Long-term follow-up of selinexor maintenance therapy has demonstrated promising efficacy in patients with TP53 wild-type endometrial cancer, according to data presented during the ASCO Plenary Series: July 2023 Session.¹ Selinexor is a selective inhibitor of nuclear export (SINE) approved for use as monotherapy in diffuse large B-cell lymphoma and in combination therapy for relapsed or refractory multiple myeloma; its use in endometrial cancer is investigational.

Results of the phase III ENGOT-EN5/GOG-3055/SIENDO study showed a substantial increase in progression-free survival benefit in the TP53 wild-type subgroup, with a median progression-free survival of 27.4 months in the experimental arm vs 5.2 months with placebo (hazard ratio [HR] = 0.42). Based on these findings, authors of the study underscored the potential opportunity for more personalized therapies in this patient population.

“The status of TP53 may serve as a robust predictive biomarker for efficacy in endometrial cancers, potentially enabling more personalized therapies in the maintenance setting.”

— Brian M. Slomovitz, MD

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“These results provide strong rationale to further evaluate selinexor as maintenance therapy in TP53 wild-type endometrial cancers, a unique patient population with a high unmet need,” said lead study author Brian M. Slomovitz, MD, Director of Gynecologic Oncology, Mount Sinai Medical Center, Miami Beach, Florida. “The status of TP53 may serve as a robust predictive biomarker for efficacy in endometrial cancers, potentially enabling more personalized therapies in the maintenance setting.”

Mechanisms of Action and Study Design

According to Dr. Slomovitz, endometrial cancer treatment has seen rapid advancements, with molecular characterization, such as microsatellite instability status, now helping to guide treatment plans. Immune checkpoint inhibitors have shown a significant benefit in patients with microsatellite-unstable or DNA mismatch repair–deficient tumors, he said. However, there remains an unmet need for patients with microsatellite-stable or mismatch repair–proficient tumors, particularly those with TP53 wild-type, which constitute approximately 50% of tumors in advanced or recurrent endometrial cancer.

Gini F. Fleming, MD, Professor of Medicine and Medical Director of Gynecologic Oncology at the University of Chicago, highlighted selinexor’s unique mechanism of action, which differs significantly from any other drug used in the treatment of gynecologic malignancies. As she explained, exportin-1 mediates the transport of proteins, including many tumor suppressor proteins such as p53, from the nucleus to the cytoplasm. Selinexor works to inhibit exportin-1, said Dr. Fleming, which leads to the accumulation of these tumor suppressor proteins in the nucleus and, in turn, enhances tumor suppressor activity and promotes tumor cell cycle arrest and apoptosis.

Gini F. Fleming, MD

The SIENDO trial is a double-blind, phase III trial evaluating selinexor as maintenance treatment in patients with stage IV or first relapse of endometrial cancer. After receiving 12 weeks of platinum-based chemotherapy and achieving either a complete or partial response, 263 patients were randomly assigned 2 to 1 to receive once-weekly oral selinexor or placebo. The primary endpoint was investigator-assessed -progression-free survival, with exploratory endpoints including histologic subtypes and molecular subclassifications.

Improved Progression-Free Survival in
Patients With TP53 Wild-Type Disease

Results from the trial showed that patients with TP53 wild-type tumors receiving selinexor maintenance therapy had a median progression-free survival of 27.4 months compared with 5.2 months in the placebo group, representing a 58% decrease in the risk of disease progression (HR = 0.42). As Dr. Slomovitz reported, the benefit was isolated to patients with TP53 wild-type disease, indicating the p53 protein is a robust biomarker for identifying patients who may respond to selinexor therapy.

A further analysis by microsatellite instability status revealed that progression-free survival improvements were observed in TP53 wild-type patients regardless of their microsatellite instability status, with the most significant benefit seen in the TP53 wild-type, mismatch repair–proficient group. In this subgroup, median progression-free survival was not reached after 27 months for those receiving selinexor, compared with 4.9 months with placebo. This represents a 68% decrease in the risk of disease progression.

Selinexor’s safety profile was generally manageable, according to Dr. Slomovitz, with the most common treatment-emergent adverse events being nausea, vomiting, and diarrhea. Rare cases of grade ≥ 3 adverse events included neutropenia, thrombocytopenia, and nausea. There was one grade 4 adverse event, a colonic abscess, in the placebo arm.

Adverse events led to dose reduction or interruption in 60% of patients in the selinexor arm; however, 16% of patients discontinued selinexor because of adverse events. The incidence and severity of adverse events were similar in the TP53-mutated group, and no grade 5 adverse events were reported.

Future Research: XPORT-EC-042 Trial

Ongoing research, including the randomized, phase III XPORT-EC-042 trial, will further evaluate selinexor as maintenance therapy for patients with TP53 wild-type endometrial cancer following response to prior systemic therapy. Researchers are looking to enroll 220 patients, who must have TP53 wild-type disease as tested by next-generation sequencing. Patients will be randomly assigned to receive oral selinexor (60 mg/wk) or placebo. The primary endpoint is investigator-assessed progression-free survival, and the key secondary endpoint is overall survival. 

DISCLOSURE: Dr. Slomovitz and Dr. Fleming reported no conflicts of interest.

REFERENCE

1. Slomovitz BM, Perez-Fidalgo JA, Hamilton EP, et al: Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A prespecified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study. ASCO Plenary Series: July 2023 Session. Abstract 427956. Presented July 25, 2023.