Menarini selinexor combo meets spleen endpoint in Phase 3 MF

Menarini Group and its oncology subsidiary Stemline Therapeutics have reported pivotal Phase 3 data showing that selinexor (NEXPOVIO) combined with ruxolitinib produced a statistically significant improvement in spleen volume reduction in frontline myelofibrosis, meeting the first of two co-primary endpoints in the SENTRY trial. The data were selected for a late-breaking oral presentation at the European Hematology Association (EHA) 2026 Congress in June.

SENTRY (NCT04562389) is a randomised, double-blind, placebo-controlled trial enrolling 353 patients, comparing selinexor 60 mg plus ruxolitinib against ruxolitinib monotherapy. The primary spleen endpoint, defined as a 35% or greater reduction in spleen volume (SVR35) at week 24, was achieved by 49.8% of patients in the combination arm versus 28.0% in the control arm. The benefit appeared early: at week 12, SVR35 rates were 49.4% versus 20.3%, and remained durable at week 36 at 46.9% versus 23.0%.

Where the trial fell short

The combination did not meet the second co-primary endpoint. Absolute total symptom score improvement at week 24 was 9.9 points in the selinexor arm versus 10.9 points with ruxolitinib alone, a difference that was not statistically significant. Symptom burden reduction is an important patient-reported outcome in myelofibrosis, and the failure on this endpoint is likely to attract scrutiny from regulators and clinicians when weighing the overall benefit-risk profile of the combination.

Nevertheless, secondary and exploratory data added to the picture. An overall survival analysis, though described as immature, showed a hazard ratio of 0.43 for the combination, representing a greater than 50% reduction in the risk of death. Variant allele frequency reduction, a marker associated with disease modification, was observed in 32% of combination patients at week 24 versus 23.9% in the control arm. Post-hoc analysis from the Phase 3 study, alongside new data from the Phase 1 SENTRY cohort, suggested SVR35 may predict overall survival, a finding the company said could strengthen the clinical rationale for the spleen endpoint.

Claire Harrison, Professor of Myeloproliferative Neoplasms and Deputy Chief Medical Officer at Guy's and St. Thomas' NHS Foundation Trust, said the spleen reduction results were "rapid, deep and durable, and associated with potential overall survival benefit for the patients receiving the combination."

The safety profile was described as consistent with the established profiles of each individual agent, with no new signals identified.

Market context and regulatory path

Myelofibrosis is a rare myeloproliferative neoplasm with an incidence of roughly one to two cases per 100,000 people annually, and a median post-diagnosis survival of approximately six years. Ruxolitinib, a JAK1/2 inhibitor marketed by Novartis, has been the backbone of frontline treatment for more than a decade, but a meaningful proportion of patients progress or achieve inadequate spleen or symptom responses on monotherapy, creating space for add-on strategies.

The selinexor combination is one of several approaches competing in this space. Pacritinib and fedratinib are approved in ruxolitinib-ineligible or refractory patients, while a number of combination programmes pairing JAK inhibitors with agents targeting BET bromodomain, MDM2, or PI3K pathways are in clinical development. Selinexor's mechanism as a first-in-class oral XPO1 inhibitor gives it a differentiated pharmacological rationale, though the failure to improve symptom scores will need to be addressed in regulatory conversations.

Menarini holds ex-US commercialisation rights to selinexor, while Karyopharm Therapeutics, which conducted the SENTRY trial in collaboration with Menarini, retains US rights. The next steps for a regulatory submission in the myelofibrosis indication have not yet been disclosed, and analysts will focus on whether the OS signal matures sufficiently in updated data cuts to support a label claim.