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SIMPLIFY-1: a Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients with Myelofibrosis Ruben A

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SIMPLIFY-1: a Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients with Myelofibrosis Ruben A SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients With Myelofibrosis Ruben A. Mesa, Mayo Clinic Jean-Jacques Kiladjian, St Louis Hospital John V. Catalano, Frankston Hospital Timothy Devos, University Hospital Leuven Miklos Egyed, Kaposi Mor Teaching Hospital Andrzei Hellmann, Medical University Gdansk Donal McLornan, Guy’s and St Thomas’ National Health Service Foundation Trust Kazuya Shimoda, University of Miyazaki Elliott Winton, Emory University Wei Deng, Emory University Only first 10 authors above; see publication for full author list. Journal Title: Journal of Clinical Oncology Volume: Volume 35, Number 34 Publisher: American Society of Clinical Oncology | 2017-12-01, Pages 3844-+ Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1200/JCO.2017.73.4418 Permanent URL: https://pid.emory.edu/ark:/25593/trfsv Final published version: http://dx.doi.org/10.1200/JCO.2017.73.4418 Copyright information: © 2017 American Society of Clinical Oncology. All rights reserved. Accessed September 30, 2021 9:14 PM EDT VOLUME 35 • NUMBER 34 • DECEMBER 1, 2017 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Na¨ıve Patients With Myelofibrosis Ruben A. Mesa, Jean-Jacques Kiladjian, John V. Catalano, Timothy Devos, Miklos Egyed, Andrzei Hellmann, Donal McLornan, Kazuya Shimoda, Elliott F. Winton, Wei Deng, Ronald L. Dubowy, Julia D. Maltzman, Francisco Cervantes, and Jason Gotlib Author affiliations and support information (if applicable) appear at the end of this ABSTRACT article. Purpose Published at jco.org on September 20, We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 2017. inhibitor (JAKi), compared with ruxolitinib, in JAKi-na¨ıve patients with myelofibrosis. Clinical trial information: NCT01969838. Patients and Methods Corresponding author: Ruben A. Mesa, MD, fi Mayo Clinic Cancer Center, 5777 E Mayo Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelo brosis Blvd, Phoenix, AZ; e-mail: mesa.ruben@ were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or mayo.edu. ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. © 2017 by American Society of Clinical The primary end point was a $ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end Oncology points were rates of symptom response and effects on RBC transfusion requirements. 0732-183X/17/3534w-3844w/$20.00 Results A $ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A $ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met (P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P # .019). The most common grade $ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade $ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment- emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade # 2) and 5% of patients who received ruxolitinib (all grade # 3). Conclusion In JAKi-na¨ıve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was asso- ciated with a reduced transfusion requirement. J Clin Oncol 35:3844-3850. © 2017 by American Society of Clinical Oncology control of symptomatic splenomegaly and consti- INTRODUCTION tutional symptoms in patients with or without the JAK2 mutation.5-7 Common hematologic adverse ASSOCIATED CONTENT Myelofibrosis (MF) is a myeloproliferative neo- events (AEs) with ruxolitinib treatment include Listen to the podcast plasm characterized by anemia, extramedullary anemia and thrombocytopenia, which can lead to 6,7 by Dr Gupta at hematopoiesis, splenomegaly, and often-debilitating dose reductions or treatment interruptions. There- ascopubs.org/jco/podcasts constitutional symptoms.1 Approximately 90% of fore, an unmet need exists for new therapeutic options Appendix patients with MF harbor mutations in JAK2, CALR, that improve responses while reducing anemia and DOI: https://doi.org/10.1200/JCO. or MPL leading to constitutive activation of Janus other toxicities associated with currently available 2017.73.4418 kinase (JAK)–signal transducers and activators of therapies. Data Supplement 2-4 DOI: https://doi.org/10.1200/JCO. transcription signaling. Currently, the only US Momelotinib is an investigational, oral, 2017.73.4418 Food and Drug Administration–approved treat- small-molecule inhibitor of JAK1/2 with selectivity 8-10 