Combined immunotherapy with nivolumab plus ipilimumab resulted in a greater objective response rate (ORR) and prolonged progression-free survival (PFS) compared to sunitinib in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma (RCC), according to findings from the CheckMate-214 study presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Greater benefit was observed in these patients, especially those with higher levels of PD-L1 expression at baseline; however, ORR and PFS were improved with sunitinib in patients with favourable risk, advanced or metastatic disease.
Bernard Escudier, Institut Gustave Roussy, Villejuif, France presented the results of the phase III, randomised, open-label CheckMate-214 study evaluating the combination of nivolumab and ipilimumab compared to sunitinib in patients with previously untreated advanced or metastatic RCC.
Adult patients with measurable clear-cell metastatic RCC, Karnofsky performance score ≥70, and available tumour tissue were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score and by region, then randomised to receive nivolumab and ipilimumab combination or sunitinib treatment. The 550 patients in the combination arm were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks and 546 patients received sunitinib at 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.
The co-primary endpoints of CheckMate-214 were ORR, PFS per independent committee and overall survival (OS) in the cohort of patients at intermediate or poor-risk. Efficacy was also evaluated according to IMDC risk group and baseline tumour PD-L1 expression.
The benefit from the immunotherapy combination in intermediate/high risk patients
After approximately 17.5 months of follow-up, CheckMate-214 met the co-primary endpoint of ORR in intermediate/poor risk patients, which was 41.6% for the nivolumab/ipilimumab combination compared to 26.5% for sunitinib (p < 0.0001) with 9.4% of patients receiving combination therapy achieving complete response (CR) compared to1.2% of patients on sunitinib.
The median duration of response (DoR) was not reached (95% confidence interval [CI] 21.82, NR) versus 18.2 months with sunitinib (95% CI 14.82, NR).
There was an improvement in median PFS with the combination in this cohort;median PFS was 11.6 months for the nivolumab and ipilimumab combination versus 8.4 months with sunitinib, hazard ratio [HR] 0.82 (p = 0.03).
The efficacy outcomes differed according to the levels of PD-L1 expression and IMDC risk group
Both the ORR per indipendent committee and PFS significantly favoured nivolumab plus ipilimumab over sunitinib in intermediate/poor risk patients having baseline PD-L1 expression ≥1% where the ORR was 58% versus 25%, and median PFS was 22.8 (95% CI 9.4, NR) months versus 5.9 (95% CI 4.4, 7,1) months, respectively, HR 0.48 (95% CI 0.28, 0.82; p = 0.0003).
The investigators found that baseline tumour PD-L1 expression was lower in the cohort of patients at favourable risk where 11% of patients on combination had PD-L1 levels ≥1% versus12% of patients on sunitinib compared to 26% versus 29% of patients at intermediate or poor risk in the respective treatment arms.
In patients at favourable risk, both the ORR and PFS were higher with sunitinib over combination; in this cohort, ORR was 29% with nivolumab/ipilimumab versus 52% with sunitinib (p = 0.0002) and median PFS was 15.3 (95% CI 9.7, 20.3) months versus 25.1 (95% CI 20.9, NR) months, respectively, HR 2.17 (95% CI 1.46, 3.22; p < 0.0001).
In the overall composite of patients at any risk, no significant difference between treatments was demonstrated in ORR (p = 0.0191) or PFS (p = 0.819).
Any grade drug-related adverse events (AEs) occurred in 509 (93%) of patients in the nivolumab/ipilimumab cohort and in 521 (97%) of patients receiving sunitinib. With the combination, 54% of patients had a grade 3 to 4 AE, and with sunitinib 63% of patients had a grade 3 to 5 AE.
Discontinuation due to an AE was reported for 22% of combination patients and 12% of sunitinib patients. Of the 159 deaths that occurred in the combination cohort, seven (1%) were considered drug-related, whereas 4 (1%) of the 202 deaths occurring in the sunitinib cohort were considered drug related.
According to the investigators, findings from this phase III trial support the use of combined nivolumab plus ipilimumab as a potential first-line treatment for patients with intermediate/poor risk metastatic RCC, particularly those patients having tumour PD-L1 expression ≥1%. However, it does not support its use in good risk patients.
Trying to address if superiority of nivolumab plus ipilimumab over sunitinib is a paradigm change in mRCC first-line treatment, Manuela Schmidinger of the Medical University of Vienna, Austria said to some extent yes as sunitinib has never been defeated before. For her it was so brave to choose it as a comparator. Nivolumab plus ipilimumab induces a high rate of objective responses. The quality of the response is highlighted by the rate of complete remissions, the duration of response and its translation into OS benefit. Checkpoint inhibitor first-line treatment is a new standard of care (with massive impact), however there is not the final picture yet. Once we will be able to properly address the biology of a patient‘s individual tumour, we may pick out the best individual treatment among various first-line options. Furthermore, multiple combinations are currently under investigation in phase III trials, some of these combinations will most likely be included in the standard of care. The current data are also encouraging news for those who conduct phase III trials with immuno-oncology-VEGF-inhibitor combinations vs sunitinib.
This trial was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical Co. Ltd.
LBA5 – Escudier B, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups.