PURPOSE: Ruxolitinib improves splenomegaly and symptoms in myelofibrosis but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in myelofibrosis. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in JAK inhibitor-naïve myelofibrosis. PATIENTS AND METHODS: In this double-blind, phase 3 trial, patients were randomized (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Co-primary endpoints were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to Week 24. RESULTS: 353 patients were randomized. At Week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58; 95% CI, 1.60 to 4.17; P<0.0001). Differences were evident by Week 12 and through Week 36. The AbsTSS co-primary endpoint was not met; however, symptom scores improved from baseline in both groups (-9.9 selinexor plus ruxolitinib, -10.9 placebo plus ruxolitinib), with no significant between-group difference.At median follow-up of ∼12 months, the overall survival (OS) hazard ratio was 0.43 (95% CI, 0.19 to 1.00; nominal P=0.022).Grade ≥3 adverse events occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early. CONCLUSIONS: In patients with JAK inhibitor-naïve myelofibrosis, selinexor plus ruxolitinib met its co-primary endpoint of improved SVR35 but did not meet the AbsTSS co-primary endpoint, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known adverse event profiles of the individual agents. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov: NCT04562389; EudraCT: 2020-003883-19.
Bose et al. (Tue,) studied this question.