ASH Clinical News July 2017 V2 - Page 31

CLINICAL NEWS Treatment consisted of six 28-day cycles: • daratumumab 16 mg/kg once weekly for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (the first dose of daratumumab was split over 2 days) • carfilzomib on days 1, 8, and 15 of each cycle (initial dose of 20 mg/m 2 and 36 mg/m 2 or 70 mg/m 2 thereafter, based on tolerability) • lenalidomide 25 mg on days 1-21 • dexamethasone 20-40 mg once weekly Per study protocol, patients were treated for a maximum of 13 cycles, or were allowed to discontinue treatment to undergo hematopoietic cell transplantation (HCT). Patients received a median of eight treatment cycles (range = 1-10 cycles), and 19 were able to tolerate the highest dose of carfilzomib (70 mg/m 2 ) by day 15 of cycle 1. Over a median follow-up of 7.4 months (range = 4.0-9.3 months), six patients (27%) discontinued treatment for the following reasons: pulmonary embolism (n=1), pro- gressive disease (n=1), and HCT (n=4). Serious adverse events (AEs) occurred in 46 percent of patients, and 14 percent of these were considered pos- sibly related to daratumumab treatment. The majority of patients (n=18; 82%) experienced a grade 3/4 treatment- related AE, the most common (occurring in >10% of patients) of which were lymphopenia (50%) and neutro- penia (23%). One of these patients experienced a grade 3 cardiac AE related to daratumumab treatment, but the episode resolved and “the patient quickly resumed study treatment with a reduced carfilzomib dose,” the authors noted. “No grade 5 treatment-emergent AE was reported.” “The addition of daratumumab to carfilzomib, lenalidomide, and dexamethasone was well tolerated,” the authors wrote, adding that “the overall safety profile was consistent with that previously reported for carfilzomib, lenalidomide, and dexamethaonse alone.” Twenty-one patients were evaluable for response at the time of presentation. All patients who received the daratumumab combination responded to treatment, for Mixed Results in Trials of Momelotinib Versus Ruxolitinib for Myelofibrosis While the investigational JAK1/2 inhibi- tor momelotinib was active in the treat- ment of myelofibrosis (MF) in phase I/II trials, updates from two phase III trials comparing momelotinib with ruxolitinib or best-available therapy (BAT) showed mixed results. SIMPLIFY 1 Ruben A. Mesa, MD, from the Mayo Clinic Cancer Center in Scottsdale, Arizona, presented results from SIMPLIFY 1, which compared momelotinib with ruxolitinib in patients with JAK inhibitor-naïve MF. 1 Results from the randomized, double- blind, multicenter study demonstrated that momelotinib was non-inferior to ruxolitinib in splenic volume reduction (primary end- point); superior to ruxolitinib in reducing rates of transfusion-dependency for MF- associated anemia; but failed to improve disease-associated symptoms. “Without question, compared [with] nothing or other standards of care like hydroxyurea, [momelotinib] is still very active, but it’s a question of how active is it compared [with] ruxolitinib,” Dr. Mesa told ASH Clinical News. “Ruxolitinib is a very solid agent for improving disease- related symptoms, so I think some of that complexity [in interpreting the study] is borne out in that difference.” SIMPLIFY 1 included 432 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF classified as high risk or intermediate-2 risk (per the International Prognostic Scoring System). All patients also had palpable sple- nomegaly. Patients who had received splenic irradiation within 3 months of treatment or who were eligible for allogeneic hematopoi- etic cell transplantation were excluded. Patients were stratified by RBC transfusion dependency and platelet levels (<100x10 9 /L, 100-200x10 9 /L, and >200 x10 9 /L), then randomized 1:1 to receive 24 weeks of treatment with either: • momelotinib 200 mg once daily plus ruxolitinib placebo (n=215) • ruxolitinib 20 mg twice-daily (or modified per label) plus momelotinib placebo (n=217) Following this double-blind phase, all patients were eligible to receive open-label momelotinib for up to 168 additional weeks. Splenic response was measured by magnetic resonance imaging or computed tomography scan, and patients self-report- ed symptoms using an electronic diary and modified Myleloproliferative Neoplasm Symptom Assessment Form Total Symp- tom Score (TSS) to monitor improvement in disease-associated symptoms. Eighty-one percent (n=175) of mom- elotinib patients and 93 percent (n=201) of ruxolitinib patients completed the 24- week treatment phase. At this timepoint, the rates of splenic response (defined as a ≥35% reduction in volume from baseline) were similar between the 184 evaluable momelotinib-treated patients and the 204 an overall response rate (defined as partial response [PR] or better) of 100 percent: • complete response: 5% • very good PR: 86% • PR: 9% The 6-month PFS rate was also 100 percent. “These data support further investigation of [this daratumumab quadruplet combination] as a frontline treatment regimen,” the authors concluded. However, the study’s findings are limited by its small population, and future studies will need to compare the safety and efficacy of this combination with other standard-of-care regimens. REFERENCE Jakubowiak AJ, Chari A, Lonial S, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with