The investigational JAK1/2 inhibitor momelotinib was active in the treatment of myelofibrosis (MF) in phase I/II trials, but updates presented at the 2017 ASCO Annual Meeting from two phase III trials comparing momelotinib with ruxolitinib or best-available therapy (BAT) showed mixed results.
Ruben A. Mesa, MD, from Mayo Clinic Cancer Center in Scottsdale, Arizona, presented results from SIMPLIFY 1, which compared momelotinib with ruxolitinib in patients with JAK inhibitor-naïve MF. Results from the randomized, double-blind, active-controlled, multicenter study demonstrated that momelotinib was non-inferior to ruxolitinib in splenic volume reduction (primary endpoint) and superior in reducing rates of transfusion-dependency for MF-associated anemia, but failed to improve disease-associated symptoms, compared with ruxolitinib.
“Without question, compared to nothing or other standards of care like hydroxyurea, [momelotinib] is still very active, but it’s a question of how active is it compared to ruxolitinib,” Dr. Mesa told ASH Clinical News. “Ruxolitinib is a very solid agent for improving disease-related symptoms, so I think some of that complexity is borne out in that difference.”
SIMPLIFY 1 included 432 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF classified as high risk or intermediate-2 risk (per the International Prognostic Scoring System). All patients also had palpable splenomegaly. Patients who had received splenic irradiation within 3 months of treatment or who were eligible for allogeneic hematopoietic cell transplantation were excluded from the trial.
Patients were stratified by RBC transfusion dependency and platelet levels (<100×109/L, 100-200×109/L, and >200 x109/L), then randomized 1:1 to receive 24 weeks of treatment with either:
- momelotinib 200 mg once daily plus ruxolitinib placebo (n=215)
- ruxolitinib 20 mg twice-daily (or modified per label) plus momelotinib placebo (n=217)
Following this double-blind phase, all patients were eligible to receive open-label momelotinib for up to 168 additional weeks.
Splenic response was measured by MRI or CT imaging, and patients self-reported symptoms using an electronic diary and modified MPN-SAF Total Symptom Score (TSS) to monitor improvement in disease-associated symptoms.
Eighty-one percent (n=175) of momelotinib patients and 93 percent (n=201) of ruxolitinib patients completed the 24-week treatment phase. At this timepoint, the rates of splenic response (defined as a ≥35% reduction in volume from baseline) were similar between the 184 evaluable momelotinib-treated patients and the 204 evaluable ruxolitinib-treated patients (26.5% vs. 29.0%; p=0.011). (Patients with missing spleen volume assessments at baseline or 24 weeks were considered non-responders.)
Momelotinib outperformed ruxolitinib in reducing rates of transfusion-dependency (defined as ≥4 units of RBC transfusions or hemoglobin <8 g/dL in prior 8 weeks), but fewer momelotinib-treated patients experienced improvement in TSS response (defined as a ≥50% reduction in TSS from baseline; TABLE 1).
Ninety-two percent and 95 percent of momelotinib- and ruxolitinib-treated patients (respectively) experienced any-grade adverse event (AE), and 34 and 44 percent experienced grade ≥3 AEs. The most common grade ≥3 AEs in each arm were:
- thrombocytopenia: 7% in the momelotinib arm and 5% in the ruxolitinib arm
- anemia: 6% in the momelotinib arm and 23% in the ruxolitinib arm
Grade ≥3 neutropenia occurred in the ruxolitinib arm (5%), but not in the momelotinib arm.
Rates of peripheral neuropathy were comparable between both treatment groups (10% [all grade ≤2] and 5% [9 grade ≤2; 1 grade 3]), and none of these cases led to study drug discontinuation. “Overall, AEs led to study drug discontinuation in 13 percent of momelotinib and 6 percent of ruxolitinib patients in the double-blind treatment phase,” Dr. Mesa reported, noting that no new safety signals were detected.
In the SIMPLIFY 2 trial, which compared momelotinib with BAT (including ruxolitinib) as second-line treatments in patients with MF who have previously received treatment with a JAK inhibitor, momelotinib failed to improve rates of splenic response (defined as a ≥35% reduction in spleen volume; primary endpoint). However, treatment was associated with improvement in disease-related symptoms and transfusion-independence, according to co-author Srdan Verstovsek, MD, PhD, from MD Anderson Cancer Center at the University of Texas in Houston, who reported the results.
