Mixed Results From SIMPLIFY-1 Complicate Myelofibrosis Treatment Decisions

The Janus kinase (JAK) inhibitor ruxolitinib is the only U.S. Food and Drug Administration–approved therapy for myelofibrosis (MF), but the resultant hematologic adverse events (AEs) can lead to dose reductions or interruptions.

In the SIMPLIFY-1 trial, Ruben A. Mesa, MD, director of the UT Health San Antonio Cancer Center in Texas, and co-authors evaluated momelotinib, an oral, small-molecule JAK1/2 inhibitor, as an alternative to ruxolitinib. Their results, published in the Journal of Clinical Oncology, were mixed: The investigational agent was non-inferior to ruxolitinib for spleen volume reduction, but ruxolitinib was superior in reducing symptom burden.

The 24-week, multicenter, randomized, double-blind, double-dummy, phase III trial enrolled 432 JAK inhibitor–naïve adult patients with primary MF (according to World Health Organization criteria), post-polycythemia vera, or post-essential thrombocythemia MF (according to International Working Group for Myelofibrosis Research and Treatment criteria). Participants also had palpable splenomegaly ≥5 cm, adequate renal and hepatic function, and an Eastern Cooperative Oncology Group performance status score of ≤2.

Patients were excluded if they had spleen irradiation within three months prior to study treatment, certain cancers, or uncontrolled concurrent illness.

Participants were stratified based on transfusion dependence (yes or no; defined as ≥4 units of red blood cells [RBCs] or hemoglobin <8 g/dL in the prior 8 weeks) and platelet count (<100×109/L, ≥100×109/L and ≤200×109/L, and >200×109/L), then randomized 1:1 to receive:

  • momelotinib 200 mg once-daily (n=215; mean age = 65.0 years; standard deviation [SD] = 10.67 years)
  • ruxolitinib 20 mg twice-daily (n=217; mean age = 64.4 years; SD=10.59 years)

Treatment discontinuation appeared to be more common in the momelotinib group (18.6%) than the ruxolitinib group (7.4%; p value not reported), and a total of 376 patients completed the 24-week phase: 175 in the momelotinib group and 201 patients in the ruxolitinib group.

The primary endpoint (spleen volume reduction ≥35% from baseline at week 24) was evaluable in 184 momelotinib-treated patients and 204 ruxolitinib-treated patients. A similar number of patients in each treatment group achieved the primary endpoint (n=57 [26.5%] vs. 63 [29.0%]), for a non-inferiority proportion difference of 0.09, making momelotinib non-inferior to ruxolitinib (p=0.01).

Ruxolitinib was better than momelotinib in reducing symptoms (secondary endpoint; defined as total symptom score [TSS] reduction >50% reduction from baseline). Of the 190 and 175 patients, respectively, available for TSS assessment, more ruxolitinib-treated patients met this endpoint (n=89 [42.2%] vs. 60 [28.4%]; n=60), and non-inferiority for momelotinib was not met (p=0.98).

However, transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib:

  • median rate of RBC transfusions: 0 units/month vs. 0.4 units/month (ranges not reported; p<0.001)
  • transfusion-independent at week 24 (66.5% vs. 49.3%; p<0.001)
  • transfusion-dependent at week 24 (30.2% vs. 40.1%; p=0.019)

The best overall response rate at 24 weeks in each cohort was low, but with a numeric advantage for the investigational agent (5.1% for momelotinib and 3.2% for ruxolitinib; p value not reported).

The mean duration of treatment exposure was 21.3 weeks (range = 0.3-26.1 weeks) with momelotinib and 23.3 weeks (range = 1.3-26.9 weeks) with ruxolitinib. Dose reductions or interruptions occurred in 26.2 percent and 56.0 percent of patients (p value not reported), respectively, most commonly because of adverse events (AEs; 17.3% vs. 35.6%, respectively).

The most common, any-grade treatment-related AEs in the momelotinib and ruxolitinib cohorts are reported in the TABLE.

Grade ≥3 AEs were reported by 35.5 percent of momelotinib-treated patients and 43.5 percent of ruxolitinib-treated patients. The most common grade ≥3 AEs in the momelotinib group were thrombocytopenia (7.0%), anemia (5.6%), diarrhea (2.8%), hypertension (2.8%), and neutropenia (2.8%), while the most common in the ruxolitinib group were anemia (23.1%), neutropenia (4.6%), thrombocytopenia (4.6%), and hypertension (4.2%). Serious AEs occurred in 22.9 percent and 18.1 percent of patients, respectively.

Treatment discontinuation occurred more frequently in the momelotinib group (13.1% vs. 5.6%; p value not reported), and seven deaths were reported in each cohort.

“Results were mixed and indicate that although momelotinib may offer less symptom control than ruxolitinib, there is a comparable spleen response and a potential benefit in terms of anemia,” the authors concluded.

The study is limited by its 24-week follow-up period. Long-term efficacy and safety evaluations are warranted, according to the authors.

Gilead supported the study.

The corresponding authors report financial support from Gilead, the manufacturer of momelotinib, and Incyte, the manufacturer of ruxolitinib. Impact Communications provided editorial support.


Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844-50.