The European Commission has approved the combination of cabozantinib plus nivolumab for use as a frontline treatment in patients with advanced renal cell carcinoma.
The European Commission (EC) has approved the combination of cabozantinib (Cabometyx) plus nivolumab (Opdivo) for use as a frontline treatment in patients with advanced renal cell carcinoma (RCC).1
The regulatory decision is based on data from the phase 3 CheckMate-9ER trial (NCT03141177), which demonstrated the superiority of the doublet over sunitinib (Sutent) in patients with advanced RCC.2
Cabozantinib/nivolumab resulted in an improvement in progression-free survival (PFS) per blinded independent central review (BICR) over sunitinib, at 16.6 months (95% CI, 12.5-24.9) vs 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.51; 95% CI, 0.41-0.64; P <.0001). The median overall survival (OS) had not yet been reached in either arm, although the doublet was found to reduce the risk of death by 40% (HR, 0.60; 95% CI, 0.40-0.89; P = .0010).
Additionally, cabozantinib plus nivolumab elicited an objective response rate (ORR) of 55.7% (95% CI, 50.1%-61.2%) vs 27.1% (95% CI, 22.4%-32.3%) with sunitinib (P <.0001). ORR was found to favor the doublet over sunitinib across all subgroups analyzed, including by International Metastatic RCC Database (IMDC) risk status, tumor PD-L1 expression, and bone metastases.
“Today’s EC approval for the use of [cabozantinib] in combination with [nivolumab] provides an important new first-line treatment option for patients living with advanced RCC,” Howard Mayer, executive vice president and head of Research and Development at Ipsen, stated in a press release. “At Ipsen, we’re proud that this, now approved, treatment option not only addresses key efficacy benefits, but also the need to maintain quality of life [QoL] for patients.”
A total of 651 patients with previously untreated advanced or metastatic RCC were enrolled to the trial. To be eligible for enrollment, patients needed to have a clear cell component. Notably, patients could fall into any IMDC risk group. Stratification factors included IMDC risk score, tumor PD-L1 expression, and geographic region.
Participants were randomized 1:1 to receive either nivolumab at 240 mg every 2 weeks plus cabozantinib at 40 mg once daily (n = 323) or sunitinib at 50 mg once daily on a cycle of 4-weeks-on and 2-weeks-off (n = 328). Treatment was given until progressive disease or intolerable toxicity. The primary end point of the research was PFS while secondary end points included OS, ORR, and safety.
The median age of patients across the arms was 61.5 years. The majority of patients were male, had an IMDC prognostic score of intermediate (1 to 2), and tumor PD-L1 expression of less than 1% of indeterminate. Forty-nine percent of patients were from the United States or Europe, while the remainder were from the rest of the world. Most patients had 2 or more sites with target or non-target lesions, and the most common site of metastasis was in the lung.
Additional results indicated that among those who achieved a response with cabozantinib/nivolumab, 8.0% experienced a complete response, 47.7% had a partial response, and 32.2% had stable disease. Moreover, 5.6% reported disease progression and 6.5% were either not evaluable or not assessed. The median time to response was 2.8 months (range, 1.0-19.4) and the median duration of response was 20.2 months (range, 17.3–not estimable [NE]).
Ninety-five percent of evaluable patients who received the doublet experienced tumor reductions, while 70% experienced a reduction of 30% or greater. In the control arm, 85% of patients experienced a reduction in tumor size, while 42% had a reduction of 30% or greater.
The median PFS per investigator assessment with cabozantinib/nivolumab vs sunitinib was 19.4 months (95% CI, 16.6-NE) vs 9.2 months (95% CI, 7.1-11.0), respectively (HR, 0.46; 95% CI, 0.36-0.57; P <.0001). The ORRs in the investigative and control arms per investigator assessment were 59.4% (95% CI, 53.9%-64.8%) and 32.0% (95% CI, 27.0%-37.4%), respectively (P <.0001).
Additional results presented during the 2021 Genitourinary Cancers Symposium showed that the superior efficacy of the doublet over sunitinib was maintained at an extended minimum follow-up of 16 months.3 The doublet reduced the risk of disease progression by 48% and the median PFS remained doubled. Moreover, cabozantinib/nivolumab resulted in a 34% reduction in the risk of death over sunitinib and the ORR remained approximately doubled.
Moreover, cabozantinib/nivolumab was also found to have health-related QoL (HRQoL) benefits over sunitinib, with statistically significant differences between the treatment arms that favored the doublet.4 When compared with single-agent sunitinib, the combination resulted in delayed deterioration and a significant decrease in risk of confirmed deterioration in HRQoL scores, including disease-related kidney cancer symptoms.
Regarding safety, all-cause toxicities were reported in 99.7% of those on the doublet vs 99.1% of those on the monotherapy.3 Moreover, 78.4% vs 73.1% of patients on the investigative and control arms, respectively, experienced effects that were grade 3 or higher in severity. Adverse effects (AEs) associated with treatment occurred in 96.9% of those who received cabozantinib/nivolumab and 93.1% of those who were given sunitinib; 62.2% vs 52.5%, respectively, were grade 3 or higher.
Approximately 23% of patients in the combination arm discontinued treatment of either nivolumab, cabozantinib, or both agents, due to treatment-related toxicities; 9.7% discontinued nivolumab only, 7.2% discontinued cabozantinib only, and 6.6% discontinued both either simultaneously or sequentially. Treatment-related AEs led to the discontinuation of treatment in 9.1% of those on the control arm.
One patient on the investigative arm died due to a treatment-related AE, as well as 2 patients on the control arm.
Moreover, 20.9% of patients who received the doublet also received corticosteroids to manage immune-mediated toxicities; 11.6% received corticosteroids continuously for 14 days or longer, while 4.4% received them for 30 days or longer.
“The combination of nivolumab and cabozantinib pairs 2 proven agents for advanced RCC that together have shown superior efficacy across key end points and subgroups of patients compared to sunitinib in the CheckMate-9ER trial,” Marc-Oliver Grimm, MD, professor of medicine and head of the Urology Department at Jena University Hospital, added in the release. “Additionally, the combination’s safety profile was manageable with known protocols, leading to a low rate of treatment-related discontinuations.”