Phase 3 dose selection for selinexor in TP53wt endometrial cancer based on exposure-response analysis.
Authors: Makker Vicky , Richardson Debra L. , Chon Hye Sook , Miller David Scott , Mau-Sørensen Morten , Cibula David , Zagouri Flora , Pérez Fidalgo Alejandro , Slomovitz Brian M. , Coleman Robert L. , Kalyanapu Pratheek , Fan Rong , Gudi Girish , Vergote Ignace 
Published: June 2024

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Background: Molecular characterization informs treatment decisions in patients (pts) with endometrial cancer (EC). Wild type TP53 ( TP53wt) is found in ~50% of advanced/recurrent EC. Currently, there are no proven p53-targeting therapies for TP53wt EC. Selinexor (SEL) is an investigational oral XPO-1 inhibitor that showed promising activity in the Phase 2 SIGN (NCT02025985) study of SEL 50 mg/m2 BIW (Part 1) in heavily pretreated, recurrent gynecological malignancies including EC. An exploratory analysis of a pre-specified subgroup of pts with TP53wt advanced/recurrent EC in the Phase 3 ENGOT-EN5/GOG-3055/SIENDO (NCT03555422) study showed a promising efficacy signal with 80 mg SEL QW as maintenance therapy following platinum-based therapy compared to placebo (PFS HR 0.46) (Scambia et al., IGCS 2023), full safety data was previously reported (Vergote et al., JCO 2023). Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted to evaluate the relationship between SEL systemic exposure and clinical endpoints to select an optimal dose that provides clinical benefit while reducing potential toxicities. Methods: A previously developed SEL PopPK model using data from 8 clinical trials of solid tumors and hematologic malignancies was updated to include pts from SIGN and SIENDO. Of the total 919 pts, 74 had gynecological cancers, of which 36 were EC. Simulations were performed to estimate the systemic exposure of SEL and maximum concentration (Cmax) and area under the curve (AUC) at steady state were derived using Empirical Bayes Estimations. The derived individual PK parameters were used for integrated E-R analyses for efficacy (PFS from SIENDO data) and safety endpoints (data from SIGN and SIENDO). Results: Significant covariate effects (time varying weight [WT] on CL/F and Vc/F, and sex on CL/F) were retained in the model. The PK of SEL in SIGN and SIENDO pts with advanced gynecologic malignancies was similar to other tumor types in female pts. E-R analysis included pts from SIGN (n=43; as of 09Jan2018) and SIENDO (SEL n=23, placebo n=88; as of 18Jan2022). No E-R trend for efficacy was observed with Week 1 PK parameters of Cmax and AUC in the broader EC population, and no E-R relationship for efficacy was detected for pts with TP53wt EC (n=7). Significant E-R relationships were observed for treatment-emergent adverse events (TEAEs) including thrombocytopenia, neutropenia, nausea/vomiting, and dose modifications. E-R simulations for 60 mg SEL QW were compared to 80 mg SEL QW and predicted an 8.4% and 4.3% reduction in ≥G3 TEAEs and nausea/vomiting ≥G2 TEAEs, respectively. Conclusions: The integrated E-R analysis demonstrates the potential for SEL 60 mg QW to be reasonably well-tolerated, while maintaining efficacy. Evaluation of 60 mg SEL QW as maintenance therapy for TP53wt advanced/recurrent EC is ongoing in the phase 3 ENGOT-EN20/GOG-3083/XPORT-EC-042 trial (NCT05611931).