Cabozantinib With Nivolumab and Ipilimumab Prolongs PFS in Renal Cell Carcinoma

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The combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) significantly improved progression-free survival (PFS) vs nivolumab and ipilimumab alone among patients with previously untreated, advanced renal cell carcinoma (RCC) who had intermediate or poor prognostic risk, according to findings from the phase 3 COSMIC-313 trial (NCT03937219).¹

With a median follow-up of 14.9 months (range, 10.8-26.0), the PFS in the experimental group which administered patients cabozantinib/nivolumab/ipilimumab was 0.57 (HR, .73; 95% CI, 0.57-0.94; P = .01) compared with 0.49 in the control arm of nivolumab and ipilimumab alone.

However, regarding safety, grade 3 or 4 adverse events were more common in the experimental group than in the control group at 79% vs 56%.

Toni K. Choueiri, MD

“We are closely entering the era of triplet combination therapies in treating patients with advanced renal cell carcinoma. With studies like these, we are hopeful that additional agents can be added and can impact outcomes. The next steps for researching the cabozantinib, nivolumab, and ipilimumab combination regimen in this kidney cancer population include looking at more mature data that will give us an answer for the important end point of overall survival,” Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, told Targeted Oncology^TM.

COSMIC-313 is a double-blind, phase 3 trial which enrolled patients aged 18 years and older with advanced clear-cell RCC who had not been given prior treatment and who had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were also required to have measurable disease per RECIST 1.1 as determined by the investigator, a Karnofsky performance status of ≥ 70%, and adequate organ and marrow function.²

The trial randomly assigned patients to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab or matched placebo in addition to nivolumab and ipilimumab. Nivolumab was given at a dose of 3 mg/kg of body weight and ipilimumab at 1 mg/kg, both of which were administered once every 3 weeks for 4 cycles. Following this, patients received nivolumab maintenance therapy at a dose of 480 mg once every 4 weeks for up to 2 years.¹

Investigators assessed the primary end point of PFS as determined by blinded independent review according to RECIST v1.1 and the secondary end point of overall survival (OS). PFS was evaluated in the first 550 patients who had undergone randomization and OS was assessed in all patients who had undergone randomization.

A total of 855 patients underwent randomization with 428 assigned to the experimental group and 427 to the control group. There were balanced baseline demographic and disease characteristics between the 2 groups in both populations.

Among the 276 patients in the experimental group and 274 in the control group who had undergone randomization, findings revealed that the probability of PFS at 12 months was 0.57 in the experimental group and 0.49 in the control group, and 43% of the patients in the experimental group vs 36% in the control group had a response.

In the experimental group, the median PFS was not reached (95% CI, 14.0 to not estimated) vs 11.3 months (95% CI, 7.7-18.2) in the control group. Findings from a prespecified subgroup analyses showed that despite in the subgroup of patients with poor IMDC risk, the PFS benefit associated with the addition of cabozantinib to nivolumab and ipilimumab was maintained.

As assessed by the investigators, responses were consistent with those as determined by blinded independent review and responses were observed in 50% (95% CI, 44-56) of the patients in the experimental arm and in 41% (95% CI, 35-47) in the control arm. In the experimental vs control arms, complete responses were observed in 3% vs 3% of patients, partial responses in 41% vs 32%, stable disease in 43% vs 36%, progressive disease in 8% vs 20%, and data could not be evaluated or were missing in 5% vs 8%.

The disease control rates were 86% and 72% in the experimental vs control arms and follow-up for overall survival is ongoing.

With the experimental combination vs control, the median duration of exposure to the trial regimen was 10.9 months (range, 0.2-28.5) and 10.3 months (range, 0.1-28.1). The median average daily dose of cabozantinib given to patients was 23.2 mg, and the median average daily dose of placebo was 36.1 mg. In the experimental group, 29% of the patients continued to receive treatment after disease progression, as did 41% of patients in the control group. Additionally, those in the experimental group had more dose modifications due to adverse events vs in the control group (91% v 71%), more dose delays of any trial-regimen component (90% v 70%) and more dose reductions of cabozantinib or placebo (54% v 20%).

More patients in the experimental group had grade 3 or 4 AEs. The most frequent across arms were alanine aminotransferase increased (27%v 6%), aspartate aminotransferase increased (20% v 5%) and hypertension (10% v 3%). Further, deaths deemed related to the trial regimen were not frequently reported in both groups.

Overall, the addition of cabozantinib to nivolumab and ipilimumab led to a longer PFS among patients with previously untreated advanced RCC with intermediate or poor prognosis but resulted in more grade 3 or 4 AEs.

REFERENCES:

1. Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851

2. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). ClinicalTrials.gov. Updated April 13, 2023. Accessed May 22, 2023. https://clinicaltrials.gov/ct2/show/NCT03937219