Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study.
Authors: Slomovitz Brian M. , Perez-Fidalgo Jose Alejandro , Hamilton Erika P. , Valabrega Giorgio , Van Gorp Toon , Sehouli Jalid , Klat Jaroslav , Levy Tally , Welch Stephen , Richardson Debra L. , Guerra Alia Eva Maria , Scambia Giovanni , Henry Stephanie , Wimberger Pauline , Martinez Jeronimo , Monk Bradley J. , Kalyanapu Pratheek , Raza Mirza Mansoor , Makker Vicky , Vergote Ignace 
Published: July 2023

427956

Background: Molecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 ( TP53wt) is found in ~75% of newly diagnosed EC and 50% of advanced/recurrent tumors; there are no specific targeted therapies available for patients with TP53wt EC. Selinexor is an investigational oral XPO1 inhibitor that drives nuclear retention and functional activation of wild type tumor suppressor proteins, including p53. Methods: SIENDO (NCT03555422) was a phase 3 double-blind study evaluating selinexor vs placebo as maintenance therapy in patients with advanced/recurrent EC following response to prior systemic therapy. The primary endpoint was progression-free survival (PFS), which was previously presented at the ESMO plenary in March 2022. Preliminary analysis of a pre-specified exploratory subgroup of patients with TP53wt EC showed a decrease in risk for progression or death with a median PFS of 13.7 months with selinexor as maintenance therapy vs 3.7 months with placebo at the time of primary PFS analysis. The safety and efficacy of selinexor as maintenance therapy was now further assessed with long-term follow-up in the pre-specified subgroup of patients with TP53wt EC. Results: 113 patients with TP53wt EC were randomly assigned to receive selinexor vs placebo as maintenance therapy (selinexor, n=77/placebo, n=36). As of data cutoff on Nov 30, 2022, median follow-up was 20.3 months, with 26.3% and 22.9% patients still on selinexor and placebo treatment, respectively. Median PFS for the TP53wt subgroup was 20.8 months with selinexor vs 5.2 months with placebo (HR [Stratified by chemotherapy response CR vs PR] 0.46; 95% CI (0.27, 0.79), nominal one-sided p=0.002). Efficacy was observed regardless of MSS/MSI status. The most common adverse events (AEs) of any grade (selinexor/placebo) were nausea (90%/34%), vomiting (61%/11%) and diarrhea (38%/34%); and most common grade 3+ AEs included: neutropenia (18%/0%), nausea (12%/0%), and thrombocytopenia (9%/0%). TEAEs leading to discontinuations were reported in 15%/0% of patients, respectively. Conclusions: Long-term follow-up of a pre-specified subgroup analysis showed durable PFS benefit with selinexor maintenance in TP53wt EC, which offers the potential to prolong response to prior systemic therapy. These data suggest that TP53 status is a robust prognostic biomarker for EC and selinexor may provide meaningful benefit in patients who have TP53wt tumors. A phase 3 trial is underway to further investigate the safety and efficacy of selinexor as maintenance therapy in patients with advanced or recurrent TP53wt EC (NCT05611931). Updated PFS and results in additional molecular subtypes (MSS/MSI) of the TP53wt subgroup will be included at the time of presentation. Clinical trial information: NCT03555422 .