P1020: selinexor (sel) plus ruxolitinib (rux) in jak inhibitor (jaki) treatment-naïve patients with myelofibrosis: updated results from xport-mf-034

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, and poor prognosis. In the Phase II ESSENTIAL study, SEL monotherapy had notable clinical activity in patients (pts) with disease refractory to a JAK inhibitor (JAKi), and a generally manageable safety profile. 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. Aims: Here, we present the results of a phase 1 dose escalation study to determine the optimal dose and preliminary efficacy of once weekly SEL in combination with RUX in pts with JAKi-naïve MF. 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, 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. Pts whose baseline total symptom score (TSS) was 0 were excluded from analysis of TSS reduction of ≥50% (TSS50). The efficacy population (EE) for evaluable pts included those with a spleen assessment or ≥1 symptom score at baseline and W24. Subgroup analysis included sex, starting dose of RUX, and baseline spleen volume. Results: As of Dec 21, 2022, 10 participants received 40 mg and 14 participants received 60 mg SEL. Of 24 pts enrolled, 22 had reached at least W24 and were included in the efficacy analysis for SVR35; 20 of 24 pts were included for TSS50. The median duration of treatment was 28 wks overall, 33 wks for 60 mg and 22.5 wks for 40 mg cohorts. The 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%). The 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 cohort, respectively. The 60 mg cohort achieved a deeper median SVR% vs the 40 mg cohort at W24 (49% vs 31%). Of the EE population, 78% (14/18) achieved SVR35 at W24 with 92 % (11/12) vs 50% (3/6) in the 60 mg vs 40 mg cohort, respectively. 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 cohort. Of the EE population, TSS50 at W24 was achieved by 62% (13/19) overall, 75 % (6/8) of the 60 mg, and 40% (2/5) of the 40 mg cohort. 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 subgroups 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 the 60 mg cohort. Summary/Conclusion: Encouraging activity with 60 mg SEL + RUX combination were observed across SVR35, TSS50 and hemoglobin levels, as well as in key subgroups including males, in pts started on low dose RUX (≤10 mg), and pts with larger baselines spleen size. Updated data will be available for presentation.Keywords: Phase I, Clinical trial, Clinical data, Myelofibrosis