ASCO Expert Perspective
"This subset analysis of the phase 3 SIENDO trial examining TP53 wild-type tumors suggests use of selinexor following paclitaxel and carboplatin may be beneficial as maintenance therapy among patients at high risk for recurrence. Should these findings be confirmed in a definitive phase III study, it will give patients with TP53 wild-type tumors a new approach for preventing recurrence.”
– Kathleen N. Moore, MD, MS, ASCO Expert in Gynecologic Cancer
In patients with wild-type TP53 advanced or recurrent endometrial cancer, the addition of maintenance therapy with selinexor following systemic therapy may prolong progression-free survival (PFS), according to research that will be presented during the July 2023 session of the American Society of Clinical Oncology (ASCO) Plenary Series.
According to the authors, approximately half of all patients with advanced or recurrent endometrial cancer have TP53 wild-type tumors and nearly all patients with advanced or recurrent endometrial cancer will experience recurrence within a short period of time. As there are currently no approved maintenance therapies for these patients, there is a critical need for effective maintenance therapies to delay cancer recurrence, which would also delay the initiation of second-line therapy.
In this subgroup analysis of the phase 3 SIENDO study, 113 patients with TP53 wild-type advanced or recurrent endometrial cancer were randomly assigned to receive selinexor (n = 77) or placebo (n = 36) as maintenance therapy following response to prior systemic therapy. At a median duration of follow up of 25.3 months, the prespecified exploratory subgroup of patients with TP53 wild type advanced/recurrent endometrial cancer had a media progression-free survival of 27.4 months vs 5.2 months in the selinexor and placebo arms, respectively. According to the authors, the data also indicate that the TP53 wild type shows preliminary evidence of being a strong prognostic biomarker for the efficacy of selinexor.
The most common adverse events that led patients to stop taking selinexor included nausea, fatigue, asthenia (physical weakness and/or lack of energy), and vomiting. A majority of adverse events were of low grade and reversible with appropriate supportive therapy.
“This is an exciting step forward in potential treatment options that will be studied further,” said Brian M. Slomovitz, MD, director of gynecologic oncology at the Mount Sinai Medical Center in Miami Beach, Florida, and the lead author of the study. “With a weekly oral dose of selinexor, there is a possibility to remain progression-free for a much longer period than the current standard of care and substantially delay the initiation of second line therapy.”
Abstract and presentation will be available here on July 25, 2023 at 3:00 PM (ET). The full embargoed abstract is available below.
Disclosures for ASCO Expert Dr. Moore: https://coi.asco.org/share/C7V-DL7S/Moore%2c%20Kathleen
Disclosures for authors: https://coi.asco.org/Report/ViewAbstractCOI?id=427956
ATTRIBUTION TO THE ASCO PLENARY SERIES IS REQUESTED IN ALL COVERAGE.
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Embargoed Abstract
Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study.
Authors: Brian M. Slomovitz, Jose Alejandro Perez-Fidalgo, Erika P. Hamilton, Giorgio Valabrega, Toon Van Gorp, Jalid Sehouli, Jaroslav Klat, Tally Levy, Stephen Welch, Debra L. Richardson, Eva Maria Guerra Alia, Giovanni Scambia, Stephanie Henry, Pauline Wimberger, Jeronimo Martinez, Bradley J. Monk, Pratheek Kalyanapu, Mansoor Raza Mirza, Vicky Makker, Ignace Vergote; Mount Sinai Medical Center, Miami Beach, FL; GEICO. Hospital Clinico Universitario de Valencia, INCLIVA, CIBERONC., Valencia, Spain; Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; MITO and Department of Oncology, University of Torino, at Mauriziano Hospital, Turin, Italy; Belgium and Luxembourg Gynaecological Oncology Group (BCOG), Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; North-Eastern German Society of Gynaecological Oncology (NOGGO) and Charite-Universitätsmedizin Berlin, Department of Gynecology with Center for Oncological Surgery, Campus Virchow Klinikum, Berlin, Germany; CEEGOG and University Hospital Ostrava and University of Ostrava, Ostrava Poruba, Czech Republic; ISGO and Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, affiliated with Sackler Faculty of Medicine, Tel Aviv, Israel; London Health Sciences Centre, London, ON; Stephenson Cancer Center/University of Oklahoma Health Sciences Center, Oklahoma City, OK; GEICO and Hospital Universitario Ramón y Cajal, Madrid, Spain; MITO and Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; BGOG and Université Catholique de Louvain, CHU UCL Namur Site Ste Elisabeth, Service d’Onco-hématologie (SORMN), Namur, Belgium; North-Eastern German Society of Gynecological Oncology (NOGGO) and Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; GEICO and Hospital Universitario Virgen de la Arrixaca, Department of Oncology, Murcia, Spain; GOG Foundation, Creighton University, University of Arizona, Phoenix, AZ; Karyopharm Therapeutics Inc., Newton Center, MA; Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; BGOG and Department of Obstetrics and Gynaecology, University of Leuven, Leuven Cancer Institute, Leuven, Belgium
Background: Molecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 (TP53wt) is found in ~75% of newly diagnosed EC and 50% of advanced/recurrent tumors; there are no specific targeted therapies available for patients with TP53wt EC. Selinexor is an investigational oral XPO1 inhibitor that drives nuclear retention and functional activation of wild type tumor suppressor proteins, including p53. Methods: SIENDO (NCT03555422) was a phase 3 double-blind study evaluating selinexor vs placebo as maintenance therapy in patients with advanced/recurrent EC following response to prior systemic therapy. The primary endpoint was progression-free survival (PFS), which was previously presented at the ESMO plenary in March 2022. Preliminary analysis of a pre-specified exploratory subgroup of patients with TP53wt EC showed a decrease in risk for progression or death with a median PFS of 13.7 months with selinexor as maintenance therapy vs 3.7 months with placebo at the time of primary PFS analysis. The safety and efficacy of selinexor as maintenance therapy was now further assessed with long-term follow-up in the pre-specified subgroup of patients with TP53wt EC. Results: 113 patients with TP53wt EC were randomly assigned to receive selinexor vs placebo as maintenance therapy (selinexor, n=77/placebo, n=36). As of data cutoff on Nov 30, 2022, median follow-up was 20.3 months, with 26.3% and 22.9% patients still on selinexor and placebo treatment, respectively. Median PFS for the TP53wt subgroup was 20.8 months with selinexor vs 5.2 months with placebo (HR [Stratified by chemotherapy response CR vs PR] 0.46; 95% CI (0.27, 0.79), nominal one-sided p=0.002). Efficacy was observed regardless of MSS/MSI status. The most common adverse events (AEs) of any grade (selinexor/placebo) were nausea (90%/34%), vomiting (61%/11%) and diarrhea (38%/34%); and most common grade 3+ AEs included: neutropenia (18%/0%), nausea (12%/0%), and thrombocytopenia (9%/0%). TEAEs leading to discontinuations were reported in 15%/0% of patients, respectively. Conclusions: Long-term follow-up of a pre-specified subgroup analysis showed durable PFS benefit with selinexor maintenance in TP53wt EC, which offers the potential to prolong response to prior systemic therapy. These data suggest that TP53 status is a robust prognostic biomarker for EC and selinexor may provide meaningful benefit in patients who have TP53wt tumors. A phase 3 trial is underway to further investigate the safety and efficacy of selinexor as maintenance therapy in patients with advanced or recurrent TP53wt EC (NCT05611931). Updated PFS and results in additional molecular subtypes (MSS/MSI) of the TP53wt subgroup will be included at the time of presentation.
Research Funding Source: Karyopharm
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