Background
Phase III, double-blind, placebo-controlled RCT (COSMIC-311). 187 patients (primary PFS analysis population) with radioiodine-refractory differentiated thyroid cancer (DTC) who had progressed after prior VEGFR-targeted therapy (lenvatinib and/or sorafenib). Randomized 2:1 to cabozantinib or placebo. Co-primary endpoints: ORR (first 100 randomized patients) and PFS (ITT population).
Interventions and follow up
Arm A: Cabozantinib 60 mg PO daily
Arm B: Placebo (crossover to open-label cabozantinib permitted at progression)
Primary endpoint: Objective response rate (ORR) and progression-free survival (PFS)
mFollow up: 6.2 months (ITT population, primary analysis)
Arm B: Placebo (crossover to open-label cabozantinib permitted at progression)
Primary endpoint: Objective response rate (ORR) and progression-free survival (PFS)
mFollow up: 6.2 months (ITT population, primary analysis)
Results
ORR: 9% vs 0% (Arm A vs Arm B), P=.017 (did not meet prespecified significance threshold)
mPFS: not reached vs 1.9 months (Arm A vs Arm B), HR 0.22, 96%CI 0.13-0.36, P<.0001
6-month PFS: 57% vs 17% (Arm A vs Arm B)
mPFS: not reached vs 1.9 months (Arm A vs Arm B), HR 0.22, 96%CI 0.13-0.36, P<.0001
6-month PFS: 57% vs 17% (Arm A vs Arm B)
Adverse events
Overall (Arm A vs Arm B): grade 3-4 AEs 57% vs 26%; serious treatment-related AEs 16% vs 2%
Most common (Arm A vs Arm B): palmar-plantar erythrodysesthesia 10% vs 0%; hypertension 9% vs 3%; no treatment-related deaths
Most common (Arm A vs Arm B): palmar-plantar erythrodysesthesia 10% vs 0%; hypertension 9% vs 3%; no treatment-related deaths
Conclusions
In patients with radioiodine-refractory DTC who progressed after prior VEGFR-targeted therapy, cabozantinib significantly prolonged PFS versus placebo, providing a new treatment option for a population with no established standard of care.
Key Limitations
The ORR co-primary endpoint did not reach prespecified statistical significance, and short median follow-up at the primary analysis limited durability and OS assessment. Crossover from placebo to cabozantinib confounds any OS interpretation. Heterogeneous prior VEGFR-targeted regimens and broad histologic inclusion limit precision for individual subgroups.
Clinical Context
COSMIC-311 led to FDA approval of cabozantinib (September 2021) for locally advanced or metastatic radioiodine-refractory DTC after prior VEGFR-targeted therapy (sorafenib and/or lenvatinib), establishing it as a standard second-line option. ESMO guidelines recognize cabozantinib in this previously-treated, RAI-refractory setting following progression on first-line multikinase inhibitor therapy.