Эффективность комбинации ленватиниба и эверолимуса при метастатическом почечно-клеточном раке у больных с резистентностью к таргетному лечению в реальной клинической практике: обзор и клинические случаи

Ежегодно в мире регистрируется 400000 новых случаев почечно-клеточного рака (ПКР) и 175000 летальных исходов. Доступные в настоящее время передовые методы лечения ПКР обладают меньшей токсичностью, чем ранее применявшиеся терапевтические средства, но лекарственная устойчивость по-прежнему остается клинически значимой проблемой. Лекарственная устойчивость возникает в результате ангиогенного перехода через активацию путей, которые не зависят от VEGF-мишеней большинства методов лечения первой линии. Ленватиниб с эверолимусом могут бороться с резистентностью для увеличения как выживаемости без прогрессирования, так и общей выживаемости у пациентов с метастатическим ПКР согласно проведенным клиническим исследованиям.

1. Song X.D., Tian Y.N., Li H. et al. Research progress on advanced renal cell carcinoma. J Int Med Res 2020; 48: 300060520924265.

2. Jonasch E NCCN Guidelines updates: management of metastatic kidney cancer. J Natl Compr Canc Netw. 2019; 17:587–589. [PubMed: 31117033]

3. Ellithi M., Elnair R., Chang G.V., Abdallah M.A. Toxicities of Immune Checkpoint Inhibitors: Itis-Ending Adverse Reactions and More. Cureus. 2020 Feb 10;12(2): e6935.

4. Escudier B., Porta C., Schmidinger M. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019; 30:706–720. [PubMed: 30788497]

5. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Kidney Cancer. Version 2.2020 https://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf; Accessed 8 November 2019.

6. Cella D., Grünwald V., Escudier B. et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol 2019; 20: 297–310.

7. Wiele A.J., Bathala T.K., Hahn A.W. et al. Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies. Oncologist. 2021 Jun;26(6):476–482.

8. Pal S.K., Puente J., Heng DYC et al. Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial. Eur Urol. 2022 Sep;82(3):283–292. doi: 10.1016/j.eururo.2021.12.024.

9. Hamieh L., Beck R.L., Le V.H., Hsieh J.J. The Efficacy of Lenvatinib Plus Everolimus in Patients with Metastatic Renal Cell Carcinoma Exhibiting Primary Resistance to Front-Line Targeted Therapy or Immunotherapy. Clin Genitourin Cancer. 2020 Aug;18(4):252–257.e2. doi: 10.1016/j.clgc.2020.03.003.

10. Zhang T., George D.J. Immunotherapy and targeted-therapy combinations mark a new era of kidney cancer treatment. Nat Med. 2021 Apr;27(4):586–588. doi: 10.1038/s41591–021–01320-x.

11. Motzer R.J., Taylor M.H., Evans TRJ et al. Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies. Expert Rev Anticancer Ther. 2022 Apr;22(4):383–400. doi: 10.1080/14737140.2022.2039123.

12. Jacob A., Shook J., Hutson T. The implementation of lenvatinib/everolimus or lenvatinib/ pembrolizumab combinations in the treatment of metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2021 Apr;21(4):365–372. doi: 10.1080/14737140.2021.1868994.

13. Leonetti A., Leonardi F., Bersanelli M., Buti S. Clinical use of lenvatinib in combination with everolimus for the treatment of advanced renal cell carcinoma. Ther Clin Risk Manag. 2017; 13:799–806. [PubMed: 28721060]

14. Hutson T.E., Michaelson M.D., Kuzel T.M. et al. A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma. Eur Urol. 2021 Aug;80(2):162–170. doi: 10.1016/j.eururo.2021.03.015.

15. Lenvima (lenvatinib) [prescribing information]: Woodcliff Lake, NJ: Eisai Inc.; 2020.

16. Molina A.M., Hutson T.E., Larkin J. et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014; 73:181–189. [PubMed: 24190702]

17. Delsante M., Monroy-Trujillo J.M., Carter-Monroe N. et al. Lenvatinib-related renal microangiopathy: a case series. Virchows Arch. 2022 Feb;480(2):467–473. doi: 10.1007/s00428–021–03114–5.

