Background
Phase II RCT of 153 patients with metastatic RCC who progressed on or within 9 months of VEGF-targeted therapy.
Interventions and follow up
Arm A: Lenvatinib 18mg/d + everolimus 5mg/d
Arm B: Lenvatinib 24mg/d
Arm C: Everolimus 10mg/d
Primary endpoint: PFS
Arm B: Lenvatinib 24mg/d
Arm C: Everolimus 10mg/d
Primary endpoint: PFS
Results
mPFS (A vs B vs C): 14.6mo vs 7.4mo vs 5.5mo
mPFS, arm A vs C: HR 0.40, 95%CI 0.24-0.68, P=.0005
mPFS, arm A vs B: HR 0.66, 95%CI 0.30-1.10, P=.12
mOS (A vs B vs C): 25.5mo vs 18.4mo vs 17.5mo
mOS, arm A vs C: HR 0.51, 95%CI 0.30-0.88, P=.024
mOS, arm B vs C: HR 0.68, 95%CI 0.41-1.14, P=.12
mPFS, arm A vs C: HR 0.40, 95%CI 0.24-0.68, P=.0005
mPFS, arm A vs B: HR 0.66, 95%CI 0.30-1.10, P=.12
mOS (A vs B vs C): 25.5mo vs 18.4mo vs 17.5mo
mOS, arm A vs C: HR 0.51, 95%CI 0.30-0.88, P=.024
mOS, arm B vs C: HR 0.68, 95%CI 0.41-1.14, P=.12
Adverse events
Grade 3 GI (A vs B vs C): diarrhea 20% vs 19% vs 2%, constipation 30% vs 0% vs 0%
Other grade 3 (A vs B vs C): hypertension 14% vs 17% vs 2%, fatigue 14% vs 8% vs 0%, anemia 8% vs 2% vs 12%
Other grade 3 (A vs B vs C): hypertension 14% vs 17% vs 2%, fatigue 14% vs 8% vs 0%, anemia 8% vs 2% vs 12%
Conclusions
Lenvatinib + everolimus improved PFS versus everolimus alone in metastatic RCC after VEGF-targeted therapy. (Lenvatinib inhibits VEGFR 1/2/3, FGFR 1-4, PDGFR-alpha, c-KIT, and RET.)
Key Limitations
Phase II, open-label, small sample; the lenvatinib-alone arm was underpowered for definitive comparison; high rates of grade 3 toxicity; everolimus comparator now considered weak and predates the IO era.
Clinical Context
Supported FDA approval of lenvatinib + everolimus (2016) for advanced RCC after one prior antiangiogenic therapy; EMA approval followed. ESMO recognizes the combination as a later-line option; first-line lenvatinib/pembrolizumab (CLEAR) has since become the more prominent lenvatinib regimen.