Maintenance Selinexor vs Placebo in Endometrial Cancer

Endometrial cancers are classified into 4 molecular groups based on their genetic characteristics. These groups include p53wt/MSS, which is characterized by a non-specific molecular profile and microsatellite stability; POLEmut, which is associated with mutations in the DNA polymerase ε exonuclease domain; MSI, which is characterized by high microsatellite instability; and p53abn, which is associated with abnormal TP53 gene expression. These are correlated with particular prognostic outcomes. Selinexor, abbreviated as SEL, is a selective inhibitor of XPO1. Its mechanism of action involves inducing nuclear retention and activation of tumor suppressor proteins, such as p53. The ENGOT-EN5/GOG-3055/SIENDO study (NCT03555422; ESMO 2022) demonstrated that SEL exhibited enhanced progression-free survival (PFS) compared to placebo (PLB) in the stratification-adjusted findings. The phase 3 SIENDO clinical trial involved 263 patients who have advanced or recurrent endometrial cancer and have undergone one line of taxane-platinum therapy resulting in partial or complete remission. The study aimed to evaluate the efficacy of SEL (80 mg once weekly) compared to PLB (2:1 randomization) as maintenance therapy. Centralized targeted sequencing and local immunohistochemistry were utilized to evaluate TP53 mutations and MSI. The categorization was established by sequencing 648 genes on neoplastic specimens obtained from 172 patients (107 on SEL). The classification was initially determined by POLE mutation, followed by MSI, and subsequently by p53 abnormality or p53 wild type (NSMP). The trial’s preliminary exploratory analyses were prespecified and conducted based on molecular classification.

The study showed a median progression-free survival (PFS) of 5.7 months for the SEL group and 3.8 months for the PLB group. The stratification-adjusted (eCRF) hazard ratio (HR) was 0.70 (P =.024), and the stratification-non-adjusted (IRT) HR was 0.76 (P=0.063). Of the 172 patients who underwent molecular classification, the subset receiving selective endoscopic resection (SEL) (107 patients) were categorized as follows: 35% (37 patients) with non-specific molecular profile (NSMP), 2% (2 patients) with POLE mutation (POLEmut), 17% (18 patients) with microsatellite instability (MSI), and 46% (50 patients) with abnormal p53 expression (p53abn). A comparable distribution was observed among individuals receiving PLB (65 patients): 20 (31%) exhibited NSMP, 4 (6%) had POLE mutations, 8 (12%) showed MSI and 33 (51%) had p53 abnormalities. A subgroup analysis was conducted on patients with TP53wt, which revealed that those who received SEL had progression-free survival (PFS) of 13.7 months, while those who received PLB had a PFS of 3.7 months (HR 0.375; 95% CI, 0.210-0.670; nominal P =.0003). Similarly, patients with MSS/pMMR disease had a PFS of 6.9 months with SEL and 5.4 months with PLB (HR 0.593; 95% CI, 0.388-0.905, nominal P =.007). A study on patients with NSMP (p53wt, MSS) revealed a significant variation in PFS between SEL and PLB. The median for SEL was not reached, while for PLB, it was 3.71 months. The hazard ratio was 0.163 with a 95% confidence interval of 0.060-0.444 and a nominal P<0.0001. The evaluations of the remaining three molecular classifications did not exhibit noteworthy variations in progression-free survival (PFS) between selective estrogen receptor degraders (SEL) and placebo (PLB). Ongoing studies are being conducted to evaluate further biomarker identification about tumor genetics and epigenetics. The stratification-adjusted analysis indicated that SEL exhibited enhanced progression-free survival (PFS) compared to PLB. As a modulator of p53, initial exploratory subgroup analyses of SEL demonstrated superior efficacy compared to PLB in patients with wild-type TP53, microsatellite stable (MSS) tumors, and non-serous, non-mucinous papillary (NSMP) endometrial cancer, which accounts for approximately half of the patients with advanced or recurrent disease.

Source: https://meetings.asco.org/abstracts-presentations/206864

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03555422

Vicky Makker, Jose Alejandro Perez-Fidalgo, Alice Bergamini, Daniel Lewis Spitz, Toon Van Gorp, Jalid Sehouli, Jaroslav Klat, Tamar Perri, Amit M. Oza, Estrid Vilma Solyom Hogdall, Jason A. Konner, Eva M. Guerra, Francesco Raspagliesi, Stephanie Henry, Bradley J. Monk, Jeronimo Martinez Garcia, Brian M. Slomovitz, Sharon Shacham, Mansoor Raza Mirza, Ignace Vergote/Randomized phase III study of maintenance selinexor versus placebo in endometrial cancer (ENGOT-EN5/GOG-3055/SIENDO): Impact of subgroup analysis and molecular classification./J Clin Oncol 40, 2022 (suppl 16; abstr 5511) DOI10.1200/JCO.2022.40.16_suppl.5511