With a median follow-up of 99.1 months, the recent analysis of the CheckMate 214 trial serves as the longest reported follow-up for any phase 3 trial of a checkpoint inhibitor combination therapy in advanced renal cell carcinoma (aRCC), which demonstrated the remarkable and durable clinical responses of nivolumab + ipilimumab as a first-line therapy for untreated aRCC.¹

Nivolumab (NIVO) is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death protein-1 (PD-1) receptor and prevents programmed death-ligand 1 (PD-L1) and PD-L2 from binding, thereby restoring T-cell immune response and antitumor activity.² Similarly, ipilimumab (IPI) is a monoclonal antibody that binds to cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and prevents the binding of its ligands, CD80 and CD86, which results in an increased T-cell activation and proliferation, including antitumor immune response.³ In the CheckMate 214 trial, the combination of NIVO + IPI had demonstrated improved survival and response rates compared to the standard of care, sunitinib (SUN), among patients with previously untreated aRCC with a median follow-up of 25.2 months.⁴ These survival benefits were sustained over a subsequent analysis at 5 years and were consistent across patients with varying risk groups defined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).^5,6 Recently, an 8-year follow-up analysis of the CheckMate 214 trial was conducted.¹

The CheckMate 214 trial was a phase 3 trial that compared the efficacy and safety of NIVO + IPI with SUN.⁴ A total of 1,096 patients aged ≥18 years with treatment-naïve measurable aRCC, a clear cell component, and a Karnofsky Performance Status (KPS) scale ≥70% were randomized (1:1) to receive NIVO + IPI (n=550) or SUN (n=546).¹ Patients were stratified according to geographic locations and IMDC risk score: favorable (0), intermediate (1-2), and poor (3-6).¹ The primary endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in IMDC intermediate/poor-risk patients.¹ Key secondary endpoints were OS, PFS, and ORR in the intent-to-treat (ITT) population, and other exploratory endpoints included OS, PFS, and ORR in IMDC favorable-risk patients, and safety outcomes in the ITT population.¹

Over 8 years of follow-up (median follow-up: 99.1 months), OS benefits facilitated by NIVO + IPI remained consistent, with a 28% (HR=0.72; 95% CI: 0.62-0.83), 31% (HR=0.69; 95% CI: 0.59-0.81), and 18% (HR=0.82; 95% CI: 0.60-1.13) risk reduction compared to the SUN group in the overall ITT population, the intermediate/poor-risk group, and the favorable-risk group, respectively.¹ Similarly, improvements in PFS were observed in the NIVO + IPI group compared to the SUN group in the ITT population, where the NIVO + IPI group had a 12%-21% reduction in risk of disease progression or death.¹  

In terms of clinical responses, the NIVO + IPI group had a higher ORR than SUN in the ITT population (39% vs. 33%) and the intermediated/poor-risk group (42% vs. 27%).¹ In addition, the median duration of response (DOR) was substantially longer for the NIVO + IPI group in the ITT population (76.2 months vs. 25.1 months; HR=0.52; 95% CI: 0.38-0.72), the intermediate/poor-risk group (82.8 months vs. 19.8 months, HR=0.48; 95% CI: 0.33-0.69) and the favorable-risk group (61.5 months vs. 33.2 months; HR=0.70; 95% CI: 0.36-1.34).¹ Complete response was also more likely to be achieved with NIVO + IPI than SUN in all risk groups (ITT population: 12% vs. 3%; intermediate/poor-risk group: 12% vs. 3%; favorable-risk: 13% vs. 6%).¹

In terms of safety, the incidence rates of treatment-related adverse events (TRAEs) were similar between the two treatment groups, with fewer grade ≥3 TRAEs observed in the NIVO + IPI group than in the SUN group (48% vs. 68%).¹ A total of 24% of patients on NIVO + IPI and 13% of patients on SUN discontinued treatment due to TRAEs.¹ Furthermore, deaths due to drug toxicity occurred in 8 patients and 5 patients in the NIVO + IPI and SUN groups, respectively.¹

In summary, the dual immunotherapy combination of NIVO + IPI induced notable survival benefits that were sustained over 8 years among patients with aRCC, regardless of patients’ IMDC risk.¹ Long-term safety data also suggest that the combination is safe with manageable side effects.¹ As such, these results continue to support the role of NIVO + IPI as the standard of care for aRCC.¹