番茄社区

PHOENIX -- Selinexor (Xpovio) improved outcomes when used as maintenance therapy for patients with advanced or recurrent endometrial cancer who responded to front-line chemotherapy, a researcher reported.

In the placebo-controlled, phase III ENGOT-EN5/GOG-3055/SIENDO study, patients in the audited intention-to-treat population who received selinexor experienced a 30% reduction in the risk of disease progression or death (hazard ratio 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 Leuven Cancer Institute and Catholic University of Leuven in Belgium.

However, the absolute improvement in median progression-free survival (PFS) was just 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 PFS benefit was substantially greater among 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) versus 3.7 months (95% 1.87-12.88) 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).

While the results appeared promising, developer on March 1, 2022 that 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, placebo-controlled, randomized study of selinexor in advanced or recurrent wild-type p53 endometrial cancer to support a .

Selinexor is an oral selective XP01 inhibitor that reactivates multiple tumor suppressive proteins, including wild-type p53, by preventing nuclear export. The agent currently has FDA approval as a treatment for and .

SGO discussant Kristin Bixel, MD, of The Ohio State University James Comprehensive Cancer Cancer Center in Columbus, commented that "Though it is exciting to see these positive results [from SIENDO], we have 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 the wild-type p53 patients was "especially impressive."

"Based on the mechanism of action of this drug, which inhibits nuclear exported tumor suppressor proteins like p53, this data makes sense," she said. "And it is exciting to see data correlate so well, suggesting this may 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 in the selinexor arm and 64.0 in the placebo arm. In the study-drug arm, 67 patients had wild-type p53 cancer versus 36 in the placebo arm.

Slightly more than 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. Recurrent disease was present in 55.2% of the patients in the selinexor arm and 51.7% of patients in the placebo arm, while partial remission at the end of the administration of chemotherapy had occurred in 59.8% and 51.7% of patients in the two arms, respectively.

Vergote reported that results by histological subtype showed that patients with an endometrioid carcinoma had a PFS of 9.2 months with selinexor compared with 3.8 months with placebo (HR 0.573, 95% CI 0.348-0.944, P=0.014).

There was no difference in PFS in those with serous cancer (3.8 months with selinexor and 3.7 months with placebo, HR 0.859, 95% CI 0.481-1.533, P=0.309). This subtype is usually p53 mutant, Vergote observed, "and we know now that this a reason why selinexor doesn't work."

As for 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 discontinuations occurred in 10.5% of patients treated with selinexor, while TEAEs leading to dose reductions and dose interruptions occurred in 49.7% and 51.5% of patients, respectively.

Quality of life outcomes were similar between the study arms.

Overall survival results were immature, with a final analysis expected in 2023, according to Vergote.

Comment