The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. ■
DISCLOSURE: Dr. Motzer has served as a consultant or advisor for Eisai, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, and Pfizer; and has received institutional research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, Novartis, and Pfizer. For disclosures of the other study authors, visit www.thelancet.com.
REFERENCES
2. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab vs sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.
