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Clinical Trial
. 2022 Sep;36(9):2261-2268.
doi: 10.1038/s41375-022-01637-7. Epub 2022 Jul 22.

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

Ruben Mesa  1 , Claire Harrison  2 , Stephen T Oh  3 , Aaron T Gerds  4 , Vikas Gupta  5 , John Catalano  6 , Francisco Cervantes  7 , Timothy Devos  8 , Marek Hus  9 , Jean-Jacques Kiladjian  10 , Ewa Lech-Maranda  11 , Donal McLornan  2 , Alessandro M Vannucchi  12 , Uwe Platzbecker  13 , Mei Huang  14 , Bryan Strouse  14 , Barbara Klencke  14 , Srdan Verstovsek  15
Affiliations
Clinical Trial

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

Ruben Mesa et al. Leukemia. 2022 Sep.

Abstract

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

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Conflict of interest statement

Ruben Mesa has received grants or contracts from Celgene/Bristol-Myers Squibb, Incye, AbbVie, Samus, Genotech, Promedior, CTI Biopharma, Constellation, and National Cancer Institute; and consulting fees from Novartis, Sierra Oncology, LaJolla, and Constellation. Claire Harrison has received grants or contracts from Celgene/Bristol-Myers Squibb, Constellation, and Novartis; consulting fees from Keros, Galecto, AOP Orphan Pharmaceuticals, and Roche; payments or honoraria from Novartis, Celgene, CTI Biopharma, AbbVie, Janssen, and Constellation; support to attending meetings from Novartis; and has participated on Data Safety Monitoring or Advisory Boards for Galecto, CTI Biopharma, Roche, Geron, Promedior, AbbVie, AOP Orphan Pharmaceuticals, and Sierra Oncology, in addition to leadership or fiduciary roles in EHA and MPN Voice. Stephen T. Oh has received consulting fees from CTI Biopharma, Celgene/Bristol-Myers Squibb, Incyte, Blueprint Medicines, AbbVie, Sierra Oncology, Disc Medicine, Constellation, and PharmaEssentia. Aaron T. Gerds has participated in Data Safety Monitoring or Advisory Boards at Sierra Oncology, CTI Biopharma, Incyte, AbbVie, Celgene/Bristol-Myers Squibb, Morphosys, Novartis, and PharmEssentia. Vikas Gupta has received consulting fees from Novartis, Celgene/Bristol-Myers Squibb, Sierra Oncology, AbbVie, Constellation, and Pfizer; payment or honoraria from Novartis, Celgene/Bristol-Myers Squibb, and Constellation; and has participated on Data Safety Monitoring or Advisory Boards for Celgene/Bristol-Myers Squibb, Roche, AbbVie, and Pfizer. John Catalano states no conflicts of interest. Francisco Cervantes has received consulting feeds from Bristol-Myers Squibb; payment or honoraria from Pfizer; and support for attending meetings from Bristol-Myers Squibb. Timothy Devos has received consulting fees for Novartis, Celgene/Bristol-Myers Squibb, Morphosys, and AbbVie. Marek Hus states no conflicts of interest. Jean-Jacques Kiladjian has received consulting fees from Novartis, Celgene/Bristol-Myers Squibb, and AOP Orphan Pharmaceuticals; payment or honoraria from Novartis; and has participated in Data Safety Monitoring or Advisory Boards for Incyte. Ewa Lech-Maranda has participated in Data Safety Monitoring or Advisory Boards for AbbVie, Roche, Gilead, and Novartis. Donal McLornan has received research funding from Novartis; royalties from a book on myelofibrosis; payment or honoraria from Nocartis, Jazz, and AbbVie, and has participated on a Data Safety Monitoring Board for the UK ALLRIC trial. Alessandro M. Vannucchi has received payment or honoraria from Novartis, AbbVie, Celgene/Bristol-Myers Squibb, and AOP Orphan Pharmaceuticals; participated in Data Safety Monitoring and Advisory Boards with Incyte, Novartis, Celgene/Bristol-Myers Squibb, AbbVie, GlaxoSmithKline, and AOP Orphan Pharmaceuticals. Uwe Platzbecker has received consulting fees from AbbVie, Novartis, Celgene/Bristol-Myers Squibb, Janssen, Curis, and Geron; payment or honoraria from Novartis, Takeda, Celgene/Bristol-Myers Squibb, Janssen, and Jazz Pharmaceuticals; and has participated on Data Safety Monitoring or Advisory Boards for Novartis, AbbVie, and Celgene/Bristol-Myers Squibb. Mei Huang, Bryan Strouse, and Barbara Klencke are employees of and claim stock options from Sierra Oncology. Srdan Verstovsek has received consulting fees from Sierra Oncology.

Figures

Fig. 1
Fig. 1. Overall survival (OS) and leukemia-free survival (LFS) of patients with MF in the phase 3 SIMPLIFY studies.
A, B OS and LFS, respectively, in JAKi-naïve patients in SIMPLIFY-1; (C, D) OS and LFS, respectively, in JAKi-exposed patients in SIMPLIFY-2. From week 24, all patients who remained on therapy received open-label momelotinib (MMB). RUX ruxolitinib, BAT best available therapy, HR hazard ratio.
Fig. 2
Fig. 2. Association between transfusion independence (TI) response at week 24 and overall survival (OS) in patients with MF.
A OS by TI response in JAKi-naïve patients in SIMPLIFY-1; (B) OS by TI response in JAKi-exposed patients in SIMPLIFY-2. TI-NR Transfusion independence non-responders, TI-R Transfusion independence responders.
Fig. 3
Fig. 3. Association between total symptom score (TSS) response at week 24 and overall survival (OS) in patients with MF.
A OS by TSS response in JAKi-naïve patients in SIMPLIFY-1; (B) OS by TSS response in JAKi-exposed patients in SIMPLIFY-2. TSS-NR total symptom score non-responders, TSS-R total symptom score responders.
Fig. 4
Fig. 4
Association between spleen volume reduction (SVR) response at week 24 and overall survival (OS) in JAKi-naïve (SIMPLIFY-1) patients with MF. Due to the low number of splenic responders in SIMPLIFY-2 (MMB arm, N = 7/104 [7%]; BAT/RUX→MMB arm, N = 3/52 [6%]), the responder analysis was not interpretable for the SVR endpoint. NR Non-responders, R Responders.
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