Selinexor Maintenance Improves PFS in Advanced or Recurrent Endometrial Cancer, Particularly p53 Wild-Type Subset

Ignace B. Vergote, MD, PhD

Selinexor (Xpovio) reduced the risk of disease progression or death by 30% in an audited intent-to-treat population of patients with advanced or recurrent endometrial cancer who received frontline chemotherapy, and by 62% in a subset of patients with p53 wild-type disease, according to data from the phase 3 SIENDO trial (ENGOT-EN5/GOG-3055; NCT03555422).¹

At a median follow-up of 10.2 months (95% CI, 8.97-13.57), the median progression-free survival (PFS) was 5.7 months (95% CI, 3.81-9.20) with selinexor (n = 174) based on audited stratification factors vs 3.8 months (95% CI, 3.68-7.39) with placebo (n = 89) in the intent-to-treat (ITT) population (hazard ratio [HR], 0.705; 95% CI, 0.499-0.996; P = .024).

In the subset of patients with p53 wild-type disease, the median PFS achieved with selinexor (n = 67) was 13.7 months (95% CI, 9.20–not reached) vs 3.7 months (95% CI, 1.87-12.88) with placebo (n = 36; HR, 0.375; 95% CI, 0.210-0.670; 1-sided P = .0003).

“Selinexor demonstrated a 30% decrease of risk for progression and/or death compared with placebo in the audited ITT population, which was statistically significant,” lead study author Ignace B. Vergote, MD, PhD, of Catholic University Leuven, Cancer Institute at University Hospitals, said in a presentation on the data during the March 2022 ESMO Virtual Plenary. “Quality-of-life [QoL] data were similar in both groups. Overall survival [OS] data are immature, and the final OS analysis is expected in quarter 1 of 2023.”

The multicenter, blinded, placebo-controlled trial enrolled a total of 263 patients with primary stage IV or recurrent endometrial cancer who achieved a partial or complete response after at least 12 weeks of standard taxane/platinum chemotherapy.

To be eligible for enrollment, patients needed to be at least 18 years of age, an ECOG performance status of 0 or 1, and acceptable bone marrow and organ function within 2 weeks before study drug initiation.²

A total of 263 participants were randomized 2:1 to receive selinexor at 80 mg weekly, and 60 mg weekly if their body mass index was less than 20 kg/m², or placebo until disease progression. Patients were stratified by whether they had primary stage IV disease vs recurrent disease, and whether they achieved a partial response (PR) or a complete response (CR) to chemotherapy.

The primary end point of the trial was investigator-associated PFS, and key secondary end points included OS, PFS per blinded independent central review, patient-reported outcomes, disease-specific survival, time to first subsequent treatment, PFS following subsequent treatment, time to second subsequent treatment, disease control rate, health-related quality of life, and treatment-emergent adverse effects (TEAEs). Predefined exploratory end points included histological subtype and molecular subclassification, which included p53, MMR, and POLE.

A total of 140 PFS events were needed to provide 80% power to detect a HR of 0.6 with a 1-sided alpha of 0.025 and a 2:1 randomization ratio favoring selinexor.

Patient characteristics were noted to be well balanced between the 2 treatment arms. The median age of those in the selinexor arm was 65.5 years (range, 40-81) vs 64.0 years (range, 33-81), with the majority of patients under 70 years of age. Regarding ECOG performance status, 56.9% of those on the investigative arm had a status of 0, 40.8% had a status of 1, and 0.6% had a status of 2; these rates were 60.7%, 39.3%, and 0%, respectively, in the control arm.

In the selinexor and placebo arms, 55.2% and 53.9% of patients, respectively, had endometrioid histology. Moreover, 55.2% of patients in the investigative arm and 51.7% of those in control arm had recurrent disease vs 44.8% and 48.3% of patients, respectively, who had primary stage IV disease. Additionally, 59.8% of patients in the selinexor arm had a PR after their most recent chemotherapy, and 40.2% had a CR; these rates were 55.1% and 44.9%, respectively.

All patients in the investigative and control arms received at least 1 dose of the agent. Moreover, 64.9% of patients on the selinexor arm discontinued treatment vs 59.1% of those on the placebo arm. The most common reason for discontinuation in the investigative arm was progressive disease (43.5%), followed by toxicity (10.5%), patient withdrawal (8.8%), physician decision (1.2%), and clinical progression (0.6%).

Investigators evaluated the primary end point of PFS in the ITT population based on audited stratification factors because in 7 patients, the stratification factor of CR/PR was incorrect, according to Vergote. Investigators corrected this before the database lock and unblinding.

The statistical analysis was validated by the independent ENGOT statistician and was greenlit by the Independent Data Monitoring Committee. Without correction of the stratification factors, the HR for ITT was 0.76 (95% CI, 0.543-1.076), which was not statistically significant.

Additional data showed that in a subset of patients with endometrioid cancer, the median PFS was 9.2 months with selinexor vs 3.8 months with placebo (HR, 0.573; 95% CI, 0.348-0.944; P = .014). In the subset of patients with serous cancer, the median PFS with selinexor and placebo was 3.8 months and 3.7 months, respectively (HR, 0.859; 95% CI, 0.481-1.533; P = .309).

With regard to QoL, no significant differences in global health, physical functioning, or symptoms were reported between the 2 treatment arms.

Regarding safety, the most common toxicities experienced with selinexor included nausea (84%), vomiting (52%), constipation (37%), thrombocytopenia (37%), decreased appetite (35%), fatigue (35%, diarrhea (34%), asthenia (31%), anemia (28%), neutropenia (25%), and abdominal pain (18%).

TEAEs resulted in dose reductions in 49.7% of those on the investigative arm and 3.4% of those on the control arm. Dose interruptions due to TEAEs were required in 51.5% of those who received selinexor vs 18.2% of those who were given placebo. Notably, 10.5% of those in the investigative arm discontinued treatment due to toxicity vs 1.1% of those in the control arm. Notably, no deaths were reported on either treatment arm.

“AEs were generally manageable with supportive care and dose modifications,” Vergote concluded. “No new safety signals were identified.”

References

1. Vergote I, 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. Presented at: March 2022 ESMO Virtual Plenary; March 16-18, 2022; virtual. Accessed March 17, 2022.
2. Maintenance with selinexor/placebo after combination chemotherapy in participants with endometrial cancer [SIENDO] (ENGOT-EN5). ClinicalTrials.gov. Updated January 28, 2022. Accessed March 17, 2022. https://clinicaltrials.gov/ct2/show/NCT03555422