Combination of pembrolizumab and lenvatinib in second-line therapy for MSS/pMMR advanced endometrial cancer: literature review and a case report

Despite the existing standard treatments for endometrial cancer, the prognosis for these patients remained poor until recently. None of currently available cytostatics ensured long-term disease control and long-term survival of patients receiving standard platinum-based therapy. Poor treatment outcomes in patients with advanced endometrial cancer necessitated changes in therapeutic approaches and development of more effective treatment regimens. Better understanding of carcinogenesis mechanisms, emergence of a new molecular classification of endometrial cancer, and implementation of tailored treatment approaches based on tumor types led to a significant breakthrough in the treatment of advanced endometrial cancer. Currently, the most effective second-line therapy for endometrial cancer with high level microsatellite instability (MSI-h) or deficient mismatch repair system (dMMR) (25 % of cases), and no indications for surgery is pembrolizumab monotherapy. Most of cancers (about 75 %) are represented by microsatellite-stable and mismatch repair proficient tumors (MSS/рMMR). Patients with such tumors demonstrating disease progression after systemic therapy should receive a combinations of the immune checkpoint inhibitor pembrolizumab and the multi-targeted tyrosine kinase inhibitor lenvatinib. In this article, we review relevant literature and report a case of successful treatment of MSS/pMMR advanced endometrial cancer with a combination of pembrolizumab and lenvatinib as a second-line therapy (after disease progression in response to platinum-containing first-line chemotherapy), which ensured long-term disease control.

1. Miller D.S., Filiaci V.L., Mannel R.S. et al. Carboplatin and paclitaxel for advanced endometrial cancer: Fnal 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

2. Miller D., Filiaci V., Fleming G. et al. Late-breaking abstract 1: Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2012;125(3):771. DOI: 10.1016/j.ygyno.2012.03.034

3. Nechushkina V.M., Kolomiets L.A., Kravets O.A. et al. Practical recommendations for drug treatment of uterine cancer and uterine sarcomas. Malignant tumors: Practical recommendations RUSSCO #3s2, 2022 (volume 12). Pp. 260–275. DOI: 10.18027/2224-5057-2022-12-3s2-260-275

4. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Uterine Neoplasms. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

5. 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;1–17. DOI: 10.1155/2020/1807929

6. 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

7. Arora S., Balasubramaniam S., Zhang W. et al. FDA Approval Summary: Pembrolizumab plus lenvatinib for endometrial carcinoma, a collaborative international review under Project Orbis. Clin Cancer Res 2020;26(19):5062–7. DOI: 10.1158/1078-0432.CCR-19-3979

8. U.S. Food and Drug Administration. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. Available at: https://www.fda.gov/drugs/resourcesinformation-approved-drugs/simultaneous-review-decisionspembrolizumabplus-lenvatinib-australia-canada-and-us.

9. Makker V., Colombo N., Herráez A.С. et al. A multicenter, openlabel, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer. Gynecol Oncol 2021;162(Suppl 1):S4. DOI: 10.1016/S0090-8258(21)00657-0

10. Colombo N., Lorusso D., Casado A. et al. Outcomes by histology and prior therapy with lenvatinib plus pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer (Study 309/KEYNOTE-775). European Society for Medical Oncology (ESMO) Congress 2021; September 16–21, 2021. Abstract 726MO.

11. Hasegawa K., Nagao S., Yasuda M. et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Clear Cell Carcinoma of the Uterine Corpus and Cervix. Int J Gynecol Cancer 2014;24(3 Suppl):S90–S95. DOI: 10.1097/IGC.0000000000000297

12. Sagae S., Susumu N., Viswanathan A.N. et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine Serous Carcinoma. Int J Gynecol Cancer 2014;24(3 Suppl):S83–S89. DOI: 10.1097/IGC.0000000000000264

13. Darenskaya A.D., Rumyantsev A.A., Gutorov S.L., Tyulyandina A.S. Evolution of systemic pharmacotherapy for disseminated endometrial cancer. Literature review. Zlokachestvennye opukholi = Malignant Tumors 2023;13(2):6. (In Russ.). DOI: 10.18027/2224-5057-2023-13-2-6