In this study, the objective response rate (ORR) was 40%, ongoing responses was seen in 42% of patients, median progression free survival (PFS) was 7.7 months, and 2-year overall survival (OS) rate was 67%. These results provided the rationale for the current phase III trial testing nivolumab + ipilimumab vs sunitinib.
Inclusion criteria for this phase III trial included (i) adults with measurable clear-cell mRCC, (iii) Karnofsky performance status ≥70, and (iii) available tumor tissue for PD-L1 testing. Patients were then randomized 1:1 (stratified by IMDC score and region) to nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg daily orally for 4 weeks (6-week cycles). The co-primary endpoints included intermediate/poor risk patient specific (i) ORR, (ii) PFS per independent committee, and (iii) OS. The overall α for treatment effect was 0.05 split among the three co-primary endpoints (0.001 ORR, 0.009 PFS, 0.04 OS). The PFS analysis had 80% power and OS analysis had 90% power to detect a statistically significant difference between the treatment arms. The number of patients estimated for randomization was ~1,070, with 820 of whom would have IMDC intermediate/poor risk disease. Secondary endpoints included intention to treat (i) ORR, (ii) PFS, and (iii) OS. Exploratory endpoints included (i) ORR, PFS, and OS in favorable risk patients, (ii) outcomes by tumor PD-L1 expression level, (iii) quality of life metrics based on FKSI-19.
There were 1096 patients randomized to nivolumab + ipilimumab (n=550) vs sunitinib (n=546). Baseline characteristics were well balance between the two groups. Median follow-up was 25.2 months, with a minimum follow-up of 17.5 months; 79% of patients in the nivolumab + ipilimumab arm received all four doses of ipilimumab. The confirmed ORR in intermediate/poor risk patients was 42% (9.4% complete response) vs 27% (1.2% CR) for nivolumab + ipilimumab vs sunitinib (P<0.0001). Furthermore, the median duration of response was not reached for the nivolumab + ipilimumab arm (NR; 95%CI 22-NR months) vs 18 months (95%CI 15-NR) in the sunitinib arm. The median PFS for intermediate/poor risk patients was 11.6 months for nivolumab + ipilimumab vs 8.4 months for sunitinib (HR 0.82, 99.1%CI 0.64-1.05), while median OS was not reached for nivolumab + ipilimumab compared to 26.0 months for sunitinib (HR 0.63, 99.8%CI 0.44-0.89). In the intention to treat group the results were as follows: (i) ORR: 39% (95%CI 35-43) for nivolumab + ipilimumab compared to 32% (95%CI 28-36) for sunitinib (p=0.02); (ii) median PFS: 12.4 months (95%CI 9.9-16.5) for nivolumab + ipilimumab compared to 12.3 months (95%CI 9.8-15.2) for sunitinib (p=0.85); (iii) median OS: not reached for nivolumab + ipilimumab compared to 32.9 months for sunitinib (HR 0.68, 99.8%CI 0.49-0.95). Interestingly, for IMDC favorable risk patients, ORR and PFS both significantly favored sunitinib. Efficacy outcomes differed by PD-L1 expression and IMDC risk group. ORR favored nivolumab + ipilimumab vs sunitinib in intermediate/poor risk patients with baseline PD-L1 expression <1% and ≥1%. A significant PFS benefit with nivolumab + ipilimumab vs sunitinib was seen in patients with PD-L1 ≥1%. Baseline PD-L1 expression was lower in favorable risk patients (≥1% in 11% nivolumab + ipilimumab vs 12% sunitinib) than in intermediate/poor risk patients. In all treated patients, drug-related adverse events occurred in 509/547 (93% any grade, 46% grade 3-4) with nivolumab + ipilimumab vs 521/535 (97% any grade, 63% grade 3-5) with sunitinib, including 22% vs 12% with adverse events leading to discontinuation. Death occurred in 159 nivolumab + ipilimumab patients (7 drug-related) and 202 sunitinib patients (4 drug-related). Health related quality of life outcomes generally favored nivolumab + ipilimumab throughout the study duration.
Dr. Escudier concluded with a number of summary points: (i) in IMDC intermediate/poor risk patients this trial demonstrated statistically significant OS benefit with nivolumab + ipilimumab vs sunitinib (37% reduction in risk of death) and significantly improved ORR with nivolumab + ipilimumab, (ii) in the intention to treat analysis, nivolumab + ipilimumab demonstrated statistically significant OS and improved ORR, (iii) patients with tumor PD-L1 ≥1% demonstrated higher ORR and improved PFS with nivolumab + ipilimumab, (iv) favorable-risk patients achieved higher ORR and longer PFS with sunitinib, and (v) the safety profile of nivolumab + ipilimumab was manageable and consistent with previous studies. According to Dr. Escudier, based on these results “nivolumab + ipilimumab is a new first-line standard of care option for patients with advanced RCC”.
1. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The CheckMate 016 study. J Clin Oncol 2017 [Epub ahead of print].
Speaker: Bernard Escudier, Gustave Roussy, University of Paris Saclay, Villejuif, France
Co-Authors: N. Tannir, D. McDermott, O. Frontera, B. Melichar, E. Plimack, P. Barthelemy, S. George, V. Neiman, C. Porta, T. Choueiri, T. Powles, F. Donskov, P. Salman, C. Kollmannsberger, B. Rini, S. Mekan, M. McHenry, H. Hammers, R. Motzer
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain