FDA Approval Sought for Selinexor Plus Ruxolitinib in Myelofibrosis

A supplemental new drug application (sNDA) has been filed with the FDA seeking approval of selinexor (Xpovio) for use in combination with ruxolitinib (Jakafi) for the treatment of patients with myelofibrosis.¹

The sNDA is supported by data from the phase 3 SENTRY trial (NCT04562389), in which adding selinexor (Xpovio) to ruxolitinib (Jakafi) produced significantly greater spleen volume reduction compared with ruxolitinib alone in patients with JAK inhibitor–naive myelofibrosis, meeting 1 of the study’s 2 coprimary end points. The trial did not meet its second primary end point of absolute change in total symptom score (TSS) from baseline at week 24. However, symptom improvements were similar between arms, with clinically meaningful TSS reductions observed in both groups.

Patients receiving selinexor plus ruxolitinib (n = 235) achieved a week-24 spleen volume reduction of at least 35% (SVR35) rate of 49.8% vs 28.0% with placebo plus ruxolitinib (n = 118; OR, 2.58; 95% CI, 1.60-4.17; 1-sided P < .0001). At 12 and 36 weeks, SVR35 rates in the selinexor arm were 49.4% and 46.9%, respectively, vs 20.3% and 23.0% in the placebo arm. The any-time SVR35 rate was 67.7% with selinexor vs 44.9% with placebo (OR, 2.59; 95% CI, 1.64-4.10; nominal P = .0001).²

Absolute changes in TSS from baseline at week 24 were similar between arms, with adjusted mean changes of –9.9 (95% CI, –1.2 to –8.6) in the selinexor arm and –10.9 (95% CI, –12.6 to –9.1) in the placebo arm (adjusted mean difference, 0.97; 95% CI, –1.07 to 3.02; 1-sided P = .825).

"Today's 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 of Karyopharm, the developer of selinexor, stated in a 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."

Overall Survival and Molecular Response

Overall survival (OS) data showed an early signal favoring the combination, with 4.7% of patients dying in the selinexor arm vs 10.2% in the placebo arm at the time of data cutoff (HR, 0.43; 95% CI, 0.19-1.00; nominal 1-sided P = .022). A landmark analysis at week 24 showed that SVR35 response predicted subsequent OS regardless of treatment arm, with 98% of SVR35 responders vs 88% of SVR35 nonresponders alive at week 72.

"The OS data are immature, and it is still early. The median follow-up is about 11 months," Mascarenhas said. "People may say, 'Is the OS signal real?' We are going to continue to follow it to document whether it is real."

Variant allele frequency (VAF) reductions of at least 20% at week 24 were observed in 32.0% of evaluable patients in the selinexor arm (n = 169) vs 23.9% in the placebo arm (n = 92). VAF reductions of at least 20% were also associated with a higher likelihood of achieving SVR35 (OR, 3.22; 95% CI, 1.81-5.72; nominal 1-sided P < .001).

Safety Profile of Selinexor Plus Ruxolitinib

Treatment-emergent adverse events (TEAEs) of any grade occurred in 99.1% of patients in the selinexor arm (n = 234) vs 97.4% in the placebo arm (n = 116). Grade 3 or higher TEAEs were more frequent in the selinexor arm (70.1%) vs the placebo arm (50.0%), as were TEAEs leading to treatment discontinuation (14.5% vs 8.6%). Serious TEAEs occurred at similar rates in the selinexor (26.9%) and placebo (24.1%) arms. Deaths due to TEAEs were numerically lower in the selinexor arm (0.9%) compared with the placebo arm (2.6%).

The most common any-grade TEAEs in the selinexor arm were thrombocytopenia (59%), anemia (57%), nausea (57%), constipation (32%), neutropenia (27%), and fatigue (26%). Grade 3 or higher TEAEs in the selinexor arm included anemia (37%), thrombocytopenia (18%), neutropenia (16%), nausea (7%), and fatigue (6%).

SENTRY Trial Design and Patient Characteristics

SENTRY is a global, double-blind, randomized, placebo-controlled phase 3 trial that enrolled JAK inhibitor–naive patients with primary or post–polycythemia vera or post–essential thrombocythemia myelofibrosis.³ Eligibility required a spleen volume of at least 450 cm³, Dynamic International Prognostic Scoring System (DIPSS) intermediate-1 or intermediate-2/high-risk scores, a symptomatic burden meeting predefined thresholds, and a platelet count of at least 100 × 10⁹/L. Patients with bone marrow or peripheral blood blasts exceeding 10%, prior JAK inhibitor treatment for myelofibrosis, or prior XPO1 inhibitor exposure were excluded.²

Patients were randomly assigned to receive oral selinexor 60 mg once weekly plus twice-daily ruxolitinib or placebo plus ruxolitinib in 28-day cycles, with randomization stratified by DIPSS risk score, baseline spleen volume, and baseline platelet count. Dual antiemetics were required during the first 2 cycles for nausea prophylaxis. A total of 353 patients were treated, with a data cutoff of February 20, 2026, and a median follow-up of approximately 11 months in both arms.

The median patient age was 66 years (range, 20-86) in the selinexor arm vs 67 years (range, 33-87) in the placebo arm. Primary myelofibrosis was present in approximately 51% of patients in each arm, post–polycythemia vera myelofibrosis in approximately 23%, and post–essential thrombocythemia myelofibrosis in approximately 25% to 27%. JAK2 mutations were present in 66.0% and 68.6% of patients in the respective arms, and high-molecular-risk mutations in 31.9% and 38.1%. Median platelet counts were 325 × 10⁹/L and 324 × 10⁹/L, and median hemoglobin was 11.4 g/dL in both arms.

REFERENCES

1. Karyopharm Therapeutics Inc. Karyopharm submits supplemental New Drug Application to the FDA for XPOVIO (selinexor) plus ruxolitinib for patients with myelofibrosis. Published August 31, 2026. Accessed September 1, 2026. https://tinyurl.com/42ccetvn

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

3. Study of selinexor in combination with ruxolitinib in myelofibrosis (SENTRY). ClinicalTrials.gov. Updated April 9, 2026. Accessed June 2, 2026. https://clinicaltrials.gov/study/NCT04562389