The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Introduction Disease-related inflammation, anemia and splenomegaly contribute to a host of burdensome symptoms in patients with myelofibrosis (MF), including fatigue, bone pain, night sweats, and others, which can negatively impact health-related quality of life (HRQoL). There are no approved treatments for patients with intermediate- and high-risk MF that specifically target anemia, and approved MF therapies for splenomegaly and symptoms often exacerbate anemia. Momelotinib (MMB) is a Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with demonstrated symptom, spleen, and anemia benefits in patients with MF. MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Herein we report the results of patient-reported health status and HRQoL analyses, including impact on fatigue and physical function, for patients treated with MMB compared to DAN in the MOMENTUM study.

Methods Patient-reported outcome (PRO) analyses were performed for the following assessments in the intent-to-treat (ITT) population: Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 TSS and individual items, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)-derived scales and items, and Patient-Reported Outcomes Measurement Information System (PROMIS) short form physical function total score 10b and additional PROMIS bank items. Analyses of PRO response were summarized by corresponding meaningful change threshold (MCT) for each PRO. Longitudinal change from baseline scores were analyzed using mixed model for repeated measures (MMRM). Longitudinal responder analyses were performed by generalized estimating equation (GEE) after multiple imputation for missing scores. Odds ratio (OR) for response, 95% confidence interval (CI), and p-value were presented as the treatment effect (MMB vs DAN). Time to first response was analyzed using the Kaplan-Meier method. A stratified log-rank test was performed to compare treatment arms, and hazard ratios (HR) were estimated from a stratified Cox regression model.

Results Proportionally greater improvements in MF-related symptoms, physical function, and global quality of life were observed with MMB versus DAN as measured at week 24 by the MFSAF, PROMIS, and EORTC QLQ-C30 questionnaires, respectively.

Improvements in all MFSAF individual item scores from baseline at week 24 were greater in the MMB group than in the DAN group based on median scores (Figure 1) and MMRM analysis (Table 1), with the greatest treatment differences noted for night sweats, abdominal discomfort, bone pain, and rib pain, favoring MMB. Longitudinal MFSAF TSS response analysis indicated a higher likelihood of response for patients in the MMB group: an overall OR of 2.50 throughout the 24-week randomized treatment period. HRs for response were greater than 1 (ranging from 1.47 - 3.82) in the time to first response analysis for MFSAF TSS and individual items, excluding itching (0.77), indicating a faster symptom response for more patients in the MMB group for TSS and 6 of 7 individual items.

Responder analyses showed that the proportion improved for fatigue was greater in the MMB group based on MFSAF fatigue (18.5% MMB, 9.2% DAN) and EORTC QLQ-C30 fatigue (41.5% MMB, 21.5% DAN), where missing data was considered nonresponse. Consistent with these results, responder analysis using the PROMIS assessments related to physical function also favored MMB (17.7% MMB, 4.6% DAN). This trend was supported by shorter times to first response for physical function in more patients in the MMB group versus the DAN group (HR = 1.93, 95% CI 0.95, 3.91). Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04).

Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF.

Mesa:Incyte: Consultancy, Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Samus: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; AOP: Consultancy; CTI: Research Funding; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy; AbbVie: Research Funding; Roche: Consultancy; Geron: Consultancy; LaJolla Pharmaceutical: Consultancy; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Blueprint: Consultancy; Imago: Research Funding. Harrison:Geron: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra: Honoraria; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; Keros: Consultancy; EHA: Other: Leadership role; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MPN voice: Other: Leadership role; Promedior: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Galacteo: Membership on an entity's Board of Directors or advisory committees. Palmer:Sierra Oncology: Consultancy; CTI BioPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; PharmaEssentia: Consultancy, Research Funding. Gupta:Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Roche: Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria. McLornan:CELGENE BMS: Research Funding, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; ABBVIE: Speakers Bureau; NOVARTIS: Honoraria, Research Funding, Speakers Bureau. McMullin:Incyte: Consultancy, Speakers Bureau; Sierra Oncology: Consultancy; CTI: Consultancy; AOP: Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Foltz:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Amgen: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months; BMS: Honoraria, Research Funding; Sierra Oncology: Other: Medical Writing, Research Funding; Constellation: Research Funding; CTI Biopharma: Research Funding; Paladin Labs Inc: Membership on an entity's Board of Directors or advisory committees, Other: Committee; Sierra: Research Funding. Platzbecker:Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria; BMS/Celgene: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; Silence Therapeutics: Honoraria; Janssen: Honoraria. Fox:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mead:Sierra Oncology: Consultancy, Speakers Bureau; Sensyn: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Alethiomics Ltd: Consultancy, Current equity holder in private company, Other: Co-founder and equity holder, Research Funding; Incyte: Consultancy, Speakers Bureau; Galecto: Consultancy, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; CTI: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ross:Keros: Consultancy; BMS: Honoraria; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Oh:Celgne/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perkins:Sierra Oncology: Honoraria, Other: Support for present manuscript; Celgene: Other: Support for meetings and/or travel; Abbvie: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kawashima:Sierra Oncology: Current Employment. Ro:Sierra Oncology: Current Employment. Donahue:Sierra Oncology: Current Employment. Verstovsek:Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Roche: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI BioPharma Corp.: Research Funding; ItalPharma: Research Funding; PharmaEssentia: Research Funding; Constellation Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy.