Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer

Abstract

PURPOSE Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422 ). RESULTS Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

Mapping three-dimensional intratumor proteomic heterogeneity in uterine serous carcinoma by multiregion microsampling

“…Notable targets among these which have demonstrated therapeutic significance when targeted in recent endometrial cancer clinical trials (Additional file 4 : Figure S4) include programmed cell death protein 1 and programmed death-ligand 1 (PD-1/PD-L1) [ 10 – 12 ]. The clinical benefit of selinexor, a selective inhibitor of exportin 1 (XPO1), as a maintenance therapy was recently demonstrated in endometrial cancer patients with wild-type tumor protein 53 (TP53) [ 30 ]. TP53 and phosphorylated (p)TP53 S15 were assayed by RPPA and not quantified by MS. Checkpoint kinase 1 (CHK1 S345 ), selectively inhibited by prexasertib (ACR-368), was exclusively quantified by RPPA and has demonstrated early promising results as a therapeutic target in platinum-resistant endometrial cancer (NCT05548296).…”

ENGOT-EN20/GOG-3083/XPORT-EC-042 – A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design

“…the improvements in median progression-free survival for the intent-to-treat population were not clinically meaningful. 5 In the long-term follow-up of the pre-specified TP53wt subgroup as of September 1, 2023, there were progression-free survival improvements in patients receiving selinexor maintenance therapy (80 mg oral once-weekly) compared with placebo (27.4 months vs 5.2 months, HR=0.41; median follow-up of 28.9 months). Further analysis suggests benefit is regardless of microsatellite stability status.…”

“…1 Approximately 25% of patients with endometrial cancer have mutations in TP53 at diagnosis and approximately 50% of advanced/recurrent endometrial cancer tumors are TP53wt, of which 40-55% are also mismatch repair proficient (pMMR) or microsatellite stable (MSS). [4][5][6] POLE, TP53wt, and pMMR subgroups are found in approximately 36% of advanced or recurrent endometrial cancer. 7 Patients with TP53wt tumors have a paucity of options and limited evidence of beneficial treatment that leaves a notable unmet need.…”

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer

“…Selinexor, an oral agent, inhibits the nuclear export protein exportin 1 (XPO1) and has shown effectiveness against solid tumors. SIENDO/ENGOT-EN5/GOG-3055 was a randomized multicenter phase 3 study evaluating the efficacy and safety for front-line maintenance therapy with selinexor (80 mg once weekly [QW]) following chemotherapy in patients with advanced or recurrent endometrial cancer [ 8 ]. Selinexor showed a 50% statistically significant improvement in median PFS compared to placebo (HR=0.70; p=0.049).…”