Combo Nivolumab and Ipilimumab: A New First-Line Standard for Advanced RCC

Currently, first-line treatment of advanced renal cell carcinoma (RCC) is most often a vascular endothelial growth factor receptor (VEGFR)–targeting tyrosine kinase inhibitor (TKI), such as sunitinib. In patients who progress on first-line treatment with TKI, immunotherapy with the programmed death receptor 1 (PD-1)–targeting antibody, nivolumab, is standard. In the phase Ib CheckMate 016 study, nivolumab in combination with the anticytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, demonstrated antitumor activity both in previously treated and treatment-naïve patients with advanced RCC.

At the 2017 European Society for Medical Oncology (ESMO) annual congress, Bernard Escudier, MD (Gustave Roussy, Villejuif, France), presented initial results from the randomized, phase III CheckMate 214 trial, which compared the combination of nivolumab and ipilimumab to sunitinib for first-line treatment of patients with advanced RCC (LBA5). Patients (N = 847) received either the nivolumab/ipilimumab combination (3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV every 3 weeks for 4 doses, followed by 3 mg/kg nivolumab IV every 2 weeks) or sunitinib (50 mg orally, once daily for 4 weeks of a 6-week cycle) until progression or unacceptable toxicity. The co-primary endpoints of this study were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), all in patients classified as intermediate and poor-risk (as defined by the International Metastatic Database Consortium [IMDC]).

At a median follow-up of 25.2 months, the use of nivolumab plus ipilimumab resulted in significantly improved ORR compared to sunitinib in patients with IMDC intermediate/poor risk (42% vs 27%; P<.0001), including a higher rate of complete response (9% vs 1%; P<.0001). The median duration of response (DoR) was not reached in patients receiving the immunotherapy combination, versus 18.2 months in patients receiving sunitinib. There was a trend toward improved PFS in patients with IMDC intermediate/poor risk receiving the nivolumab/ipilimumab combination, but this had not reached statistical significance by the time of the presentation (11.6 months vs 8.4 months; HR 0.82 [99.1% CI: 0.64-1.05], P = .0331). However, nivolumab plus ipilimumab significantly improved OS compared to sunitinib in this patient group (median OS not reached vs 26.0 months; HR 0.63 [99.8% CI: 0.44-0.89], P<.0001).

In the intent-to-treat population (ITT), the nivolumab plus ipilimumab combination did not result in statistically significant improvements in ORR or PFS; however, OS was significantly improved in patients receiving the nivolumab combination (median OS not reached vs 32.9 months; HR 0.68 [99.8% CI: 0.49-0.95], P = .0003). Interestingly, an exploratory analysis found that patients with IMDC favorable risk had significantly improved ORR and PFS with sunitinib compared to nivolumab plus ipilimumab (ORR: 52% for sunitinib vs 29%; P = .0002; PFS: 25.1 months vs 15.3 months; HR 2.18 [99.1% CI: 1.29-3.68], P<.0001).

Programmed death-ligand 1 (PD-L1) expression level impacted response to nivolumab plus ipilimumab, regardless of risk category. In patients with IMDC intermediate/poor risk and PD-L1 ≥1%, ORR was 58% with nivolumab plus ipilimumab, versus 22% with sunitinib (P<.0001). By comparison, if patients with IDMC intermediate/poor risk had PD-L1 <1%, ORR with nivolumab plus ipilimumab was 37%, compared to 22% with sunitinib (P = .0252). Results in the ITT population showed that nivolumab plus ipilimumab was associated with a statistically significant improvement in ORR in patients with PD-L1 ≥1% (53% vs 22%; P<.0001), but not for patients with PD-L1 <1% (36% vs 35%; P = .8799).

The nivolumab plus ipilimumab combination was generally associated with lower rates of treatment-related adverse events (TRAEs) versus sunitinib, including fewer grade 3-5 TRAEs (46% vs 63%). However, there were more TRAEs leading to discontinuation in the nivolumab plus ipilimumab arm (22% vs 12%), and more patients died due to treatment on nivolumab plus ipilimumab (n = 7 vs 4). The most common any grade immune-related AEs in patients treated with nivolumab plus ipilimumab include rash (17%), diarrhea/colitis (10%), hypothyroidism (19%), and hyperthyroidism (12%). Approximately 60% of patients treated with nivolumab plus ipilimumab required systemic corticosteroids to treat an AE.

In his conclusion, Dr Escudier stated that the results from CheckMate 214 support the use of nivolumab plus ipilimumab as a new first-line standard of care for patients with advanced RCC, highlighting the improvements in OS seen in all patients, regardless of risk, the improved PFS and ORR in patients with PD-L1 ≥1%, and the manageable toxicity profile of this combination. In her discussion, Manuela Schmidinger, MD (Medical University of Vienna, Austria), agreed, commenting that no previous first-line treatment for advanced RCC has surpassed the benefit seen with sunitinib, much less with the “massive impact” seen with nivolumab plus ipilimumab. She indicated that it will be important moving forward to use the biology of a patient’s individual tumor to identify the best treatment regimen from among the available first-line options.

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