The addition of cabozantinib to nivolumab and ipilimumab also appears to improve responses in patients with advanced renal cell carcinoma in the phase 3 COSMIC-313 trial.
Treatment with cabozantinib (Cabometyx) plus nivolumab (Opdivo) and ipilimumab (Yervoy) produced improvement in progression-free survival (PFS) compared with nivolumab and ipilimumab alone in previously untreated, intermediate- or poor prognosis–risk advanced renal cell carcinoma (RCC), according to findings from the phase 3 COSMIC-313 RCC trial (NCT03937219).
The 12-month PFS probability was 0.57 (95% CI, 0.50-0.63) in the cabozantinib-based experimental treatment group (n = 276) vs 0.49 (95% CI, 0.42-0.55) in the control treatment group (n = 274; Hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01). The median PFS in each respective group was not reached (95% CI, 14.0 months-not evaluable [NE]) and 11.3 months (95% CI, 7.7-18.2). Treatment with cabozantinib plus nivolumab and ipilimumab yielded PFS improvements across all subgroups except for those with poor International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk (HR, 1.04; 95% CI, 0.65-1.69).
Based on blinded independent review, the median PFS in the experimental group was 16.9 months (95% CI, 11.5-NE) vs 11.3 months (95% CI, 7.7-14.0) in the control group (HR, 0.74; 95% CI, 0.58-0.94). The investigator-assessed median PFS in each respective group was 13.8 months (95% CI, 9.7-15.9) vs 11.2 months (95% CI, 7.6-14.0; HR, 0.79; 95% CI, 0.63-0.98). In the intent-to-treat (ITT) population, blinded independent review indicated a median PFS of 15.3 months (95% CI, 12.7-22.5) in the experimental group (n = 428) vs 11.3 months (95% CI, 9.3-14.0) in the control group (n = 427; HR, 0.74; 95% CI, 0.61-0.90).
“We are hopeful that additional agents can be added and can impact outcomes,” lead study author Toni K. Choueiri, MD, stated in a written comment to CancerNetwork®. “We are closely entering the era of triplet combination therapies in treating patients with advanced RCC.”
Choueiri is the director of Lank Center for Genitourinary Oncology and director of the Kidney Cancer Center at Dana-Farber Cancer Institute as well as a Jerome and Nancy Kohlber Chair and professor of Medicine at Harvard Medical School.
In the double-blind, phase 3 COSMIC-313 trial, patients were randomly assigned to receive 40 mg of cabozantinib daily or matched placebo in combination with nivolumab and ipilimumab. Investigators administered 3 mg/kg of body weight of nivolumab plus 1 mg/kg of ipilimumab once every 3 weeks for 4 cycles followed by nivolumab maintenance at a dose of 480 mg once every 4 weeks.
The primary end point was PFS based on RECIST v1.1 criteria. Secondary end points included objective response rate (ORR), duration of response, overall survival (OS), and safety.
Patients 18 years and older with a histologically confirmed diagnosis of advanced or metastatic RCC with a clear-cell component and intermediate or poor IMDC risk were eligible for enrollment on the trial. Additional eligibility criteria included having measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of at least 70, and availability of tumor tissue for quantifying PD-L1 status.
Investigators noted that baseline demographic and disease characteristics were balanced between the 2 treatment groups in both the PFS and the ITT populations. In the ITT population, most patients in the experimental and control groups, respectively, were male (76% vs 73%), White (79% vs 78%), had intermediate IDMC–risk disease (75% vs 75%), and a Karnofsky performance status of 90 or 100 (59% vs 63%). Among those in the ITT population, 30% were still receiving treatment in the experimental group along with 32% of those in the control group at the time of data cutoff.
In the PFS population, the ORR per blinded independent review was 43% (95% CI, 37%-49%) in the experimental group vs 36% (95% CI, 30%-42%) in the control group. Investigators reported that 3% of patients in both groups experienced a complete response. Subgroup analyses highlighted favorable ORRs for patients in the experimental group except for patients 65 years and older, those who had poor IMDC risk, and those with a PD-L1 tumor proportion score of at least 1%.
Per investigator assessment, the ORR was 50% (95% CI, 44%-56%) in the experimental group vs 41% (95% CI, 35%-47%) in the control group.
Grade 3/4 adverse effects (AEs) occurred in 79% of patients in the experimental group compared with 56% of those in the control group. The most common grade 3/4 AEs in each respective group included increased alanine aminotransferase levels (27% vs 6%), increased aspartate aminotransferase levels (20% vs 5%), and hypertension (10% vs 3%).
Overall, 45% of patients in the experimental group and 24% of those in the control group discontinued treatment due to treatment-related AEs (TRAEs). Five patients in the experimental group died due to TRAEs, including 1 incidence each of acute hepatic failure, gastrointestinal hemorrhage, hepatic failure, immune-mediated hepatitis, and respiratory failure, each. Four patients in the control group died due to TRAEs, including 1 instance of myocarditis, perforated ulcer, renal failure, and sudden death.
“The next steps [for the COSMIC-313 trial] include looking at more mature data that will give us an answer for the important end point of OS,” Choueiri concluded.
Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388:1767-1778. doi:10.1056/NEJMoa2212851