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1733 Clinical Outcomes of Myelofibrosis Patients Following Immediate Transition to Momelotinib from Ruxolitinib

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, MPN, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, therapy sequence, Myeloid Malignancies, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Ruben Mesa, MD, FACP1, Srdan Verstovsek, MD, PhD2, Uwe Platzbecker, MD3*, Vikas Gupta, MD, FRCP, FRCPath4, David Lavie, MD5*, Pilar Giraldo, PhD6, Jean-Jacques Kiladjian, MD7, Stephen T Oh, MD, PhD8, Timothy Devos, MD, PhD9, Francesco Passamonti, MD10*, Miklos Egyed, MD, PhD11*, Alessandro Vannucchi, MD12, Andrzej Pluta, MD13*, Donal P McLornan, MD, MRCP, PhD, FRCPath14*, Jun Kawashima, MD15*, Mei Huang, MS15*, Bryan Strouse, MSc15* and Claire N. Harrison, DM16

1Mays Cancer Center at UT Health San Antonio, San Antonio, TX
2MD Anderson Cancer Center, University of Texas, Houston, TX
3Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
4Division of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada
5Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
6Miguel Servet University Hospital and Centro de Investigacion Biomedica en Red de Enfermadades Raras (CIBERER), Zaragoza, Spain
7Université de Paris, AP-HP, Hôpital Saint-Louis, Centre d’Investigations Cliniques, Paris, France
8Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO
9Department of Hematology and Department of Microbiology and Immunology, University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
10University of Insubria, Varese, Italy
11Somogy County Mór Kaposi General Hospital, Kaposvár, Hungary
12University of Florence, Azienda Ospedaliero Universitaria Careggi, CRIMM, Florence, Italy
13Szpital Specjalistyczny w Brzozowie Podkarpacki Ośrodek Onkologiczny im. Ks. B. Markiewicza, Brzozów, Poland
14Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
15Sierra Oncology Inc., San Mateo, CA
16Guy's and St Thomas' NHS Foundation Trust, London, ENG, United Kingdom

Introduction: Approved JAK inhibitors (JAKi; ruxolitinib [RUX], fedratinib, and pacritinib) provide symptom and spleen benefit in myelofibrosis (MF), but can worsen cytopenias and provoke transfusion dependence. Anemia and transfusion dependence are critical negative prognostic indicators of overall survival (OS) in MF. Momelotinib (MMB) is a potent and selective small-molecule inhibitor of ACVR1, JAK1, and JAK2, resulting in symptomatic and splenic benefits and a restoration of iron homeostasis and erythropoiesis, facilitating anemia benefits including transfusion independence (TI). TI response with MMB has been associated with improved OS (Mesa et al, 2022). A majority of patients are at risk for poor OS after discontinuing RUX (Palandri et al, 2020). Also, prognostic negative risk factors of spleen length, RUX dose reduction, and RBC transfusion requirement predict poor OS following 6 months of RUX treatment (Maffioli et al, 2022). Phase 3 studies of MMB have provided extensive experience with MMB administered immediately post-RUX, without RUX tapering or washout. Here, we describe a retrospective analysis of data focusing upon the timing and clinical experience of directly transitioning patients from RUX to MMB.

Methods: In the Phase 3 SIMPLIFY-1 study (S1), JAKi-naïve patients with MF (n=432) were randomized 1:1 to MMB or RUX. In SIMPLIFY-2 (S2), MF patients previously treated with RUX (n=156) were randomized 2:1 to MMB or best available therapy (BAT). For S2, taper and washout of active MF therapy was prohibited prior to randomization. RUX was included as BAT and 88.5% of S2 control arm received RUX. In both S1 and S2, following the 24-week (6 month) randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX or BAT crossed over to open-label (OL) MMB (RUX/BAT→MMB) immediately without the need for tapering or washout.

