FDA Approves Nivolumab/Ipilimumab Combo for Frontline Treatment of Advanced RCC

The FDA has approved the combination of immunotherapy drugs nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for patients with advanced renal cell carcinoma (RCC).

The approval is based on encouraging results of the phase III CheckMate-214 trial, in which frontline treatment with the combination of nivolumab and ipilimumab reduced the risk of death by 32% compared with sunitinib (Sutent) for patients with metastatic RCC.

The risk reduction was 37% in patients with intermediate- and poor-risk RCC—about 75% of the intent-to-treat (ITT) population.

In the randomized trial, the median overall survival (OS) in the overall population was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003). In those patients with intermediate- and poor-risk RCC, the median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001). There was not a benefit for the combination versus sunitinib in those with favorable risk.

“Physicians treating advanced RCC have had few options to help achieve the goal of improved survival. Data from the CheckMate-214 trial demonstrated superior overall survival with Opdivo plus Yervoy, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC," Robert J. Motzer, MD, medical oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial Sloan Kettering Cancer Center, said in a statement.

"What's more, the combination resulted in fewer overall grade 3 and 4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels,” added Motzer.

CheckMate-214 Trial Design

CheckMate-214 included patients with advanced or metastatic clear cell RCC who were treatment-naïve. Patients were randomized 1:1 to nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg, every 3 weeks for 4 doses, followed by nivolumab, 3 mg/kg every 2 weeks; or to receive oral sunitinib, 50 mg a day for 4 weeks in 6-week cycles. Patients were stratified by risk group and region, and treatment was continued until disease progression or unacceptable toxicity.

In the 1096 patients in the ITT population, 23% were considered favorable risk, 61% as intermediate risk, and 17% as poor risk in each arm. Additionally, about one-fourth in the ITT population had PD-L1 expression ≥1%. Among the 847 patients in the intermediate- or poor-risk groups, 79% were classified as intermediate risk (IMDC 1-2) and 21% as poor risk (IMDC 3-6) in each treatment arm. About one-fourth of the patients in each arm had PD-L1 expression ≥1%.

The most common sites of metastasis were the lung (approximately 70%), lymph nodes (approximately 50%), liver (approximately 20%), and bone (approximately 20%). Coprimary endpoints were overall response rate (ORR) per independent radiology review committee (IRCC), progression-free survival (PFS; per IRRC), and OS.

Results of the Study

Across the full ITT, the median PFS was not improved (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23; P = .8498). PFS in the intermediate- and poor-risk group was 11.6 months with the combination versus 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05; P = .0331). A P value of .009 was required for significance.

Across the full study, the confirmed ORR was 39% and 32% (P = .0191) in the nivolumab/ipilimumab and sunitinib groups, respectively. The confirmed ORR in the intermediate/poor risk patients was 42% in patients assigned to nivolumab plus ipilimumab compared with 27% in those assigned to sunitinib (P <.0001). Nine percent of patients in the nivolumab/ipilimumab group had a complete response (CR) and 32% had a partial response, compared with 1% CR and 25%, respectively, in the sunitinib group. The median duration of response was significantly superior with nivolumab/ipilimumab compared with sunitinib (not reached vs 18.2 months).

Favorable risk patients, in contrast, had a significantly higher confirmed ORR with sunitinib versus the combination arm (52% vs 29%; P =.0002), as well as a significantly longer PFS (25.1 vs 15.3 months; P <.0001).

In those with PD-L1 expression ≥1%, the median PFS was significantly longer with the immunotherapy combination than with sunitinib (22.9 vs 5.9 months; HR, 0.48; P = .0003). Those with PD-L1 expression <1% did not benefit from the combination (HR, 1.00; P = .9670).

Among all treated patients, with a median follow-up of 25.2 months, 77% of patients assigned to nivolumab plus ipilimumab and 82% assigned to sunitinib discontinued treatment. The main reason for discontinuation in each group was disease progression (42% in the combination immunotherapy group and 55% in the sunitinib group). The median duration of therapy was 7.9 and 7.8 months, respectively. In the immunotherapy arm, the median number of nivolumab doses received was 14 and the median number of ipilimumab doses received was 4. Seventy-four percent of patients received all 4 doses of ipilimumab.

Adverse events (AEs) leading to discontinuation occurred in 22% of patients in the combination immunotherapy group compared with 12% in the sunitinib group. The most common grade 3/4 AEs in the combination group were fatigue (4%) and diarrhea (4%). In the sunitinib group, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), and Palmar-plantar erythrodysesthesia syndrome (9%). There were 7 treatment-related deaths in the combination group and 4 in the sunitinib group.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.