In CheckMate 914, phase III study that assessed adjuvant nivolumab plus ipilimumab combination versus placebo for the treatment of patients with localised renal cell carcinoma (RCC) who are at high risk of post-nephrectomy recurrence, the primary efficacy endpoint of disease-free survival (DFS) by masked independent central review was not met. DFS was also not significantly different between the nivolumab plus ipilimumab and placebo groups, as assessed by the study investigators. DFS was similar between the treatment groups across most key subgroups. Nivolumab plus ipilimumab was associated with higher rates of grade 3–5 adverse events of any cause, treatment-related adverse events, and adverse events leading to treatment discontinuation compared with placebo. However, the overall safety of adjuvant nivolumab plus ipilimumab in this study was consistent with the known profile for the combination in patients with advanced RCC. The CheckMate 914 findings are published by Prof. Robert J. Motzer of the Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 9 February 2023 in the Lancet.

The authors wrote in the background that efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced RCC, together with their ability to provide enduring responses, has provided much of the rationale for evaluation of adjuvant immune checkpoint blockade in patients with localised RCC. Adjuvant pembrolizumab showed DFS benefits compared with placebo in patients with high-risk clear cell RCC in the prespecified first interim analysis of the KEYNOTE-564 study. However, reports from the IMmotion010 of adjuvant atezolizumab and PROSPER RCC of perioperative nivolumab have shown no improvement in the primary endpoints of DFS or recurrence-free survival.

Nivolumab monotherapy has previously shown efficacy as an adjuvant treatment in multiple malignancies, including high-risk muscle-invasive urothelial carcinoma in CheckMate 274, resected oesophageal or gastro-oesophageal junction cancer in CheckMate 577, and stage III–IV melanoma in CheckMate 238. Dual immune checkpoint blockade with nivolumab plus ipilimumab has shown significant long-term survival and durable response benefits compared with sunitinib in previously untreated patients with advanced RCC, supporting evaluation of this regimen as an adjuvant treatment for localised disease.

The double-blind, randomised, phase III CheckMate 914 study enroled patients with localised clear cell RCC who were at high risk of relapse after radical or partial nephrectomy between 4 to 12 weeks before random assignment. Part A, reported in the latest Lancet article, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab, 240 mg intravenously every 2 weeks for 12 doses plus ipilimumab, 1 mg/kg intravenously every 6 weeks for 4 doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays.

Randomisation was stratified by TNM stage and nephrectomy (partial versus radical). The primary endpoint was DFS according to masked independent central review; safety was a secondary endpoint. DFS was analysed in all randomly assigned patients that comprised intention-to-treat population; exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug.

Between 28 August 2017 and 16 March 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). A total, 580 of 816 patients (71%) were male and 236 patients (29%) were female. With a median follow-up of 37.0 months, median DFS was not reached in the nivolumab plus ipilimumab group and was 50.7 months (95% confidence interval [CI] 48.1 to not estimable) in the placebo group (hazard ratio 0.92, 95% CI 0.71–1.19; p = 0.53).

The number of events required for the planned overall survival (OS) interim analysis was not reached at the time of the data cut-off, and only 61 events occurred, 33 in the nivolumab plus ipilimumab group and 28 in the placebo group.

In total, 155 of 404 patients (38%) who received nivolumab plus ipilimumab and 42 of 407 patients (10%) who received placebo had grade 3–5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 of 404 treated patients (32%) and of placebo in 9 of 407 treated patients (2%). Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo.

The authors concluded that adjuvant nivolumab plus ipilimumab combination did not show DFS benefits compared with placebo in patients with localised RCC who were at high risk of post-nephrectomy recurrence. Patient disease characteristics, adverse events leading to treatment discontinuation, and length of drug exposure might have contributed to the absence of efficacy observed in this study.

Currently, pembrolizumab is the only ICI approved as an adjuvant treatment for patients with localised RCC after nephrectomy, with specific approval in patients at an increased risk of recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions. This approval was based on data from the phase III KEYNOTE-564 study. The primary outcomes of CheckMate 914, IMmotion010, and PROSPER contrast with those of KEYNOTE-564, possibly reflecting differences in the patient populations and dosing schedules, and distinctions in the mechanism of action of the ICIs tested.

In an accompanied editorial article, Prof. Thomas Powles of the Barts Cancer Centre, Queen Mary University of London in London, UK and colleagues wrote that the study was well done, with a robust statistical analysis plan. The study design largely mirrored the KEYNOTE-564 study. However, there are issues with the drug regimen and duration in this study as ipilimumab was given every 6 weeks rather than every 3 weeks as is the case in advanced disease. Furthermore, only 6 months of treatment rather than a year of adjuvant treatment was given, as was the case with adjuvant pembrolizumab. There was less tolerance of the side effects of the drug combination in the adjuvant setting compared with in the advanced disease setting. These issues might have affected the results by reducing drug delivery. However, a signal towards improved efficacy with the combination would still be expected, and was largely absent in this study.

The results of this study raise also questions about how much benefit ipilimumab adds to single agent nivolumab. A randomised study comparing the combination of ipilimumab and nivolumab with nivolumab alone in advanced disease is ongoing and until this study is published, it is hard to quantify the exact benefit of ipilimumab plus nivolumab.

The editorialists underlined that adjuvant pembrolizumab has robust DFS, a promising OS signal, and an acceptable tolerability profile. Other negative adjuvant studies in RCC raise uncertainty and challenge many assumptions. A plateau in drug development in RCC might be being reached. Robust biomarker studies to identify patients who might benefit have been lacking, and such research is essential to improve the rational application of ICIs in the adjuvant setting.

The study was supported by Bristol Myers Squibb and Ono Pharmaceutical.