Selinexor/Ruxolitinib Combo Elicits Sustained Spleen Responses, Improves Symptoms in Myelofibrosis

The combination of selinexor (Xpovio) at 60 mg and ruxolitinib (Jakafi) induced rapid and durable spleen responses and improved symptoms at weeks 12 and 24 in patients with treatment-naïve myelofibrosis, according to updated data from the phase 1 XPORT-MF-034 trial (NCT04562389) presented at the 2023 AACR Annual Meeting.^1,2

In the efficacy-evaluable patients who were given selinexor at a weekly dose of 60 mg combined with ruxolitinib, 83.3% (n = 10/12) experienced at least a 35% reduction in spleen volume (SVR35) at week 12 and 80.0% (n = 8/10) achieved at least a 50% reduction in total symptom score (TSS50). In the intention-to-treat (ITT) population, 71.4% (n = 10/14) achieved SVR35 at this time point and 66.7% (n = 8/12) had TSS50. At week 24, 91.7% (n = 11/12) of efficacy-evaluable patients achieved SVR35 and 77.8% (n = 7/9) had TSS50. In the ITT population, these rates were 78.6% (n = 11/14) and 58.3% (n = 7/12), respectively.

“We are enthusiastic about the impressive spleen volume reductions and robust symptom improvement observed with the 60-mg dose of selinexor and ruxolitinib combination at week 24, which represent very meaningful improvements relative to the current standard of care of ruxolitinib alone,” Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, stated in a press release. “These data suggest that the combination of selinexor and ruxolitinib has the potential to be a transformative therapy for first-line myelofibrosis patients.”

The trial enrolled patients with primary myelofibrosis or post-essential thrombocytopenia or post–polycythemia vera who had measurable splenomegaly during the screening period and who fell into the dynamic international prognostic scoring system (DIPSS) risk category of intermediate-1, intermediate-2, or high risk.³ Patients are required to be at least 18 years of age, an ECOG performance status of 0 to 2, a platelet count of at least 100 x 109/L, an absolute neutrophil count of at least 1.5 x 109/L, and a serum direct bilirubin up to 1.5 x upper limit of normal.

The trial was comprised of a phase 1a dose-escalation portion and a phase 1b dose-expansion portion. In phase 1a, selinexor was explored at 2 dose levels: level 1 was 40 mg weekly (n = 3) and level 2 was 60 mg weekly (n = 3).

Enrollment has completed for phase 1b. Of the 24 patients enrolled, 10 have been assigned to receive selinexor at 40 mg weekly and 14 have been assigned to receive it at 60 mg weekly. All patients received ruxolitinib at 15/20 mg twice daily.

The primary end points of the trial were to identify the maximum tolerated dose and the recommended phase 2 dose, as well as to evaluate safety. Secondary end points comprised SVR35, TSS50, overall survival, anemia response, toxicities, objective response rate, and a pharmacokinetic analysis.

The median age in the 40-mg cohort was 57.5 years (range, 44-71) and 64.5 years (range, 58-77) in the 60-mg cohort; 30.0% and 35.7% of patients, respectively, were female. Regarding DIPSS risk 30.0% and 57.1% of patients in the 40-mg and 60-mg cohorts had intermediate-2 risk; 30.0% and 21.4% of patients, respectively, had high risk.

Moreover, high-risk mutations were noted in 60% of those in the 40-mg cohort and 35.7% of those in the 60-mg cohort. The median starting dose of ruxolitinib in the 40-mg cohort was 17.5 mg; in the 60-mg cohort, it was 15.0 mg.

Additional data showed that in the efficacy-evaluable population who received 40 mg weekly of selinexor plus ruxolitinib, 30.0% of patients (n = 3/10) experienced SVR35 at week 12 and 66.7% of patients (n = 6/9) had TSS50. For the ITT population, 30.0% of patients (n = 3/10) had SVR35 at this time point and 60.0% of patients (n = 6/10) achieved TSS50.

At week 24, 50.0% of patients in the efficacy-evaluable population (n = 4/8) had achieved SVR35 and 57.1% (n = 4/7) had TSS50. In the ITT population, 40.0% (n = 4/10) and 40.0% (n = 4/10) achieved SVR35 and TSS50, respectively.

SVR35 responses were observed in all evaluable patients at any time and rates proved to be consistent irrespective of the subgroups analyzed, including those who received a low dose of ruxolitinib and male participants.

Improvement in major spleen and cytokine-release symptoms were reported across all Myelofibrosis Symptom Assessment Form domains.

Selinexor was found to be well tolerated overall, at both dose levels examined. The majority of patients were able to continue to receive treatment for up to 68 weeks as of the data cutoff date.

The most frequently experienced treatment-emergent toxicities at the 40- and 60-mg dose levels plus ruxolitinib included nausea (70.0%; 78.6%), anemia (40.0%; 64.3%), and fatigue (60.0%; 57.1%). The majority of these effects were grade 1 or 2 in severity. The most common grade 3 or higher adverse effects were anemia (30.0%; 42.9%), thrombocytopenia (10.0%; 28.6%), and neutropenia (20.0%; 7.1%).

Two patients experienced treatment-related AEs that resulted in discontinuation: one patient had thrombocytopenia and one had peripheral neuropathy.

The data support that the recommended dose of selinexor be 60 mg in combination with ruxolitinib.

Karyopharm announced plans to initiate a double-blind, randomized, phase 3 trial examining selinexor at 60 mg plus ruxolitinib compared with placebo plus ruxolitinib in patients with myelofibrosis who are JAK inhibitor naïve in the first half of 2023.

References

1. Karyopharm announces presentation of updated phase 1 selinexor data in patients with treatment-naïve myelofibrosis at AACR 2023. News release. Karyopharm Therapeutics, Inc. April 18, 2023. Accessed April 19, 2023. https://investors.karyopharm.com/
2. AACR 2023 – update on data in treatment-naïve myelofibrosis. Karyopharm Therapeutics, Inc. April 18, 2023. Accessed April 19, 2023. https://investors.karyopharm.com/events-presentations?item=67
3. A study to evaluate safety and efficacy of selinexor in combination with ruxolitinib in participants with myelofibrosis. ClinicalTrials.gov. Updated January 31, 2023. Accessed April 19, 2023. https://clinicaltrials.gov/ct2/show/NCT04562389