Trials Support Use of Momelotinib After JAK Inhibition for Anemic MF

Salman Fazal, MD

Director, Cell Transplantation Program,

Division of Hematology & Cellular Therapy

Allegheny Health Network

Pittsburgh, PA

Targeted Oncology: What data supported the use of momelotinib (Ojjaara) in patients with primary myelofibrosis (MF) and hematologic toxicity?

SALMAN FAZAL, MD: This is the SIMPLIFY-2 trial [NCT02101268]. This was a trial for patients who had prior previous treatments with ruxolitinib [Jakafi] and became transfusion dependent or were cytopenic. They were randomly assigned [on a 2:1 basis] to receive momelotinib vs a best available therapy [BAT] arm. Interestingly, there was no washout period, and these patients who were cytopenic on ruxolitinib moved on to receive momelotinib or continued BAT. In the BAT arm, most of the patients continued to receive ruxolitinib. The primary end point was spleen volume reduction [SVR] of 35% and total symptom score [TSS] improvement.

Looking at the baseline characteristic, most of the patients had intermediate-2 or high-risk MF [per Dynamic International Prognostic Scoring System​], and the transfusion independent rate was about 30% [31% in the momelotinib arm and 37% in the BAT arm]. The rest of the patients were cytopenic.¹

How did the study drug perform in terms of the primary and secondary end points?

The responses seen in the momelotinib vs BAT arm were 7% vs 6%, respectively, for SVR 35% reduction. In terms of their TSS improvement, momelotinib did better compared with BAT arm [26% for momelotinib vs 6% for BAT], but for SVR, there was no difference between the momelotinib vs BAT arm.¹

Looking at the transfusion independence rate between the arms in the study—this was not the primary end point of the study, [but]…there was again lesser transfusion dependence with the BAT arm vs the momelotinib [43% transfusion independent at week 24 with momelotinib vs 21% with BAT].

They looked at a post hoc analysis of the overall survival [OS] by transfusion independence between the patients who became transfusion independent on momelotinib vs non-transfusion independent with momelotinib [OS favoring transfusion independence non-transfusion independent with a HR of 0.771; P = .4193]. For the BAT arm, [OS also favored transfusion-independent patients vs non-transfusion independent, with an HR of 0.479; P = .2326].²

In terms of the adverse events [AEs], there was some diarrhea and peripheral neuropathy seen, but most of the peripheral neuropathy was grade 1 or 2.

What did the phase 3 MOMENTUM study (NCT04173494) show about the efficacy and safety of momelotinib in the MF population?

This is the most recent publication for momelotinib. The study investigated a group of patients who have been previously treated with a JAK inhibitor and have symptoms and anemia. This was defined as hemoglobin less than 10 g/dL. These patients would have a 2-week washout period, and then they were randomly assigned [on a 2:1] basis to receive momelotinib at 200 mg daily plus a placebo vs danazol 600 mg daily plus a placebo. The primary end point was looking at the TSS response rate; the secondary end points included improvement in the SVR of 35%.

At week 24, 25% of patients met the TSS improvement end point on momelotinib vs 9% on danazol. [At week 48, momelotinib had a 45% TSS improvement and those in the danazol group who crossed over to momelotinib had a TSS improvement of 50%]. Looking at the transfusion independence rate at week 24 [was 30% for momelotinib, 20% for danazol] and at week 48, [it was 57% for momelotinib, 60% in patients who crossed over]. Then, looking at the SVR 35% seen between the danazol and momelotinib arm, [it was 22% for momelotinib and 3% for danazol at week 24, then 43% and 13% for the momelotinib and crossover groups, respectively].³

They also looked at the other AEs and this is a 5-year follow-up of the study.⁴ The bottom line is that they did not see any increased risk of any toxicity with time. They did see infections and most of those infections were mild in nature, but there was herpes zoster reactivation reported. There were secondary malignancies, and risk of acute myeloid leukemia and cardiovascular toxicity, but those toxicities were not considered at very high risk [since there were not] high numbers.

In terms of toxicity, peripheral neuropathy led to discontinuation in 1.8% of patients in the study [whereas diarrhea led to discontinuation in 1.1%].

_References:

_{1. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(17)30237-5}

_{2. Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36(9):2261-2268. doi:10.1038/s41375-022-01637-7}

_{3. Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. doi:10.1016/S2352-3026(23)00174-6}

_{4. Verstovsek S, Mesa R, Gupta V, et al. Momelotinib long-term safety and survival in myelofibrosis: integrated analysis of phase 3 randomized controlled trials. Blood Adv. 2023;7(14):3582-3591. doi:10.1182/bloodadvances.2022009311}