FDA Receives sNDA for Selinexor Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis

A supplemental new drug application (sNDA) has been submitted to the FDA seeking the accelerated approval of selinexor (Xpovio) in combination with ruxolitinib (Jakafi) for the treatment of patients with JAK inhibitor–naive myelofibrosis, according to a news release from Karyopharm Therapeutics.¹

The application was submitted under the accelerated approval pathway with a request for priority review, and the company expects to receive notice of the FDA’s filing acceptance and review timelines in the fourth quarter of 2026.

The sNDA is supported in part by data from the phase 3 SENTRY trial (NCT04562389), which met a co-primary end point of a spleen volume reduction of at least 35% (SVR35) at week 24.^1,2 SVR35 at week 24 was achieved by 49.8% of patients treated with selinexor plus ruxolitinib (n = 235) vs 28.0% of those given placebo plus ruxolitinib (n = 118; difference, 21.8%; odds ratio [OR], 2.58; 95% CI, 1.60-4.17; one-sided P < .0001).²

The trial did not meet its other co-primary end point of absolute change in total symptom score (TSS) from baseline at week 24, although meaningful changes were observed in both groups. The adjusted mean change in absolute TSS was –9.9 with the experimental combination vs –10.9 with ruxolitinib plus placebo (adjusted mean difference, 0.97; 95% CI, –1.07 to 3.02; one-sided P = .825).

A prespecified secondary analysis showed an overall survival (OS) signal favoring the combination (HR, 0.43; 95% CI, 0.19-1.00; nominal one-sided P = .022), with deaths occurring in 4.7% of patients in the selinexor arm vs 10.2% of those in the control arm at a median follow-up of 11.6 and 12.6 months, respectively.

“Today’s [FDA] submission is an important step toward our goal of bringing the combination of selinexor plus ruxolitinib to patients with myelofibrosis who continue to face a significant unmet need,” Reshma Rangwala, MD, PhD, chief medical officer and head of research at Karyopharm Therapeutics, stated in the news release.¹ “The SENTRY trial generated compelling and consistent results, including rapid, deep and sustained spleen responses across a broad range of patients, together with a promising overall survival signal and important evidence of disease modification. We believe the strength of these data underscores the potential of this novel combination to deliver meaningful long-term benefits and fundamentally change the treatment of patients with myelofibrosis.”

Notably, in July 2026, OncLive reported that Karyopharm had announced its plans to submit the sNDA to the FDA in the third quarter of 2026.³

What is the mechanism of action of selinexor?

Selinexor is a first-in-class, oral selective inhibitor of exportin 1 (XPO1), a nuclear export protein that shuttles tumor suppressor proteins and oncoprotein mRNAs out of the nucleus. By selectively binding to and inhibiting XPO1, selinexor is designed to restore nuclear localization and function of tumor suppressor proteins, promote apoptosis, and reduce malignant clonal burden. According to the company, XPO1 activity is essential for the survival of myeloproliferative neoplasm cells, and pairing XPO1 inhibition with JAK inhibition targets two complementary drivers of myelofibrosis biology: the JAK-STAT signaling that fuels malignant clone proliferation, splenomegaly, and disease-related symptoms, and the XPO1-mediated nuclear export that MPN cells depend on.

How was the SENTRY trial designed?

SENTRY was a global, double-blind, randomized, placebo-controlled phase 3 study that enrolled 353 patients with JAK inhibitor–naive primary, post–polycythemia vera, or post–essential thrombocythemia myelofibrosis.² Eligible patients had a spleen volume of at least 450 cm³, intermediate-1, intermediate-2, or high-risk disease per Dynamic International Prognostic Scoring System criteria, symptomatic disease (an average symptom score of at least 5 or a TSS of at least 12 by the Myelofibrosis Symptom Assessment Form v4.0), and a platelet count of at least 100 × 10⁹/L.

Patients were randomly assigned 2:1 to receive selinexor at 60 mg orally once per week plus ruxolitinib twice daily or placebo once per week plus ruxolitinib twice daily, with ruxolitinib dosed according to baseline platelet count per prescribing information.

The co-primary end points were SVR35 at week 24 and the absolute change in TSS from baseline at week 24; select secondary end points included OS and safety; variant allele frequency (VAF) reduction was an exploratory end point.

Baseline characteristics were balanced between the arms. Across the combination and control arms, respectively, the median age was 66 years (range, 20-86) and 67 years (range, 33-87); 50.6% and 50.8% of patients had primary myelofibrosis JAK2 mutations were present at respective rates of 66.0% and 68.6%, CALR mutations in 24.3% and 17.8%, and MPL mutations in 5.5% and 6.8%. The median spleen volume was 1385 cm³ and 1448 cm³, respectively.

What additional efficacy and safety data were presented from SENTRY?

The SVR35 benefit was consistent across prespecified subgroups, and spleen responses were rapid, deep, and sustained; at any time, 67.7% of patients in the combination arm achieved SVR35 vs 44.9% of those in the control arm (OR, 2.59; 95% CI, 1.64-4.10; nominal P < .0001). A higher proportion of patients treated with selinexor plus ruxolitinib achieved a driver gene VAF reduction of at least 20% at week 24 across JAK2, CALR, and MPL mutations (32.0% vs 23.9%; OR, 3.22; 95% CI, 1.81-5.72; nominal one-sided P < .001), and a VAF reduction of at least 20% was associated with a higher likelihood of achieving SVR35. In a landmark analysis, SVR35 at week 24 predicted OS irrespective of treatment arm, with 98% of SVR35 responders vs 88% of nonresponders alive at week 72.

The safety profile of the combination was manageable and consistent with the known profiles of both agents. Among the 234 selinexor-treated patients and 116 placebo-treated patients evaluated for safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.1% and 97.4% of patients, respectively; grade 3 or higher TEAEs occurred at respective rates of 70.1% and 50.0%; and serious TEAEs occurred in 26.9% and 24.1% of patients, respectively. TEAEs led to treatment discontinuation in 14.5% of patients in the combination arm vs 8.6% of those in the control arm, and TEAEs led to death in 0.9% vs 2.6% of patients, respectively.

The most common any-grade TEAEs in the selinexor arm were thrombocytopenia (59%; grade ≥3, 18%), anemia (57%; grade ≥3, 37%), and nausea (57%; grade ≥3, 7%), followed by constipation (32%), neutropenia (27%; grade ≥3, 16%), and fatigue (26%). Transformation to acute myeloid leukemia was rare and occurred at an equivalent rate of 1.7% in each arm.

References

1. Karyopharm submits supplemental new drug application to the FDA for Xpovio (selinexor) plus ruxolitinib for patients with myelofibrosis. News release. Karyopharm Therapeutics Inc. August 31, 2026. Accessed August 31, 2026. https://investors.karyopharm.com/2026-08-31-Karyopharm-Submits-Supplemental-New-Drug-Application-to-the-FDA-for-XPOVIO-R-selinexor-Plus-Ruxolitinib-for-Patients-with-Myelofibrosis
2. Mascarenhas J, Ali H, Al-Ali H, et al. Selinexor plus ruxolitinib in JAK inhibitor–naïve myelofibrosis: phase 3 SENTRY trial. J Clin Oncol. 2026;44(suppl 17):LBA6500. doi:10.1200/jco.2026.44.17_suppl.LBA6500