Phase 2 trial of encorafenib plus binimetinib for patients with BRAF V600 mutated relapsed/refractory hairy cell leukemia Free

Background: Hairy cell leukemia (HCL) is an indolent B-cell leukemia characterized by durable complete remissions to purine analogs cladribine or pentostatin, but repeated relapses and cumulative toxicity to repeated purine analog courses. Vemurafenib, targeting the BRAF V600E mutation expressed by >90% of classic HCL, achieved complete remission (CR) rates of 35-42% after a 16-18-week course. All evaluated CRs were positive for HCL minimal residual disease (MRD) by bone marrow immunohistochemistry (IHC) and median relapse free survival (RFS) was 19 months. Vemurafenib was combined with rituximab, achieving 57% MRD-free CRs. Combined BRAF-MEK inhibition using dabrafenib-trametinib respectively was superior to vemurafenib for BRAF V600E+ melanoma, and in 55 HCL patients achieved CR rate 65.5%, with 12.7% MRD-free by bone marrow aspirate (BMA) flow cytometry (FC), 2-year response duration 97.7% and progression-free survival 94.4%. The most common toxicity was pyrexia (fever, 58.2%) often associated with severe rigors and/or need for discontinuation or steroids. To avoid pyrexia, we began a phase 2 trial of combined BRAF-MEK inhibition using encorafenib-binimetinib, which in melanoma was reported to effectively target BRAF-MEK without fever.

Patients and Methods: Twenty-eight patients with BRAF V600-mutated HCL were treated with encorafenib 450 mg/day and binimetinib 45 mg twice daily, both orally. The primary endpoint was to rule out a CR rate of 35% in favor of 55%. The most important secondary endpoint was to reduce the rate of pyrexia compared to dabrafenib-trametinib. Eligibility required prior purine analog and need for treatment including neutrophils <1/nL, hemoglobin <10 g/dL, platelets <100/nL, symptomatic splenomegaly, or HCL mases >2cm in short axis. CR criteria were consistent with HCL consensus guidelines. Response was assessed after three 4-week cycles (pre-cycle 4), pre-cycle 7, yearly until 2.5 years after starting, then biannually. MRD was assessed by marrow IHC and FC of blood and BMA. Encorafenib and/or binimetinib could be interrupted or dose-reduced for toxicity, to a minimum of 75 and 15 mg/day, respectively.

Results: Of 28 patients enrolled, 26 (93%) achieved CR. Time to CR was 2.5-40.5 (median 3.0) months, with 19 (68%) of 28 patients achieving CR by the earliest (12-week) restaging time point. At 3.3-56.5 (median 26.1) months of follow-up, only 1 of the 26 CRs relapsed. CRs achieved by encorafenib-binimetinib were MRD-free in 25/26 (96%) by IHC but only 3/26 (12%) by BMA FC. One patient achieved MRD-free CR at 12 weeks, was still MRD-free prior to cycle 20, stopped encorafenib-binimetinib pre-cycle 25, and was still MRD-free 1 year later. One patient achieved MRD-free CR pre-cycle 34 but was MRD+ at the next assessment pre-cycle 55. The 3^rd patient first achieved MRD-free CR pre-cycle 19 after over a year in CR. For patients with MRD+ CR lasting at least a year, the protocol allowed patients to continue encorafenib-binimetinib while receiving rituximab 375 mg/m² every 2 weeks for 8 doses. Of 6 patients so far who received rituximab during MRD+ CR, 3 (50%) achieved MRD-free CR by all tests and stopped therapy without MRD-relapse after up to 2 years of follow-up. Most patients underwent one or several dose reductions from the initial dose level to better tolerate chronic dosing. Toxicity was consistent with events reported in melanoma and other malignancies, and nearly always resolved rapidly with dose-reduction. Common (>20%) adverse events related to encorafenib included elevated lipase (57%) and amylase (36%) only rarely associated with symptomatic pancreatitis, reversible thinning (43%) and abnormal texture (21%) of hair, abdominal pain (36%), nausea (32%), loose stools (29%), skin lesions (36%), myalgias (29%) and fatigue (25%). Those related to binimetinib included serous retinopathy (43%), usually asymptomatic, blurred vision (25%), elevated creatine kinase (32%), and dry skin (25%).

Conclusion: Encorafenib-binimetinib is highly effective in relapsed/refractory HCL and was well tolerated when dose reductions occurred as needed. Compared to dabrafenib-trametinib, the lower incidence of fever (11% vs 58%, p<0.0001) is a major advantage. The CR rate of 93% without rituximab is unprecedented for BRAF inhibition in HCL. With rituximab, MRD-free CR is achievable. Encorafenib-binimetinib adds to the options for BRAF treatment of this disease.