PLX151611

GSE141147: Selinexor, a First-in-Class XPO1 Inhibitor, Is Efficacious and Tolerable in Patients with Myelodysplastic Syndromes Refractory to Hypomethylating Agents

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

PURPOSE The median overall survival (OS) of patients with high-risk myelodysplastic syndromes (MDS) refractory to hypomethylating agents is less than 6 months and there is no standard therapy for such patients. Preclinical studies have shown that inhibition of the nuclear export protein XPO1 causes nuclear accumulation of p53 and disruption of NF-B signaling, both relevant targets for MDS. We therefore sought to determine the safety, efficacy, and potential molecular correlates of response to selinexor, an oral selective inhibitor of XPO1, in MDS. PATIENTS AND METHODS We report the results of a phase 2 clinical trial of selinexor in high-risk MDS patients refractory to hypomethylating agents. The primary endpoint was overall response rate (ORR) and secondary endpoints included safety, response duration, and OS. RESULTS In 19 evaluable patients, ORR was 32% (95% CI, 13-57) with an additional 42% (95% CI, 24-71) achieving stable disease (SD). Median OS was 9.6 months (95% CI, 8.5-17.1) with median follow-up of 2.1 years. Grade 3 or 4 adverse events (AEs) in the first 3 patients (thrombocytopenia [n=3] and hyponatremia [n=1]) led to dose reduction to 60mg flat dose twice-weekly for two weeks followed by one week off, resulting in significantly improved tolerability. The most frequent adverse event (AE) thereafter was grade 1 or 2 nausea, anorexia and fatigue. These and other AEs were manageable with supportive care implementation. The presence of an SF3B1 mutation was significantly associated with response to selinexor (p=0.02) and correlative studies suggest splicing alterations were induced by selinexor and affected inflammatory pathways such as NF-B. CONCLUSIONS Selinexor is safe and tolerable in MDS when given at 60mg twice weekly for two weeks with one week off. Responses were enriched in SF3B1 mutated patients. SOURCE: Justin Taylor (taylorj7@mskcc.org) - Memorial Sloan Kettering Cancer Center