KEYNOTE-426 trial

Background

Phase III RCT (N=861) of treatment-naive metastatic clear-cell RCC (IMDC favorable 32%, intermediate 55%, poor 13%).

Interventions and follow up

Arm A: Pembrolizumab 200mg IV q3wk (up to ~2yr) PLUS axitinib 5mg PO BID
Arm B: Sunitinib 50mg/d 4wk on / 2wk off
Primary endpoints: OS and PFS in the ITT population
Median follow-up: 30.6mo

Results

mOS, entire population (A vs B): not reached vs 35.7mo; HR 0.68, 95% CI 0.55-0.85, P=.0003
OS, favorable risk: HR 1.06, 95% CI 0.60-1.86, P=.58
OS, int/poor risk: HR 0.63, 95% CI 0.50-0.81, P=.0001
mPFS, entire population: 15.4mo vs 11.1mo; HR 0.71, 95% CI 0.60-0.84, P<.0001
PFS, favorable risk: HR 0.79, 95% CI 0.57-1.09, P=.078
PFS, int/poor risk: HR 0.69, 95% CI 0.56-0.84, P=.0002
ORR (A vs B): 60% vs 40%

Adverse events

Grade 3-5 AEs (A vs B): 67% vs 62%
Hepatic: transaminitis ~20% with combination (notable overlap of pembrolizumab and axitinib hepatotoxicity)
Discontinuation due to AEs (A vs B): 25% vs 10%

Conclusions

Pembrolizumab plus axitinib significantly improved OS, PFS, and ORR versus sunitinib across all IMDC risk groups in the ITT population, with the OS benefit driven by intermediate/poor-risk patients.

Key Limitations

Favorable-risk subgroup did not show a significant OS or PFS benefit; overlapping hepatotoxicity complicates attribution; clear-cell histology only.

Clinical Context

FDA approved pembrolizumab plus axitinib (Apr 2019) for first-line advanced RCC across all risk groups. A preferred first-line IO-TKI combination per ASCO/ESMO, including favorable-risk disease where IO-IO is not preferred.

References