Selinexor Doubles Spleen Response, Misses Symptoms

Karyopharm Therapeutics (Nasdaq: KPTI) reported topline results from its Phase III SENTRY trial in myelofibrosis, showing that selinexor combined with ruxolitinib nearly doubled the rate of spleen volume reduction compared to ruxolitinib alone, though the combination failed to separate from the comparator on symptom improvement. The mixed outcome on co-primary endpoints sets up a complex regulatory discussion for the Newton, Massachusetts–based company, which plans to meet with the FDA to explore a potential supplemental new drug application.

The SENTRY trial (XPORT-MF-034; NCT04562389) is a randomized, double-blind, placebo-controlled Phase III study that enrolled 353 JAK inhibitor–naïve myelofibrosis patients with platelet counts above 100 × 10⁹/L. Patients were randomized 2:1 to receive 60 mg selinexor once weekly plus ruxolitinib or placebo plus ruxolitinib. The trial had two co-primary endpoints: spleen volume reduction of 35% or more (SVR35) at week 24, and mean change in absolute total symptom score (Abs-TSS) over 24 weeks relative to baseline. Data are reported as of a February 20, 2026 cut-off.

On the first co-primary endpoint, 50% of patients in the combination arm achieved SVR35 at week 24 compared to 28% with ruxolitinib alone (one-sided p<0.0001). Spleen responses appeared early, with 49% of combination-arm patients reaching SVR35 by week 12 versus 20% in the control arm, and were sustained at week 36 (47% versus 23%). On the second co-primary endpoint, however, the trial did not reach statistical significance: patients receiving selinexor plus ruxolitinib reported a 9.89-point improvement in Abs-TSS versus a 10.86-point improvement with ruxolitinib alone. Both arms achieved similar symptom relief relative to baseline, meaning the addition of selinexor did not confer a detectable symptom benefit over ruxolitinib monotherapy.

An exploratory overall survival analysis yielded a hazard ratio of 0.43 (95% CI [0.19, 1.00]; nominal one-sided p=0.0222), suggesting a reduction in risk of death with the combination. The company noted these data are immature and intends to continue follow-up. A pre-specified exploratory endpoint examining variant allele frequency (VAF) reduction showed 32% of combination-arm patients achieving 20% or greater VAF reduction for driver mutations (JAK2, MPL, CALR) at week 24, compared to 24% with ruxolitinib alone (n=261). Other secondary endpoints, including progression-free survival, hemoglobin stabilization, and bone marrow fibrosis improvement, showed no meaningful difference between arms at the data cut-off.

The safety profile was consistent with the known effects of both agents. The most common adverse events in the combination arm were thrombocytopenia (59% versus 43% in the control arm), anemia (57% versus 58%), nausea (57% versus 17%), constipation (32% versus 36%), and neutropenia (27% versus 9%). Grade 3 or higher adverse events occurred in 70% of patients receiving the combination versus 50% in the control arm. Treatment discontinuation due to adverse events was 15% in the combination arm compared to 9% with ruxolitinib alone. Rates of leukemic transformation were identical at 1.7% in both arms.

Selinexor is a first-in-class oral inhibitor of exportin 1 (XPO1), a nuclear transport protein responsible for shuttling tumor suppressor proteins and growth regulators out of the nucleus. By blocking XPO1, selinexor forces retention of these proteins in the nucleus, restoring their function and inducing cell death in malignant cells. This mechanism is distinct from JAK pathway inhibition, and the rationale for combining selinexor with ruxolitinib rests on targeting complementary biological pathways in myelofibrosis.

The spleen volume reduction rate of 50% at week 24 in the combination arm compares to historical SVR35 rates for ruxolitinib monotherapy in the range of 40–42% observed in the COMFORT trials, though the 28% rate in SENTRY's control arm fell below those benchmarks. Cross-trial comparisons are limited by differences in study design, patient selection, and duration. Within the SENTRY trial itself, the internal comparison is more interpretable, and the near-doubling of SVR35 at week 12 (49% versus 20%) suggests the combination accelerates spleen response. Whether this translates into durable clinical benefit remains to be established as survival and other endpoints mature.

The myelofibrosis treatment landscape remains anchored by JAK inhibitors. Ruxolitinib, approved by the FDA in 2011, is the standard frontline therapy. Fedratinib, pacritinib, and momelotinib have since received approval, each addressing specific patient subpopulations defined by platelet counts or anemia burden. No approved therapy in the frontline setting has demonstrated an overall survival benefit in a randomized trial, making the immature OS signal from SENTRY a point of interest, though the wide confidence interval spanning 1.00 warrants caution. The field has seen several combination approaches fail to improve on JAK inhibitor monotherapy, including navitoclax plus ruxolitinib, where regulatory setbacks have underscored the difficulty of demonstrating added benefit over established JAK inhibition.

The regulatory path forward for Karyopharm is uncertain. Meeting one co-primary endpoint while missing the other creates ambiguity, and the FDA's willingness to consider an sNDA based on SVR35 alone, alongside immature survival data, will depend on the agency's assessment of the totality of evidence. The company stated it plans to present additional data at an upcoming medical meeting and submit a manuscript for peer-reviewed publication, with potential compendia inclusion anticipated in the second half of 2026.

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