Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naive patients with myelofibrosis: Updated results from XPORT-MF-034

7063 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, and poor prognosis. Activity has been shown with the combination of SEL + the JAKi RUX in preclinical studies. Specific subgroups with lower response rates to RUX monotherapy, such as males vs females (25% vs 59%) and those with a lower (≤15 mg vs 20 mg) RUX starting dose (22-27% vs 43%), highlight unmet need in specific groups (grps). Methods: XPORT-MF-034 is a Phase 1/2, open-label study evaluating safety and efficacy of SEL at 40 mg and 60 mg once-weekly plus RUX per standard of care in 28-day cycles. Assessments included safety, spleen/symptom response, survival, and hemoglobin levels. The primary analysis population included those who had baseline assessment and were treated to at least Week 24 (W24) or discontinued before W24. Two pts with baseline total symptom score (TSS) = 0 were excluded from analysis of TSS reduction of ≥50% (TSS50). Results: As of Dec 21, 2022, 10 participants received 40 mg and 14 participants received 60 mg SEL; 22 of the 24 pts enrolled had reached at least W24 and were included in the efficacy analysis. The median duration of treatment was 28 wks overall, 33 wks for 60 mg and 22.5 wks for 40 mg grps. Most common adverse events (AEs) by dose (60/40 mg) were nausea (79%/70%; majority grade 1-2), anemia (79%/50%), and fatigue (57%/60%). Most common Grade ≥3 AEs were anemia (50%/40%), thrombocytopenia (29%/10%), and neutropenia (7%/20%). AEs were reversible with dose modifications. Two patients discontinued treatment due to treatment-related AEs (thrombocytopenia and neuropathy); 3 deaths have occurred in the study, none related to SEL. Overall, 64% (14/22) achieved SVR35 at W24, with 79% [11/14] vs 38% [3/8], in the 60 mg vs 40 mg grp, respectively. The 60 mg grp achieved a deeper median SVR response vs the 40 mg grp at W24 (49% vs 31%). At W24, TSS50 was achieved by 45% (9/20) overall, 58% [7/12] of the 60 mg, and 25% [2/8] of the 40 mg grp. Among 11 pts with baseline hemoglobin < 10 g/dL, median hemoglobin decreased by 0.5 g/dL from baseline to W12 and increased by 0.8 g/dL from baseline to W24. Similar efficacy was observed across all subgrps with 60 mg. Reduction of variant allele frequency from baseline to W24 was > 10% in 50% (4/8) and > 20% in 25% (2/8) of evaluable pts for 60 mg grp. Conclusions: Encouraging activity with 60mg SEL + RUX combination were observed in TSS50, SVR and hemoglobin levels overall, as well as in key subgroups including males, in pts started on low dose RUX (≤15 mg), and pts with larger baselines spleen size. Updated data will be available for presentation. Clinical trial information: NCT04562389 . [Table: see text]