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

Vergote, I.; Perez-Fidalgo, J. A.; Hamilton, E. P.; Valabrega, G.; Van Gorp, T.; Sehouli, J.; Cibula, D.; Levy, T.; Welch, S.; Richardson, D. L.; Guerra, E. M.; Scambia, G.; Henry, S.; Wimberger, P.; Miller, D. S.; Klat, J.; Martinez-Garcia, J.; Raspagliesi, F.; Pothuri, B.; Romero, I.; Bergamini, A.; Slomovitz, B.; Schochter, F.; Hogdall, E.; Farinas-Madrid, L.; Monk, B. J.; Michel, D.; Kauffman, M. G.; Shacham, S.; Mirza, M. R.; Makker, V.

doi:10.1200/JCO.22.02906

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 5 .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 5 .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.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer / Vergote, I.; Perez-Fidalgo, J. A.; Hamilton, E. P.; Valabrega, G.; Van Gorp, T.; Sehouli, J.; Cibula, D.; Levy, T.; Welch, S.; Richardson, D. L.; Guerra, E. M.; Scambia, G.; Henry, S.; Wimberger, P.; Miller, D. S.; Klat, J.; Martinez-Garcia, J.; Raspagliesi, F.; Pothuri, B.; Romero, I.; Bergamini, A.; Slomovitz, B.; Schochter, F.; Hogdall, E.; Farinas-Madrid, L.; Monk, B. J.; Michel, D.; Kauffman, M. G.; Shacham, S.; Mirza, M. R.; Makker, V.. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - 41:35(2023), pp. 5400-5410. [10.1200/JCO.22.02906]