Background
Phase III, double-blind, placebo-controlled, multicenter RCT (SELECT) of 392 patients with progressive, radioactive-iodine-refractory differentiated thyroid cancer, randomized 2:1. Up to one prior VEGF-targeted therapy was permitted.
Interventions and follow up
Arm A: lenvatinib 24 mg orally daily in 28-day cycles
Arm B: placebo (with optional crossover to open-label lenvatinib on progression)
Primary endpoint: progression-free survival
Secondary endpoints: response rate, OS, safety
mFollow up: 17.1 months
Arm B: placebo (with optional crossover to open-label lenvatinib on progression)
Primary endpoint: progression-free survival
Secondary endpoints: response rate, OS, safety
mFollow up: 17.1 months
Results
mPFS: 18.3mo vs 3.6mo (arm A vs B); HR 0.21, 99% CI 0.14-0.31; P<.001
ORR: 64.8% vs 1.5%
mOS: not reached in either group (no significant difference, confounded by crossover)
ORR: 64.8% vs 1.5%
mOS: not reached in either group (no significant difference, confounded by crossover)
Adverse events
Most common (any grade, lenvatinib): hypertension 67.8%, diarrhea 59.4%, fatigue/asthenia 59.0%, decreased appetite 50.2%, weight loss 46.4%, nausea 41.0%
Discontinuations due to AEs (arm A vs B): 14.2% vs 2.3%; 6 of 20 deaths during treatment were considered drug-related in the lenvatinib group
Discontinuations due to AEs (arm A vs B): 14.2% vs 2.3%; 6 of 20 deaths during treatment were considered drug-related in the lenvatinib group
Conclusions
Lenvatinib significantly improved progression-free survival and response rate versus placebo in progressive, radioactive-iodine-refractory differentiated thyroid cancer, at the cost of more adverse events requiring active toxicity management.
Key Limitations
OS not interpretable due to placebo-to-lenvatinib crossover; substantial toxicity necessitating dose reductions/interruptions; no head-to-head comparison with sorafenib. Generalizability to less-fit, older patients limited given frequent severe AEs.
Clinical Context
SELECT led to FDA and EMA approval of lenvatinib for progressive, radioactive-iodine-refractory differentiated thyroid cancer. ESMO guidelines recommend lenvatinib (or sorafenib) as standard systemic therapy for progressive RAI-refractory disease.