Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.

BACKGROUND: The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib. METHODS: In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA. Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a day with at least one of grade 3 thrombocytopenia, anaemia, or bleeding at grade 3 or worse, with palpable spleen of at least 5 cm and without grade 2 or greater peripheral neuropathy were included in the study. Patients were randomly assigned (2:1) to either 24 weeks of open-label momelotinib 200 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions), after which all patients could receive extended momelotinib treatment. Patients were randomly assigned to treatment by an interactive web response system and the randomisation was stratified by transfusion dependence and by baseline total symptom score (TSS). Results were analysed on an intention-to-treat basis. The primary endpoint was a reduction by at least 35% in the spleen volume at 24 weeks compared with baseline. Safety analyses included adverse event monitoring. The trial is registered with ClinicalTrials.gov, number NCT02101268. FINDINGS: Between June 19, 2014, and July 28, 2016, 156 patients were recruited to the study; 104 received momelotinib and 52 received BAT. BAT was ruxolitinib in 46 (89%) of 52 patients. 73 (70%) of 104 patients in the momelotinib group and 40 (77%) of 52 patients in the BAT group completed the 24-week treatment phase. Seven (7%) of 104 patients in the momelotinib group and three (6%) of 52 in the BAT group had a reduction in the spleen volume by at least 35% compared with baseline (proportion difference [Cochran-Mantel-Haenszel method], 0·01; 95% CI -0·09 to 0·10), p=0·90). The most common grade 3 or worse adverse events were anaemia (14 [14%] of 104 in the momelotinib group vs seven [14%] of 52 in the BAT group), thrombocytopenia (seven [7%] vs three [6%]), and abdominal pain (one [1%] vs three [6%]). Peripheral neuropathy occurred in 11 (11%) of 104 patients receiving momelotinib (one of which was grade 3) and in no patients in the BAT group. Serious events were reported for 36 (35%) patients in the momelotinib group and 12 (23%) of patients in the BAT group. Deaths due to adverse events were reported for six patients (6%) receiving momelotinib (acute myeloid leukaemia [n=2], respiratory failure [n=2, with one considered possibly related to momelotinib], cardiac arrest [n=1, considered possibly related to momelotinib], and bacterial sepsis [n=1]); and four patients (8%) receiving BAT (lung adenocarcinoma [n=1], myelofibrosis [n=1], and sepsis [n=2]). INTERPRETATION: In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the reduction of spleen size by at least 35% compared with baseline. FUNDING: Gilead Sciences, Inc.