Selinexor Plus Ruxolitinib Yields Superior Spleen Responses, OS Signal in JAK Inhibitor–Naïve Myelofibrosis

The addition of selinexor (Xpovio) to ruxolitinib (Jakafi) significantly improved spleen volume reduction (SVR) at week 24 compared with ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, meeting a co-primary end point of the phase 3 SENTRY trial (NCT04562389), data from which were presented at the 2026 ASCO Annual Meeting.¹

The study did not meet its other co-primary end point, absolute change in total symptom score (TSS) from baseline at week 24. However, improvements were similar between the 2 groups, with meaningful reductions in TSS.

Patients who received selinexor plus ruxolitinib (n = 235) achieved a 24-week SVR of at least 35% (SVR35) rate of 49.8% vs 28.0% patients who received placebo plus ruxolitinib (n = 118; odds ratio [OR], 2.58; 95% CI, 1.60-4.17; one-sided P < .0001).

Moreover, at 12 and 36 weeks from baseline, patients in the selinexor arm achieved respective SVR35 rates of 49.4% and 46.9% compared with 20.3% and 23%, respectively, for the placebo arm. Overall, patients in the selinexor arm achieved an any-time SVR35 rate of 67.7% vs 44.9% for the placebo arm (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) 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).

"Selinexor plus ruxolitinib represents a novel treatment approach in JAK inhibitor–naïve myelofibrosis," said John Mascarenhas, MD, during a presentation of the data.

“The kinetics of that [SVR35] reduction were quite rapid, deep, durable, and sustained, suggesting much better disease control,” lead study author John Mascarenhas, MD, said in an interview with OncLive^®. “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 ruxoltinib].”

Masacarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of Mount Sinai Tisch Cancer Center in New York, New York.

How was the SENTRY trial conducted?

The global, double-blind, randomized, placebo-controlled study enrolled patients who were JAK inhibitor–naive with primary or post–polycythemia vera or –essential thrombocythemia myelofibrosis. Eligible patients also needed to have a spleen volume of at least 450 cm³, Dynamic International Prognostic Scoring System (DIPSS) scores of intermediate-1 or intermediate-2/high risk, a symptomatic burden meeting predefined thresholds, and a platelet count of at least 100 × 10⁹/L.

If patients had blasts higher than 10% in bone marrow or blood, received prior JAK inhibitor treatment for myelofibrosis, or received prior selinexor or other XPO1 inhibitors, they were not included in the trial.²

Patients were randomly assigned to receive 60 mg oral once-weekly doses of selinexor in addition to twice-daily ruxolitinib or placebo plus ruxolitinib in 28-day treatment cycles. Dual antiemetics were required during the first 2 cycles of treatment for nausea prophylaxis. Randomization was stratified by DIPSS risk score, baseline spleen volume (< 1800 cm³ vs ≥ 1800 cm³), and baseline platelet count (100–200 × 10⁹/L vs > 200 × 10⁹/L).

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.

Baseline characteristics revealed that patients had a median age of 66 years (range, 20-86) in the selinexor arm vs 67 years (range, 33-87) in the placebo arm. Myelofibrosis subtypes in each arm broke down as primary myelofibrosis (selinexor, 50.6%; placebo, 50.8%), post-polycythemia vera myelofibrosis (23.8%; 22%), and post–essential thrombocythemia myelofibrosis (25.1%; 27.1%). Most patients in each arm had an ECOG performance status of 1 (52.8%; 51.7%).

Median platelet counts for patients in the selinexor arm were 325 x 10⁹L (range, 67-1313) compared with 324 x 10⁹L (range, 101-2001) in the placebo arm. Both arms had a median hemoglobin level of 11.4 g/DL and a median peripheral blasts rate of 0%. JAK2 mutations were present in 66% and 68.6% of patients in each of the respective arms, with high-molecular-risk mutations being found in 31.9% and 38.1% of each arm.

What were the additional efficacy and safety data for selinexor plus ruxolitinib in myelofibrosis?

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

“[OS] data are immature, and it’s still early—the median follow-up is about 11 months,” Mascarenhas said. “People may say, ‘Is [the OS signal] real?’ We’re going to continue to follow it, to document [if] it’s 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 reduction rates of at least 20% were also associated with a higher likelihood of achieving SVR35 (OR, 3.22; 95% CI, 1.81-5.72; nominal one-sided P < .001).

Regarding treatment exposure, patients in the selinexor arm had a median weekly selinexor dose, daily ruxolitinib dose, and follow-up at cutoff of 51.7 mg, 23 mg, and 11.2 months, respectively. Additionally, the placebo arm had a median weekly placebo dose, daily ruxolitinib dose, and follow-up at cutoffs of 60 mg, 29.9 mg, and 11.1 months, respectively.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 99.1% of patients who were evaluated for safety in the selinexor arm (n = 234) vs 97.4% in the control 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%; 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 common any-grade TEAEs in the selinexor arm included anemia (57%), thrombocytopenia (59%), nausea (57%), constipation (32%), fatigue (26%), and neutropenia (27%). Grade 3 or higher TEAEs occurring in the selinexor arm included anemia (37%), thrombocytopenia (18%), nausea (7%), fatigue (6%), and neutropenia (16%).

References

1. 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
2. Study of selinexor in combination with ruxolitinib in myelofibrosis (SENTRY). ClincalTrials.gov. Updated April 9, 2026. Accessed June 2, 2026. https://clinicaltrials.gov/study/NCT04562389