Selinexor Maintenance Yields Prolonged PFS Benefit in TP53wt Endometrial Cancer

A subgroup of patients with TP53 wild-type advanced/recurrent endometrial cancer experienced a long-lasting improvement in progression-free survival (PFS) following treatment with maintenance selinexor (Xpovio) vs placebo, according to data from a pre-specified subgroup analysis of the phase 3 ENGOT-EN5/GOG-3055/SIENDO trial (NCT03555422) that were presented during the July 2023 American Society of Clinical Oncology Plenary Session.

"These results clearly show that the benefit was isolated to those patients who were TP53 wild-type and that this is a robust biomarker for identifying patients who may, in fact, respond to selinexor therapy," according to Brian Slomovitz, MD, the director of gynecologic oncology at Mount Sinai Medical Center.

When investigators assessed long-term outcomes in patients based on TP53 status, they reported that selinexor yielded 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 the placebo arm in those with TP53 wild-type disease (HR, 0.42; 95% CI, 0.25-0.70; one-sided nominal P-value = .0003). In the TP53 mutant/aberrant population, the median PFS was 4.2 months (95% CI, 3.6-5.6) vs 5.4 months, respectively (95% CI, 3.7-7.2; HR, 1.34; 95% CI, 0.89-2.02; P = .9202).

Outcomes were further assessed in the TP53 wild-type group based on microsatellite instability status. In those with microsatellite stable (MSS)/mismatch repair proficient (pMMR) disease, the median PFS was not reached (95% CI, 20.8-NR) following treatment with selinexor compared with 4.9 months (95% CI, 2.0-NR; HR, 0.32; 95% CI, 0.16-0.66; P = .0006). Median PFS in those with microsatellite instability–high/MMR deficient (dMMR) endometrial cancer was 13.1 months (95% CI, 3.6-NR) vs 3.7 months (95% CI, 1.9-NR; P = .0643; HR, 0.45; 95% CI, 0.16-1.27; one-sided nominal P = .0643).

“In the TP53 wild-type subgroup, long-term follow-up shows a substantial increase in PFS benefit,” according to Brian Slomovitz, MD. He continued, “These results clearly show that the benefit was isolated to those patients who were TP53 wild-type and that this is a robust biomarker for identifying patients who may, in fact, respond to selinexor therapy.”

Slomovitz is the director of gynecologic oncology at Mount Sinai Medical Center.

The study included a total of 263 adult patients with stage IV or first-relapsed endometrial cancer. Patients who enrolled on the trial needed to have been treated with at least 12 weeks of platinum-based chemotherapy. Those who previously received treatment with surgery, radiotherapy, or hormonal therapy were eligible to enroll. Patients were randomly assigned 2:1 following complete response (CR) or partial response (PR) to first-line chemotherapy to receive either 80 mg of selinexor or placebo by mouth weekly.

Patients were stratified based on whether they had primary stage IV or recurrent disease, as well as PR or CR.

The study’s primary end point was investigators assessed PFS, with key secondary end points including PFS by blinded independent central review, overall survival, time to first subsequent therapy, and health-related quality of life. There were also several exploratory end points, including histological subtype and molecular subclassification.

In the TP53 wild-type population, most patients in both the selinexor arm and placebo arm, respectively, had endometrioid histology (84.4% vs 80.6%) and MSS/pMMR disease (61.0% vs 63.9%). Additionally, 40.3% vs 44.4% of patients had a CR following their most recent treatment with chemotherapy.

In those with TP53 mutant/aberrant disease, 26.6% vs 29.8% had endometrioid and 72.2% vs 78.7% had MSS/pMMR disease in the selinexor and placebo arms, respectively. A total of 44.3% vs 40.4% of patients in each respective arm achieved a CR after their last treatment with chemotherapy.

In terms of treatment-emergent adverse events (TEAEs) in the TP53 wild-type subgroup, common any-grade toxicities in the selinexor and placebo groups, respectively, included nausea (90.8% vs 34.3%), vomiting (60.5% vs 11.4%), diarrhea (39.5% vs 34.3%), constipation (34.2% vs 40.0%), and asthenia (35.5% vs 25.7%). High-grade TEAEs in the selinexor cohort included neutropenia (18.4%), nausea (11.8%), thrombocytopenia (9.2%), and fatigue (7.9%) compared with constipation (5.7%), abdominal pain (2.9%), and vomiting (2.9%) in the placebo group.

TEAEs resulted in discontinuation in 15.8% of those in the selinexor cohort vs none in the control arm.

Reference

Slomovitz B. 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. American Society of Clinical Oncology Plenary Series. July 25, 2023; virtual; abstract 427956.