ROAR (HCL cohort)

Background

Phase 2, open-label, single-arm basket study (ROAR), HCL cohort. N=55 patients with BRAF V600E-mutated R/R classic HCL who had received ≥1 prior therapy. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) provides more complete MAPK pathway blockade and may overcome resistance to single-agent BRAF inhibition. Published Blood 2023.

Interventions and follow up

Regimen: Dabrafenib 150 mg PO BID + trametinib 2 mg PO daily continuously — BRAF V600E-mutated R/R hairy-cell leukemia (HCL cohort of ROAR basket)
Primary endpoint: ORR (investigator-assessed, standard HCL criteria)
mFollow up: 27.3 months

Results

ORR: 89%
CR: 56%
PR: 33%
mDOR: Not reached
2-yr PFS: 78%
2-yr OS: 94%

Adverse events

Constitutional/Cutaneous: Pyrexia any grade 37% (dabtram class effect); fatigue 35%; rash any grade 46%, grade ≥3 9%; peripheral edema 41%
Hematologic/Metabolic: Anemia grade ≥3 17%; hyperglycemia grade ≥3 11%
Other: Grade ≥3 AEs 44%; diarrhea any grade 33%; discontinuation due to AEs 22%; no new safety signals

Conclusions

Dabrafenib + trametinib achieved an 89% ORR and 56% CR in R/R BRAF V600E-mutated HCL, with a 2-year PFS of 78%, establishing the BRAF + MEK inhibitor doublet as an effective continuous oral option without the need for IV infusions.

Key Limitations

Single-arm basket cohort: No comparator; modest sample size
Continuous therapy: Indefinite dosing with attendant chronic toxicity and discontinuation (22%)
BRAF V600E only: Not applicable to HCL variant; no head-to-head vs vemurafenib+rituximab

Clinical Context

Dabrafenib + trametinib is FDA-approved (tissue-agnostic) for BRAF V600E-mutated solid tumors and is used off-label for BRAF V600E-mutated R/R HCL, offering an effective all-oral regimen. It is an alternative to vemurafenib+rituximab, particularly when an IV anti-CD20 schedule is impractical. Like all BRAF-targeted approaches, it is ineffective in BRAF-wild-type HCL variant.

References