Reference Detail

Ref Type

Journal Article

PMID

(36108341)

Authors

Kreitman RJ, Moreau P, Ravandi F, Hutchings M, Gazzah A, Michallet AS, Wainberg ZA, Stein A, Dietrich S, de Jonge MJA, Willenbacher W, De Grève J, Arons E, Ilankumaran P, Burgess P, Gasal E, Subbiah V

Title

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	141	9	2023 Mar 02	996-1006	Blood

URL

Abstract Text

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	hairy cell leukemia	sensitive	Dabrafenib + Trametinib	Phase II	Actionable	In a Phase II trial (ROAR), treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) demonstrated safety and resulted in an overall response rate of 89.1% (49/55; 36 complete responses, 13 partial responses) in patients with heavily pretreated recurrent/refractory hairy cell leukemia harboring BRAF V600E, with 24-month duration of response, progression-free-survival, and overall survival rates of 97.7%, 94.4% and 94.5%, respectively (PMID: 36108341; NCT02034110).	36108341