Selinexor Plus Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Patients with Myelofibrosis: Long Term Follow up from XPORT-MF-034 Suggestive of Disease Modification

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, and inflammation due to unregulated, clonal proliferation of hematopoietic stem cells in the bone marrow. Common genetic drivers include JAK2, CALR, and MPL. Although improvements in splenomegaly and symptoms occur with the current approved therapies, additional assessments are needed to understand the impact of therapies on disease modification. Increased burden of variant allele frequency (VAF) of driver mutations is associated with poor disease outcomes, and increased expression of pro-inflammatory cytokines is implicated in disease pathophysiology and symptoms burden. Selinexor (SEL) is an investigational oral XPO1 inhibitor that may inhibit multiple MF-relevant pathways including STAT, ERK, and AKT. Preclinical studies have shown potential synergy between SEL and ruxolitinib (RUX) treatment in vivo. Safety and efficacy analysis of SEL plus RUX in JAKi treatment-naïve MF in a Phase 1 study supported a 60 mg SEL dose as the recommended dose in a Phase 3 study. Here we include exploratory analyses of a range of biomarkers in the Phase 1 study of SEL and RUX in JAKi-naïve myelofibrosis.

Methods: Phase 1 of XPORT-MF-034 (NCT04562389) is an open-label study evaluating the safety and efficacy of SEL at 40mg and 60mg once weekly plus RUX with JAKi-naïve MF. Assessments included safety and rates of spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50). Platelet and hemoglobin levels were also assessed. Longitudinal clinical biomarker assessments included %VAF change at week 24 for driver genes and plasma cytokine levels at week 4 (Cycle 2 Day 1). Bone marrow (BM) biopsies were obtained at screening and week 24, then evaluated for bone marrow fibrosis (BMF) and other BM cellular markers (CD61, CD71).

Results: As of April 10, 2023, a total of 24 patients (pts) received at least one dose of SEL (40 mg: n=10; 60 mg n=14). The most common adverse events (AEs) overall of any grade were nausea (75% majority grade 1-2), fatigue (58%), anemia (54%), and thrombocytopenia (54%). Those receiving a prophylactic anti-emetic reported lower incidence and severity of nausea AEs compared to those that did not; pts experienced a median weight increase of 3.3 kg at week 24. Two pts discontinued treatment due to treatment-related AEs (thrombocytopenia and neuropathy). Generally stable hemoglobin levels were observed in 48% of transfusion-independent pts. Median hemoglobin levels were 10.1 g/dL at baseline, 9.3 g/dL at week 12, and 10.2 g/dL at week 24. Median platelet counts remained generally stable with median values of 258 k/uL at baseline, 164 k/uL at week 12, and 193 k/uL at week 24. SVR35 at week 24 in the intent-to-treat (ITT) population was achieved by 40% of the 40 mg cohort and 79% of the 60 mg cohort and TSS50 was achieved by 10% and 58%, respectively.

Mutation analysis showed no pts were triple negative, with 18 harboring JAK2 mutations, 5 with CALR, and 1 with MPL. Of 13 pts with available data at week 24, 5 pts (38%) had a reduction of VAF that was ≥20%, and 3/5 of these pts had high VAF (>50%) driver mutations at baseline and were also characterized as HMR. A panel of 74 cytokines was evaluated in 21 MF pts with baseline and week 2 samples (including 10 with end-of-treatment [EOT] samples), and in 10 healthy donors. Comparing baseline MF to healthy samples, 50% of the analyzed cytokines were elevated. A rapid and durable decrease of pro-inflammatory MF-relevant cytokines including TGF-β1, IFNɣ, TNF-α, IL-7, IL-1Ra, and IL-16 was observed in the majority of pts at week 2 and continued into EOT. Notably, the reduction in IL-18 correlated to SVR and TSS response at week 24, with R² values of 0.29 and 0.28, respectively. BM analysis at week 24 showed an increased number of erythroid CD71+ elements in 3/14 pts.

Conclusions: SEL plus RUX was generally well tolerated and manageable. Evidence of potential disease modification in pts with JAKi-naïve MF patients was seen via rapid stabilization of platelets and maintaining hemoglobin levels, VAF reduction, and pro-inflammatory cytokine reduction. Promising biomarker and efficacy data suggests that SEL in combination with RUX has the potential to become a novel, first-line treatment for pts with MF. Updated clinical data with longer follow-ups and additional subgroup analyses will be available at the time of presentation.