Selinexor plus ruxolitinib met the SVR co–primary end point but missed the symptom score end point in the phase 3 SENTRY trial in myelofibrosis.
The addition of selinexor (Xpovio) to ruxolitinib (Jakafi) led to a statistically significant improvement in spleen volume reduction of 35% or more (SVR35) compared with placebo plus ruxolitinib in the frontline treatment of patients with myelofibrosis, meeting a co–primary end point of the phase 3 SENTRY trial (NCT04562389).1
However, a statistically significant difference in absolute total symptom score (TSS) at week 24 was not observed for the experimental vs control regimens.
Findings announced by Karyopharm Therapeutics showed that the SVR35 rate at week 24 was 50% in the selinexor plus ruxolitinib arm vs 28% in the placebo plus ruxolitinib arm (1-sided P < .0001). At week 12, these respective rates were 49% and 20%, and at week 36, they were 47% and 23%.
Regarding symptoms, patients treated with the selinexor-based combination achieved a 9.89-point improvement in absolute TSS at week 24, compared with 10.86 points in those treated with ruxolitinib plus placebo.
Although overall survival (OS) data were immature, a trend favoring the selinexor arm was observed (HR, 0.43; 95% CI, 0.19-1.00; 1-sided P = .0222).
Karyopharm Therapeutics intends to meet with the FDA to discuss the SENTRY data and a plan for filing a supplemental new drug application for the combination. Detailed findings from SENTRY will be submitted for presentation at an upcoming medical meeting.
"The results from SENTRY are an important development for patients, as the combination of selinexor plus ruxolitinib meaningfully improved spleen response, and we observed a promising signal in OS. Reducing spleen volume remains one of the most important treatment goals in myelofibrosis since achieving SVR35 is associated with improvement in overall survival," John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine and director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai, stated in a news release. "While the symptom end point did not reach statistical significance, patients treated in both arms achieved similar symptom improvement relative to baseline. Importantly, while JAK inhibitors have been the backbone of therapy, continued progress requires new therapies that target additional biological pathways. Inhibition of XPO1 represents a differentiated mechanism that has the potential to address these pathways and evolve treatment beyond JAK inhibition alone."
The phase 3 portion of SENTRY was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients at least 18 years of age with primary, post–essential thrombocythemia, or post–polycythemia vera myelofibrosis who had at least 2 active symptoms per the Myelofibrosis Symptom Assessment Form v4.0. Patients needed to have intermediate-1–, intermediate-2–, or high-risk disease per Dynamic International Prognostic Scoring System criteria. Measurable splenomegaly during screening and an ECOG performance status of 0 to 2 were also required.
Investigators excluded patients who had a blast level of more than 10% in peripheral blood or bone marrow, those who received prior treatment with JAK inhibitors for myelofibrosis, and patients who had previous treatment with selinexor or another XPO1 inhibitor.
Patients were randomly assigned 2:1 to receive selinexor at 60 mg once per week in each 28-day cycle plus ruxolitinib at 15 or 20 mg twice per day; or placebo plus ruxolitinib.1,2
Along with the co–primary end points of SVR35 and absolute TSS, secondary end points comprised OS and progression-free survival.2
Karyopharm Therapeutics also announced that selinexor plus ruxolitinib displayed a manageable safety profile that was consistent with the known profiles of the individual components, and no new safety signals were reported.1
In the experimental combination arm (n = 234), the most common any-grade treatment-emergent adverse effects (TEAEs) included thrombocytopenia (selinexor/ruxolitinib arm, 59%; placebo/ruxolitinib, 43%), anemia (57%; 58%), nausea (57%; 17%), constipation (32%; 36%) and neutropenia (27%; 9%). Grade 3 or higher TEAEs occurred in 70% of patients in the experimental arm vs 50% of those in the placebo arm (n = 116). TEAEs led to treatment discontinuation in 15% of patients treated with selinexor plus ruxolitinib vs 9% of those given placebo plus ruxolitinib. Confirmed leukemic transformations occurred in 1.7% of patients in both arms.
“The myelofibrosis community is waiting for new treatment options that can build upon the benefit of JAK inhibitors. Improving overall survival is the ultimate goal for people living with myelofibrosis, and I am incredibly encouraged by these results,” Kapila Viges, chief executive officer of the MPN Research Foundation, added in a news release. “These results are an exciting development for the myelofibrosis community.”
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