Dr Singer on the Efficacy of IO/TKI Doublets in Advanced RCC

Adam E. Singer, MD, PhD, Health Sciences Clinical Instructor, medicine, division lead, kidney cancer, Division of Hematology/Oncology, UCLA Health, discusses currently available combination treatment regimens for the first-line treatment of patients with renal cell carcinoma (RCC), highlighting key findings from the phase 3 CheckMate 9ER trial (NCT03141177) investigating nivolumab (Opdivo) plus cabozantinib (Cabometyx) in patients with advanced RCC.

In the frontline treatment of patients with RCC, multiple VEGFR/TKI and checkpoint inhibitor combinations are available, offering improved tolerability over traditional monotherapies, such as sunitinib (Sutent), Singer begins. Three prominent IO/TKI combinations include axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib plus nivolumab, and lenvatinib (Lenvima) plus pembrolizumab, he says. Additionally, dual checkpoint inhibition with ipilimumab (Yervoy) plus nivolumab is approved for this patient population.

Data from the CheckMate 9ER trial, which were presented at the 2024 ASCO Annual Meeting, showed that patients who received cabozantinib plus nivolumab stayed on therapy for a longer duration than those who received sunitinib monotherapy, reflecting the improved safety profile of the combination regimen, Singer explains. The 48-month mean time on protocol treatment among patients with grade 2 or higher treatment-related adverse effects (TRAEs) was 8.3 months in the combination arm vs 6.7 months in the sunitinib monotherapy arm (difference, 1.7; 95% CI, 0.1-3.2). These respective values among patients without grade 2 or higher TRAEs were 14.3 months and 7.4 months (difference, 6.8; 95% CI, 4.8-8.8).

Moreover, patients who discontinued cabozantinib plus nivolumab generally delayed the initiation of a subsequent therapy for a longer duration than those who discontinued sunitinib, indicating a post-discontinuation benefit with the combination, he notes. At 48 months of follow-up, the mean treatment-free survival (TFS) post–study treatment in patients without grade 2 or higher TRAEs was 3.0 months in the combination arm vs 2.3 months in the sunitinib arm (difference, 0.7; 95% CI, –0.4 to 1.8). In these respective populations, the mean TFS in those with grade 2 or higher TRAEs was 3.9 months vs 2.3 months (difference, 1.6; 95% CI, 0.5-2.8). This effect may stem from the extended half-lives of immunotherapies, which potentially offer prolonged efficacy even after treatment cessation, Singer concludes.