Selinexor Maintenance Leads to PFS Benefit in TP53 Wild-Type Advanced/Recurrent Endometrial Cancer

Maintenance therapy with selinexor (Xpovio) improved progression-free survival (PFS) compared with placebo in patients with TP53 wild-type advanced or recurrent endometrial cancer, regardless of microsatellite instability (MSI) status, according to long-term follow-up data from the phase 3 ENGOT-EN5/GOG-3055/SIENDO trial (NCT03555422)presented at the 2023 IGCS Annual Global Meeting.¹

At a median follow-up of 28.9 months and a data cutoff of September 1, 2023, patients with TP53 wild-type disease who were treated with selinexor (n = 77) achieved a median PFS of 27.4 months (95% CI, 13.1–not reached [NR]) vs 5.2 months (95% CI, 2.0-13.1) in those who received placebo (n = 36; HR, 0.41; 95% CI, 0.25-0.69; 1-sided nominal P = .0002).

“Although immune checkpoint inhibitors showed significant benefit in patients with mismatch repair–deficient [dMMR]/MSI-high [MSI-H] tumors, there is a high unmet need in those with mismatch repair–proficient [pMMR] tumors, for which there is limited evidence of benefit,” lead study author Giovanni Scambia, MD, of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS and the Università Cattolica del Sacro Cuore in Rome, Italy, said in a presentation of the data.

TP53 is a prognostic marker for endometrial cancer, and approximately 50% of advanced or recurrent endometrial cancer tumors are TP53 wild-type; however, approximately 40% to 55% are also pMMR. Selinexor is an investigational oral XPO1 inhibitor that blocks the XPO1-mediated export of many tumor suppressor proteins, including p53 wild-type.^1-3

“Among these mechanisms of XPO1 in endometrial cancer, the primary mechanism is believed to be through the nuclear retention and reactivation of tumor-suppressive proteins, such as TP53 wild-type,” Scambia noted.¹ “The primary analysis of [the SIENDO] study did not show an improvement in median PFS for patients [in the intention-to-treat population] treated with [selinexor], but a prespecified analysis of a subgroup of patients with [TP53 wild-type] endometrial cancer showed a promising efficacy signal.”

Between January 2018 and December 2021, SIENDO enrolled 263 female adult patients with stage IV or primary relapsed endometrial cancer. Patients needed to have received at least 12 weeks of platinum-based chemotherapy. Patients who had received prior surgery, hormonal therapy, or radiotherapy were permitted to enroll.

Following a complete response (CR) or partial response (PR) with first-line chemotherapy per RECIST v1.1 criteria, patients were randomly assigned 2:1 to receive either oral selinexor at 80 mg once per week or weekly oral placebo. Patients were stratified by whether they had primary stage IV vs recurrent disease and whether they achieved a CR or PR following first-line chemotherapy.

Investigator-assessed PFS served as the primary end point. Key secondary end points included PFS by blinded independent central review per RECIST v1.1 criteria, overall survival (OS), time to first subsequent therapy, and health-related quality of life. Exploratory end points included histological subtype and molecular subclassification, assessed by immunohistochemistry and DNA sequencing, of TP53 mutation status, MSI status, and POLE exonuclease domain mutation status.

At baseline, patients in the TP53 wild-type cohort who received selinexor had a median age of 64.0 years (range, 40-81), and 29.9% were at least 70 years of age. Patients in the TP53 wild-type cohort who received placebo had a median age of 61.5 years (range, 33-74), and 22.2% were at least 70 years of age. Most patients in both cohorts were White (97.4% vs 94.4%, respectively), had an ECOG performance status of 0 (55.8% vs 61.1%), and had endometrioid disease histology (84.4% vs 80.6%). In the selinexor arm, 44.2% and 53.2% of patients had primary stage IV disease and recurrent disease, respectively. In the placebo arm, these rates were 47.2% and 50.0%, respectively.

Furthermore, 40.3% and 59.7% of patients in the selinexor arm achieved a CR and PR to f, respectively, after their most recent line of chemotherapy, compared with 44.4% and 55.6% of patients, respectively, in the placebo arm. In the selinexor arm, 61.0%, 26.0%, and 13.0% of patients had pMMR/microsatellite stable (MSS) disease, dMMR/MSI-H disease, or disease with an unknown molecular characterization, respectively. In the placebo arm, these rates were 63.9%, 25.0%, and 11.1%, respectively.

Additional data showed patients with TP53 wild-type/pMMR/MSS disease experienced benefit with selinexor vs placebo. At a median follow-up of 31.6 months, patients in this subgroup who received selinexor (n = 47) achieved a median PFS that was NR (95% CI, 19.3-NR) vs 4.9 months (95% CI, 2.0-NR) in those who received placebo (n = 23; HR, 0.32; 95% CI, 0.16-0.64; 1-sided nominal P = .0004).

Among patients with TP53 wild-type/dMMR/MSI-H disease, at a median follow-up of 27.3 months, the selinexor population (n = 20) achieved a median PFS of 13.1 months (95% CI, 3.6-NR) vs 3.7 months (95% CI, 1.9-NR) in those who received placebo (n = 9; HR, 0.45; 95% CI, 0.16-1.27; 1-sided nominal P = .0643).

“The [PFS] benefit [with selinexor] was [observed] across all prespecified subgroups,” Scambia emphasized. “Particularly, it is clearly evident that the activity of the drug was not dependent on the response to chemotherapy.”

Preliminary OS data in the TP53 wild-type population, which were at 26.6% maturity at a median follow-up of 28.9 months, the median OS was NR (95% CI, NR-NR) and NR (95% CI, 35.19 months-NR) for selinexor and placebo, respectively (HR, 0.76; 95% CI, 0.36-1.59; 1-sided nominal P = .24). In the TP53 wild-type/pMMR/MSS population, the OS data were 30.0% mature at a median follow-up of 31.6 months, the median OS that was NR (95% CI, NR-NR) for selinexor vs 35.19 months (95% CI, 28.68-NR) for placebo (HR, 0.57; 95% CI, 0.24-1.35; 1-sided nominal P = .098). In the TP53 wild-type/dMMR/MSI-H population, the OS data, which were at 10.3% maturity at a median follow-up of 27.3 months, showed a median OS that was NR (95% CI, NR-NR) in both arms (HR, 0.62; 95% CI, 0.06-6.81; 1-sided nominal P = .35).

Regarding safety, in the selinexor arm, the most common treatment-emergent adverse effects (TEAEs) were nausea (any-grade, 90%; grade 3/4, 12%), vomiting (60%; 3%), diarrhea (42%; 4%), constipation (33%; 0%), asthenia (36%; 5%), fatigue (36%; 8%), thrombocytopenia (42%; 10%), decreased appetite (36%; 0%), neutropenia (34%; 18%), anemia (33%; 7%), and abdominal pain (26%; 0%). In the placebo arm, the most common TEAEs were nausea (any-grade, 34%; grade 3/4, 0%), vomiting (11%; 3%), diarrhea (37%; 0%), constipation (40%; 6%), asthenia (26%; 0%), fatigue (20%; 0%), thrombocytopenia (3%; 0%), decreased appetite (3%; 0%), neutropenia (6%; 0%), anemia (3%; 0%), and abdominal pain (14%; 3%).

In the selinexor arm, the rates of discontinuation any-grade and grade 3/4 TEAEs were 16% and 7%, respectively. The reasons for treatment discontinuation included nausea (n = 5), fatigue (n = 3), vomiting (n = 3), and asthenia, cataract, and general physical health deterioration, (n = 1 each). No patients in the placebo arm discontinued treatment because of TEAEs. One patient, who was enrolled in the placebo arm, experienced a TEAE that led to death. The reason for this death is unknown/missing.

“TP53 wild-type status may represent a robust predictive biomarker for selinexor efficacy,” Scambia concluded. “These results highlight the potential opportunity to further personalize therapy and provided a strong rationale to the further study that is now ongoing.”

The phase 3 ENGOT-EN20/GOG-3083/XPORT-EC-042 trial (NCT05611931) is actively enrolling and is evaluating selinexor maintenance after systemic therapy in patients with TP53 wild-type advanced or recurrent endometrial cancer.

Disclosures: This study was funded by MSD Italia Srl. Dr Scambia reports consulting/advisory board roles with TESARO Bio Italy Srl and Johnson & Johnson, as well as honoraria/expenses from Clovis Oncology Italy Srl.

References

1. Scambia G, Vergote I, Hamilton E, et al. Long-term follow up of selinexor maintenance for patients with TP53wt advanced or recurrent endometrial cancer: a pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study. Presented at: 2023 IGCS Annual Global Meeting. November 5-7, 2023. Seoul, Korea.
2. Fung H, Chook Y, et al. Atomic basis of CRM1-cargo recognition, release, and inhibition. Semin Cancer Biol. 2014;27:52-61. doi:10.1016/j.semcancer.2014.03.002
3. Makker V, Perez-Fidalgo JA, Bergamini A, et al. 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. 2022;40(suppl 16):5511. doi:10.1200/JCO.2022.40.16_suppl.5511