Results of the phase III CheckMate 9ER trial show that the combination of nivolumab and cabozantinib significantly delays disease progression and prolongs the survival of previously untreated patients with advanced renal cell carcinoma (aRCC) compared to sunitinib. These findings mark nivolumab-cabozantinib as yet another treatment option in this setting.
In this trial involving patients with previously untreated aRCC, CABO-NIVO had significant benefits over SUN with respect to PFS, OS, and a higher likelihood of an objective response. Of note, the CABO-NIVO combination did come with some important toxic effects as 19.7% of the patients in the combination group had to discontinue at least one of the trial drugs prematurely. Dr. Lybaert: “This study is the last one in the list of studies assessing immunotherapy-based combination strategies in the frontline treatment of aRCC. These studies already led to the registration of nivolumab-ipilimumab, axitinib-avelumab, axitinib-pembrolizumab as first-line therapies for these patients and the excellent PFS, OS and ORR data reported will likely add CABO-NIVO to this list. Unfortunately, we currently don’t have a biomarker to help us in choosing the best option for the individual patient. Also the optimal treatment choice for aRCC patients relapsing after first-line therapy remains to be determined.”
Nivolumab, a PD-1/L-1 inhibitor (NIVO), and cabozantinib (CABO), a tyrosine kinase inhibitor, are both approved single-agent therapies for advanced renal cell carcinoma (aRCC). Showing efficacy together in a phase I trial, NIVO plus CABO have since demonstrated superior efficacy and safety over sunitinib (SUN) in the phase III CheckMate 9ER trial, involving advanced renal cell carcinoma patients. This open-label trial enrolled 651 aRCC patients with a clear cell component, randomising these patients 1:1 to receive either NIVO plus CABO (NIVO: 240mg every 2 weeks. CABO: 40mg once daily) or SUN (50mg once daily for 4 weeks; 6-week cycles) until disease progression or unacceptable toxicity, for a total of 2 years treatment duration with NIVO. In this updated analysis, patients were stratified by the presence of sarcoid features.
The median age of patients in the study was 62 years and approximately 20% had a poor prognostic IMDC score. About 80% of patients had two or more metastatic lesions. The median progression-free survival (PFS) was reported at 16.6 months with the CABO-NIVO combination which is twice as long as the 8.3 months median PFS seen with SUN (HR[95%CI]: 0.52[0.41-0.64]; p< 0.001). At 12 months, this translates into a PFS rate of 57.6% for CABO-NIVO and 36.9% with SUN. Also the objective response rate (ORR) was significantly higher with CABO-NIVO than with SUN at 55.7% and 27.1%, respectively. A complete response was seen in 8% of CABO-NIVO patients as compared to 4.6% with SUN. Nivolumab plus cabozantinib also had a significant overall survival benefit over sunitinib. The probability of overall survival at 12 months was 85.7% with CABO-NIVO and 75.6% with SUN (HR[98.89%CI]: 0.60[0.40 to 0.89]; p= 0.001). The benefits of nivolumab plus cabozantinib over sunitinib with respect to progression-free survival, overall survival, and objective response were generally consistent across subgroups, including IMDC risk status, tumor PD-L1 expression, and the presence or absence of bone metastases.
Adverse events (AEs) of any cause of grade 3 or higher occurred in 75.3% of the patients in the CABO-NIVO group and in 70.6% of those in the SUN group. AEs of any cause led to discontinuation of a trial drug in 19.7% of the patients treated with CABO-NIVO (6.6% discontinued NIVO only, 7.5% discontinued CABO only, and 5.6% discontinued both) and in 16.9% of the patients treated with SUN. Despite this higher rate of treatment discontinuation with CABO-NIVO, the quality of life was maintained at a high level.
Robert J Motzer et al., Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. Presented at ASCO GU 2021; Abstract no. 308.