Selinexor/Ruxolitinib Combo Shows Early Activity, Tolerability in Treatment-Naïve Myelofibrosis

Haris Ali, MD

A combination comprised of selinexor (Xpovio) and ruxolitinib (Jakafi) induced rapid spleen responses at week 12 and showcased a manageable toxicity profile in patients with treatment-naïve myelofibrosis, according to data from a phase 1 trial (NCT04562389) presented during the 2022 EHA Congress.

Results indicated that 75% of evaluable patients (n = 8) achieved a spleen volume reduction of at least 35% (SVR35) with the doublet by week 12. The combination was also found to induce a rapid reduction in total symptom score (TSS) at that time point.

“The combination of selinexor and ruxolitinib has been well tolerated and with a manageable [adverse] effect [AE] profile,” lead study author, Haris Ali, MD, an associate professor in the Department of Hematology and Hematopoietic Cell Transplantation, of the Division of Leukemia, at City of Hope Comprehensive Cancer Center, and colleagues, wrote in a poster on the data. “No dose-limiting toxicities [DLTs] were observed in patients with treatment-naïve myelofibrosis who received once weekly oral selinexor at 40 mg or 60 mg in combination with standard-dose ruxolitinib.”

In a mouse model of JAK2V617F-driven myeloproliferative neoplasm, the combination has previously been found to result in a significant reduction in white blood cells, granulocytes, spleen green fluorescent protein–positive cells, and spleen weight on day 28 (P < .05).

Additionally, treatment with single-agent selinexor has been found to resulted in 40% of patients with myelofibrosis whose disease was refractory to JAK inhibitors having achieved SVR35 at 24 or more weeks; the agent was also noted to have an acceptable toxicity profile.

The phase 1 trial is enrolling patients with treatment-naïve myelofibrosis who have a spleen volume of ≥ 450 cm³ by MRI or CT and Dynamic International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk disease. To be eligible for enrollment, patients are also required to have an ECOG performance status of 0 to 2, and a platelet count of ≥ 100 x 10⁹/L.

In the dose-escalation, phase 1a portion of the trial, investigators examined 2 dose levels of the combination. Those who received the regimen at dose level 1 (n = 3) were administered selinexor at a weekly dose of 40 mg plus ruxolitinib at a standard twice-daily dose of 15/20 mg. Those who were given the combination at dose level 2 (n = 3) received selinexor at a weekly dose of 60 mg with standard ruxolitinib.

The dose-expansion phase of the research will include approximately 15 patients who will received weekly selinexor at the recommended dose in combination with standard ruxolitinib.

The primary end points of the trial include identifying the maximum tolerated dose and recommended phase 2 dose of the regimen, and to evaluate AEs. Secondary end points included SVR35, SVR25, TSS50, overall survival, anemia response, AEs, overall response rate, and pharmacokinetics. Digital monitoring via a smart watch was leveraged to examine quality of life, which serves as an exploratory end point of the research.

As of May 1, 2022, a total of 15 patients were dosed with the regimen; 3 patients received selinexor at 40 mg, and 12 received selinexor at 60 mg. The median age of study participants was 64 (range, 45-76). Most patients (n = 10) were male. Four patients had post–essential thrombocytopenia disease, 8 patients had primary disease, and 3 patients had post–polycythemia vera disease.

Regarding DIPSS risk, 5 patients had intermediate-1 risk disease, 7 had intermediate-2 risk disease, and 3 had high-risk disease. Moreover, 3 patients had a driver mutation of CALR, and the remaining patients had JAK2. Only 2 of the 15 patients were transfusion dependent.

All 15 patients who received at least 1 dose of selinexor were included in the safety population. Eight patients were determined to be spleen evaluable; these patients underwent at least 1 spleen assessment post baseline. Moreover, 7 patients were symptom evaluable because they had available data and at received at least 12 weeks of treatment. Lastly, 10 patients were anemia evaluable; these patients were transfusion independent at baseline and had received at least 8 weeks of treatment.

Additional data showed that 5 of the 10 transfusion-independent patients who received at least 8 weeks of treatment had maintained stable hemoglobin or improved hemoglobin level.

Regarding safety, the most common treatment-emergent AEs with the regimen included nausea (grade 1, 27%; grade 2, 7%; grade 3/4, 7%), dysgeusia (grade 1, 20%; grade 2, 7%), hyponatremia (grade 1, 20%), dizziness (grade 1, 20%), vomiting (grade 1, 13%; grade 2, 7%), headache (grade 1, 7%; grade 2, 13%), anorexia (grade 1, 7%; grade 3/4, 7%), atrial fibrillation (grade 3/4, 20%), failure to thrive (grade 3/4, 7%), pulmonary hypertension (grade 3/4, 7%), tumor lysis syndrome (grade 3/4, 7%), neutropenia (grade 1, 13%; grade 3/4, 20%), anemia (grade 1, 7%; grade 2, 13%; grade 3/4, 20%), and thrombocytopenia (grade 1, 7%; grade 2, 7%; grade 3/4, 27%).

Hematologic toxicities were noted to be reversible with dose interruptions and reductions. At the time of the last follow-up, 53% of patients had a dose reduction of ruxolitinib, and 20% had a dose reduction of selinexor.

One patient discontinued treatment after 5 months because of unrelated AEs in the form of dizziness, atrial fibrillation, and pulmonary hypertension. Another patient discontinued the regimen following 8 weeks of treatment because their disease progressed to acute myeloid leukemia.

The trial is currently enrolling patients, according to Ali.

Reference

Ali H, Kishtagari A, Maher K, et al. A phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1005.