The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of nivolumab combined with low-dose ipilimumab as a frontline treatment for patients with intermediate- and poor-risk advanced renal cell carcinoma.
Arvin Yang, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of nivolumab (Opdivo) combined with low-dose ipilimumab (Yervoy) as a frontline treatment for patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC), according to Bristol-Meyers Squibb (BMS), the developer of both immunotherapy agents.
“There remains a high unmet medical need for patients with advanced renal cell carcinoma,” Arvin Yang, MD, PhD, development lead, melanoma and genitourinary cancers, BMS, said in a statement. “We are encouraged by today’s positive opinion from the CHMP and look forward to potentially bringing the first immuno-oncology combination therapy to appropriate RCC patients across the [European Union].”
The CHMP recommendation is based on findings from the phase III CheckMate-214 trial, which demonstrated that the combination of nivolumab plus ipilimumab led to a 37% reduction in the risk of death versus standard sunitinib (Sutent) in intermediate- and poor-risk patients with advanced RCC, regardless of PD-L1 expression status (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001).
In the open-label, randomized CheckMate-214 study, patients were randomized 1:1 to receive the combination of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 2 weeks off in every cycle (n = 425) or sunitinib at 50 mg once daily for a 4-weeks-on/2-weeks-off schedule (n = 422). After completion of 4 doses with the combination, nivolumab was given 240 mg intravenously every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes until disease progression or unacceptable toxicity.
Patients enrolled on the study had advanced or metastatic disease with no prior therapy. In the 1096 patients in the intent-to-treat (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 and 21% as poor risk in each treatment arm. Approximately one-quarter of patients in each arm had PD-L1 expression ≥1%.
The coprimary endpoints were overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) as determined by an independent radiographic review committee in intermediate- and poor-risk patients.
Results showed that the median OS in intermediate- and poor-risk patients treated with the PD-1/CTLA-4 inhibitor regimen was not yet reached (95% CI, 28.2 months-not estimable) versus 25.9 months for those who received sunitinib. In the overall population, the median 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).
Moreover, the combination was associated with an ORR of 41.6% (95% CI, 36.9%-46.5%; P <.0001) versus 26.5% for sunitinib (95% CI, 22.4-31.0) in the intermediate- and poor-risk patient populations. The median duration of response was not yet reached for the combination (95% CI, 21.8 to NE) versus 18.2 months for sunitinib (95% CI, 14.8-NE).
However, favorable-risk patients had a significantly higher confirmed ORR with sunitinib versus nivolumab/ipilimumab at 52% versus 29% (P =.0002) and a significantly longer PFS (25.1 vs 15.3 months; P <.0001). Across the full ITT population, the ORRs were 39% and 32% (P = .0191) in the nivolumab/ipilimumab and sunitinib groups, respectively.
In the ITT population, the median PFS was not improved (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23; P = .8498). The median 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.
The overall safety profile was consistent with prior trials of nivolumab/ipilimumab. Adverse events (AEs) leading to discontinuation of treatment occurred in 22% of patients receiving nivolumab/ipilimumab 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 arm, 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.
The FDA approved the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC, also based on the CheckMate-214 data, in April 2018.
Motzer RJ, Tannir NM, McDermott DF, Frontera OA, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.