DOI: https://doi.org/10.1200/JCO.2017. ment of MF is ruxolitinib, a JAK inhibitor (JAKi) over other tyrosine and serine/threonine kinases. In 73.4418 that has demonstrated therapeutic benefitinthe preclinical studies, momelotinib has also demonstrated 3844 © 2017 by American Society of Clinical Oncology Momelotinib v Ruxolitinib in JAK Inhibitor–Naı¨ve Myelofibrosis inhibition of the bone morphogenic protein receptor kinase activin 2 weeks during the double-blind phase. Patients completed the modified A receptor, type I (ACVR1)–mediated expression of hepcidin in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom liver, thereby increasing iron availability for erythropoiesis.10 Thus, Score (TSS) using an electronic diary daily from screening through the double-blind phase. Eastern Cooperative Oncology Group performance there is a rationale for the use of momelotinib in patients with MF status and laboratory assessments were done during clinic visits, and ab- where anemia remains a challenging clinical problem. A phase I/II dominal magnetic resonance imaging (MRI) or computed tomography (CT) study evaluating momelotinib in MF demonstrated reduction in scans were performed every 12 weeks. A record of all transfusions received spleen volume, improvement of MF-associated symptoms, and during screening and throughout the study was kept in the patients’ diaries. reduction of RBC transfusion requirements in patients with MF.11 In this analysis, we report the results of the phase III trial, Momelotinib Statistical Analysis and End Points Versus Ruxolitinib in Subjects With Myelofibrosis (SIMPLIFY-1) in The primary end point was a reduction of $ 35% in spleen volume JAKi-na¨ıve patients with MF that compares the efficacy and safety of from baseline at week 24 (spleen response rate, SRR24), as assessed by MRI momelotinib versus ruxolitinib. A companion trial, SIMPLIFY-2, or CT scan and evaluated by a blinded central reader. The primary hy- compares momelotinib with best available therapy in MF in pa- pothesis was that momelotinib is noninferior to ruxolitinib. On the basis of tients who experienced either suboptimal responses or toxicity to the assumption of the common treatment effect on SRR being 34% (lower bound of the 95% CI on the ruxolitinib effect on SRR) that was observed in ruxolitinib.12 the Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment (COMFORT-1)7, a total sample size of 420 provides . 90% power for testing the noninferiority hypothesis on SRR24. Noninferiority of mome- PATIENTS AND METHODS lotinib was determined by whether the lower bound of the two-sided 95% CI for the noninferiority difference (SRR24 of momelotinib 2 0.6 3 SRR24 of . Patient Eligibility, Stratification, and Treatment ruxolitinib) was 0 and was calculated based on the stratum-adjusted Patients were $ 18 years of age with palpable splenomegaly $ 5cm Cochran-Mantel-Haenszel (CMH) proportion. below the left costal margin and a confirmed diagnosis of primary MF Four end points at week 24 were designated as secondary end points (WHO criteria13) or post–polycythemia vera or post–essential throm- for which sequential testing was performed in the order listed to control bocythemia MF (International Working Group for Myelofibrosis Research the type 1 error rate: TSS response rate (proportion of patients who $ and Treatment [IWG-MRT] criteria14). Patients were classified as In- achieved a 50% reduction from baseline to week 24 on the basis of the fi ternational Prognostic Scoring System15 high risk, intermediate-2 risk, or modi ed Myeloproliferative Neoplasm Symptom Assessment Form TSS intermediate-1 risk with symptomatic splenomegaly or hepatomegaly or diary); RBC transfusion-independence rate (proportion of patients who anemia (hemoglobin [Hb] , 10.0 g/dL) and/or unresponsive to available were transfusion-independent at week 24 [absence of RBC transfusions , non-JAKi therapy. Within 14 days before the first dose of study treat- and no Hb 8 g/dL in the prior 12 weeks]); RBC transfusion-dependence $ ment, the following laboratory tests were required: absolute neutrophil rate (proportion of patients who were transfusion-dependent [ 4 units of , count $ 0.75 3 109/L in the absence of growth factor therapy in the prior RBC transfusions, or Hb 8 g/dL in the prior 8 weeks]); and rate of RBC 7 days; platelet count $ 50 3 109/L ($ 100 3 109/L if ASTor ALT $ 2 3 transfusion (average number of RBC units per
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