Momelotinib Trial in Myelofibrosis Fails to Meet Primary Endpoint

The Janus kinase (JAK) inhibitor ruxolitinib is the only treatment approved by the U.S. Food and Drug Administration for patients with myelofibrosis (MF), and patients who experience disease progression or inadequate response to this treatment have limited options.

In the phase III SIMPLIFY 2 study, Claire N. Harrison, DM, of the Guy’s and St. Thomas’ National Health Service Foundation Trust in London, and co-authors compared momelotinib, a JAK1 and JAK2 inhibitor, with best available therapy (BAT) in ruxolitinib-treated patients with MF. Momelotinib failed to improve rates of splenic response (defined as ≥35% reduction in spleen volume; primary endpoint), according to results published in The Lancet Haematology. However, the investigators reported that treatment appeared to be associated with improvement in disease-related symptoms and red blood cell (RBC) transfusion–independence.

The international, multicenter, randomized, open-label trial enrolled 156 patients from 52 clinical centers in Canada, France, Germany, Israel, Italy, Spain, the United Kingdom, and the United States between June 19, 2014, and July 28, 2016. All participants were receiving or previously received ruxolitinib for at least 28 days and required dose adjustments for grade ≥3 hematologic toxicity or were transfusion-dependent (defined as ≥4 units of RBCs or a hemoglobin level of <8 g/dL in the 8 weeks prior to randomization). Those with previous splenectomy, spleen irradiation, grade ≥2 peripheral neuropathy, or uncontrolled concurrent illness were excluded.

Patients were stratified by transfusion dependence (yes vs. no) and baseline total symptom score (TSS; <18 vs. ≥18), then randomized 2:1 to receive momelotinib 200 mg once-daily (n=104; mean age = 66.5 years; standard deviation [SD] = 8.1 years) or BAT administered according to standard of care and investigator’s discretion (n=52; mean age = 69 years; SD=7.4 years).

Most patients in the momelotinib and BAT cohorts had intermediate-2 disease (per Dynamic International Prognostic Scoring System; 60% and 54%, respectively), had an Eastern Cooperative Oncology Group score of 1 (59% and 50%), and were treated previously for 12 or more weeks with ruxolitinib (72% and 64%).

While the intent of the study was to compare safety and efficacy of momelotinib and BAT other than ruxolitinib, 46 patients (89%) in the BAT cohort received ruxolitinib while on study, and 14 patients (27%) received ruxolitinib plus additional therapies (most commonly hydroxyurea [n=9; 17%] and corticosteroids [n=6; 12%]). “At the time the study protocol was developed, [we] anticipated that most patients in the BAT group would be receiving drugs [other than ruxolitinib] or would be on sub-therapeutic doses of ruxolitinib,” the authors noted. “However, as dosing guidelines become more widely available for ruxolitinib, … patients were increasingly being maintained on ruxolitinib at therapeutic doses.”

The median treatment exposure duration was 23.9 weeks (interquartile range [IQR] = 15.9-24.0 weeks) for momelotinib and 24.1 weeks (IQR=23.7-24.3 weeks) for BAT. Patients were followed for a median of 168 days in both the momelotinib (IQR=142-170 days) and BAT (IQR=165-169 days) groups.

More than one-third of patients (n=35; 34%) in the momelotinib group discontinued treatment within the first 24 weeks, most frequently because of adverse events (AEs; n=14; 14%). Seventeen patients receiving momelotinib required dose reductions or interruptions – again, most frequently because of AEs (n=14; 14%). Data on treatment discontinuation in the BAT cohort were inconsistently reported because changes in therapy or change to no active therapy were permissible options for this group.

Primary endpoint analysis was available in 70 momelotinib-treated patients (67%) and 39 BAT-treated patients (75%). Only seven people (7%) in the momelotinib group and three people (6%) in the BAT group experienced spleen volume reduction of ≥35 percent or more from baseline (proportion difference = 0.01; 95% CI –0.09-0.10; p=0.90).

All responders in the BAT group were receiving ruxolitinib, the authors reported. They suggested that the poor responses in both groups “could be explained by the fact that there was no washout period for patients receiving MF therapy before study entry or the unique patient population … who had either suboptimal responses or hematologic toxic effects with ruxolitinib.”

The most common grade ≥3 AEs associated with momelotinib and BAT were anemia (n=14 [14%] vs. 7 [14%]), thrombocytopenia (n=7 [7%] vs. n=3 [6%]), and abdominal pain (n=1 [1%] vs. n=3 [6%]). Eleven patients (11%) treated with momelotinib reported peripheral neuropathy, while this did not occur in the BAT group. Three momelotinib-treated patients discontinued treatment because of peripheral neuropathy.

“Although this study did not meet the primary endpoint of spleen volume reduction, the data from this study suggest that momelotinib therapy might provide meaningful results for patients previously treated with ruxolitinib, including improved anemia responses, fewer transfusion requirements, and symptom improvement,” the authors reported.

More patients in the momelotinib group (n=27/103; 26%) had a >50 percent reduction in TSS from baseline, compared with those in the BAT group (n=3/51; 6%; p values not reported), “indicating greater symptomatic improvement.” Momelotinib treatment also appeared to reduce transfusion burden. At baseline, approximately half of the patients in each group (n=58/104 [56%] for momelotinib and n=27/54 [52%] for BAT) were transfusion-dependent; at week 24, more patients who received momelotinib were transfusion-independent (n=45/104 [43%] vs. n=11/52 [21%]; p=0.0012).

The study is limited by the amount of missing or incomplete data about patients’ duration of ruxolitinib treatment prior to randomization. Longer-term follow-up is needed to confirm any observed benefit in secondary endpoints, the researchers added.

The authors report financial relationships with Novartis, Gilead Sciences, CTI BioPharma, and Shire.


Reference

Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 December 20. [Epub ahead of print]

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