Selinexor Delays Wild-type TP53 Endometrial Cancer Progression

In a phase III trial, women with certain TP53 wild-type endometrial cancers who received selinexor (Xpovio; Karyopharm Therapeutics) as a maintenance therapy experienced an “unprecedented” 58% improvement in progression-free survival (PFS) regardless of microsatellite stability status.

However, among those with TP53-mutated tumors who received the drug, the median PFS was numerically worse with selinexor than with placebo—4.2 months versus 5.4 months, respectively.

“These results clearly show that the benefit was isolated to those patients who are p53 wild type, and that this is a robust biomarker for identifying patients who may in fact respond to selinexor therapy,” said investigator Brian Slomovitz, MD, of Mount Sinai Medical Center in Miami Beach, FL. He presented the findings during the July session of the American Society of Clinical Oncology plenary series.

Selinexor inhibits the nuclear export receptor XPO1, resulting in retention and reactivation of tumor suppressor proteins in the nucleus, and selectively kills cancer cells while largely sparing normal ones. It is FDA approved for certain multiple myelomas and diffuse large B-cell lymphomas but has not been greenlighted to treat any solid tumors.

Initial results of the ENGOT-EN5/GOG-3055/SIENDO trial, which included 263 women with advanced or recurrent endometrial cancer, were presented in March 2022 during a European Society for Medical Oncology virtual plenary. As the investigators reported at that time, the improvement in PFS with maintenance selinexor was modest and “not clinically meaningful” compared with placebo—5.7 months versus 3.8 months, respectively, at a median follow-up of 10.2 months.

But an exploratory analysis showed a clear PFS benefit for selinexor maintenance therapy in patients with wild-type TP53 endometrial cancer—13.7 months versus 3.7 months, respectively.

The new analysis examined PFS over a longer period and assessed the subgroup of 113 patients with TP53 wild-type disease. After a median follow-up of 25.3 months, the PFS was 27.4 months among those who received selinexor compared with 5.2 months among those who received placebo. PFS improvements with selinexor were independent of microsatellite stability status, although the greatest benefit was seen among patients with microsatellite-stable tumors, with the median PFS not reached after 27.2 months with selinexor compared with 4.9 months for the placebo.

“This is an unprecedented benefit in this population,” said discussant Gini Fleming, MD, of The University of Chicago in Illinois, who was not involved in the research.

Even so, “we have no reports of overall survival with selinexor to date. The question is going to be, if there should be no overall survival benefit, ‘Is the toxicity of the treatment low enough that we really should be using it as maintenance?’” she commented.

Treatment-emergent adverse events with selinexor included a higher incidence of nausea, vomiting, diarrhea, fatigue, and cytopenia than with placebo. In all, 60% of patients who took the drug required dose reductions, 70% had dose interruptions, and 16% discontinued therapy, noted discussant Martina Murphy, MD, of the University of Florida in Gainesville, who focused her remarks on safety and quality of life.

“I think from a ‘Does this make sense?’ perspective, maintenance therapy [with selinexor] in advanced endometrial cancer certainly does,” she said. “We know that this is a patient population that historically has a short response to systemic therapy, and we don't have a lengthy list of effective treatment options in the later lines” of treatment.

However, the therapeutic landscape for endometrial cancer is changing, with checkpoint inhibitors likely to be incorporated into maintenance strategies, Murphy noted, “so it's a little unclear how this subset analysis will play into that.” –Neil Osterweil