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391 Treatment with Combination of Dabrafenib and Trametinib in Patients with Recurrent/Refractory BRAF V600E–Mutated Hairy Cell Leukemia (HCL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Novel Therapies and Prognostic Assessment in Hairy Cell Leukemia and Indolent Non-Hodgkin Lymphoma
Hematology Disease Topics & Pathways:
Biological, Diseases, Therapies, Clinically relevant, Lymphoid Malignancies, TKI
Sunday, December 2, 2018: 12:00 PM
Ballroom 20A (San Diego Convention Center)

Robert J. Kreitman, MD1, Philippe Moreau2*, Martin Hutchings, MD3*, Anas Gazzah, MD4*, Jean-Yves Blay, MD, PhD5*, Zev A. Wainberg, MD6*, Alexander Stein, MD7*, Sascha Dietrich, MD8, Maja J.A. de Jonge, MD9*, Wolfgang Willenbacher, MD, PhD10, Jacques De Greve, MD11*, Evgeny Arons, PhD1*, Farhad Ravandi, MBBS12, Fatima Rangwala13*, Paul Burgess14*, Bijoyesh Mookerjee13* and Vivek Subbiah, MD12*

1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Department in Hematology, CHU de Nantes, Nantes, France
3Department of Oncology, Rigshospitalet, Copenhagen, Denmark
4Gustave Roussy Cancer Institute, Villejuif, France
5Centre Léon Bérard, Lyon, France
6Department of Medicine, University of California Los Angeles, Los Angeles, CA
7Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
8University of Heidleberg, Heidelberg, Germany
9Erasmus MC Kanker Instituut, Rotterdam, Netherlands
10Innsbruck University Hospital & Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria
11University Hospital Brussels, Brussels, Belgium
12Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX
13Global Clinical Program, Novartis Pharmaceuticals Corporation, East Hanover, NJ
14Oncology Global Development Unit, Novartis Pharma AG, Basel, Switzerland

BACKGROUND: Hairy cell leukemia is a rare, indolent, B-cell lymphoproliferative disease characterized by the BRAF V600E mutation in 90% to 100% of patients. Few treatment options are available for patients who progress on first-line therapy with a purine analogue and/or rituximab. The efficacy of combined BRAF and MEK inhibition is well established in BRAF V600–mutated melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. Here we report interim results of treatment with the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in patients with recurrent/refractory BRAF V600E–mutated HCL.

METHODS: In this phase 2, open-label trial (ROAR; NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HCL, received continuous dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) until unacceptable toxicity, disease progression, or death. For the HCL cohort, eligible patients had histologically confirmed HCL (according to WHO classification) that was refractory to first-line treatment with a purine analogue or relapsed after ≥ 2 prior lines of treatment. The presence of a BRAF V600E mutation was assessed locally and confirmed by a central laboratory. The primary endpoint was investigator-assessed overall response rate (ORR) based on criteria adapted from NCCN guidelines. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Minimal residual disease (MRD) status was assessed by flow cytometry in both peripheral blood and bone marrow aspirates. For complete response (CR) without MRD, both peripheral blood and bone marrow aspirate samples had to be negative.

RESULTS: At the data cutoff (January 3, 2018), 43 patients with HCL had enrolled. Median age was 67 years (range, 40-81) and 38 (88%) were male. Twenty-one patients (49%) had received ≥ 4 prior treatments. At the time of data cutoff, 35 patients (81%) remained on study treatment, 5 (12%) in follow-up; 2 (5%) had withdrawn from study (loss to follow-up and consent withdrawal [n = 1 each]), and 1 (2%) had died. Eight patients had discontinued therapy due to adverse events (AEs; 5 [12%]), study withdrawal (2 [5%]), or disease progression (1 [2%]). Median time on study treatment was 17 months (range, 1-39). Among 41 patients evaluable for response, the investigator-assessed confirmed ORR was 78% (32/41; 95% CI, 62%-89%) with 20 (49%) having CR, (6 [15%] CR without MRD and 14 [34%] CR with MRD), and 12 (29%) partial response. All responses were ongoing at the data cutoff; 16 (50%) responses were lasting ≥ 18 months. PFS and OS rates at 12 months were both 97.6% (95% CI, 83.9%-99.7%). The most common AEs in patients with HCL were pyrexia (67%), chills (51%), hyperglycemia (44%), nausea (44%), peripheral edema (42%), cough (40%), and fatigue (40%). Grade 3/4 AEs were reported in 49% of patients, with the most common (> 5%) being hyperglycemia (9%), anemia (7%), and neutropenia (7%). AEs led to dose reduction and treatment interruption in 42% and 56% of patients, respectively. AEs led to permanent discontinuation in 5 patients (12%; headache and malaise [n = 1]; pyrexia, chills and palmar-plantar erythrodysesthesia syndrome [n = 1]; fat necrosis [n = 1]; hyperglycemia and pancreatic adenocarcinoma [n = 1]; Hodgkin lymphoma [n = 1]).

CONCLUSIONS: Dabrafenib + trametinib was well tolerated and demonstrated a high rate of durable responses in patients with heavily pretreated recurrent/refractory BRAF V600E–mutated HCL.

Disclosures: Kreitman: NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox. Moreau: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Blay: Roche: Honoraria, Other: Non-financial support, Research Funding; Novartis: Honoraria, Other: Non-financial support, Research Funding. Wainberg: Merck: Consultancy; EMD Serono: Consultancy; Lilly: Consultancy; Five Prime: Consultancy; Novartis: Consultancy. Stein: Novartis: Other: Patient documentation fees; GSK: Other: Patient documentation fees. Willenbacher: Merck: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Other: Steering board, Research Funding. Ravandi: Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Burgess: Novartis: Employment. Mookerjee: Novartis: Employment. Subbiah: Roche/Genentech: Research Funding; LOXO: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bayer: Research Funding.

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