Background
Phase III double-blind RCT (DECISION). N=417 patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC: papillary, follicular, Hürthle cell, or poorly differentiated variants) with radiologic progression within 14 months. ECOG PS 0–2. Enrolled 2009–2011 at 77 global sites. Sorafenib is an oral multikinase inhibitor targeting VEGFR1–3, PDGFR, RAF kinases (BRAF, CRAF), and others. First phase III trial of a targeted agent to demonstrate PFS benefit in RAI-refractory DTC.
Interventions and follow up
Arm A: Sorafenib 400 mg oral twice daily continuously until PD or unacceptable toxicity
Arm B: Placebo (crossover to sorafenib permitted at PD)
Primary endpoint: PFS
mFollow up: 34.5 month
Arm B: Placebo (crossover to sorafenib permitted at PD)
Primary endpoint: PFS
mFollow up: 34.5 month
Results
mPFS: 10.8 months (sorafenib) vs 5.8 months (placebo), HR 0.59 (95% CI 0.45–0.76), P<.001
ORR: 12.2% vs 0.5%
OS: Not significant (HR 0.80, P=.14) — confounded by crossover (71.4% of placebo patients crossed over)
ORR: 12.2% vs 0.5%
OS: Not significant (HR 0.80, P=.14) — confounded by crossover (71.4% of placebo patients crossed over)
Adverse events
Main adverse events: Grade ≥3 AEs: 37.2% (sorafenib) vs 26.3% (placebo). Most common grade 3 sorafenib-specific: palmar-plantar erythrodysesthesia (PPE/hand-foot syndrome) 20.3%, hypertension 9.9%, weight loss 6.0%, diarrhea 5.6%. Dose reductions in 64.3%; permanent discontinuation 18.8%.
Conclusions
Sorafenib significantly improved PFS by 5 months (HR 0.59) vs placebo in RAI-refractory DTC, with an ORR of 12.2% (partial responses) and high disease stabilization rate. No OS benefit demonstrated, partly due to high crossover. DECISION established sorafenib as the first FDA-approved targeted therapy for RAI-refractory DTC (2013).
Key Limitations
Key Limitations: Modest ORR (12.2%); most benefit was disease stabilization. OS was confounded by 71.4% crossover rate. Toxicity was substantial — PPE in 20% at grade 3, leading to frequent dose reductions. PFS improvement of 5 months without OS benefit limits the magnitude of clinical impact. Lenvatinib (SELECT trial) subsequently showed superior PFS (18.3 vs 3.5 months, HR 0.21) with higher ORR (65%) and is now preferred over sorafenib in first-line RAI-refractory DTC. Sorafenib has largely been displaced as the preferred first-line agent.
Clinical Context
FDA approved sorafenib for RAI-refractory DTC in November 2013 based on DECISION. However, lenvatinib (2015) demonstrated superior efficacy and has become the preferred first-line agent for most patients with progressive RAI-refractory DTC. Sorafenib is now considered a second-line or alternative option. Combination lenvatinib + pembrolizumab is under investigation. For BRAF V600E-mutant thyroid cancers (including papillary), dabrafenib + trametinib represents an alternative targeted approach.
References
References: Brose MS et al, Lancet 2014 (primary)