Selinexor in combination with R-CHOP for frontline treatment of non-Hodgkin lymphoma: results of a phase 1 study.

Background The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin's lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP activity in NHL by targeted inhibition of XPO1 using the Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor and eltanexor. Methods We evaluated the anti-tumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo Newly diagnosed NHL patients in a phase 1 dose escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western Blotting and RNA-seq was performed on patient blood samples. Results SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase 1 study, selinexor was dosed at 60 mg (n=6) and 80 mg (n=6). The most common adverse events (AEs) among 12 patients were fatigue (67%) and nausea (100%). Grade 3-4 AEs were infrequent. 10 evaluable patients had an ORR of 100% and CR rate of 90% with sustained remissions (median follow up: 476 days). Maximally tolerated dose (MTD) was not reached, however the recommended Phase 2 dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed down-regulation of XPO1 and several pro-survival markers. Conclusion SINE compounds enhance the activity of CHO in vitro and in vivo Selinexor in combination with R-CHOP was generally well-tolerated and showed encouraging efficacy in NHL. (NCT03147885).