Background
ROAR (Rare Oncology Agnostic Research) — Phase II non-randomized, open-label basket study. ATC cohort: N=36 patients with unresectable or metastatic anaplastic thyroid cancer (ATC) harboring BRAF V600E mutation, confirmed by local or central testing. Enrolled at global sites under NCT02034110. Dabrafenib (BRAF V600E inhibitor) + trametinib (MEK1/2 inhibitor) was the experimental regimen. ATC is an extremely aggressive malignancy (median OS historically <6 months) — BRAF V600E occurs in ~25–40% of ATC cases. Updated analysis with ~4 additional years of follow-up beyond the original interim (23-patient) analysis that led to FDA approval.
Interventions and follow up
Regimen: Dabrafenib 150 mg PO BID + trametinib 2 mg PO QD until progression in BRAF V600E-mutant anaplastic thyroid cancer (ATC cohort, N=36)
Primary endpoint: ORR (investigator-assessed, RECIST 1.1)
mFollow up: 11.1 months (range 0.9–76.6 months)
Primary endpoint: ORR (investigator-assessed, RECIST 1.1)
mFollow up: 11.1 months (range 0.9–76.6 months)
Results
ORR: 56% (95% CI 38.1–72.1%), including 3 complete responses
12-month DOR rate: 50%
mPFS: 6.7 months
mOS: 14.5 months
12-month OS rate: 51.7%; 24-month OS rate: 31.5%
12-month DOR rate: 50%
mPFS: 6.7 months
mOS: 14.5 months
12-month OS rate: 51.7%; 24-month OS rate: 31.5%
Adverse events
Main adverse events: Consistent with established tolerability of dabrafenib + trametinib. Common: pyrexia, fatigue, nausea, diarrhea. Grade 3–4: manageable. No new safety signals with extended follow-up. Dabrafenib + trametinib combination reduces paradoxical MAPK activation vs dabrafenib monotherapy.
Conclusions
Dabrafenib + trametinib achieved a 56% ORR — the highest ORR reported for any systemic therapy in BRAF V600E ATC — with a median OS of 14.5 months vs historical <6 months and a 24-month OS rate of 31.5%. This represents transformative benefit in an otherwise uniformly fatal malignancy. Durable responses in 3 patients with CRs and 50% maintaining response at 12 months confirm meaningful long-term benefit in a subset.
Key Limitations
Single-arm basket design without a concurrent control; comparison to historical controls is inherently limited. N=36 is small. Most patients had short follow-up due to disease severity — median follow-up 11.1 months despite enrollment over years. Only BRAF V600E-positive ATC (~25–40% of all ATC) is eligible — molecular testing required at diagnosis. Median PFS 6.7 months indicates most patients ultimately progress. No validated biomarker predicts which BRAF V600E ATC patients will achieve durable responses.
Clinical Context
FDA approved dabrafenib + trametinib for BRAF V600E-mutant ATC in May 2018 based on earlier interim analysis (23 patients, ORR 69%), making it the first drug approved specifically for ATC. ROAR updated analysis confirmed durable benefit. BRAF V600E testing is now mandatory at ATC diagnosis. The combination is recommended as systemic therapy for BRAF V600E ATC by NCCN and ESMO alongside multimodal management (surgery if resectable, RT). Concurrent immunotherapy combinations (e.g., with anti-PD-1) are under investigation. ATC remains associated with poor outcomes even with targeted therapy, underscoring the need for clinical trial enrollment.