Combination of Ipilimumab and Nivolumab is one of the first line treatment recommended in patients with advanced renal-cell carcinoma with intermediate or poor prognostic risk according to International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) categories[1]. However, in the CheckMate 214 trial [2], which studied nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma, 20% of the patients on nivolumab and ipilimumab had progressive disease.
In an exploratory analysis in the CheckMate 9ER trial [3], which studied the combination of cabozantinib, a multi- tyrosine kinase inhibitor, in combination with nivolumab compared to sunitinib in previously untreated advanced renal cell carcinoma, a small subset of patients who received cabozantinib in combination with nivolumab-ipilimumab showed that this combination had clinical activity and acceptable safety profile.
With this, the COSMIC 313 trial [4] aims to evaluate this triple agent combination compared to nivolumab and ipilimumab with placebo in patients with previously untreated renal cell carcinoma who have intermediate or poor risk according to IMDC category.
COSMIC 313 – Trial population and design
Patients 18 years of age or older and had histologically confirmed advanced or metastatic renal-cell carcinoma with a clear cell component were eligible, provided that they had IMDC risk intermediate or poor.
Patients were randomly assigned in a 1:1 ratio to receive cabozantinib in addition to nivolumab-ipilimumab (experimental group) or placebo in addition to nivolumab-ipilimumab (control group). Both groups received nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four cycles, followed by nivolumab maintenance therapy (480 mg every 4 weeks) for up to 2 years. Cabozantinib (40 mg) or placebo was administered orally once daily. Patients were treated until a loss of clinical benefit was observed or unacceptable toxic effects occurred. A total of 855 eligible patients underwent randomisation, with 428 patients assigned to the experimental group and 427 patients assigned to the control group.
Results of Combination Cabozantinib with Ipilimumab-Nivolumab
The median follow-up of 17.7 months (range, 10.2 to 31.3) in the intention-to-treat population.
The probability of progression-free survival at 12 months was 0.57 (95% confidence interval [CI], 0.50 to 0.63) in the experimental group and 0.49 (95% CI, 0.42 to 0.55) in the control group (hazard ratio for disease progression or death, 0.73; 95% CI, 0.57 to 0.94; P = 0.01). Based on the hazard ratio, it shows that patients in the experimental group had a 27% lower risk of disease progression and death compared to the control group.
The median progression-free survival was not reached (95% CI, 14.0 months to “could not be estimated”) in the experimental group and was 11.3 months (95% CI, 7.7 to 18.2) in the control group. In prespecified subgroup analyses, the progression-free survival benefit associated with the addition of cabozantinib to nivolumab and ipilimumab was maintained, except in the subgroup of patients who had poor IMDC risk.
Source: Choueiri TK, et al. 2023;388(19):1767–78
Safety of Three-Agents Use
The median duration of exposure to the trial regimen was 10.9 months (range, 0.2 to 28.5) in the experimental group and 10.3 months (range, 0.1 to 28.1) in the control group. The median average daily dose of cabozantinib was 23.2 mg, and the median average daily dose of placebo was 36.1 mg.
A grade 3 (severe, but not life threatening) or 4 (life threatening) adverse event occurred in 79% of the patients in the experimental group and in 56% in the control group. Grade 3 or 4 adverse events that occurred more frequently in the experimental group than in the control group included increased alanine aminotransferase level, increased aspartate aminotransferase level and hypertension.
Deaths that were related to the trial regimen and occurred within 100 days before the last dose of the trial regimen were observed in 5 patients (1%) in the experimental group.
Conclusion
The COSMIC 313 trial is the first study to report successful treatment intensification using triplet therapy in advanced renal cell carcinoma. It answers the important clinical question of whether cabozantinib added to dual checkpoint inhibitors can improve the outcomes of untreated poor to intermediate IMDC risk advanced renal cell carcinoma. Additional survival data will be required to further strengthen the evidence to support the use of this triplet therapy in treatment of advanced renal-cell carcinoma.
Reference:
- Esmo. EUpdate – renal cell carcinoma treatment recommendations [Internet]. [cited 2023 Jun 1]. Available from: https://www.esmo.org/guidelines/guidelines-by-topic/genitourinary-cancers/renal-cell-carcinoma/eupdate-renal-cell-carcinoma-treatment-recommendations-4
- Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New England Journal of Medicine. 2018;378(14):1277–90. doi:10.1056/nejmoa1712126
- Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab Plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine. 2021;384(9):829–41. doi:10.1056/nejmoa2026982
- Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. New England Journal of Medicine. 2023;388(19):1767–78. doi:10.1056/nejmoa2212851
