The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.
Methods
In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. 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 (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.
Results
Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P=0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.
Conclusions
Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219. opens in new tab.)
Investigators of the COSMIC-313 have recently published data for patients previously untreated with metastatic renal-cell carcinoma (mRCC) who had intermediate or poor prognostic risk according to the IMDC risk-factors [1]. This is the first study to evaluate a “triplet” therapy against a contemporary immuno-oncology (IO) “doublet” control. A total of 855 patients were included in this phase 3, multinational, randomised, double-blinded, place-controlled trial. A total of four cycles of nivolumab/ipililumab +/- cabozantinib were given and afterwards patients were started on nivolumab maintenance. Treatment with cabozantinib plus nivolumab and ipilimumab offered significantly longer progression-free-survival (PFS) than treatment with nivolumab plus Ipilimumab alone, at a cost of higher Grade 3 or 4 adverse events (79% in experimental group vs 56% in control group) [1]. Taking a closer look at results, it appears that patients who received the “triplet” had a 12 months-PFS of 57%, while those who received the “doublet” had a 12 months-PFS of 49%.
The rationale for combination therapies is the immune-enhancement effect: TKI promotes T-cells infiltration in tumour cells and IO primes, activates, and induces T-cell-mediated tumour cell death. Combining VEGFR-TKI inhibitor to dual IO/IO immune checkpoint inhibitor decreases 20% of the early progressive disease rate shown by the IO/IO combo alone.
Do all patients with mRCC equally benefit from triplet therapy? Clearly one size does not fit all. The improvement in PFS evidenced in COSMIC-313 comes with trade-off adverse events that can significantly impair patients’ quality of life. Currently, biomarkers have failed to adequately personalise treatment, so we still rely on clinical features to establish care pathways. Cancer cell death to treatment response is inversely proportional to tumour burden at time of treatment. The results of KeyNote 564 on adjuvant pembrolizumab have shown such an improvement in PFS on M1 but no evidence of disease at baseline subgroup ( 81.4% vs 47.4%, HR 0.28, CI 0.11-0.73); thus probably metastatic volume may play an important role on therapy selection for upfront therapy in first line mRCC. Further follow-up and subgroup analysis on COSMIC-313 and other first-line trials might provide some answers to personalised therapy.
Reference:
[1] International mRCC Database Consortium, https://www.imdconline.com/