FDA sNDA Submission Is Planned for Selinexor Plus Ruxolitinib in Myelofibrosis

An FDA submission is planned for a supplemental new drug application (sNDA) seeking accelerated approval of selinexor (Xpovio) in combination with ruxolitinib (Jakafi) for the treatment of patients with myelofibrosis.¹

Submission by Karyopharm Therapeutics is anticipated in August 2026, and the company intends to seek priority review of the application.

The planned filing follows written FDA feedback that a spleen volume reduction of at least 35% (SVR35) appears to qualify as a reasonably likely surrogate end point to predict overall survival (OS) and can be used to support an sNDA under the accelerated approval pathway.¹ Karyopharm plans to use overall survival (OS) data from long-term follow-up of the phase 3 SENTRY trial (NCT04562389) to verify clinical benefit.

Data from SENTRY, which will support the sNDA, were presented at the 2026 ASCO Annual Meeting and showed that selinexor plus ruxolitinib (n = 235) produced an SVR35 rate at week 24 of 49.8% vs 28.0% with placebo plus ruxolitinib (n = 118; difference, 21.8%; odds ratio [OR], 2.58; 95% CI, 1.60-4.17; one-sided P < .0001), meeting one of the trial's co-primary end points.²

The study did not meet its other co-primary end point of absolute change in total symptom score (TSS) from baseline at week 24, but improvements were similar between the 2 groups, with meaningful reductions in TSS observed. Data showed adjusted mean changes of −9.9 (95% CI, −11.2 to −8.6) and −10.9 (95% CI, −12.6 to −9.1) for the selinexor and placebo arms, respectively (adjusted mean difference, 0.97; 95% CI, −1.07 to 3.02; one-sided P = .825).

“The SENTRY trial generated one of the most compelling frontline datasets in myelofibrosis to date,” John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders in New York, New York, stated in a news release.¹ “The combination of selinexor and ruxolitinib demonstrated compelling spleen responses across a broad range of subgroups. The spleen responses were rapid, deep, and sustained, with promising OS findings and important evidence of disease modification. These results have the potential to redefine frontline treatment and establish a new treatment paradigm for patients with myelofibrosis.”

At a median follow-up of 11.6 months for the selinexor arm vs 12.6 months for the placebo arm, a meaningful OS trend was observed with the experimental combination (HR, 0.43; 95% CI, 0.19-1.00; nominal 1-sided P = .022).²

How was the SENTRY trial designed?

SENTRY was a global, randomized, double-blind, placebo-controlled phase 3 study that enrolled JAK inhibitor–naïve patients with primary or post–essential thrombocythemia/post–polycythemia vera myelofibrosis who had a spleen volume of at least 450 cm³, Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk disease, symptomatic disease, and a platelet count of at least 100 × 10⁹/L.²

Patients were randomly assigned 2:1 to receive selinexor at 60 mg orally once weekly plus ruxolitinib twice daily or placebo plus ruxolitinib twice daily.

The co-primary end points were SVR35 at week 24 and the absolute change in TSS from baseline at week 24. Secondary end points included OS and safety; VAF reduction was an exploratory end point.

What additional efficacy data will support the sNDA?

In a landmark analysis, SVR35 at week 24 predicted OS irrespective of treatment assignment, with 98% of SVR35 responders vs 88% of nonresponders alive at week 72. In the exploratory analysis, a driver gene VAF reduction of at least 20% at week 24 was observed in 32.0% of patients in the selinexor arm vs 23.9% in the placebo arm (OR, 3.22; 95% CI, 1.81-5.72; nominal one-sided P < .001), and VAF reduction of at least 20% was associated with a higher likelihood of achieving SVR35.

What is the safety profile of selinexor plus ruxolitinib?

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 99.1% of patients in the selinexor arm and 97.4% of patients in the placebo arm; grade 3 or higher TEAEs occurred in 70.1% and 50.0%, respectively.

Serious TEAEs were reported at respective rates of 26.9% vs 24.1%. TEAEs led to treatment discontinuation in 14.5% vs 8.6% of patients, respectively, and TEAEs led to death in 2 patients (0.9%) vs 3 patients (2.6%), respectively.

The most common TEAEs of any grade in the selinexor arm were thrombocytopenia (59%; grade ≥3, 18%), anemia (57%; grade ≥3, 37%), nausea (57%; grade ≥3, 7%), and constipation (32%). Transformation to acute myeloid leukemia was 1.7% in each arm. Investigators reported that the safety profile was manageable and consistent with the known profiles of both agents.

References

1. Karyopharm plans to submit sNDA for selinexor plus ruxolitinib in myelofibrosis under accelerated approval pathway. News release. Karyopharm Therapeutics Inc. July 30, 2026. Accessed July 31, 2026. https://investors.karyopharm.com/2026-07-30-Karyopharm-Plans-to-Submit-sNDA-for-Selinexor-Plus-Ruxolitinib-in-Myelofibrosis-Under-Accelerated-Approval-Pathway
2. Mascarenhas J, Ali H, Al-Ali H, et al. Selinexor plus ruxolitinib in JAK inhibitor–naïve myelofibrosis: phase 3 SENTRY trial. 2026;44(suppl 17):LBA6500. doi:10.1200/jco.2026.44.17_suppl.LBA6500