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SIENDO: long-term PFS findings of maintenance selinexor in TP53wt endometrial cancer

Endometrial cancer is the most common gynecological cancer, where approximately 417,000 cases and 100,000 deaths were reported worldwide in 2020.1 The incidence of endometrial cancer has additionally increased in higher-income countries due to the obesity epidemic,2 highlighting the need for novel treatment strategies. Whilst combination therapy with carboplatin and paclitaxel is the standard of care in patients with advanced or metastatic disease, there are no effective treatment options in the second-line setting3 and patients subsequently often have a poor prognosis.

Selinexor is a first-in-class selective inhibitor of nuclear export (SINE), specifically targeting exportin 1 (XPO1).4 To date, selinexor is currently indicated by the FDA for heavily-pretreated relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL).5,6 Previous Phase I (NCT02269293) and II (NCT02025985) clinical trials assessing selinexor alone or with chemotherapy in gynecological malignancies including endometrial cancer have demonstrated encouraging anti-tumor activity.7,8

The Phase III SIENDO trial (NCT03555422) assessed selinexor as maintenance therapy in patients with advanced or recurrent TP53 wild-type (TP53wt) endometrial cancer. 263 patients, who have been pretreated with taxane plus platinum chemotherapy, were enrolled and were randomized 1:1 to receive selinexor or a placebo once weekly, with progression-free survival (PFS) being the primary endpoint. Previous findings presented at the 2022 ESMO Virtual Plenary demonstrated the promising nature of selinexor, where PFS was 13.7 and 3.7 months and in the selinexor and placebo arms respectively (95% CI 0.210-0.670, p=0.0006).9

Results from a long-term follow up of the SIENDO trial were additionally presented at the 2023 ASCO July Plenary Series. At a median follow up of 25.3 months, PFS was 27.4 (95% CI, 13.1-not reached [NR]) and 5.2 months (95% CI, 2.0-13.1) in patients with TP53wt disease receiving selinexor and placebo respectively. In patients with TP53 mutant disease, a PFS of 4.2 months (95% CI, 3.6-5.6) was reached in the selinexor arm compared with 5.4 months (95% CI, 3.7-7.2) in the placebo arm. Selinexor was also efficacious in patients regardless of microsatellite instability status. Adverse events mainly consisted of low grade nausea, vomiting and diarrhea.10

The  SIENDO trial has overall illustrated the benefits of selinexor in the maintenance setting for patients with endometrial cancer. Durable responses were observed and TP53 wild-type has also been identified as a potential predicative biomarker. In light of the recent FDA approval of dostarlimab with chemotherapy for advanced or recurrent endometrial cancer,11 the treatment landscape is rapidly evolving, and selinexor may soon be another addition to the current armamentarium.

Written by Simon Ng

References:

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209–49. doi:10.3322/caac.21660
  2. Mullins MA, Cote ML. Beyond obesity: The rising incidence and mortality rates of uterine corpus cancer. Journal of Clinical Oncology. 2019;37(22):1851–3. doi:10.1200/jco.19.01240
  3. Kelkar SS, Prabhu VS, Zhang J, Corman S, Macahilig C, Rusibamayila N, et al. Treatment patterns and real-world clinical outcomes in patients with advanced endometrial cancer that are non-microsatellite instability high (non-msi-high) or mismatch repair proficient (pmmr) in the United States. Gynecologic Oncology Reports. 2022;42:101026. doi:10.1016/j.gore.2022.101026
  4. Bogani G, Monk BJ, Coleman RL, Vergote I, Oakin A, Ray-Coquard I, et al. Selinexor in patients with advanced and recurrent endometrial cancer. Current Problems in Cancer. 2023;100963. doi:10.1016/j.currproblcancer.2023.100963
  5. Center for Drug Evaluation and Research. FDA approves selinexor for refractory or relapsed multiple myeloma [Internet]. FDA; 2020. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-refractory-or-relapsed-multiple-myeloma
  6. Center for Drug Evaluation and Research. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma [Internet]. FDA; 2020 [cited 2023 Aug 16]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma
  7. Rubinstein MM, Grisham RN, Cadoo K, Kyi C, Tew WP, Friedman CF, et al. A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers. Gynecologic Oncology. 2021;160(1):71–6. doi:10.1016/j.ygyno.2020.10.019
  8. Vergote IB, Lund B, Peen U, Umajuridze Z, Mau-Sorensen M, Kranich A, et al. Phase 2 study of the exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies. Gynecologic Oncology. 2020;156(2):308–14. doi:10.1016/j.ygyno.2019.11.012
  9. Vergote IB, Fidalgo AP, Hamilton E, Valabrega G, Van Gorp T, Sehouli J, et al. VP2-2022: 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 or recurrent endometrial cancer. Annals of Oncology. 2022;33(4):448–50. doi:10.1016/j.annonc.2022.02.223
  10. Slomovitz BM, Perez-Fidalgo JA, Hamilton EP, Valabrega G, Van Gorp T, Sehouli J, et al. 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. Journal of Clinical Oncology. 2023;41(36_suppl):427956–427956. doi:10.1200/jco.2023.41.36_suppl.427956
  11. Center for Drug Evaluation and Research. FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer [Internet]. FDA; 2023 [cited 2023 Aug 16]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dostarlimab-gxly-chemotherapy-endometrial-cancer