Patients enrolled in the phase III, randomized, open-label, multicenter SIMPLIFY 2 trial met the same eligibility criteria as those in the SIMPLIFY 1 trial, with the exception that patients had received ruxolitinib for ≥4 weeks and were transfusion-dependent or required dose adjustments for grade ≥3 hematologic toxicity.
Patients were stratified according to transfusion dependency and baseline TSS score (<18 or ≥18), then randomized 2:1 to receive 24 weeks of either momelotinib 200 mg once-daily (n=104; mean age = 66.4 years) or BAT (n=52; mean age = 69.4 years). This was an “advanced” group of patients, Dr. Verstovsek noted, with median times from MF diagnosis to enrollment of 3.7 years (range = 0.3-33.5 years) and 4.0 years (0.2-24.9 years), respectively.
“About one-third (n=38; 31%) of the patients on momelotinib discontinued treatment within the first 24 weeks, and about a quarter of patients in the BAT arm (n=14; 23%),” Dr. Verstovsek reported. “There were more adverse events – although low-grade – in the momelotinib arm that led to discontinuation.”
As seen in TABLE 2, the study failed to meet its primary endpoint of momelotinib’s non-inferiority to BAT in terms of splenic response rate at 24 weeks. However, momelotinib was superior to ruxolitinib for the secondary endpoints of reducing symptom burden, increasing rates of transfusion-independence, and reducing rates of transfusion-dependence.
“A great majority of patients (88%) randomized to the BAT arm continued ruxolitinib and, in fact, 27 percent of those patients had a combination of ruxolitinib with another agent,” he added. “Only four patients did not receive ruxolitinib.”
More patients in the momelotinib arm than the BAT arm experienced grade ≥3 treatment-related AEs (60% and 38%), and, again, anemia and thrombocytopenia were the most common grade ≥3 AEs in both treatment arms:
- anemia: 13% in the momelotinib arm and 13% in the ruxolitinib arm
- thrombocytopenia: 7% in the momelotinib arm and 6% in the ruxolitinib arm
Eleven patients (11%) in the momelotinib arm experienced treatment-emergent peripheral neuropathy, three of whom discontinued treatment, but no patients in the BAT arm experienced peripheral neuropathy. Overall, Dr. Verstovsek said, “we did not see new safety concerns emerging with momelotinib in this study.”
Both studies are limited by the use of patient self-report to monitor symptoms.
“For now, ruxolitinib will remain the only drug approved for myelofibrosis,” Dr. Mesa concluded. “There are ongoing discussions [about whether momelotinib] has a place in MF, and, if so, what niche would that be and what the regulatory bodies would accept as a reasonable path [to approval].”
- Mesa RA, Kiladjian JJ, Catalano JV, et al. Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF). Abstract #7000. Presented at the 2017 ASCO Annual Meeting, June 6, 2017; Chicago, Illinois.
- Harrison CN, Vannucchi AM, Platzbecker U, et al. Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX). Abstract #7001. Presented at the 2017 ASCO Annual Meeting, June 6, 2017; Chicago, Illinois.
|TABLE 1. SIMPLIFY 1: Primary and Secondary Endpoints at 24 Weeks|
|Splenic response rate, %||26.5||29.0||0.011*|
|TSS response rate, %||28.4||42.2||0.98*|
|Transfusion-independence rate, %||66.5||49.3||<0.001**|
|Transfusion-dependence rate, %||30.2||40.1||0.019**|
|Transfusion requirements (units/month), median||0.0||0.4||<0.001**|
|TSS = total symptom score; *test for non-inferiority; **test for superiority|
|TABLE 2. SIMPLIFY 2: Primary and Secondary Endpoints at 24 Weeks|
|Splenic response rate, %||6.7||5.8||0.90|
|TSS response rate, %||26.2||5.9||<0.001|
|Transfusion requirements (units/month), median||0.5||1.2||0.39|
|Transfusion-independence rate, %||43.3||21.2||0.001|
|Transfusion-dependence rate, %||50.0||63.5||0.10|
BAT = best available therapy