Maintenance Selinexor May Boost PFS in TP53 Wild-Type Advanced Endometrial Cancer

SEOUL, South Korea — Maintenance therapy with selinexor (Xpovio) seemed to substantially extend progression-free survival (PFS) in patients with wild-type TP53 advanced or recurrent endometrial cancer, according to data from the SIENDO trial.

The updated, long-term data from the phase III study showed that, at a median follow-up of 25.3 months, median PFS was 27.4 months for 77 patients with TP53 wild-type tumors who received selinexor compared with 5.2 months among 36 patients who received placebo (HR 0.41, 95% CI 0.25-0.69, P=0.0002), reported Giovanni Scambia, MD, of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome.

Moreover, a “strong PFS signal” was observed with selinexor maintenance therapy in the 47 patients with TP53 wild-type mismatch repair proficient (pMMR) disease — a patient population with a high unmet need and for whom there is limited benefit with available therapies — with PFS not reached versus 4.9 months in the 23 who received placebo (HR 0.32, 95% CI 0.16-0.64, P=0.0004), he said at the International Gynecologic Cancer Society annual meeting.

While not as strong, a PFS benefit was also demonstrated in 20 patients with TP53 wild-type mismatch repair deficient (dMMR) disease compared with the nine patients who received placebo (13.1 months versus 3.7 months, HR 0.45, 95% CI 0.16-1.27, P=0.0643).

“We know that TP53 wild-type status may represent a robust predictive biomarker for selinexor efficacy in endometrial cancer,” Scambia said, adding that the results “highlight the potential opportunity to further personalize therapies” while providing a rationale for further evaluation of selinexor as maintenance therapy in the phase III XPORT-EC-042 trial.

Scambia also reported preliminary survival results showing a positive overall survival (OS) trend with selinexor at a median follow-up of 28.9 months (HR 0.76, 95% CI 0.36-1.59, P=0.24) that was mostly driven by the TP53 wild-type pMMR group (HR 0.57, 95% CI 0.24-1.35, P=0.098).

Selinexor is an oral selective XP01 inhibitor that reactivates multiple tumor suppressive proteins, including wild-type p53, by preventing nuclear export. It currently has FDA approval as a treatment for multiple myeloma and diffuse large B-cell lymphoma.

The ENGOT-EN5/GOG-3055/SIENDO trial evaluated selinexor as maintenance treatment in patients with stage IV disease or a 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 2:1 to receive once-weekly oral selinexor or placebo.

In results reported at the 2022 Society of Gynecologic Oncology meeting, median PFS was 5.7 months with selinexor and 3.8 months with placebo at a median follow-up of 10.2 months. This was an absolute improvement of 1.9 months with selinexor that “was not clinically meaningful,” Scambia said.

However, the PFS benefit was substantially greater among a subgroup of TP53 wild-type patients, with a median PFS for patients in the selinexor group of 13.7 months versus 3.7 months in the placebo group, translating into a 62% reduction in the risk of disease progression or death (HR 0.375, 95% CI 0.210-0.670, P=0.0003).

Thus, Scambia and colleagues focused this long-term follow-up on the group of 113 patients with wild-type TP53 tumors.

The most common adverse events (AEs) at any grade with selinexor were nausea, vomiting, and diarrhea, and the most common grade 3 or higher AEs were neutropenia, nausea, and thrombocytopenia.

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