Background
Phase 3, global, randomised, double-blind, placebo-controlled trial. N=153 previously treated adults with locally advanced or metastatic, radioactive iodine (RAI)-refractory BRAF V600E-positive differentiated thyroid cancer (DTC), ECOG 0–2, across 42 sites in 11 countries. Tests BRAF + MEK inhibition (86% of enrollees Asian).
Results
Interventions and follow up: Arm A: Dabrafenib 150 mg PO BID + trametinib 2 mg PO once daily (n=101)
Arm B: Matching placebo (n=52); randomised 2:1
Primary endpoint: PFS by blinded independent review per RECIST 1.1
mFollow up: 17.4 months
Results: PFS: 12.8 vs 3.7 mo; HR 0.38, 95% CI 0.25–0.57, P<.0001.
ORR: 57% vs 4%; stratified difference 53%, 95% CI 42–64, P<.0001.
OS (interim): HR 0.66, 95% CI 0.36–1.19, P=.083 (NS).
DoR: not reached (experimental arm).
Arm B: Matching placebo (n=52); randomised 2:1
Primary endpoint: PFS by blinded independent review per RECIST 1.1
mFollow up: 17.4 months
Results: PFS: 12.8 vs 3.7 mo; HR 0.38, 95% CI 0.25–0.57, P<.0001.
ORR: 57% vs 4%; stratified difference 53%, 95% CI 42–64, P<.0001.
OS (interim): HR 0.66, 95% CI 0.36–1.19, P=.083 (NS).
DoR: not reached (experimental arm).
Adverse events
Serious AE (any grade): 43% vs 25%.
Most common grade ≥3: pneumonia 8% vs 2%.
Most common any-grade: pyrexia 48%.
Ocular: serous retinopathy 7% vs 0%.
Discontinuation (AE): 8% vs 6%; one treatment-related death (cerebrovascular accident).
Most common grade ≥3: pneumonia 8% vs 2%.
Most common any-grade: pyrexia 48%.
Ocular: serous retinopathy 7% vs 0%.
Discontinuation (AE): 8% vs 6%; one treatment-related death (cerebrovascular accident).
Conclusions
Dabrafenib plus trametinib significantly prolonged PFS and markedly increased ORR versus placebo in previously treated RAI-refractory BRAF V600E DTC, with no new safety signals. This is the first phase 3 validation of BRAF/MEK-directed therapy in this setting and supports its second-line use.
Key Limitations
OS immature and not significant at interim; predominantly Asian population (86%) may limit generalizability; placebo (not an active multikinase TKI such as lenvatinib or sorafenib) comparator, so relative benefit versus standard-of-care TKIs is untested; modest N; second-line and beyond.
Clinical Context
Dabrafenib + trametinib already holds FDA tumor-agnostic accelerated approval for BRAF V600E solid tumors (2022, ROAR basket). This trial provides the first randomised confirmation specifically in RAI-refractory BRAF V600E DTC, positioning BRAF/MEK targeted therapy alongside multikinase TKIs (lenvatinib, sorafenib). NCCN and ATA recognize BRAF-directed therapy as an option for BRAF-mutant RAI-refractory DTC.