Selinexor Significantly Prolongs PFS in Advanced/Recurrent Endometrial Cancer, Warranting sBLA Submission

Vicky Makker, MD

Frontline maintenance treatment with selinexor (Xpovio) achieved a statistically significant improvement in progression-free survival (PFS), compared with watchful waiting, in patients with advanced or recurrent endometrial cancer, meeting the primary end point of the phase 3 Selinexor In ENDOmetrial Cancer (SIENDO) study.¹

Results announced in a press release by Karyopharm Therapeutics, Inc also indicated that the PFS benefit was durable and treatment with selinexor was well-tolerated with no new safety signals shown.

"Women with advanced or recurrent endometrial cancer face a poor prognosis," said Vicky Makker, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center, in the press release "Following standard-of-care, platinum-based chemotherapy, the current paradigm of watchful waiting for recurrence is simply inadequate. Therefore, there is a dire need for new and innovative treatment options for this heterogeneous malignancy that is rising in incidence and disease-related mortality."

The SIENDO trial (ENGOT-EN5; NCT03555422)2 is a prospective, multicenter, double-blind, placebo-controlled, randomized phase 3 study that includes approximately 248 patients with advanced or recurrent endometrial cancer. Patients in the SEINDO study were randomized 2:1 to receive either selinexor (80 mg or 60 mg on day 1, 8, 15, and 22 of each 28-day cycle) or matching placebo (watch and wait). In addition to the primary end point, the study is evaluating PFS by blinded independent central review, disease-specific survival, overall survival, time to first subsequent treatment, PFS after subsequent treatment, disease control rate, health-related quality of life, the number of patients with treatment-emergent adverse events, and the number of patients with significant results from a physical examination laboratory test or vital signs.²

The median PFS shown with selinexor was 5.7 months compared with 3.8 months in the placebo arm, achieving a 50% improvement and a 30% reduction in the risk of disease progression or death (HR, 070; P = .0486). At the 12-month mark, there was a 37% increase in the probability that patients in the selinexor arm would be in remission compared with those who received placebo, or the watch and wait approach.

Among the subgroup of patients with wild-type p53 status, the statistically significant improvement in PFS was even more defined with a median PFS of 13.7 months in the selinexor arm compared with 3.7 months with placebo, reducing the risk for disease progression or death by 63% (HR, 0.38; P = .0006). Based on this finding, the developer plans to submit a supplemental biologics license application to the FDA in the first half of 2022. Full evaluation of these preliminary findings is ongoing.

"As an oral, chemotherapy-free treatment, selinexor has the potential to transform the way advanced or recurrent endometrial cancer is treated and I am intrigued to learn more about the patients with the wild-type p53," said principal investigator Ignace Vergote, gynecologist oncologist, Belgium and Luxembourg Gynaecological Oncology Group (BGOG), University of Leuven, Leuven Cancer Institute, Leuven, Belgium. "This study brings us one step closer to offering patients a treatment option that can give them more time with their friends and families.¹"

Overall, the rate of treatment discontinuation due to adverse events (AEs) was low in the study at 10.5%. Based on the label for selinexor, the most common AEs observed in the multiple myeloma population include fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. The label warnings for selinexor include thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurological toxicity, embryo-fetal toxicity, and cataract.

"We are thrilled to see a statistically significant improvement in median progression-free survival from the Phase 3 SIENDO study because of what it represents for patients," said Sharon Shacham, PhD, MBA, chief scientific officer of Karyopharm, in the press release. "If approved, XPOVIO would be the first and only maintenance therapy in advanced or recurrent endometrial cancer, following response to chemotherapy."

_References:

_{1. Karyopharm announces phase 3 SIENDO study meets primary endpoint with statistically significant increase in progression-free survival in patients with advanced or recurrent endometrial cancer. News release. February 8, 2022. Accessed February 8, 2022. https://bit.ly/3B5NPc9}

_{2. Maintenance with selinexor/placebo after combination chemotherapy in participants with endometrial cancer [SIENDO] (ENGOT-EN5). Clinicaltrials.gov. Accessed February 8, 2022. https://bit.ly/3B5zKLV}