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

Abstract

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.

Conflict of interest statement

Conflict-of-interest disclosure: R.J.K. reports grants and nonfinancial support from Novartis during the conduct of the study; grants and nonfinancial support from AstraZeneca/MedImmune/Innate Pharma and Genentech; and nonfinancial support from Teva, outside of the submitted work. In addition, he is a co-inventor on the NIH patent for moxetumomab pasudotox and receives royalties from NIH. P.M. reports personal fees from Celgene, Janssen, Takeda, Amgen, and AbbVie outside the submitted work. F.R. reports personal fees from Novartis during the conduct of the study, personal fees from Novartis, Celgene, BMS, Astellas, Xencor, Agios, Amgen, Orsenix, AstraZeneca, and Jazz Research, and research funding from BMS, AbbVie, Amgen, Macrogenics, Xencor, Orsenix, and Astex outside of the submitted work. M.H. reports research funding from AbbVie, Celgene, Genentech, Genmab, Incyte, Novartis, Roche, Sanofi, and Takeda and personal fees from Genmab, Roche, and Takeda outside of the submitted work. Z.A.W. reports personal fees from Eli Lilly, Bayer, Merck, Daiichi, Novartis, Ipsen, Array BioPharma, and Five Prime Therapeutics outside of the submitted work. A.S. reports grants from Bristol Myers Squibb, Merck KgA, and Servier and personal fees from Bristol Myers Squibb, MSD, Merck KgA, Roche, Amgen, Sanofi, Servier, and Eli Lilly outside of the submitted work. P.I. is an employee of Novartis and reports stock ownership in Novartis. P.B. is an employee of Novartis and owns stock from Novartis and GlaxoSmithKline. E.G. is a former employee of Novartis and owns stock. V.S. reports grants and other support from LOXO Oncology/Eli Lilly, Novartis, PharmaMar, and MedImmune; grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, the National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals; and other support from Helsinn, R-Pharma US, INCYTE, QED Pharma, ASCO, ESMO, and Medscape during the conduct of the study. The remaining authors declare no competing financial interests.

The current affiliation for E.G. is Innovent Biologics (USA) Inc, Rockville, MD.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Treatment duration and best response (intent-to-treat population). A swimmer plot for individual patients’ treatment duration and time to events is shown. The color code shows investigator-assessed best response for each patient. Arrows designate patients with ongoing study treatment. Circles represent the time at which disease progressed. Triangles represent the time to first response. Asterisks represent treatment discontinuation owing to adverse events.

Figure 2.

PFS (A) and OS (B) for patients included in the intent-to-treat population treated with dabrafenib plus trametinib.