Responses to Momelotinib Observed up to 48 Weeks in Anemic Myelofibrosis

Long-lasting symptom, transfusion independence (TI), and splenic responses were observed following treatment with momelotinib up to 48 weeks in a population diagnosed with anemic myelofibrosis who received a prior JAK inhibitor, according to findings from the phase 3 MOMENTUM trial (NCT04173494) that were presented at the 2022 American Society for Hematology (ASH) Annual Meeting.¹

Findings showed that in the open-label continuation phase where patients stayed on momelotinib or crossed over from danazol to receive momelotinib, the week 24 symptom responses were sustained through week 48 of treatment in 97% of patients on the momelotinib-to-momelotinib arm and 100% in the danazol-to-momelotinib arm.

Additionally, 29% of patients who did not have a Total Symptom Score (TSS) response to danazol and crossed over to momelotinib at week 24 achieved TSS responses at 48 weeks. Twenty percent of patients who continued momelotinib in the open-label phase from momelotinib in the double-blind phase were also new responders at week 48.

“In this updated analysis of open-label momelotinib, the patients maintained week 24 symptom, transfusion, and spleen responses and continued with a safety profile that was very consistent with the overall [intent-to-treat] analysis,” lead study author Aaron T. Gerds, MD, an assistant professor in medicine (hematology and medical oncology), Cleveland Clinic Taussig Cancer Institute, said in a presentation of the data. “These findings support the potential use of momelotinib as an effective treatment in patients with myelofibrosis, particularly in patients with anemia and thrombocytopenia.”

Momelotinib is a JAK1, JAK2, and ACVR1 inhibitor designed to address myelofibrosis symptoms, spleen, and anemia. In August 2022, the FDA accepted a new drug application for momelotinib for the treatment of patients with myelofibrosis, based on preliminary MOMENTUM findings.²

In the prior results, which comprised data at week 24, the Myelofibrosis Symptom Assessment Form TSS response rate achieved with momelotinib was 24.6% vs 9.2% with danazol (P = .0095); the TI response rates were 30.8% vs 20.0%, respectively (noninferior 1-sided P = .0064), and the splenic response rate (SRR) with a 35% reduction (SRR35) was 23.1% vs 3.1%, respectively (P = .0006).³

The double-blind, international, ongoing, phase 3 MOMENTUM trial enrolled patients with myelofibrosis who were symptomatic (TSS ≥100), anemic (hemoglobin [HgB] <10 g/dL), and platelet levels at least 25 x 10⁹/L. Patients were randomly assigned 2:1 to receive momelotinib at 200 mg daily plus placebo (n = 130) or danazol at 600 mg daily plus placebo (n = 65). All patients had to have received prior treatment with a JAK inhibitor.

Early crossover to momelotinib was permitted if disease progression was confirmed. In the open-label crossover phase after 24 weeks of treatment, momelotinib was given at 200 mg daily.

Patients were stratified by TSS, palpable spleen length, transfused units in prior 8 weeks, and study site.

Regarding baseline characteristics, the median age was 70.6 years, and 64.3% of patients were male. The mean HgB was 8.0 g/dL, and approximately 48% of patients had a HgB greater than 8 g/dL. Approximately half of patients across both arms (50.4%) were transfusion dependent and the transfusion receiving rate was 35.4%.

As of May 17, 2022, 40 of the patients who were initially on the danazol arm crossed over to receive momelotinib. In the next 24 weeks of treatment in the open-label phase, 20.0% of these patients (n = 27) discontinued momelotinib therapy due to investigator’s discretion (n = 3), adverse effects (AEs; n = 1), patient decision (n = 3), insufficient efficacy (n = 2), death (n = 2), leukemic transformation (n = 1), and disease progression (n = 1). Of those who were on momelotinib in both phases, 20.8% (n = 13) discontinued momelotinib due to investigator’s discretion (n = 3), AEs (n = 11), patient decision (n = 3), insufficient efficacy (n = 3), death (n = 6), and disease progression (n = 1).

The primary end point of the trial was TSS response rate at week 24. Secondary end points included TI and SRR at week 24.

Further data showed that through week 48, the week 24 TI response was maintained in 90% of patients on the momelotinib-to-momelotinib arm and 77% of those in the danazol-to-momelotinib arm. All patients who had splenic responses that were reported at week 24 maintained their spleen volume below baseline on both arms.

An additional analysis of momelotinib presented during the 2022 ASH Annual Meeting looked at the consecutive 12-week TI-response rate with the 2 arms, which was 44.6% and 29.2% with momelotinib to momelotinib and danazol to momelotinib, respectively.⁴

Gerds noted that no new safety signals were reported in the open-label phase of momelotinib treatment and were similar between arms. In the momelotinib-to-momelotinib arm, grade 3 or higher AEs and serious AEs occurred in 49.5% and 31.2% of patients, respectively. The grade 3 or higher AEs were comprised of thrombocytopenia (8.6%), anemia (8.6%), neutropenia (5.4%), COVID-19 (pneumonia; 5.4%), asthenia (3.2%), and diarrhea (1.1%).

In the danazol-to-momelotinib arm, 46.3% and 29.3% of patients experienced grade 3 or higher and serious AEs, respectively. Grade 3 or higher AEs included thrombocytopenia (14.6%), hypertension (2.4%), and anemia (2.4%).

Additional data showed that TI response with momelotinib at 24 weeks was associated with overall survival (OS) and leukemia-free survival. However, Gerds cautioned that due to this being a crossover study, OS is difficult to analyze.

Efficacy was also analyzed in patients with thrombocytopenia. For patients whose baseline platelet counts were less than 100 x 10⁹/L, week 24 responses in TSS at 50% reduction, TI-R, and SRR35 were also well maintained during the open-label period. For these patients with thrombocytopenia on momelotinib-to-momelotinib (n = 46) and danazol-to-momelotinib (n = 24), grade 3 or higher bleeding events occurred in 15% and 4%, respectively; major adverse cardiovascular events were reported in 7% and 0% of patients, respectively. Overall, Gerds said that the safety findings in this subset, which included 47.9% grade 3 or higher AEs and 28.8% serious AEs, were consistent with what was observed the intent-to-treat population.

OS was also analyzed up to 48 weeks in the thrombocytopenic patients whose baseline platelet counts were less than 50 x 10⁹/L (HR, 0.123; 95% CI, 0.014-1.062) and less than 100 x 10⁹/L (HR, 0.958. 95% CI, 0.424-2.212). While encouraging, Gerds noted the small sample size for this subgroup and that it warrants further investigation.

References

1. Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in sympatomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 627
2. US FDA accepts new drug application for GSK’s momelotinib for the treatment of myelofibrosis. News release. GSK. August 17, 2022. Accessed December 12, 2022. https://bit.ly/3K4Azcq
3. Verstovsek S, Vannucchi A, Gerds AT, et al. MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S195
4. Verstovsek S, Oh ST, Kiladjian J-J, et al. Transfusion independence response as a potential surrogate for overall survival in JAKi-experienced patients with myelofibrosis from Momentum.Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 3028