Current approaches to first-line therapy for endometrial cancer: the role of lenvatinib and pembrolizumab combination therapy

Cover Page
  • Authors: Nechushkina V.M.1,2, Khokhlova S.V.3,4, Nosov D.A.5, Ulrikh E.A.6,7,8, Kolomiets L.A.9,10, Rumyantsev A.A.11, Raskin G.A.12,13
  • Affiliations:
    1. Privolzhsky Research Medical University, Ministry of Health of Russia
    2. Autonomous non-commercial organization “Scientific and Educational Center “Eurasian Oncology Program” EAFO
    3. V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia
    4. Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia
    5. Central Clinical Hospital with Polyclinic, Administration of the President of the Russian Federation
    6. N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia
    7. I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
    8. V.A. Almazov National Medical Research Centre
    9. Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
    10. Siberian State Medical University, Ministry of Health of Russia
    11. N.N. Blokhin National Medical Research Center of Oncology
    12. Saint Petersburg State University
    13. Medical Institute named after Berezin Sergey
  • Issue: Vol 21, No 2 (2025)
  • Pages: 127-134
  • Section: GYNECOLOGY. REVIEWS
  • Published: 03.08.2025
  • URL: https://ojrs.abvpress.ru/ojrs/article/view/1384
  • DOI: https://doi.org/10.17650/1994-4098-2025-21-2-127-134
  • ID: 1384

Cite item

Full Text

Abstract

Endometrial cancer (EC) remains the most common gynecologic oncology disease in Russia, with a tendency toward increasing incidence and associated mortality. In recent years, significant progress has been made in understanding the molecular mechanisms underlying the disease, leading to the development of a molecular classification of EC, which has enabled the implementation of personalized treatment approaches. Determining the status of microsatellite instability (MSI) and deficiency in the mismatch repair system (dMMR), as well as identifying mutations in the POLE and TP53 genes, has become a key component in diagnosis and decision-making regarding therapy.
The combination of lenvatinib and pembrolizumab has demonstrated clinical efficacy in pMMR / MSS EC in the second-line setting. The Study 309 and LEAP-001 trials confirm the clinical benefit of lenvatinib and pembrolizumab in patients with pMMR / MSS tumor phenotypes following prior systemic therapy. Expert consensus highlights the necessity of testing all patients for dMMR / MSI at initial EC diagnostics and supports the early use of immunotargeted therapy with lenvatinib and pembrolizumab already in the setting for patients with pMMR / MSS phenotype and prior adjuvant systemic therapy. The aim of this review is to analyze current approaches to systemic therapy for EC, assess the clinical significance of lenvatinib and pembrolizumab therapy, and examine the role of molecular diagnostics in guiding treatment decisions.

About the authors

V. M. Nechushkina

Privolzhsky Research Medical University, Ministry of Health of Russia; Autonomous non-commercial organization “Scientific and Educational Center “Eurasian Oncology Program” EAFO

Author for correspondence.
Email: drnechushkina@mail.ru
ORCID iD: 0000-0002-1855-9692

18 / 1 Verkhnevolzhskaya Naberezhnaya, Nizhny Novgorod 603155

1 Volokolamskoe Shosse, Moscow 125080

Russian Federation

S. V. Khokhlova

V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia; Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia

ORCID iD: 0000-0002-4121-7228

4 Akademika Oparina St., Moscow 117997

Build. 1, 2 / 1 Barrikadnaya St., Moscow 125993

 

Russian Federation

D. A. Nosov

Central Clinical Hospital with Polyclinic, Administration of the President of the Russian Federation

ORCID iD: 0000-0001-8415-5197

15 Marshala Timoshenko St., Moscow 121359

Russian Federation

E. A. Ulrikh

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia; I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia; V.A. Almazov National Medical Research Centre

ORCID iD: 0000-0002-2701-8812

68 Leningradskaya St., Pesochnyy Settlement, Saint Petersburg 197758

41 Kirochnaya St., Saint Petersburg 191015

2 Akkuratova St., Saint Petersburg 197341

Russian Federation

L. A. Kolomiets

Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences; Siberian State Medical University, Ministry of Health of Russia

