Selinexor Maintenance Offers Durable Benefit in Advanced Endometrial Cancer

Selinexor (Xpovio) maintenance therapy showed sustained clinical benefit in patients with TP53 wild-type advanced or recurrent endometrial cancer, improving progression-free survival (PFS), time to first and second subsequent therapies (TFST, TSST), and PFS2 compared with placebo, regardless of mismatch repair status, according to long-term results from the phase 3 SIENDO trial (NCT03555422) presented at the 2025 ESMO Gynecological Cancers Congress.¹

Selinexor improved outcomes for patients with endometrial cancer regardless of mismatch repair status.

Findings showed that as of April 1, 2024, 113 of 263 patients (43.0%) had TP53 wildtype disease, including 77 patients in the selinexor arm and 36 in the placebo group. In the TP53 wild-type/mismatch repair–proficient (pMMR) subgroup, the median progression-free survival (PFS) was 39.5 months with selinexor vs 4.9 months with placebo (HR, 0.36; one-sided nominal P = .0011). In the TP53 wild-type/MMR-deficient (dMMR) subgroup, the median PFS was 13.1 months vs 3.7 months, respectively (HR, 0.49; P = .0825).

“Consistent improvements in time to first subsequent therapy [TFST], time to second progression [PFS2], and time to second subsequent therapy [TSST], as signals of treatment durability and cumulative effectiveness of subsequent treatment, may further characterize clinical benefits of selinexor in TP53 wild-type endometrial cancer and the potential to prolong systemic therapy benefit,” J. Alejandro Pérez Fidalgo, MD, of Hospital Clinico Universitario Valencia, and colleagues wrote in a posted presentation. “PFS2 data in the dMMR subgroup in both arms may be an observation of patients receiving immunotherapy as subsequent therapy, suggesting that selinexor does not negatively impact the efficacy of subsequent immunotherapy use.”

Study Breakdown

SIENDO was a randomized, double-blind, multicenter, phase 3 trial designed to evaluate selinexor as maintenance therapy in patients with advanced or recurrent endometrial cancer following a response to first-line platinum-based chemotherapy.

Eligible patients included those with stage IV or recurrent endometrial cancer who had achieved a complete or partial response after at least 12 weeks of platinum-based chemotherapy. Notably, prior surgery, radiotherapy, or hormonal therapy were allowed.

Patients were stratified by measurable disease status (stage IV vs recurrent) and response to chemotherapy (complete response vs partial response), and then randomly assigned in a 2:1 ratio to receive either oral selinexor at 80 mg once weekly or placebo. Those with a BMI of less than 20 kg/m² received selinexor at 60 mg once per week or placebo. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent.

In a long-term follow-up analysis, intermediate end points were evaluated in patients with TP53 wild-type tumors, further stratified by MMR status. This exploratory analysis aimed to assess the association of MMR status with clinical outcomes in the TP53 wild-type population receiving selinexor maintenance. Key intermediate end points included PFS, durable clinical benefit, and PFS2.

The primary end point of the SIENDO trial was investigator-assessed PFS in the intent-to-treat population. Secondary end points included overall survival, PFS2, and safety.

Efficacy and Safety Continued

In regard to TFST, data favored selinexor across both MMR-defined subgroups. In the overall TP53 wild-type subgroup, the median TFST was 31.7 months with selinexor vs 10.6 months with placebo (HR, 0.41; P = .0002). In the TP53 wild-type/dMMR subgroup, median TFST was 25.7 months vs 4.8 months, respectively (HR, 0.47; 95% CI, 0.17-1.28; P = .0659). In the pMMR subgroup, the respective median TFSTs were not reached (NR) and 8.5 months (HR, 0.31; 95% CI, 0.16-0.61; P =. 0002). TSST was not reached in patients in both MMR subgroups receiving selinexor.

Median PFS2 was 43.9 months with selinexor vs 30.1 months with placebo in the TP53 wild-type/pMMR subgroup (HR, 0.56; 95% CI, 0.28-1.18; P = .0611). In TP53 wild-type/dMMR patients, median PFS2 was not reached in either arm (HR, 0.43; 95% CI, 0.10-1.84; P = .1229).

Among 76 patients treated with selinexor, the most frequently reported treatment-emergent adverse effects (TEAEs) of any grade reported in at least 20% of patients included nausea (90%), vomiting (60%), diarrhea (45%), constipation (33%), asthenia (32%), fatigue (30%), thrombocytopenia (42%), decreased appetite (36%), neutropenia (34%), anemia (33%), and abdominal pain (26%).

Grade 3 or higher TEAEs were less common but still notable for neutropenia (20%), thrombocytopenia (10%), nausea (13%), anemia (7%), and vomiting (3%). Constipation and asthenia were not associated with grade 3 or higher effects in the selinexor arm.

In comparison, the placebo group (n = 35) reported lower overall frequencies of TEAEs, with the most common any-grade toxicities being nausea (40%), constipation (40%), vomiting (14%), fatigue (26%), and decreased appetite (20%). Grade 3 or higher TEAEs in the placebo arm were rare and included constipation (6%), vomiting (3%), and anemia (3%).

TEAEs leading to discontinuation occurred in 16% of patients receiving selinexor vs no patients in the placebo arm. No TEAEs leading to death were reported in either treatment arm.

“The currently enrolling phase 3 XPORT-EC trial [NCT05611931] will further investigate selinexor maintenance in this setting,” study authors concluded.

Reference

Pérez Fidalgo JA, Vergote I, Pujade-Lauraine E, et al. Long-term follow-up of selinexor maintenance in TP53 wild-type advanced/recurrent endometrial cancer: results from the ENGOT-EN5/GOG-3055/SIENDO study. Presented at: 2025 ESMO Gynecological Cancers Congress; June 19-21, 2025; Vienna, Austria. Abstract 44P.