Background
Phase III RCT (N=651) of treatment-naive advanced or metastatic clear-cell RCC (IMDC favorable 23%, intermediate 58%, poor 19%).
Interventions and follow up
Arm A: Nivolumab 240mg IV q2wk PLUS cabozantinib 40mg PO daily
Arm B: Sunitinib 50mg/d 4wk on / 2wk off
Primary endpoint: PFS
Median follow-up: 18.1mo
Arm B: Sunitinib 50mg/d 4wk on / 2wk off
Primary endpoint: PFS
Median follow-up: 18.1mo
Results
mPFS (A vs B): 16.6mo vs 8.3mo; 1-yr PFS 57.6% vs 36.9%; HR 0.51, 95% CI 0.41-0.64, P<.001
mOS (A vs B): not reached in either arm; 12-mo OS 85.7% vs 75.6%; HR 0.60, 98.89% CI 0.40-0.89, P=.001
ORR (A vs B): 55.7% vs 27.1%, P<.001
mPFS by risk (A vs B): favorable not reached vs 12.8mo; intermediate 17.7mo vs 8.5mo; poor 12.3mo vs 4.2mo
mOS (A vs B): not reached in either arm; 12-mo OS 85.7% vs 75.6%; HR 0.60, 98.89% CI 0.40-0.89, P=.001
ORR (A vs B): 55.7% vs 27.1%, P<.001
mPFS by risk (A vs B): favorable not reached vs 12.8mo; intermediate 17.7mo vs 8.5mo; poor 12.3mo vs 4.2mo
Adverse events
Grade ≥3 AEs (A vs B): 60.6% vs 50.9%
Immune-related: 19.1% of arm A required glucocorticoids for immune-mediated AEs
Discontinuation of any drug (A vs B): 19.7% vs 16.9%
Immune-related: 19.1% of arm A required glucocorticoids for immune-mediated AEs
Discontinuation of any drug (A vs B): 19.7% vs 16.9%
Conclusions
Nivolumab plus cabozantinib significantly improved PFS, OS, and ORR versus sunitinib across all IMDC risk groups in first-line advanced clear-cell RCC.
Key Limitations
Relatively short follow-up at primary report with OS not reached; clear-cell histology only; overlapping toxicity management between checkpoint inhibitor and TKI.
Clinical Context
FDA approved nivolumab plus cabozantinib (Jan 2021) for first-line advanced RCC. A preferred first-line IO-TKI combination across risk groups per ASCO/ESMO, alongside pembrolizumab/axitinib and pembrolizumab/lenvatinib.