Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Myelofibrosis: Phase III SENTRY Trial.
Key claim: In JAK inhibitor-naïve myelofibrosis, selinexor plus ruxolitinib significantly improved spleen volume reduction at week 24 versus ruxolitinib alone but did not improve symptom scores, with an early overall-survival signal and expected additive hematologic toxicity.
Abstract
PURPOSE: Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in Janus kinase inhibitor-naïve MF. METHODS: In this double-blind, phase III trial, patients were randomly assigned (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Coprimary end points were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. RESULTS: A total of 353 patients were randomly assigned. 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];< .0001). Differences were evident by week 12 and through week 36. The AbsTSS coprimary end point 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 a median follow-up of approximately 12 months, the overall survival (OS) hazard ratio was 0.43 ([95% CI, 0.19 to 1.00]; nominal= .022). Grade ≥3 adverse events (AEs) 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. CONCLUSION: In patients with JAK inhibitor-naïve MF, selinexor plus ruxolitinib met its coprimary end point of improved SVR35 but did not meet the AbsTSS coprimary end point, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known AE profiles of the individual agents.
Why this matters
For symptom management in MF, SENTRY is another late-phase demonstration that spleen shrinkage and symptom relief are dissociable endpoints: selinexor + ruxolitinib enlarged the spleen-directed toolkit but did not move the needle on the total symptom score that patients actually feel. This matters because clinicians and patients weighing combination regimens for symptom burden — fatigue, early satiety, night sweats — cannot assume that a better SVR35 translates into better quality of life, and additive cytopenias may worsen fatigue via anemia.