Study: Selinexor Shows Improved Progression-Free Survival in Endometrial Cancers

In the SIENDO trial, the data showed that selinexor improved progression-free survival (PFS) over the placebo in individuals with wild type TP53 with non-specific molecular profile typically with microsatellite stability (NSMP, p53wt/MSS) endometrial cancers based on a stratification adjusted analysis, according to a presentation at the 2022 American Society of Clinical Oncology Annual Meeting.

Preliminary exploratory subgroup analyses of selinexor showed improvement of the placebo amongst individuals with NSMP, p53wt, and MSS endometrial cancers.

Endometrial cancers are stratified into 4 molecular categories including NSMP, p53wt/MSS, DNA polymerase ε exonuclease domain mutated (POLEmut), microsatellite instability high (MSI), and TP53 abnormal (p53abn), and they are associated with specific prognoses. As a specific XPO1 inhibitor, selinexor can lead to the nuclear retention and activation of tumor suppressor proteins, including p53.

During the SIENDO trial, which was a multicenter, double-blind, placebo-controlled phase 3 study, investigators aimed to compare selinexor at the 80 mg dosage given once a week to the placebo as maintenance therapy in 263 individuals with advanced or recurrent endometrial cancers following 1 line of taxane-therapy with partial or complete remission. In order to accomplish this goal, TP53 and MSI was assessed by centralized targeting sequencing and local immunohistochemistry. Additionally, classification was based on sequencing 648 genes on tumor samples from 172 individuals, with 107 patients receiving Selinexor. Patients were then assigned first by POLE mut, then MSI, then p53abn or p53wt; these molecular classifications were prespecified.

Investigators found that individuals receiving selinexor had a median PFS of 5.7 months compared to 3.8 for those on the placebo, with a stratification adjusted hazard ratio of 0.70. Additionally, among the 172 individuals who underwent molecular classification, the 107 receiving selinexor were classified as 25% NSMP, 2% POLEmut, 17% MSI, and 46% p53abn.

Similarly, 65 individuals who received the placebo were classified as 31% NSMP, 6% POLEmut, 12% MSI, 51% p53abn.

The subgroup analysis of individuals with TP53wt showed a PFS of 13.7 months of those treated with selinexor and 3.7 months for those treated with the placebo. Individuals with MSS/pMMR disease had a PFS of 6.9 months when treated with selinexor and 5.4 months when treated with the placebo.

Investigators reported the median PFS for individuals with NSMP receiving selinexor was not reported, while for those given the placebo the median PFS was reported as being 3.71 months.In the analyses, the other molecular categories did not show significant differences in PFS between the selinexor arm and the placebo arm. Further, additional biomarker identification studies that assess tumor genetics and epigenetics remain ongoing.

Reference

Maker V, Perez-Fidalgo JA, Bergamini A, Spitz DL, et al. Randomized phase III study of maintenance selinexor versus placebo in endometrial cancer (ENGOT-EN5/GOG-3055/SIENDO): Impact of subgroup analysis and molecular classification. Journal of Clinical Oncology. 2022. doi:10.1200/JCO.2022.40.16_suppl.5511