18. Hamieh L., Beck R.L., Le V.H., Hsieh J.J. The efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front–line targeted therapy or immunotherapy. Clin Genitourin Cancer. 2020; 18:252–7.e2.

19. Yamamoto Y., Matsui J., Matsushima T. et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014; 6:18. [PubMed: 25197551]

20. Okamoto K., Kodama K., Takase K. et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013; 340:97–103. [PubMed: 23856031]

21. Matsuki M, Adachi Y, Ozawa Y, et al. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci. 2017; 108:763–771. [PubMed: 28107584]

22. Molina A.M., H utson T.E., Larkin J. et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol 2014; 73: 181–89.

23. Zielli T., Gnetti L., Buti S. Activity of lenvatinib plus everolimus combination in a heavily pretreated patient with papillary renal cell carcinoma: a case report. Tumori. 2020 Dec;106(6): NP79-NP83. doi: 10.1177/0300891620924472.

24. Liao Y., Hou H., Han Z., Liu Y. Systemic therapies for metastatic renal cell carcinoma in the second-line setting: A systematic review and network meta-analysis. Medicine (Baltimore). 2022 Sep 16;101(37): e30333. doi: 10.1097/MD.0000000000030333.

25. C. Lee, Y. Wan, A. Smit. Quality-adjusted time without symptoms or toxicity (Q-TWiST) for lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell сarcinoma. European urology open science 31(2021) 1–9.

26. Saad A.M., Gad M.M., Al-Husseini M.J., Ruhban I.A., Sonbol M.B. Ho T.H. Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: A SEER-based study. Clin Genitourin Cancer. 2019; 17:46–57. e5.

27. Sonpavde G., Willey C.D., Sudarshan S. Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma. Expert Opin Investig Drugs 2014; 23: 305–15.

28. Matsuki M., Adachi Y., Ozawa Y. et al. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci. 2017 Apr;108(4):763–771. doi: 10.1111/cas.13169.

29. Tannir N.M., Pal S.K., Atkins M.B. Second-line treatment landscape for renal cell carcinoma: A comprehensive review. Oncologist. 2018; 23:540–555.

30. FDA approves Lenvima (lenvatinib) for the treatment of patients with advanced renal cell carcinoma. Available at: https://www.drugs.com/newdrugs/fda-approves-lenvima-lenva-tinib-patients-advanced-renal-cell-carcinoma-4382.

31. Motzer R.J., Hutson T.E., Glen H. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015; 16:1473–1482.

32. Shah A.Y., Kotecha R.R., Lemke E.A. et al. Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second line VEGFR-TKI after first-line immune checkpoint inhibitors. Eur J Cancer. 2019; 114:67–75.

33. Deuker M., Chun FKH. Karakiewicz PI. Second-line tyrosine kinase inhibitor-therapy after immunotherapy-failure. Curr Opin Support Palliat Care. 2020; 14:276–285.

34. Lee C.H., Motzer R.J., Glen H. et al. Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. Br J Cancer. 2021 Jan;124(1):237–246. doi: 10.1038/s41416–020–01092–0.

35. Matsubara N., Naito Y., Nakano K. et al. Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study. Int J Urol. 2018; 25:922–928.

36. Motzer R., Alekseev B., Rha S.Y. et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289–1300. doi: 10.1056/NEJMoa2035716.

37. Wiele A.J., Bathala T.K., Hahn A.W. et al. Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies. The oncologist. 2021.

38. Tremblay G., McElroy H.J., Westley T., Meier G., Misurski D., Guo M. Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma. PLoS One. 2019;14.

39. Karner C., Kew K., Wakefield V., Masento N., Edwards S.J. Targeted therapies for previously treated advanced or metastatic renal cell carcinoma: Systematic review and network meta-analysis. BMJ Open. 2019;9.

40. Hamieh L., Beck R.L., Le V.H. et al. The efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front-line targeted therapy or immunotherapy. Clin Genitourin Cancer 2020; 18:252–257.e2