Nivolumab Plus Ipilimumab Yields Long-Term Efficacy Advantage in Advanced RCC

Michael B. Atkins, MD

Administration of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) may confer overall survival (OS) benefit and prolong responses vs sunitinib (Sutent) in patients with International Metastatic RCC Database Consortium (IMDC) favorable-risk advanced renal cell carcinoma (RCC), according to long-term follow-up data from the phase 3 CheckMate 214 trial (NCT02231749) presented during the 2024 Kidney Cancer Research Summit (KCRS).¹

Across the intent-to-treat (ITT) population, the median OS was 52.7 months (95% CI, 45.8-64.5) in patients who received nivolumab/ipilimumab (n = 550) compared with 37.8 months (95% CI, 31.9-43.8) in those who received sunitinib (n = 546; HR, 0.72; 95% CI, 0.62-0.83). Additionally, the median progression-free survival (PFS) was 12.4 months (95% CI, 9.9-16.8) vs 12.3 months (95% CI, 9.8-15.2) in each respective arm (HR, 0.88; 95% CI, 0.75-1.03).

Data highlighted an objective response rate (ORR) of 39% (95% CI, 35%-44%) with the nivolumab combination compared with 33% (95% CI, 29%-37%) with sunitinib. In each respective arm, 12% vs 3% of patients had complete responses (CRs), and 27% vs 29% had partial responses (PRs). Additionally, the median duration of response (DOR) was 76.2 months (95% CI, 59.1-not evaluable [NE]) vs 25.1 months (95% CI, 19.8-33.2) in each respective arm (HR, 0.52; 95% CI, 0.38-0.72).

Among patients with favorable-risk disease, the median OS was 77.9 months (95% CI, 64.6-91.6) in those who received nivolumab/ipilimumab (n = 125) vs 66.7 months (95% CI, 56.0-79.9) in those treated with sunitinib (n = 124; HR, 0.82; 95% CI, 0.60-1.13). The OS rates in each arm were 85.1% vs 88.4% at 24 months, 52.3% vs 46.4% at 72 months, and 42.8% vs 34.4% at 90 months.

Treatment yielded a median PFS of 12.4 months (95% CI, 10.3-18.0) and 28.9 months (95% CI, 23.2-42.8) in the nivolumab/ipilimumab and sunitinib arms, respectively (HR, 1.76; 95% CI, 1.25-2.48). Additionally, the PFS rates were 36.5% vs 58.5% at 24 months, 17.0% vs 17.0% at 72 months, and 12.7% vs 17.0% at 90 months in each respective arm.

The ORR across the favorable-risk population was 30% (95% CI, 22%-38%) with the nivolumab combination vs 52% (95% CI, 43%-61%) with sunitinib, and the CR rates were 13% vs 6% in each arm. Data showed a median DOR of 61.5 months (95% CI, 27.8-NE) vs 33.2 months (95% CI, 24.8-51.4) in each respective arm (HR, 0.70; 95% CI, 0.36-1.34). Additionally, 68% vs 66%, 37% vs 14%, and 37% vs 14% of patients in each arm had ongoing responses at 24 months, 72 months, and 90 months, respectively.

In the CheckMate 214 trial, patients with previously untreated advanced RCC were randomly assigned 1:1 to receive nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by maintenance nivolumab or sunitinib at 50 mg orally once daily for 4 weeks as part of every 6-week cycle. The median follow-up was 99.1 months.

The trial assessed OS, PFS, and ORR among those with intermediate- or poor-risk disease in the primary population. The ITT population was evaluated as part of a secondary analysis, and those with favorable-risk disease were assessed in an exploratory analysis.

Patients 18 years and older who received no prior systemic therapy for histologically confirmed advanced or metastatic RCC harboring a clear cell component were eligible for enrollment on the trial.² Additional requirements for study entry included having a Karnofsky performance status of 70% or higher and measurable disease based on RECIST v1.1 guidelines.

Investigators noted that baseline characteristics between treatment arms were comparable regardless of IMDC risk.

Exploratory post hoc analysis findings indicated that 41% (n = 31/75) of deaths in the nivolumab arm across the favorable-risk population occurred within 3 years of beginning treatment. Additionally, 44% (n = 12/27) of patients who received the nivolumab combination and 8% (n = 2/26) of those who received sunitinib died within 3 years following disease progression and did not receive systemic therapy in the second-line setting. Data also showed that 5% (n = 2/43) and 20% (n = 11/54) in each respective arm died after progressive disease and did not receive subsequent treatment beyond 3 years.

According to hazard function curve analysis, the risk of death was increased with the nivolumab combination vs sunitinib within 3 years of beginning study treatment (HR, 1.19; 95% CI, 0.70-2.01). With 3 or more years of follow-up, however, the risk of death was lower in the nivolumab arm (HR, 0.66; 95% CI, 0.44-0.97).

“The disproportionate number of [favorable]-risk patients in the [nivolumab/ipilimumab] arm who died within 3 years of randomization after progression without receiving subsequent therapy may have affected the HR for OS early on,” the study authors wrote. “Crossing of the [hazard function] curves at [approximately] 2 years in [favorable]-risk patients and the subsequent lower risk of death in the [nivolumab/ipilimumab] arm at most time points through 8 years of follow-up may have important implications for understanding long-term survival in this patient population.”

The rates of any-grade treatment-related adverse effects (TRAEs) were 98% vs 99% with nivolumab/ipilimumab vs sunitinib, respectively. Additionally, grade 3 or higher TRAEs affected 50% and 71% of patients in each respective arm. Two patients, including 1 each in the nivolumab/ipilimumab and sunitinib arms, died from treatment-related toxicity within 100 days of the final dose.

References

1. Atkins MB, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable-risk patients from the phase 3 CheckMate 214 trial. Presented at the 2024 Kidney Cancer Research Summit; July 11-12, 2023; Boston, MA. Abstract 8.
2. Nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 214). ClinicalTrials.gov. Accessed July 11, 2024. https://tinyurl.com/2efbcw89