Long-term follow-up data from the phase 3 SIENDO trial (NCT03555422) presented at the 2025 ESMO Gynecological Cancers Congress demonstrate that selinexor (Xpovio) maintenance therapy continues to provide sustained clinical benefit in patients with TP53 wild-type advanced or recurrent endometrial cancer, with efficacy observed regardless of mismatch repair status.
Significant Progression-Free Survival Improvements
As of April 1, 2024, 113 of 263 patients (43.0%) had TP53 wild-type disease, including 77 patients in the selinexor arm and 36 in the placebo group. The results showed particularly striking benefits in the TP53 wild-type/mismatch repair-proficient (pMMR) subgroup, where median progression-free survival (PFS) reached 39.5 months with selinexor compared to 4.9 months with placebo (HR, 0.36; one-sided nominal P = .0011).
In the TP53 wild-type/MMR-deficient (dMMR) subgroup, median PFS was 13.1 months versus 3.7 months with placebo (HR, 0.49; P = .0825), demonstrating benefit across both mismatch repair phenotypes.
Durable Treatment Benefits Across Multiple Endpoints
The analysis revealed consistent improvements in time to first subsequent therapy (TFST) favoring selinexor across both MMR-defined subgroups. In the overall TP53 wild-type subgroup, median TFST was 31.7 months with selinexor versus 10.6 months with placebo (HR, 0.41; P = .0002).
For the TP53 wild-type/dMMR subgroup, median TFST was 25.7 months versus 4.8 months with placebo (HR, 0.47; 95% CI, 0.17-1.28; P = .0659). In the pMMR subgroup, median TFST was not reached with selinexor compared to 8.5 months with placebo (HR, 0.31; 95% CI, 0.16-0.61; P = .0002).
Time to second subsequent therapy (TSST) was not reached in patients in both MMR subgroups receiving selinexor, indicating prolonged treatment benefit.
Second Progression-Free Survival Data
Median PFS2 was 43.9 months with selinexor versus 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).
According to J. Alejandro Pérez Fidalgo, MD, of Hospital Clinico Universitario Valencia, and colleagues, "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 Design and Patient Population
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. Prior surgery, radiotherapy, or hormonal therapy were allowed.
Patients were stratified by measurable disease status (stage IV versus recurrent) and response to chemotherapy (complete response versus partial response), 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.
Safety Profile Remains Manageable
Among 76 patients treated with selinexor, the most frequently reported treatment-emergent adverse effects (TEAEs) of any grade in at least 20% of patients included nausea (90%), vomiting (60%), diarrhea (45%), thrombocytopenia (42%), decreased appetite (36%), neutropenia (34%), anemia (33%), constipation (33%), asthenia (32%), fatigue (30%), and abdominal pain (26%).
Grade 3 or higher TEAEs were less common but notable for neutropenia (20%), nausea (13%), thrombocytopenia (10%), 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%), fatigue (26%), decreased appetite (20%), and vomiting (14%). 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 versus no patients in the placebo arm. No TEAEs leading to death were reported in either treatment arm.
Future Research Directions
The researchers noted that "consistent improvements in time to first subsequent therapy, time to second progression, and time to second subsequent therapy, 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."
The currently enrolling phase 3 XPORT-EC trial (NCT05611931) will further investigate selinexor maintenance in this setting, potentially expanding the evidence base for this therapeutic approach in advanced endometrial cancer.
