Karyopharm Therapeutics (NASDAQ:KPTI) reported top-line results from its phase III SENTRY trial evaluating selinexor in combination with ruxolitinib in JAK inhibitor-naive (frontline) myelofibrosis, highlighting a statistically significant improvement in spleen volume reduction versus ruxolitinib alone, a similar symptom improvement between arms, and what management and the trial’s principal investigator described as a promising early overall survival signal.
Trial design and endpoints
On the conference call, company executives outlined that SENTRY enrolled frontline myelofibrosis patients with baseline platelet counts above 100,000. Patients were randomized 2-to-1 to receive selinexor 60 mg plus label-dosed ruxolitinib or placebo plus ruxolitinib, for a total of 353 patients randomized.
SVR35 met; symptom endpoint not statistically significant
Karyopharm said SENTRY met the first co-primary endpoint. At week 24, SVR35 was 50% for the selinexor plus ruxolitinib arm versus 28% for ruxolitinib alone (p<0.0001). The company emphasized response kinetics and durability, pointing to SVR35 rates at:
- Week 12: 49% (combination) vs. 20% (ruxolitinib alone)
- Week 36: 47% (combination) vs. 23% (ruxolitinib alone)
Management also described deeper spleen volume reductions over time with the combination compared to ruxolitinib alone.
For symptoms, the company reported that the difference on the absolute TSS endpoint was not statistically significant. Mean change in total symptom score at week 24 was described as similar across the two arms, with approximately a 10-point improvement for the combination and an 11-point improvement for ruxolitinib. In Q&A, executives and principal investigator Dr. John Mascarenhas of the Icahn School of Medicine at Mount Sinai said ruxolitinib and other JAK inhibitors are already potent at reducing symptom burden, making incremental superiority on symptoms a “hard bar to overcome” in an active-control phase III setting. They emphasized that symptom improvement relative to baseline was meaningful and that there was no detriment in symptom control with the combination.
Early overall survival and VAF observations
Karyopharm characterized overall survival as “arguably the most important endpoint” and highlighted an early signal favoring selinexor plus ruxolitinib. At a median follow-up of approximately 12 months, overall survival events were reported at 4.7% in the combination arm versus 10.2% in the ruxolitinib arm, corresponding to a hazard ratio of 0.43 and a nominal p-value of 0.0222. Management noted the number of events was still limited and said the company would continue to follow the signal to maturity; it also noted there was no crossover in the study.
In response to analyst questions, the company said causes of death were consistent with expectations in myelofibrosis and it did not see patterns or discrepancies between arms. It also said ruxolitinib overall survival landmarks were consistent with published data, indicating no unusual over- or under-performance in the control arm.
The company also highlighted VAF reductions as a potential marker of disease modification. VAF reduction of at least 20% at week 24 was observed in 32% of evaluable patients in the combination arm versus 24% in the ruxolitinib arm. Executives and Dr. Mascarenhas linked this finding to the proposed biology of XPO1 inhibition and described it as supportive of potential disease modification rather than symptom management alone.
Safety profile and adverse events
Karyopharm said no new safety signals were identified and that the safety and tolerability profile was consistent with the known profiles of selinexor and ruxolitinib.
The five most common treatment-emergent adverse events in the combination arm were reported as:
- Thrombocytopenia: 59%
- Anemia: 57%
- Nausea: 57%
- Constipation: 32%
- Neutropenia: 27%
The company noted nausea rates were lower than what was reported in the phase I SENTRY study due to the incorporation of prophylactic antiemetics. Grade 3 or higher treatment-emergent adverse events were observed in approximately 70% of patients in the combination arm versus 50% with ruxolitinib alone. Discontinuations due to treatment-emergent adverse events were 14.5% versus 8.6%, respectively. Confirmed leukemic transformations were reported as the same in each arm at 1.7%.
Regulatory and next steps; financing update
Management said it plans to meet with the FDA to discuss the totality of the SENTRY data and a potential supplemental NDA (sNDA) filing plan. It also intends to present the phase III data at an upcoming medical meeting and submit a manuscript to a peer-reviewed journal. Executives said they hoped to finalize next steps with the FDA and the sNDA path forward “hopefully in the next six months.”
During Q&A, Dr. Mascarenhas discussed how physicians may view the combination if it is endorsed by NCCN guidelines, citing the example of luspatercept use in myelofibrosis in the commercial setting based on guideline endorsement. He also said selinexor is already an approved drug (in multiple myeloma), which could influence familiarity in the community.
The company also referenced a financing announced the same morning, stating it provides $30 million at closing, with additional funding if associated warrants are exercised. Management said the financing extends its cash runway into late Q3 and supports continued work on SENTRY-related efforts and the company’s endometrial cancer program XPORT-EC-042, which it said remains on track for top-line data in mid-2026.
About Karyopharm Therapeutics (NASDAQ:KPTI)
Karyopharm Therapeutics (NASDAQ: KPTI) is a clinical-stage biopharmaceutical company focused on discovering and developing novel first-in-class drugs that target the nuclear export protein XPO1. The company’s lead product, selinexor (marketed as XPOVIO), is an oral selective inhibitor of nuclear export (SINE) compound approved for treatment of multiple myeloma and diffuse large B-cell lymphoma. In addition to selinexor, Karyopharm’s pipeline includes second-generation SINE compounds and combination studies in solid tumors and hematologic malignancies.
Founded in 2008 and headquartered in Newton, Massachusetts, Karyopharm has built a research platform around modulation of nuclear export pathways.
