Selinexor proven in advanced or recurrent endometrial cancer
PHOENIX – Selinexor (Xpovio) improved outcomes when used as maintenance therapy for patients with advanced or recurrent endometrial cancer who responded to first-line chemotherapy, a researcher reported.
In the Phase III placebo-controlled study ENGOT-EN5/GOG-3055/SIENDO, patients in the audited intention-to-treat population who received selinexor had a 30% reduction in the risk of disease progression or death (relative risk 0.705, 95% CI 0.499-0.996, P=0.024) at a median follow-up of 10.2 months, reported Ignace Vergote, MD, PhD, of the Louvain Cancer Institute and the Catholic University of Louvain in Belgium.
However, the absolute improvement in median progression-free survival (PFS) was only 1.9 months – 5.7 months for selinexor (95% CI 3.81-9.20) versus 3.8 months (95% CI 3.68-7.39) with placebo, he said in a presentation at the Society of Gynecologic Oncology (SGO) meeting.
Vergote and colleagues observed that the benefit of PFS was significantly greater in a subgroup of wild-type p53 patients, with a median PFS for patients in the selinexor group of 13.7 months (95% CI 9.20 – not reached) compared to 3.7 months (95% 1.87 -12.88) in the placebo group, resulting in a 62% reduction in the risk of disease progression or death (HR 0.375, 95% CI 0.210-0.670, P=0.0003).
While the results looked promising, the developer Karyopharm Therapeutics announced on March 1, 2022, the FDA said the data from SIENDO was unlikely to support a Supplemental New Drug Application (sNDA) approval. Thus, the company plans to initiate a new randomized, placebo-controlled study of selinexor in advanced or recurrent wild-type p53 endometrial cancer to support a future sNDA with the FDA.
Selinexor is an oral selective XP01 inhibitor that reactivates several tumor suppressor proteins, including wild-type p53, by preventing nuclear export. The agent currently has FDA approval as a treatment for multiple myeloma and diffuse large B-cell lymphoma.
SGO commentator Kristin Bixel, MD, of the James Comprehensive Cancer Center at Ohio State University in Columbus, commented that “While it is exciting to see these positive results [from SIENDO]we need to weigh this 1.9-month improvement in median PFS against the potential treatment-related toxicities and financial costs.”
But she agreed that the PFS benefit achieved in wild-type p53 patients was “particularly impressive”.
“Based on the mechanism of action of this drug, which inhibits nuclear-exported tumor suppressor proteins like p53, these data make sense,” she said. “And it’s exciting to see the data correlated so well, suggesting that this could be a predictive marker.”
SIENDO included 263 patients who were randomized 2:1 to receive selinexor (80 mg once weekly) or placebo. Participants had a median age of 65.6 years in the selinexor arm and 64.0 years in the placebo arm. In the study drug arm, 67 patients had wild-type p53 cancer versus 36 in the placebo arm.
Just over half of patients in the selinexor and placebo arms (55.2% and 53.9%, respectively) had endometrioid carcinoma, while 28.2% and 31.5% had serous cancer. Disease recurrence was present in 55.2% of patients in the selinexor arm and 51.7% of patients in the placebo arm, while partial remission at the end of chemotherapy administration occurred in 59.8 % and 51.7% of patients in both arms, respectively.
Vergote reported that results by histological subtype showed that patients with endometrioid carcinoma had a PFS of 9.2 months with selinexor versus 3.8 months with placebo (HR 0.573, 95% CI 0.348- 0.944, P=0.014).
There was no difference in PFS in people with serous cancer (3.8 months with selinexor and 3.7 months with placebo, RR 0.859, 95% CI 0.481-1.533, P=0.309). This subtype is usually a p53 mutant, Vergote observed, “and we now know that’s why selinexor doesn’t work.”
With respect to safety, the most common treatment-emergent adverse events (TEAEs) of any grade with selinexor were nausea (84%), vomiting (52%), constipation (37%), thrombocytopenia (37%), decreased appetite (35%), fatigue (35%), diarrhea (34%), asthenia (31%), anemia (28%), neutropenia (25%) and abdominal pain (18 %).
TEAEs leading to dose interruptions occurred in 10.5% of selinexor-treated patients, while TEAEs leading to dose reductions and dose interruptions occurred in 49.7% and 51.5% of patients, respectively.
Quality of life results were similar between study arms.
Overall survival results were immature, with a final analysis expected in 2023, according to Vergote.
The study was funded by Karyopharm Therapeutics.
Vergote has disclosed relationships with, and/or endorsement of, Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb (2021), Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent AS, Seagen, Sotio as, Verastem Oncology, Zentalis, KULeuven, Oncoinvent AS (2019-2020), Amgen and Tesaro.