SUMMARY: The American Cancer Society estimates that approximately 66,200 new cases of uterine cancer will be diagnosed in 2023 and about 13,030 individuals will die of the disease. Endometrial carcinoma is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been increasing. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, Type 2 diabetes, family history, diet and exercise, drugs such as Tamoxifen, and delayed menopause. Patients with advanced or recurrent endometrial cancer are often treated with a combination of Carboplatin and Paclitaxel. Treatment options following failure of first-line therapy for this patient group however are limited, with single agent response rates of 10-15% and 5-year survival rates of approximately 17%. There are no approved therapies in the maintenance setting for patients with advanced or recurrent endometrial cancer.
It is estimated that of the endometrial carcinoma molecular subtypes, TP53 wild-type tumors represent 75% of the newly diagnosed endometrial carcinoma and 50% of advanced/recurrent tumors. There are no specific targeted therapies available for patients with TP53 wild-type endometrial carcinoma.
Exportin 1 (XPO1) is an important nuclear export protein overexpressed in endometrial cancers. High XPO1 levels facilitate increased nuclear export of tumor suppressor proteins such as P53, P73, IkB and FOXO3a, pRb, BRCA1, as well as growth regulators such as Glucocorticoid Receptor and oncoprotein mRNA. This enables cancer cells to escape tumor suppressor protein mediated cell cycle arrest and apoptosis.
Selinexor (XPOVIO®) is first-in-class, oral selective XPO1 inhibitor that reactivates the tumor suppressor proteins by preventing nuclear transport and inhibits oncoprotein translation. Selinexor is approved in the US for the treatment of patients with Multiple Myeloma and Diffuse Large B-Cell Lymphoma. Selinexor demonstrated antitumor activity among patients with endometrial carcinoma in Phase I and II trials.
SIENDO/EC-042 is a Phase III randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Selinexor as maintenance therapy in patients with TP53 wild-type advanced or recurrent endometrial carcinoma who have achieved a Partial or Complete Response after completing at least 12 weeks of platinum combination chemotherapy with or without immunotherapy for primary Stage IV or recurrent disease. Comprehensive tissue-based genomic profiling testing was performed, to identify and enroll patients whose tumors were TP53 wild-type. In this study, 263 eligible patients were randomly assigned in a 2:1 ratio to receive Selinexor 60 mg orally once weekly (N=174) or placebo weekly (N=89). The prespecified TP53 wild-type subgroup included 113 women assigned to Selinexor (N=77) or Placebo (N=36). The median age in the TP53 wild-type subgroup was 63 years and most patients had endometrioid histology and MSS/MMR proficient tumors. Patients were stratified based on whether they had primary Stage IV or recurrent disease, as well as Partial or Complete response to platinum combination chemotherapy before they were started on maintenance therapy with Selinexor. The Primary endpoint was investigator-assessed Progression Free Survival (PFS), with exploratory endpoints including histologic subtype and molecular subclassifications. Secondary end points included PFS by Blinded Independent Central Review, Overall Survival (OS), time to first subsequent therapy, and Health-Related Quality of Life. The primary analysis of Selinexor maintenance therapy showed improvements in median PFS for the intent-to-treat (ITT) population but were not clinically meaningful.
However, an exploratory analysis of a pre-specified subgroup of patients with TP53 wild-type endometrial cancer showed significant findings. At a median follow up of 25.3 months, it was noted that patients with TP53 wild-type tumors receiving Selinexor maintenance therapy had a median PFS of 27.4 months compared with 5.2 months in the placebo group, representing a 58% decrease in the risk of disease progression (HR=0.42; P=0.0003). This efficacy was observed regardless of MSS/MSI status, but women in the TP53 wild-type subgroup who had MSS/MMR proficient tumors demonstrated the greatest PFS benefit with Selinexor. In the subgroup with TP53 mutations/aberrations, the median PFS was shorter with Selinexor (4.2 months versus 5.4 months with placebo; HR=1.34: P=0.92). The most common adverse events with Selinexor in the TP53 wild-type subgroup included nausea (90.8%), vomiting (60.5%) and diarrhea (39.5%). Grade 3-4 events included neutropenia (18.4%) and thrombocytopenia (9.2%).
The authors concluded that TP53 status is a robust prognostic biomarker for endometrial carcinoma and Selinexor maintenance in TP53 wild-type endometrial carcinoma demonstrated durable Progression Free Survival benefit in a pre-specified subgroup analysis, and offers the potential to prolong response to prior systemic therapy.
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. Slomovitz B. American Society of Clinical Oncology Plenary Series. July 25, 2023; virtual; abstract 427956.