Results: In S1, 197 patients transitioned from RUX→MMB at week 25, all of whom initiated MMB at the 200 mg daily dose with highly comparable dose intensity between MMB→MMB (171 patients) and RUX→MMB; 81% of the active patients were receiving 200 mg daily 12 weeks following crossover. Of note, over the 4 weeks prior to crossover, 71/197 (36%) patients were receiving an average RUX dose of ≤10 mg BID. At the first assessment following crossover to MMB, there was rapid improvement in mean Hgb (≈1 g/dL), and mean spleen volume was maintained (≈1700 cm3) post-crossover for both MMB→MMB and RUX→MMB patients (Figure 1). Furthermore, of the 92 RUX patients who were not TI responders at Week 24 (W24), 46% became TI responders 12 weeks after RUX→MMB. Of the 71 patients who received a mean of ≤10 mg BID RUX over the 4 weeks prior to crossover, only 10% achieved a spleen response (≥35% volume reduction from baseline) prior to W24 crossover. Post RUX→MMB, 23% achieved or maintained spleen response at Week 48.

Safety observations in S1 during the immediate 2‑week period following RUX→MMB revealed excellent tolerability; new onset Grade 3/4 anemia and thrombocytopenia were experienced by only 3% and 2% of patients respectively and there were no cases of RUX discontinuation syndrome. More broadly, all AE terms of any grade experienced within 2 weeks of RUX→MMB transition occurred at ≤7%. Weight gain associated with RUX was ~4-fold higher than that observed with MMB and did not further increase after cross-over.

Similar to S1, in S2 the crossover at W24 from BAT (mainly RUX) to MMB was associated with a rapid improvement in mean Hgb and stable or improved spleen volume.

MFSAF total symptom scores (TSS) were not collected during OL MMB treatment in S1 or S2; however, S2 provided TSS data on 79 of the 102 patients randomized to MMB who received RUX until the day immediately prior to initiation of MMB. W24 TSS improved by ≥50% from pre-study baseline in 26% of MMB patients, including in 22% of those who were on RUX therapy pre-study, immediately prior to starting MMB.

Conclusion: MMB is a promising new therapy for MF, and data provide confidence in an immediate transition to MMB from RUX without washout or tapering, which is likely to rapidly improve anemia without compromising safety or control of symptoms and spleen. In addition, no withdrawal effects were noted following transition from RUX→MMB. Patients may be better served by timely transition to therapy able to improve anemia while maintaining or improving splenic and symptom responses.

Disclosures: Mesa: AOP: Consultancy; Genotech: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Promedior: Research Funding; LaJolla Pharmaceutical: Consultancy; Sierra Oncology: Consultancy, Research Funding; CTI: Research Funding; Geron: Consultancy; Blueprint: Consultancy; Samus: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Research Funding; Incyte: Consultancy, Research Funding; AbbVie: Research Funding; Roche: Consultancy; Novartis: Consultancy; Gilead: Research Funding; Imago: Research Funding. Verstovsek: Constellation Pharmaceuticals: Consultancy; Gilead: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Promedior: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; CTI BioPharma Corp.: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy. Gupta: Sierra Oncology: Consultancy; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; Roche: Other: Participation on a Data Safety or Advisory board; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria. Giraldo: Takeda: Consultancy, Honoraria; Acindes: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ZeroLMC Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Kiladjian: Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Oh: Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: 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; 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; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgne/BMS: 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; Novartis: 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; Bristol Myers Squibb: Consultancy; Cogent: Consultancy. Devos: Alexion: Honoraria, Speakers Bureau; Novartis: Consultancy; BMS/Celgene: Honoraria, Speakers Bureau; Morphosys: Consultancy; Incyte: Consultancy. Passamonti: BMS: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy; AOP Orphan: Consultancy; Karyiopharma: Consultancy; Kyowa Kirin and MEI: Consultancy; Novartis: Honoraria. Vannucchi: Roche: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kawashima: Sierra Oncology: Current Employment. Huang: Sierra Oncology: Current Employment. Strouse: Sierra Oncology: Current Employment. Harrison: Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; EHA: Other: Leadership role; Janssen: Membership on an entity's Board of Directors or advisory committees; Sierra: Honoraria; MPN voice: Other: Leadership role; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Keros: Consultancy; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, 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.

*signifies non-member of ASH