Randomized phase III study of maintenance selinexor versus placebo in endometrial cancer (ENGOT-EN5/GOG-3055/SIENDO): Impact of subgroup analysis and molecular classification.

Abstract

5511 Background: Endometrial cancers (ECs) are stratified into four molecular categories: wild type TP53 with non-specific molecular profile typically with microsatellite stability (NSMP, p53wt/MSS), DNA polymerase ε exonuclease domain-mutated (POLEmut), microsatellite instability high (MSI) and TP53 abnormal (p53abn). These are associated with specific prognoses. Selinexor (SEL) is a specific XPO1 inhibitor that leads to the nuclear retention and activation of tumor suppressor proteins (TSP) including p53. SEL showed improved progression-free survival (PFS) over placebo (PLB) in the stratification adjusted results of the ENGOT-EN5/GOG-3055/SIENDO study (NCT03555422; ESMO 2022). Methods: The SIENDO study is a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of SEL (80 mg once weekly) vs. PLB (2:1 randomization) as maintenance therapy in 263 patients (pts) with advanced or recurrent EC after one line of taxane-platinum therapy with partial or complete remission. TP53 mutations and MSI were assessed by centralized targeted sequencing and local immunohistochemistry. Classification was based on sequencing 648 genes on tumor samples from 172 pts (107 on SEL), assigned first by POLEmut, then MSI, then p53abn or p53wt (NSMP). Preliminary exploratory analyses based on molecular classification were prespecified in the trial. Results: The SIENDO study resulted in a median progression-free survival (PFS) of 5.7 months (SEL) vs. 3.8 months (PLB), with a stratification adjusted (eCRF) hazard ratio (HR) of 0.70 (p =.024; and a stratification non-adjusted (IRT) HR of 0.76 (p=0.063). Among the 172 patients who underwent molecular classification, those on SEL (107 pts) were classified as follows: 37 (35%) NSMP, 2 (2%) POLEmut, 18 (17%) MSI, and 50 (46%) p53abn. A similar distribution was seen in those on PLB (65 pts): 20 (31%) NSMP; 4 (6%) POLEmut; 8 (12%) MSI; 33 (51%) p53abn. Subgroup analysis of pts with TP53wt showed a PFS of 13.7 mo with SEL vs. 3.7 mo with PLB (HR 0.375; 95% CI, 0.210-0.670; nominal p =.0003) and pts with MSS/pMMR disease had a PFS of 6.9 mo with SEL vs. 5.4 with PLB (HR 0.593; 95% CI, 0.388-0.905, nominal p =.007). An analysis of patients with NSMP (p53wt, MSS) showed a substantial difference in PFS for SEL vs. PLB: medians NR and 3.71 months, respectively (HR 0.163; 95% CI, 0.060-0.444; nominal p <.0001). Analyses of the other 3 molecular categories did not show significant differences in PFS between SEL and PLB. Additional biomarker identification studies assessing tumor genetics and epigenetics are ongoing. Conclusions: SEL showed improved PFS over PLB in the SIENDO study based on the stratification adjusted analysis. As an indirect p53 activator, preliminary exploratory subgroup analyses of SEL showed improvement over PLB amongst the patients with TP53wt, MSS, and the NSMP EC comprising approximately 50% of patients with advanced/recurrent EC. Clinical trial information: NCT03555422.

Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple‐negative breast cancer

“…5 In the placebo-controlled ENGOT-EN5/GOG-3055/SIENDO study (ClinicalTrials.gov identifier NCT03555422), an analysis of maintenance therapy with selinexor showed prolonged median PFS in patients with refractory endometrial cancer (5.7 vs. 3.8 months). 6 In the same trial, preliminary analysis of an exploratory subset of patients who received selinexor with p53 wild-type disease experienced improved PFS compared with those who had p53-mutant disease (13.7 vs. 3.7 months). 7 XPO1 is associated with the transport of cancer-related proteins in multiple solid tumors, including triple-negative breast cancer (TNBC) and sarcomas.…”

“…In the same year, the FDA granted accelerated approval for selinexor‐based monotherapy for relapsed or refractory, diffuse large B‐cell lymphoma after at least two lines of therapy based on a median overall survival (OS) and PFS of 9 and 2.6 months, respectively, and an overall response rate (ORR) of 28% 5 . In the placebo‐controlled ENGOT‐EN5/GOG‐3055/SIENDO study (ClinicalTrials.gov identifier NCT03555422), an analysis of maintenance therapy with selinexor showed prolonged median PFS in patients with refractory endometrial cancer (5.7 vs. 3.8 months) 6 . In the same trial, preliminary analysis of an exploratory subset of patients who received selinexor with p53 wild‐type disease experienced improved PFS compared with those who had p53‐mutant disease (13.7 vs. 3.7 months) 7…”