Momelotinib (MMB) Long-Term Safety: Pooled Data from Three Phase 3 Randomized-Controlled Trials (RCTs)

Abstract

Introduction: MMB, an oral JAK1/JAK2/ACVR1 inhibitor, was evaluated in 3 RCTs (SIMPLIFY-1 [S1], SIMPLIFY-2 [S2], and MOMENTUM) in patients (pts) with high- and intermediate-risk myelofibrosis (MF). We conducted an integrated analysis of MMB to characterize its long-term safety, with pooled data from the 3 RCTs, representing a spectrum of MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Methods: Adult pts with high- and intermediate-risk MF were randomized to receive MMB or ruxolitinib (RUX; S1); MMB or best available therapy, which was RUX in 89% (S2) of patients; and MMB or danazol (MOMENTUM). At the end of the 24-week randomized treatment period, pts in the MMB arms could continue treatment with open-label (OL) MMB, and pts in the control arms could cross over to receive OL MMB. Pts from all 3 RCTs continued to receive long-term extended access to MMB in the extended access protocol (XAP) study. Median follow-up time was 20 months in S1, 10 months in S2, and 7 months in MOMENTUM. Results: As of December 3, 2021, across these 3 studies, 725 pts (1261 person-years) with MF received MMB; 12% remained on therapy for ≥5 years, with a median MMB exposure of 11.3 months, and mean (range) MMB exposure of 20.3 (0.1-90.4) months. Nonhematologic treatment-emergent adverse events (TEAEs) were mostly grade 1/2, with diarrhea (26.8% any grade, 2.6% grade ≥3) and nausea (19.4% any grade, 1.1% grade ≥3) the most frequent TEAEs, in the absence of antidiarrheal and antiemetic prophylaxis. The most frequently occurring hematologic any-grade TEAEs included thrombocytopenia (23.4%), anemia (23.0%), and neutropenia (5.7%). Infections occurred in 55.4% of patients, but serious opportunistic infections were rare (1.5%). Study drug discontinuations due to any treatment-related adverse events (AEs) were not common (15.6%). Thrombocytopenia most frequently led to study discontinuation but only occurred in 3.7% of pts. Malignancies (13.4%), including nonmelanoma skin cancer (4.8%), were infrequent. Acute myeloid leukemia (AML), or leukemic transformation, occurred in 3.0% of pts, and led to MMB discontinuation in 2.1% of pts. Peripheral neuropathy was infrequent (14.8% any grade), rarely severe (n=2 (1.2%) grade ≥3, both resolved on MMB withdrawal), mostly sensory, and rarely led to treatment discontinuation. Frequent and clinically important AEs did not increase in incidence over time (Table). Mean baseline hemoglobin and platelet count levels were and 9.9 g/dL and 238.9 x 109/L, respectively. Hemoglobin levels were increased at first on-study assessment (week 2) on MMB and were maintained thereafter. Hemoglobin levels increased in the OL phase in pts who switched to MMB from RUX (Figure A); platelet counts improved or were maintained (Figure B). Conclusion: We report the largest trial safety database to date for a JAK inhibitor in MF. MMB demonstrated a consistent safety profile without unexpected long-term or cumulative toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal