Cabozantinib, nivolumab and ipilimumab in advanced renal-cell carcinoma

The multi-tyrosine kinase inhibitor cabozantinib added to dual immune checkpoint inhibition with nivolumab and ipilimumab can improve outcomes in untreated first-line poor- and intermediate-risk renal-cell carcinoma patient population, as shown by the phase III COSMIC-313 trial recently published in The New England Journal of Medicine.

The study enrolled 855 patients with advanced renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab and ipilimumab were administered once every 3 weeks for four cycles; patients then received nivolumab maintenance therapy once every 4 weeks for up to 2 years. The probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group; 43% of the patients in the experimental group and 36% in the control group had a response. COSMIC-313 is the first study that reported successful treatment intensification by the use of triplet therapy in metastatic renal-cell carcinoma, but overall survival  data are not yet mature. Patients experienced the benefit of superior disease control, but also additional toxicities: grade 3 or 4 adverse events and discontinuations were more common in the experimental group than in the control group. Trial limitations, according to investigators, include the relatively short duration of follow-up and the lack of mature overall survival data; the follow-up therefore is still ongoing.