ORCID iD: 0000-0002-6854-8940

5 Kooperativnyy Pereulok, Tomsk 634009

2 Moskovskiy Trakt, Tomsk 634050

Russian Federation

A. A. Rumyantsev

N.N. Blokhin National Medical Research Center of Oncology

ORCID iD: 0000-0003-4443-9974

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

G. A. Raskin

Saint Petersburg State University; Medical Institute named after Berezin Sergey

ORCID iD: 0000-0002-7522-6552

7 / 9 Universitetskaya Naberezhnaya, Saint Petersburg 199034

43 Karla Marksa St., Pesochnyy Settlement, Saint Petersburg 197758

Russian Federation

References

  1. Malignant tumors in Russia in 2023 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, А.О. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2024. 250 p. (In Russ.)
  2. Gao S., Wang J., Li Z. et al. Global Trends in incidence and mortality rates of endometrial cancer among individuals aged 55 years and above from 1990 to 2021: An analysis of the global burden of disease. Int J Womens Health 2025;17:651–62. doi: 10.2147/IJWH.S499435
  3. Getz G., Gabriel S.B., Cibulskis K. et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497(7447):67–73. doi: 10.1038/nature12113
  4. Di Dio C., Bogani G., Di Donato V. et al. The role of immunotherapy in advanced and recurrent MMR deficient and proficient endometrial carcinoma. Gynecol Oncol 2023;169:27–33. doi: 10.1016/j.ygyno.2022.11.031
  5. Miller D.S., Filiaci V.L., Mannel R.S. et al. Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/ GOG0209). J Clin Oncol 2020;38(33):3841–50. doi: 10.1200/JCO.20.01076
  6. Gordhandas S., Zammarrelli W.A., Rios-Doria E.V. et al. Current evidence-based systemic therapy for advanced and recurrent endometrial cancer. J Natl Compr Cancer Netw 2023;21(2):217 26. doi: 10.6004/jnccn.2022.7254
  7. Clarke M.A., Devesa S.S., Harvey S.V., Wentzensen N. Hysterectomy-corrected uterine corpus cancer incidence trends and differences in relative survival reveal racial disparities and rising rates of nonendometrioid cancers. J Clin Oncol 2019;37(22): 1895–908. doi: 10.1200/JCO.19.00151
  8. Kedrova А.G., Berishvili А.I., Greyan T.A. Lenvatinib and pembrolizumab in patients with advanced uterine cancer. Opukholi zhenskoy reproduktivnoy systemy = Tumors of Female Reproductive System 2020;16(3):72–80. (In Russ.). doi: 10.17650/1994-4098-2020-16-3-72-80
  9. Rumyantsev A.A., Protasova A.E., Grechkina A.A. et al. Efficacy and safety of lenvatinib plus pembrolizumab in patients with endometrial cancer: data from an extended study of routine clinical practice in Russia. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of Female Reproductive System 2024;20(4):111–8. (In Russ.). doi: 10.17650/1994-4098-2024-20-4-111-118
  10. American Cancer Association. Cancer facts & figures 2023. Atlanta Am Cancer Soc 2023:1–4. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf.
  11. Khokhlova S.V., Kolomiets L.A., Kravets O.A. et al. Practical recommendations for drug treatment of patients with uterine cancer. Zlokachestvennye opukholi = Malignant Tumors 2013;2013:149–58. (In Russ.)
  12. Nechushkina V.M., Kolomiets L.A., Kravets O.A. et al. Practical recommendations for drug treatment of uterine body cancer and uterine sarcomas. Zlokachestvennye opukholi = Malignant Tumors 2020;10(3s2–1):242–56. (In Russ.). doi: 10.18027/2224-5057-2020-10-3s2-14
  13. Nechushkina V.M., Kolomiets L.A., Kravets O.A. et al. Uterine body cancer and uterine sarcomas. RUSSCO practical recommendations, part 1.2. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2):165–88. Available at: https://rosoncoweb.ru/standarts/RUSSCO/2024/2024-1_2-06.pdf. (In Russ.).
  14. Uterine body cancer and uterine sarcomas: clinical guidelines. Ministry of Health of Russia, 2024. (In Russ.).
  15. Lorenzi M., Amonkar M., Zhang J. et al. Epidemiology of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in solid tumors: A structured literature review. J Oncol 2020. doi: 10.1155/2020/1807929
  16. Eskander R.N., Sill M.W., Beffa L. et al. Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: Overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial. Nat Med 2025;31:1539–46. doi: 10.1038/s41591-025-03566-1
  17. Scott B. Advancements in endometrial cancer research in 2024. EMJ Oncol 2024;13(Suppl):2–13. doi: 10.33590/emjoncol/11000026
  18. Rumyantsev A.A. Efficient sequence of therapy for advanced and metastatic endometrial cancer. Opukholi zhenskoy reproduktivnoy systemy = Tumors of female reproductive system 2022;18(2):119–26. (In Russ.). doi: 10.17650/1994-4098-2022-18-2-119-126
  19. Fleming G.F. Second-line therapy for endometrial cancer: The need for better options. J Clin Oncol 2015;33(31):3535–40. doi: 10.1200/JCO.2015.61.7225
  20. Makker V., Taylor M.H., Aghajanian C. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 2020;38(26):2981–92. doi: 10.1200/JCO.19.02627
  21. Makker V., Colombo N., Herráez A.C. et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: Updated efficacy and safety from the randomized phase III Study 309/KEYNOTE-775. J Clin Oncol 2023;41(16):2904–10. doi: 10.1200/JCO.22.02152
  22. Marth C., Moore R.G., Bidzinski M. et al. Lenvatinib plus pembrolizumab versus chemotherapy as first-line therapy for advanced or recurrent endometrial cancer: Primary results of the phase 3 ENGOT-en9/LEAP-001 study. Int J Gynecol Cancer 2024. doi: 10.1136/ijgc-2024-esgo.1115
  23. Marth C., Tarnawski R., Tyulyandina A. et al. Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer 2022. doi: 10.1136/ijgc-2021-003017
  24. Kurman R.J., Carcangiu M.L., Herrington C.S., Young R.H. WHO Classification of Tumours of Female Reproductive Organs. World Heal Organ Classif Tumours 2014.
  25. NCCN Clinical Practice Guidelines in Oncology. Uterine Neoplasms. 2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.
  26. León-Castillo A., Britton H., McConechy M.K. et al. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 2020;250(3):323–35. doi: 10.1002/path.5372
  27. Yu S., Sun Z., Zong L. et al. Clinicopathological and molecular characterization of high-grade endometrial carcinoma with POLE mutation: A single center study. J Gynecol Oncol 2022;33(3):e38. doi: 10.3802/jgo.2022.33.e38
  28. Jumaah A.S., Al-Haddad H.S., Salem M.M. et al. Mismatch repair deficiency and clinicopathological characteristics in endometrial carcinoma: A systematic review and meta-analysis. J Pathol Transl Med 2021;55(3):202–11. doi: 10.4132/JPTM.2021.02.19
  29. Momeni-Boroujeni A., Dahoud W., Vanderbilt C.M. et al. Clinicopathologic and genomic analysis of TP53-mutated endometrial carcinomas. Clin Cancer Res 2021;27(9):2613–23. doi: 10.1158/1078-0432.CCR-20-4436

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c)


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 36991 от  21.07.2009.