TP53WT in Endometrial Cancer May Be a Predictive Biomarker for Selinexor

Brian M. Slomovitz, MD

Durable progression-free survival (PFS) benefit has been demonstrated with selinexor (Xpovio) maintenance therapy in patients with tp53 wild-type (tp53wt) endometrial cancer (EC), according to long-term follow-up results from the phase 3 SIENDO study (NCT05887492).¹

The findings were presented by Brian M. Slomovitz, MD, director of Gynecologic Oncology, and co-chair of the Cancer Research Committee at Mount Sinai Medical Center, and professor of obstetrics and gynecology at Florida International University during the ASCO Plenary Series: July 2023 Session. Data were from 263 female patients treated with either oral selinexor at 80 mg once weekly (QW; n = 76) or oral placebo, QW (n =35).

“This represents a unique patient population with a high unmet need for which there’s limited evidence of benefit with currently available therapies,” said Slomovitz during the presentation. “This also represents a potential opportunity to further personalize therapies in this maintenance setting.”

At a median follow-up of 25.3 months in the tp53wt subgroup, the median PFS was 27.4 months (95% CI, 13.1 months to not reached [NR]) with selinexor vs 5.2 months (95% CI, 2.0-13.1 months) with placebo (HR, 95% CI, 0.25-0.70; 1-sided nominal P = .0003). In another subgroup of patients with tp53 mutated/abnormal (tp53mut/abn) advanced/recurrent EC, the median PFS was 4.2 months (95% CI, 3.6-5.6 months) with selinexor vs 5.4 months (95% CI, 3.7-7.2 months) with placebo (HR, 1.34; 95% CI, 0.89-2.02 1-sided nominal P = .9202).

Having followed patients in the tp53wt population for a median of 27.2 months, investigators also assessed PFS based on microsatellite instability (MSI) status. Among patients with microsatellite stable and mismatch repair (MRR) proficient disease, the median PFS was NR (95% CI, 20.8 months to NR). In patients with MSI-high and MMR deficient disease, the median PFS was 13.1 months (95% CI, 3.6 months to NR) compared with 3.7 months (95% CI, 1.9 months to NR) in the placebo arm (HR, 0.45; 95% CI, 0.16-1.27; 1-sided P =.0643).

Survival results from the tp53wt and tp53mut/abn populations are more favorable than what was observed in the overall population of the SIENDO study, according to Slomovitz.

"The update presented at the ASCO Plenary Series demonstrated that the p53 wild-type group, had a progression-free survival of 20.8 months compared to 5.2 months. This, I think, was the additional data that the FDA was really looking for, and this benefit was regardless of microsatellite stability status. So, I think this is really beneficial data for these patients, and especially in an area, we really have no good alternative for them,” John P. Diaz, MD, director of Robotic Surgery, Baptist Health; lead physician for clinical trials in gynecologic oncology, at Miami Cancer Institute, as well as the director of the Center of Excellence in Minimally Invasive Gynecologic Surgery at Baptist Health, and director of Ambulatory Surgery Center at Baptist Health Cancer Care told Targeted Oncology.

Previously, results from SIENDO were presented at the European Society of Medical Oncology Gynecologic Cancer Congress. In the audited intent-to-treat population of 263 patients with advanced recurrent EC, the median PFS observed with selinexor maintenance was 5.7 months vs 3.8 months with placebo, resulting in a 33% reduction in the risk of disease progression or death compared with placebo (HR, 0.705; 95% CI, 0.499-0.996; 1-sided P =.024).

Safety findings presented during the ASCO Plenary Series: July 2023 Session showed that the most common treatment-emergent adverse events (TEAEs) of any grade in the selinexor arm vs the placebo arm, respectively, were nausea (90.8% v 34.3%), vomiting (60.5% v 11.4%), diarrhea (39.5% v 34.3%), constipation (34.3% v 40.0%), and asthenia (35.5% v 25.7%). The most common grade 3/4 TEAEs in the selinexor arm were neutropenia (18.4%), nausea (11.8%), and thrombocytopenia (9.2%). In comparison, the most common grade 3/4 TEAEs in the placebo arm was constipation (5.7%).

The occurrence of TEAEs led to treatment discontinuation in 15.8% of the selinexor group, but no patients discontinued placebo. There were no deaths resulting from TEAEs in either treatment arm.

“There was 1 grade 4 event, [which was] a colonic abscess in the placebo arm. Sixty percent of patients in the selinexor arm had a dose reduction and/or interruption,” explained Slomovitz.

Slomovitz also stated that the subgroup analysis provides rationale to continue the study of maintenance selinexor in patients with tp53wt advanced/recurrent EC. The phase 3 XPORT-EC-042 study (NCT05611931) is currently underway.

_REFERENCE:

_{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. Presented at: 2023 July ASCO Plenary Series. Abstract 427956.}