Nivolumab Plus Ipilimumab versus Sunitinib in First-Line Treatment for Advanced or Metastatic RCC.
Bernard Escudier, Institut Gustave Roussy, Villejuif, France presented the results of the phase III, randomised, open-label CheckMate-214 study evaluating the combination of nivolumab and ipilimumab compared to sunitinib in patients with previously untreated advanced or metastatic RCC.
Patients with measurable clear-cell metastatic RCC, Karnofsky performance score ≥70, and available tumour tissue were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score and by region, and randomised to receive nivolumab and ipilimumab combination or VEGFR-inhibitor sunitinib.
The 550 patients in the combination arm were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks and 546 patients received sunitinib at 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.
Co-primary endpoints of CheckMate-214 were ORR, PFS per independent committee and overall survival (OS) in the cohort of patients at intermediate or poor-risk. Efficacy was also evaluated according to IMDC risk group and baseline tumour PD-L1 expression.
Intermediate/poor risk patients
ORR in intermediate/poor risk patients was 41.6% for the nivolumab/ipilimumab combination compared to 26.5% for sunitinib (p < 0.0001) with 9.4% of patients receiving combination therapy achieving complete response (CR) compared to 1.2% of patients on sunitinib.
Median duration of response (DoR) was not reached (95% confidence interval [CI] 21.82, NR) versus 18.2 months with sunitinib (95% CI 14.82, NR).
Median PFS was 11.6 months for the nivolumab and ipilimumab combination versus 8.4 months with sunitinib, hazard ratio [HR] 0.82 (p = 0.03).
Favourable risk patients
In patients at favourable risk, both the ORR and PFS were higher with sunitinib over combination; in this cohort, ORR was 29% with nivolumab/ipilimumab versus 52% with sunitinib (p = 0.0002) and median PFS was 15.3 (95% CI 9.7, 20.3) months versus 25.1 (95% CI 20.9, NR) months, respectively, HR 2.17 (95% CI 1.46, 3.22; p < 0.0001).
In the overall composite of patients at any risk, no significant difference between treatments was demonstrated in ORR (p = 0.0191) or PFS (p = 0.819).
Any grade drug-related adverse events (AEs) occurred in 509 (93%) of patients in the nivolumab/ipilimumab cohort and in 521 (97%) of patients receiving sunitinib. With the combination, 54% of patients had a grade 3 to 4 AE, and with sunitinib 63% of patients had a grade 3 to 5 AE.
Discontinuation due to an AE was reported for 22% of combination patients and 12% of sunitinib patients. Of the 159 deaths that occurred in the combination cohort, seven (1%) were considered drug-related, whereas 4 (1%) of the 202 deaths occurring in the sunitinib cohort were considered drug related.
This is the first phase III trial investigating (combination) immunotherapy nivolumab plus ipilimumab versus (standard) sunitinib TKI as first-line treatment in mRCC. CheckMate-214 phase III trial support the use of combined nivolumab plus ipilimumab as a first-line treatment for patients with intermediate/poor risk mRCC, particularly those patients with tumour PD-L1 expression ≥1%. CheckMate-214 does not support the use of nivolumab/ipilimumab in good risk mRCC patients.