ABSTRACT Background Janus kinase inhibitors (JAKis), the current standard of care for myelofibrosis (MF), provide clinical benefit, but responses are frequently incomplete, non‐durable, and associated with cytopenias, underscoring the need for therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of Exportin 1 (XPO1), modulates nuclear‐cytoplasmic transport, inflammatory signaling, and cancer cell proliferation. Methods XPORT‐MF‐035, a global, Phase 2, randomized, open‐label study comparing selinexor monotherapy with physician's choice (PC) in MF previously treated with JAKi, randomized patients 1:1 to selinexor or PC, with crossover permitted upon disease progression or inadequate spleen response. Primary endpoint was spleen volume reduction ≥ 35% (SVR35). Additional endpoints included symptom improvement, hematologic outcomes, plasma cytokine analyses, and safety. Results Twenty‐four patients were enrolled and treated. In the efficacy‐evaluable population, SVR35 at any time was achieved by 29% (2/7) and 13% (1/8) of selinexor‐ and PC‐treated patients, respectively; 8% (1/12) in each arm achieved SVR35 at Week 24 in the intent‐to‐treat population. Among evaluable patients, 40% (2/5) achieved SVR35 following selinexor crossover. Symptom improvement was observed with selinexor but not PC. Selinexor‐treated patients experienced fewer Grade ≥ 3 anemia events with lower transfusion burden and reductions in multiple proinflammatory cytokines. Selinexor was generally well tolerated; common treatment‐emergent adverse events (TEAEs) included anemia, asthenia, and decreased weight. One TEAE leading to death occurred in the selinexor and two in PC; none were considered treatment‐related. Conclusions Despite limited sample size, XPORT‐MF‐035 provides descriptive data on the safety, tolerability, and biological activity of selinexor monotherapy in previously treated MF, supporting further evaluation in this population. Trial Registration ClinicalTrials.gov identifier: NCT04562870
Grosicki et al. (Mon,) studied this question.