CLEAR trial

Background

Phase III RCT of 1,069 patients with previously untreated advanced clear-cell RCC (IMDC favorable 31%, intermediate 60%, poor 9%). Evaluated first-line lenvatinib-based combinations versus sunitinib.

Interventions and follow up

Arm A: Lenvatinib 20mg PO daily + pembrolizumab 200mg IV q3w
Arm B: Lenvatinib 18mg PO daily + everolimus 5mg PO daily
Arm C: Sunitinib 50mg 4wk on, 2wk off
Primary endpoint: PFS
Median follow-up: 26.6mo

Results

mPFS, arm A vs C: 23.9mo vs 9.2mo, HR 0.39, 95%CI 0.32-0.49, P<.001
mPFS, arm B vs C: 14.7mo vs 9.2mo, HR 0.65, 95%CI 0.53-0.80, P<.001
mOS, arm A vs C: HR 0.66, 95%CI 0.49-0.88, P=.005
mOS, arm B vs C: HR 1.15, 95%CI 0.88-1.50, P=.30
ORR, arm A vs C: 71% vs 36%

Adverse events

Grade ≥3 overall (A vs B vs C): 82.4% vs 83.1% vs 71.8%
Common toxicities: hypertension, diarrhea, fatigue; lenvatinib dose reductions frequent

Conclusions

First-line lenvatinib + pembrolizumab significantly improved PFS, OS, and ORR versus sunitinib in advanced RCC; lenvatinib + everolimus improved PFS but not OS.

Key Limitations

Open-label design; high rate of grade ≥3 toxicity and dose modifications with lenvatinib combinations; sunitinib comparator no longer a preferred first-line standard; cross-trial comparison with ipilimumab/nivolumab and other IO-TKI doublets limited by absence of head-to-head data.

Clinical Context

FDA approved lenvatinib + pembrolizumab (Aug 2021) for first-line advanced RCC; EMA approval followed. ESMO guidelines list IO-TKI doublets including lenvatinib/pembrolizumab among preferred first-line options across IMDC risk groups. Final OS analysis maintained the survival benefit.

References