Multinational phase 3 trial of selinexor plus ruxolitinib for JAK inhibitor-naïve myelofibrosis

Ruxolitinib improves splenomegaly and symptoms in patients with myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. The multinational phase 3 SENTRY trial evaluated selinexor plus ruxolitinib in JAK inhibitor-naïve MF. In this trial 353 patients were randomized 2:1 to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Co-primary endpoints were spleen volume reduction of at least 35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. At week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolinib group versus 28.0% of the placebo plus ruxolitinib group (OR2.58; p<0.0001). Differences were evident by week 12 and through week 36. The AbsTSS endpoint was not met; symptom scores improved from baseline in both groups, with no significant between-group difference. At a median follow-up of 12 months, the overall survival HR was 0.43 (p=0.022). Grade ≥ 3 adverse events occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib group or the placebo plus ruxolitinib group, respectively, with adverse events consistent with known safety profile of the individual agents. The authors conclude that in patients with JAK inhbitor-naïve MF, selinexor plus ruxolitinib compared with placebo plus ruxolitinib improved SVR35 but did not improve AbsTSS. An early overall survival benefit was observed.