A new study in the New England Journal of Medicine showed that a regimen of nivolumab plus ipilimumab showed significantly higher overall survival (OS) and objective response rates (ORR) when compared with sunitinib for intermediate- and poor-risk patients with previously untreated advanced renal cell carcinoma (RCC).
Previous studies have shown that combination therapy with nivolumab, a programmed cell death 1 (PD-1) immune checkpoint inhibitor antibody, and ipilimumab, an anti-cytotoxic T-lymphocyte–associated antigen 4 antibody, resulted in higher rates of response than either agent alone.
The CheckMate 214 study, led by Robert J. Motzer, MD, from the Memorial Sloan Kettering Cancer Center in New York, NY, was a randomized, open-label, phase 3 trial that evaluated nivolumab plus ipilimumab followed by nivolumab monotherapy vs sunitinib monotherapy.
Patients with previously untreated clear cell advanced RCC were randomly assigned treatment at 175 sites in 28 countries; 1082 patients received treatment. The intent-to-treat (ITT) population consisted of 547 patients with nivolumab plus ipilimumab and 535 with sunitinib. Of those patients, 423 and 416, respectively, had intermediate or poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Nivolumab 3 mg/kg and ipilimumab 1 mg/kg were administered intravenously every three weeks for four doses (induction phase), followed by nivolumab monotherapy of 3 mg/kg every two weeks (maintenance phase). Sunitinib was administered at a dose of 50 mg orally daily for 4 weeks of each 6-week cycle.
A protocol amendment permitted crossover from the sunitinib group to the nivolumab-plus-ipilimumab group after the primary end point had been met.
The primary endpoints in patients with intermediate or poor prognostic risk included OS, ORR, and progression-free survival (PFS).
Secondary endpoints in the ITT population included ORR, PFS, OS, and incidence rate of adverse events among all treated patients.
Exploratory endpoints included the ORR, PFS, and OS among favorable-risk patients.
Additional exploratory endpoints included outcomes according to the PD-1 levels, as well as health-related quality of life based on the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy–Kidney Symptom Index (NFKSI-19) in intermediate- and poor-risk patients.
Results showed that nivolumab plus ipilimumab had a significant OS benefit over sunitinib. The 12-month OS rates were 80% and 72%, respectively, and the 18-month OS rates were 75% and 60%, respectively.
ORR was 42% in the combination group vs 27% in the sunitinib group (P < 0.001), and complete response was seen in 40 patients (9%) vs 5 patients (1%), respectively.
Median PFS was 11.6 months with nivolumab plus ipilimumab and 8.4 months with sunitinib.
In addition, OS favored nivolumab plus ipilimumab over sunitinib across subgroups, and the ORR was higher with nivolumab plus ipilimumab than with sunitinib in all subgroups.
In the ITT population, 12-month OS was 83% vs 77%; 18-month OS was 78% vs 68% with nivolumab plus ipilimumab compared to sunitinib. Nivolumab plus ipilimumab had a significant OS benefit over sunitinib (P < 0.001), however, PFS did not differ significantly between the two groups.
Among patients with ≥1% PD-L1 expression, longer PFS was observed with nivolumab plus ipilimumab than with sunitinib, but this did not hold true among those with <1% PD-L1 expression. In contrast, longer OS and a higher ORR were observed with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients across tumor PD-L1 expression levels. This suggests that response to and the OS benefit of the combination cannot be predicted based on PD-L1 expression.
The authors noted that the favorable-risk group had a higher ORR and longer PFS with sunitinib than with nivolumab plus ipilimumab, although these differences did not translate into a significant survival advantage. They suggested that this highlights the need to better understand the underlying biologic processes driving responses to the different treatment regimens.
Treatment-related adverse events occurred in 93% and 97% of patients in the nivolumab-plus-ipilimumab vs sunitinib groups, respectively. Grade 3 or 4 events occurred in 46% and 63% of patients, and discontinuation due to treatment-related adverse events occurred in 22% and 12% of patients in the respective groups.
The mean baseline of the NFKSI-19 was similar in the two groups among patients with intermediate or poor risk. At each assessment during the first six months, the mean change from baseline was greater in the combination group than in the sunitinib group (P < 0.001).
“This trial showed an efficacy and overall survival benefit of nivolumab plus ipilimumab over sunitinib in the first-line treatment of intermediate- or poor-risk advanced clear cell renal cell carcinoma,” the authors concluded.
To read more about this study, click here.