Selinexor maintenance extends PFS in endometrial cancer subgroup with high unmet need
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Key takeaways:
- The oral agent reduced risk for disease progression by 58% vs. placebo among women with TP53 wild-type tumors.
- Those with microsatellite stable/mismatch-repair proficient tumors derived the greatest benefit.
Selinexor maintenance after systemic therapy extended median PFS more than four times longer than placebo for women with advanced or recurrent TP53 wild-type endometrial cancer, according to phase 3 study results.
Long-term follow-up of the SIENDO trial, presented during an ASCO Plenary Series session, showed a significant PFS benefit among this prespecified subgroup regardless of microsatellite instability status.
The results suggest “p53 status may represent a robust predictive biomarker for efficacy in endometrial cancers,” Brian M. Slomovitz, MD, director of gynecologic oncology at Mount Sinai Medical Center in Florida, said during a presentation.
Methodology
About half of advanced or recurrent endometrial cancer tumors are TP53 wild-type, and about 70% of those are also microsatellite stable/mismatch-repair proficient (MSS/pMMR), Slomovitz said.
Selinexor (Xpovio, Karyopharm Therapeutics) is an investigational oral inhibitor of the nuclear export protein XPO1. The drug binds with and inhibits XPO1, leading to the accumulation and functional activation of wild-type tumor suppressor proteins, including p53, in the cell nucleus.
The randomized, double-blind SIENDO trial assessed maintenance therapy with selinexor among 263 women with stage IV or first relapsed endometrial cancer who received at least 12 weeks of platinum-based chemotherapy. After exhibiting a partial or complete response per RECIST, the women underwent random assignment in a 2-to-1 ratio to 80 mg selinexor or placebo once weekly.
Investigator-assessed PFS served as the primary endpoint.
Although selinexor did not confer clinically meaningful improvements in median PFS among the intent-to-treat population, an exploratory analysis showed a promising efficacy signal among women with TP53 wild-type tumors.
The prespecified TP53 wild-type subgroup included 113 women assigned to selinexor (n = 77; median age, 64 years) or placebo (n = 36; median age, 61.5 years). Most had endometrioid histology and MSS/pMMR tumors.
Median follow-up was 25.3 months.
Results
Long-term follow-up showed 58% lower risk for disease progression with selinexor vs. placebo among the TP53 wild-type subgroup (27.4 months vs. 5.2 months; HR = 0.42; 95% CI, 0.25-0.7). In contrast, the subgroup of women with TP53 mutations/aberrations had shorter median PFS with selinexor (4.2 months vs. 5.4 months; HR = 1.34; 95% CI, 0.89-2.02).
“These results clearly show that the benefit was isolated to those patients who were p53 wild-type, and that this is a robust biomarker for identifying patients who may, in fact, respond to selinexor therapy,” Slomovitz said.
Women in the TP53 wild-type subgroup who had MSS/pMMR tumors demonstrated the greatest PFS benefit with selinexor vs. placebo (median, not reached vs. 4.9 months; HR = 0.32; 95% CI, 0.16-0.66) compared with women in the subgroup who had MSI-high/mismatch repair-deficient tumors (median, 13.1 months vs. 3.7 months; HR = 0.45; 95% CI, 0.16-1.27).
The TP53 wild-type/MSS/pMMR subgroup “represents a unique patient population with a high unmet need for which there is limited evidence of benefit with currently available therapies,” Slomovitz said.
The most common treatment-emergent adverse events with selinexor in the TP53 wild-type subgroup included nausea (90.8%), vomiting (60.5%) and diarrhea (39.5%). Grade 3 to grade 4 events included neutropenia (18.4%), nausea (11.8%) and thrombocytopenia (9.2%). No grade 5 events occurred.
Twelve patients in the selinexor group (15.8%) experienced treatment-emergent adverse events leading to discontinuation of therapy.
Implications
Selinexor maintenance is being evaluated further in the XPORT-EC-042 trial, which is enrolling women with TP53 wild-type advanced or recurrent endometrial cancer, Slomovitz said.
Discussant Gini Fleming, MD, professor of medicine at The University of Chicago, described the PFS benefit with selinexor among this population as unprecedented.
“There is a plausible biologic hypothesis for this subset benefit,” she noted. “How we will use this or sequence it with immunotherapy will need future thoughtful trial design. These are trials that we very much look forward to.”
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Slomovitz BM, et al. Abstract 427956. Presented at: ASCO Plenary Series: July 2023 Session; July 25, 2023.
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