For the majority of patients with advanced clear cell renal cell cancer (RCC), initial treatment includes an angiogenesis-targeting therapy, such as the multikinase tyrosine kinase inhibitor (TKI) sunitinib. However, despite the notable efficacy of multikinase inhibitors, responses to these agents are usually not durable, and complete responses are rare. Immunotherapy with immune checkpoint inhibitors has recently emerged in RCC. Based on its favorable safety profile, durable responses, and long-term survival benefit, the PD-1 inhibitor nivolumab is a standard treatment option for patients with advanced RCC who progressed on prior antiangiogenic therapy. To further enhance antitumor efficacy of PD-1 blockade, combination treatment strategies with other immune checkpoint inhibitors or angiogenesis inhibitors are being evaluated in patients with advanced RCC.
In the large, randomized phase III CheckMate 214 trial (N = 1096), the safety and efficacy of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) four doses followed by nivolumab monotherapy was compared to standard sunitinib (50 mg daily four weeks on, two weeks off) in newly diagnosed patients with advanced RCC. The coprimary endpoints for this study were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate- and poor-risk patients. Objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib (42% vs 27%; P<.001), including a greater number of complete responses (9% vs 1%). Progression-free survival was 3.2 months longer for patients receiving combination immunotherapy than for patients receiving sunitinib, but this difference did not meet the prespecified threshold for significance (11.6 months vs 8.4 months; HR 0.82, P = .03). The 18-month OS rate was 75% with nivolumab plus ipilimumab, and 60% with sunitinib. The median OS had not yet been reached in patients treated with nivolumab plus ipilimumab, and was 26 months in patients treated with sunitinib and (HR 0.63, P<.001). The OS benefit of nivolumab plus ipilimumab was observed across all prespecified subgroups, including patients with <1% PD-L1 expression. However, the benefit was higher in patients with 1% or greater PD-L1 expression.
Of note, in the favorable-risk patients, sunitinib was associated with a significantly higher ORR (52% vs 29%; P<.001) and prolonged PFS (25.1 months vs 15.3 months; HR 2.18, P<.001) compared to immunotherapy combination. This difference did not translate into significant survival benefit, though (HR 1.45, P = .27).
Rates of grade 3/4 treatment-related adverse events (AEs) were lower with nivolumab/ipilimumab than with sunitinib (46% vs 63%), but more patients receiving nivolumab plus ipilimumab discontinued treatment due to AEs (22% vs 12%). Treatment-related deaths occurred in 8 patients in the nivolumab/ipilimumab group and 4 patients in the sunitinib group.
The investigators concluded that few studies have addressed efficacy of first-line therapy in intermediate- and poor-risk patients with advanced RCC and that the results of CheckMate 214 support the use of nivolumab/ipilimumab combination in these patients. In an accompanying editorial, Brendan Curti, MD (Providence Cancer Institute, Portland, Oregon, United States), praised the study for its efforts to advance immunotherapy in the first-line setting, calling it a “step in the right direction” in the ultimate goal of curing advanced RCC.