At ESMO 2020, Dr. Choueiri presented the first results of the phase III CheckMate 9ER trial comparing nivolumab plus cabozantinib vs. sunitinib as a first-line treatment option for patients with advanced renal cell carcinoma (aRCC). In this trial, the nivolumab-cabozantinib combination was found to be associated with a significantly longer progression-free and overall survival compared to sunitinib, with a significantly higher overall response rate (ORR). In addition, the safety profile of this combination was found to be manageable and consistent with the known safety profile of nivolumab and cabozantinib as single agents.
Both nivolumab and cabozantinib are approved therapies for the treatment of patients with aRCC and demonstrated significant improvements in overall survival (OS) in phase III clinical trials. While nivolumab promotes the antitumour responses by preventing cancer from evading immune detection, cabozantinib has antiangiogenic and immunomodulatory properties that may counteract tumour-induced immunosuppression. Combining nivolumab and cabozantinib showed promising preliminary antitumour activity in a phase I study in patients with advanced genitourinary malignancies, providing a rationale for this combination. At ESMO 2020, Dr. Choueiri presented the first results of the phase III CheckMate 9ER trial comparing nivolumab plus cabozantinib to sunitinib as a first-line treatment option for aRCC. In total, 651 previously untreated advanced or metastatic RCC patients were randomised (1:1) to nivolumab (240 mg flat dose intravenously [IV] once every two weeks [Q2W] plus cabozantinib (40 mg, orally, once a day) or sunitinib (50 mg, orally in cycles of 4 weeks on, 2 weeks off) until disease progression or unacceptable toxicity. Baseline demographic and disease characteristic were well balanced between both treatment arms and largely representative of treatment-naïve aRCC patients.
After a median follow-up of 18.1 months, all three efficacy endpoints of the CheckMate 9ER trial were met. The median PFS was 16.6 months with the combination of nivolumab and cabozantinib, as compared to only 8.3 months with sunitinib, representing a significant 49% reduction in the risk of disease progression or death (HR [95%CI]: 0.51 [0.41-0.64], p<0.0001). In addition, the risk of death was reduced by a significant 40% (HR [98.89%CI]: 0.60 [0.40-0.89], p=0.0010; medians not reached). These results were consistent across prespecified subgroups such as International Metastatic RCC Database Consortium (IMDC) risk status, tumour PD-L1 expression and bone metastases. The objective response rate (ORR) doubled from 27.1% with sunitinib to 55.7% with the combination of nivolumab and cabozantinib (p<0.0001). In total, respectively 8.0% and 4.6% of the patients achieved a complete response upon study treatment. Also, the median duration of response was in favour of the nivolumab plus cabozantinib combination (20.2 vs. 11.5 months) compared to sunitinib. With the combination therapy, 70% of evaluable patients experienced a reduction in the tumour size of at least 30% from baseline, as compared to 42% of evaluable patients in the sunitinib arm.
Treatment-related adverse events (TRAEs) of any-grade occurred in 96.6% of the patients treated with the combination, while this was the case for 93.1% of patients treated with sunitinib. Respectively 60.6% and 50.9% of patients experienced a grade ≥3 TRAE. Dose reductions of nivolumab were not allowed in the study design but 56.3% of patients required a dose reduction of cabozantinib and 51.6% a reduction in sunitinib dosing. Despite the higher incidence of TRAEs in the combination arm, only 3.1% of patients discontinued both nivolumab and cabozantinib while 8.8% discontinued sunitinib. Immune-mediated adverse events in patients treated with nivolumab and cabozantinib were mostly low grade. One treatment-related death occurred with nivolumab plus cabozantinib as compared to two with sunitinib. Finally, health-related quality of life as compared to baseline score improved for patients treated with nivolumab and cabozantinib while quality of life decreased for patients in the sunitinib arm.
Nivolumab plus cabozantinib is associated with a significantly superior PFS, OS and ORR compared to sunitinib as a first-line treatment for patients with aRCC. The safety profile of this treatment combination was manageable and consistent with the known safety-profile of the individual agents. Interestingly, patients treated with the nivolumab-cabozantinib combination experienced a significantly better quality of life compared to patients in the sunitinib arm. As such, the results of the CheckMate 9ER trial support nivolumab plus cabozantinib as a potential new standard first-line treatment option for patients with aRCC.
Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Presented at ESMO 2020; Abstract 696O_PR.