In the SIENDO clinical trials, selinexor show progression-free survival benefit in patients with select endometrial cancer subtypes.
Patients with endometrial cancer who received selinexor (Xpovio) demonstrated a 30% decrease in the risk of disease progression or death compared with patients who received placebo during the phase 3 ENGOT-EN5/GOG-3055/SIENDO trial (NCT03555422), according to results presented by Vicky Makker, MD, at the European Society of Medical Oncology (ESMO) Gynaecological Cancers Congress 2022 in June.1
In the audited intention-to-treat (ITT) population, investigators reported the median progression-free survival (PFS) was 5.7 months in the treatment arm compared with 3.8 months in the control arm (HR, 0.705; 95% CI, 0.499-0.996; 1-sided P = .024). In the nonaudited ITT population, the HR was 0.76 (95% CI, 0.543-1.076; 1-sided P = .063).
In 7 patients (2.7%), the CR (complete response)/PR (partial response) was incorrect (unaudited) and was corrected (audited) by the investigators prior to locking the database and unblinding, said Makker, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.
The double-blind, multicenter trial evaluated 263 patients who had a PR or CR after completing 12 weeks of taxane-platinum combination therapy for primary stage IV disease and recurrent disease.2 Patients were stratified by primary stage IV disease vs first recurrence at the time of taxane-platinum therapy and disease status after chemotherapy (PR vs CR).
At trial enrollment, patients were randomly assigned 2:1 and received 80 mg of selinexor (n = 174) or placebo (n = 89). For both arms, treatment continued until disease progression.
The primary end point was investigator-assessed PFS, and secondary end points were overall survival (OS), PFS, and disease control rate. Predefined exploratory end points included histological subtype and molecular subclassification, including TP53 mutation status, microsatellite instability status, and POLE exonuclease domain mutation.
“Patient baseline characteristics in the ITT population were well balanced between the 2 arms,” Makker said. Both groups had similar median age and ECOG performance status. Of note, in the selinexor group, 55.2% had endometrioid histology vs 53.9% in the placebo group. At the time that audited patients received taxane-platinum combination therapy, 55.2% of patients treated with selinexor had recurrent disease and 51.7% of patients who received placebo had recurrent disease. In the selinexor group, 40.2% had a CR vs 44.9% in the control group, and 59.8% vs 55.1% had a PR, respectively.
Preliminary analysis of the histological prespecified exploratory subgroup “showed a benefit to selinexor [in patients with] the endometrioid adenocarcinoma, in which PFS in the selinexor arm was 9.2 months vs 3.8 months in the placebo arm,” Makker said. The audited HR was 0.57 (98.5% CI, 0.35-0.94; 1-sided P = .014). The unaudited HR was 0.66 (95% CI, 0.40-1.07; 1-sided P = .046).
“This benefit was not observed in the serous subtype,” Makker said. In patients with p53 wild-type endometrial cancer, median age was similar for both the selinexor (n = 67) and placebo (n = 36) arms. Thirty of the patients (44.8%) who received selinexor and 13 patients (36.1%) who received placebo had an ECOG performance status of 1.
Comparing histologies, 82.1% of patients in the selinexor arm and 77.8% in the treatment arm had endometrioid histology.
Prespecified exploratory subgroup analysis performed in patients with p53 wild-type endometrial cancer revealed a median PFS of 13.7 months in the selinexor arm (n = 67; 95% CI, 0.20-not reached) vs 3.7 months in the placebo arm (n = 36; 95% CI, 1.87-12.88). Audited HR was 0.375 (95% CI, 0.210-0.670; 1-sided P = .0003) and unaudited HR was 0.407 (95% CI, 0.229-0.724; 1-sided P = .00008).
Turning to adverse events (AEs), selinexor was generally well tolerated, with the majority of AEs being grade 1 or 2. Grade 3 or greater treatment-emergent AEs were reported in 47% of patients overall. The most common grade 3 AEs in the selinexor arm were nausea (10%); neutropenia (9%); and thrombocytopenia, fatigue, and asthenia (6% each).
Regarding safety, no deaths were reported for either arm. In the selinexor arm (n = 171), 49.7% of patients experienced a dose reduction and 51.5% experienced dose interruptions. In the placebo arm (n = 88), 3.4% experienced a dose reduction and 18.2% experienced dose interruptions.
“Encouragingly, quality of life [and] patient-reported outcomes revealed no clinically significant differences between selinexor or placebo arms with regards to symptoms, physical functioning, or global health status,” Makker said.
Overall, selinexor led to decreases in the risk for progression and/or death in the audited ITT population. Patients with endometrioid histology demonstrated a marked decrease in risk for progression and/or death in exploratory preliminary analysis. Further, patients with the p53 wild-type subgroup achieved a 62% decrease in risk of progression and/or death compared with placebo.
AEs were generally manageable with supportive care and dose modifications, and no new safety signals were observed, Makker concluded.
1. Vergote I, Fidalgo AP, Hamilton EP, et al. Prospective double-blind, randomized phase III ENGOT-EN5/GOG-3055/SIENDO study of oral selinexor/placebo as maintenance therapy after first-line chemotherapy for advanced recurrent endometrial cancer. Presented at: ESMO Gynaecological Cancers Congress 2022; June 17-18, 2022; Valencia, Spain; virtual. Accessed July 15, 2022. https://bit.ly/3z2NXbZ
2. Vergote I, Perez-Fidalgo JA, Hamilton EP, et al; SIENDO/ENGOT-EN5/GOG-3055: a randomized phase 3 trial of maintenance selinexor versus placebo after combination platinum-based chemotherapy in advanced or recurrent endometrial cancer. J Clin Oncol. 2021;39(suppl 15):TPS5610. doi:10.1200/JCO.2021.39.15_suppl.TPS5610