Selinexor Plus Ruxolitinib Improves Spleen Responses, Shows OS Signal in Frontline Myelofibrosis

Adding selinexor (Xpovio) to ruxolitinib (Jakafi) produced significantly greater spleen volume reduction compared with ruxolitinib alone in patients with JAK inhibitor-naive myelofibrosis, meeting one of two coprimary end points in the phase 3 SENTRY trial (NCT04562389), according to data presented at the 2026 ASCO Annual Meeting.¹

The trial did not meet its second co-primary endpoint 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; odds ratio [OR], 2.58; 95% CI, 1.60-4.17; one-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).

Absolute changes in TSS from baseline at week 24 were similar between arms, with adjusted mean changes of -9.9 (95% CI, -11.2 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).

"Selinexor plus ruxolitinib represents a novel treatment approach in JAK inhibitor-naive myelofibrosis," said lead study author John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai in New York, during a presentation of the data. "The kinetics of that spleen volume reduction were quite rapid, deep, durable, and sustained, suggesting much better disease control. The symptom improvement was not different between the 2 arms — technically, that was not a positive finding, but if you put it into perspective, we saw very deep, rapid spleen responses and great symptom control with selinexor plus ruxolitinib."

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 one-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 non-responders 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 was a global, double-blind, randomized, placebo-controlled phase 3 trial enrolling JAK inhibitor-naive patients with primary or post-polycythemia vera or post-essential thrombocythemia myelofibrosis.² 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.¹

Patients were randomized 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 two 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.

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 25-27%. 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. Mascarenhas J, Ali H, Al-Ali H, et al. Selinexor plus ruxolitinib in JAK inhibitor-naive myelofibrosis: phase 3 SENTRY trial. J Clin Oncol. 2026;44(suppl 17):LBA6500. doi:10.1200/jco.2026.44.17_suppl.LBA6500

2. 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