The FDA has granted a priority review to a supplemental biologics license application (sBLA) for use of the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced renal cell carcinoma (RCC).UPDATE 4/16/2018: FDA Approves Nivolumab/Ipilimumab for Frontline RCC
The sBLA is based on the phase III CheckMate-214 trial, in which frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with sunitinib (Sutent) for patients with mRCC.
In the randomized trial, the median overall survival (OS) 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 specifically with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat (ITT) population, median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm, a 37% reduction in the risk of death (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.
The regimen previously received an FDA breakthrough therapy designation in this setting. The agency is scheduled to make its final decision on the sBLA on or before April 16, 2018.
“Breakthrough therapy designation and today’s filing acceptance for the Opdivo plus Yervoy combination are an important step in our ongoing efforts to advance therapies to address a high unmet need in first-line treatment of kidney cancer in intermediate- and poor-risk patients,” Murdo Gordon, executive vice president and chief commercial officer, Bristol-Myers Squibb, said in a press release.
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. As well, 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 ORR per independent radiology review committee (IRCC), progression-free survival (PFS; per IRRC), and OS.
Across the full ITT, the median PFS was not improved, which had been announced prior to the ESMO meeting (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23; P
= 0.8498). 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
= 0.0331). A P value of .009 was required for significance.
Across the full study, the confirmed overall response rate (ORR) was 39% and 32% (P
= 0.0191) in the nivolumab/ipilimumab group and sunitinib group, 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
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