Selinexor Maintenance After First-Line Chemotherapy Extends PFS in TP53 Wild-Type Advanced Endometrial Cancer

Brian Slomovitz, MD

Selinexor (Xpovio) maintenance generated an improvement in progression-free survival (PFS) compared with placebo in patients with TP53 wild-type advanced or recurrent endometrial cancer who responded to first-line chemotherapy, according to updated data from a prespecified subgroup analysis of the phase 3 SIENDO trial (NCT03555422).¹

Long-term findings presented at the 2023 ASCO July Plenary Series showed that at a median follow-up of 25.3 months, patients with TP53 wild-type disease treated with selinexor (n = 77) achieved a median PFS of 27.4 months (95% CI, 13.1-not reached [NR]) compared with 5.2 months (95% CI, 2.0-13.1) in those treated with placebo (n = 36; HR, 0.42; 95% CI, 0.25-0.70; 1-sided nominal P = .0003).

Conversely, at a median follow-up of 22.9 months for patients harboring TP53 mutations or aberrations, those in the selinexor arm (n = 79) experienced a median PFS of 4.2 months (95% CI, 3.6-5.6) compared with 5.4 months (95% CI, 3.7-7.2) for those in the placebo arm (n = 47; HR, 1.34; 95% CI, 0.89-2.02; 1-sided nominal P = .9202).

“[TP53] status may represent a robust, predictive biomarker for efficacy in [patients with] endometrial cancers,” lead study author Brian Slomovitz, MD, director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, said in a presentation of the data. “These results provide strong rationale to further evaluate selinexor as maintenance therapy."

Previously reported data from SIENDO showed that at a median follow-up of 10.2 months (95% CI, 8.97-13.57), patients in the intent-to-treat population treated with selinexor (n = 174) experienced a median PFS of 5.7 months (95% CI, 3.81-9.20) compared with 3.8 months (95% CI, 3.68-7.39) for those given placebo (HR, 0.705; 95% CI, 0.499-0.996; 1-sided P = .024).2 In patients with TP53 wild-type disease, the median PFS was 13.7 months (95% CI, 9.20-NR) for selinexor vs 3.7 months (95% CI, 1.87-12.88) for placebo (HR, 0.375; 95% CI, 0.21-0.67; 1-sided P = .0003).

“An exploratory analysis of [a] prespecified subgroup of patients with TP53 wild-type endometrial cancer did show a promising efficacy signal,” Slomovitz said.

The randomized, double-blind SIENDO study enrolled adult patients with stage IV or first relapsed endometrial cancer who received at least 12 weeks of platinum-based chemotherapy. Prior surgery, radiotherapy, or hormonal therapy were permitted.¹

Those who achieved a complete response (CR) or partial response (PR) following chemotherapy were randomly assigned 2:1 to 80 mg of oral selinexor or matching placebo once per week. Patients were stratified by disease at the time of chemotherapy (primary stage IV vs recurrent) and chemotherapy response type (CR vs PR).

Investigator-assessed PFS served as the trial’s primary end point. Secondary end points included PFS per RECIST v1.1 criteria via blinded independent central review, overall survival, time to first subsequent therapy, and health-related quality of life. Exploratory end points consisted of histological subtype and molecular subclassification per DNA sequencing and immunohistochemistry (IHC), including TP53 mutation status, microsatellite instability status, and POLE-EDM mutation status.

TP53 status was determined by next-generation sequencing (NGS). If NGS was not available, status was confirmed through IHC.

Regarding baseline characteristics, Slomovitz pointed out that the majority of patients with TP53 wild-type disease treated with selinexor (84.4%) and placebo (80.6%) had endometrioid histology. In those harboring TP53 mutations, the majority of patients administered selinexor (54.4%) and placebo (51.1%) had serous histology.

Among patients with TP53 wild-type disease, 40.3% of patients in the selinexor arm experienced a CR following their most recent chemotherapy compared with 44.4% of patients in the placebo arm. In those with TP53-mutated disease, the CR rates following chemotherapy were 44.3% for the selinexor arm and 40.4% for the placebo arm.

In the TP53 wild-type subgroup, rates of patients with microsatellite stable/mismatch repair–proficient (MSS/pMMR) disease were 61.0% for the selinexor arm and 63.9% for the placebo arm. In the TP53-mutated subgroup, those rates were 72.2% for the selinexor arm and 78.7% for the placebo arm.

Additional data showed that at a median follow-up of 27.2 months for patients with TP53 wild-type endometrial cancer who were MSS/pMMR, selinexor (n = 47) elicited a median PFS that was NR (95% CI, 20.8-NR) compared with 4.9 months (95% CI, 2.0-NR) for placebo (n = 23; HR, 0.32; 95% CI, 0.16-0.66; 1-sided P = .0006). At a median follow-up of 22.6 months for patients with TP53 wild-type, microsatellite instability–high/mismatch repair–deficient disease, the median PFS was 13.1 months (95% CI, 3.6-NR) for selinexor (n = 20) vs 3.7 months (95% CI, 1.9-NR) for placebo (n = 9; HR, 0.45; 95% CI, 0.16-1.27; 1-sided P = .0643).

Among patients with TP53 wild-type disease evaluable for safety in the selinexor (n = 76) and placebo (n = 35) arms, the most common any-grade treatment-emergent adverse effects (TEAEs) included nausea (90.8% vs 34.3% for selinexor and placebo, respectively), vomiting (60.5% vs 11.4%), diarrhea (39.5% vs 34.3%), constipation (34.2% vs 40.0%), asthenia (35.5% vs 25.7%), fatigue (35.5% vs 20.0%), thrombocytopenia (42.1% vs 2.9%), decreased appetite (35.5% vs 2.9%), neutropenia (34.2% vs 5.7%), anemia (32.9% vs 2.9%), and abdominal pain (26.3% vs 14.3%).

TEAEs led to treatment discontinuation in 15.8% of patients in the selinexor arm and no patients in the placebo arm. No TEAEs leading to death were reported in either arm.

“The AE incidence and severity were generally similar to the TP53-mutated group,” Slomovitz said.

The ongoing and actively enrolling phase 3 XPORT-EC-042 trial (NCT05611931) is further evaluating selinexor maintenance in patients with TP53 wild-type advanced or recurrent endometrial cancer who experienced a response following systemic therapy. The trial is enrolling patients with primary stage IV or first recurrent endometrial cancer who received at least 12 weeks of platinum-based chemotherapy and/or immunotherapy. Patients are being randomly assigned to 60 mg of selinexor or matching placebo once per week. PFS is the primary end point, and OS is a key secondary end point.

Disclosures: Dr Slomovitz reported serving in a consulting or advisory role with AstraZeneca, Genentech, Incyte, Agenus, GlaxoSmithKline, the GOG Foundation, Myriad Genetics, Merck, Eisai, Onconova Therapeutics, EQRx, Nuvation Bio, Regeneron, and Lilly.

References

1. Slomovitz B, Fidalgo AP, Hamilton E, et al. 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. J Clin Oncol. 2023;41(suppl 36):427956. doi:10.1200/JCO.2023.41.36_suppl.427956
2. Vergote IB, Fidalgo AP, Hamilton E, et al. Prospective double-blind, randomized phase III ENGOT-EN5/GOG-3055/SIENDO study of oral selinexor/placebo as maintenance therapy after first-line chemotherapy for advanced or recurrent endometrial cancer. Ann Oncol. 2022; 33(4):448-450. doi:10.1016/j.annonc.2022.02.223