New capabilities of 2^nd and subsequent therapy lines in metastatic urothelial cancer

According to the World Health Organization data, in 2022 bladder cancer (BC) was the 9^th (614,298) most common cancer. In Russia, most patients (58.8 %) were diagnosed with non-muscle invasive BC (stage I) but the percentage of muscle invasive cancer (stages II–III) and metastatic BC (mBC) remains high: 32.1 and 8.3 % cases, respectively. Mortality in patients with BC in the first year since diagnosis remains high: 12.28 %. Decrease in BC mortality in the last 10 years in Russia by 22.84 % is probably due to development of new more effective drugs for mBC treatment which are the subject of this literature review.

Currently, the 2^nd line standards of treatment of patients with mBC changed due to appearance in the guidelines of the majority of the world oncological societies of new drugs classified as conjugated and targeted drugs. In patients with progression during platinum-based chemotherapy and/or immune checkpoint inhibitors, therapy with conjugate enfortumab vedotin (EV) is possible.

Enfortumab vedotin is the first of its class drug, a conjugate of a monoclonal antibody against the nectin-4 protein which is highly expressed by urothelial carcinoma and a cytotoxic chemotherapy drug monomethyl auristatin E (ММАЕ) affecting microtubules. EV was approved by the US Food and Drug Administration (FDA) in December of 2019 based on phase II trial EV-201 as part of the expedited review program due to high rate of objective responses in patients with inoperable locally advanced and mBC who previously received platinum-based chemotherapy and immune checkpoint inhibitors. In Russia, the drug was approved in 2023.

Median overall survival in all phase I–III EV trials were around 1 year and varied between 11.7 and 12.91 months, progression-free survival was a little below 6 months and varied between 5.5 and 5.8 months. In the UNITE trial based on routine practice data, median progression-free survival and overall survival since the start of EV therapy were a little higher than in the randomized trails: 6.8 and 14.4 months, respectively. Objective response rate in all clinical trials was above 40 %; in particular, in phase I trial EV-101 it was 43 %, in phase II trial EV-201 – 44 %, in phase III trial EV-301 – 41 %, and in UNITE – 52 %, while complete response rates were 5; 12; 6.9 and 7 %, respectively. In phase III clinical trial EV-301, EV therapy decreased the risk of death by 30 % compared to standard treatment (ST) and significantly increased overall survival from 8.94 months in the ST group to 12.91 months in the EV group. The risk of progression and death decreased by 37 % in the EV group, and median progression-free survival increased from 3.71 months in the ST group to 5.5 months in the EV group (p <0.00001). Additionally, objective response rate was more than 2-fold higher for EV compared to ST: 41.32 % versus 18.58 %. Approximately 30 % of patients in the EV group are alive at year 2 of the study compared to 20 % in the ST group. Safety profile also demonstrates similar results to the intermediate and primary analyses. The rates of treatment-associated adverse events of grade III or higher in the EV group in both intermediate and primary analyses of the EV-301 trial (51.4 and 52.4 %, respectively) were similar to the rates in the ST group (49.8 % and 50.5 %, respectively). The most common adverse events in the EV therapy group were rash, hyperglycemia, and peripheral neuropathy. At the same time, quality of life in the EV therapy group was higher compared to the standard therapy which confirms safety and effectiveness of EV in patients with urothelial carcinoma.

1. Ferlay J., Ervik M., Lam F. et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer, 2024. Available at: https://gco.iarc.who.int/today

2. Malignant tumors in Russia in 2023 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2024. 276 p. (In Russ.).

3. Von der Maase H., Hansen S.W., Roberts J.T. et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18(17):3068–77. DOI: 10.1200/JCO.2000.18.17.3068

4. De Santis M., Bellmunt J., Mead G. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/ vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30(2):191–9. DOI: 10.1200/JCO.2011.37.3571

5. Bellmunt J., von der Maase H., Mead G.M. et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30(10):1107–13. DOI: 10.1200/JCO.2011.38.6979

6. Powles T., Park S.H., Voog E. et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383(13):1218–30. DOI: 10.1056/NEJMoa2002788

7. Bellmunt J., de Wit R., Vaughn D.J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–26. DOI: 10.1056/NEJMoa1613683

8. Powles T., Durán I., van der Heijden M.S. et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748–57. DOI: 10.1016/S0140-6736(17)33297-X

9. Knowles M.A., Hurst C.D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015;15(1):25–41. DOI: 10.1038/nrc3817

10. Loriot Y., Necchi A., Park S.H. et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381(4):338–48. DOI: 10.1056/NEJMoa1817323

11. Black P.C., Alimohamed N.S., Berman D. et al. Optimizing management of advanced urothelial carcinoma: a review of emerging therapies and biomarker-driven patient selection. Can Urol Assoc J 2020;14:E373–82. DOI: 10.5489/cuaj.6458

12. Nadal R., Bellmunt J. Management of metastatic bladder cancer. Cancer TreatRev 2019;76:10–21. DOI: 10.1016/j.ctrv.2019.04.002

13. Patel V.G., Oh W.K., Galsky M.D. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin 2020;70(5):404–23. DOI: 10.3322/caac.21631

14. EAU Guidelines. Edn. presented at the EAU Annual Congress Paris 2024. ISBN 978-94-92671-23-3

15. Flaig T.W., Spiess P.E., Abern M. et al. NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024. J Natl Compr Canc Netw 2024;22(4):216–25. DOI: 10.6004/jnccn.2024.0024

16. Tagawa S., Balar A.V., Petrylak D.P. et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39(22):2474–85. DOI: 10.1200/JCO.20.03489

17. Gilead provides update on U.S. indication for Trodelvy in metastatic urothelial cancer. News release. October 18, 2024. Accessed October 18, 2024. Available at: https://www.gilead.com/company/company-statements/2024/gilead-provides-update-on-us-indication-for-trodelvy-in-metastatic-urothelial-cancer

18. Bellmunt J., Théodore C., Demkov T. et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009;27(27):4454–61. DOI: 10.1200/JCO.2008.20.5534

19. Bellmunt J., Fougeray R., Rosenberg J.E. et al. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum based chemotherapy. Ann Oncol 2013;24(6):1466–72. DOI: 10.1093/annonc/mdt007

20. Dreicer R., Manola J., Schneider D.J. et al. Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group. Cancer 2003;97(11):2743–7. DOI: 10.1002/cncr.11413

21. McCaffrey J.A., Hilton S., Mazumdar M. et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional cell carcinoma. J Clin Oncol 1997;15(5):1853–7. DOI: 10.1200/JCO.1997.15.5.1853

22. Vaughn D.J., Broome C.M., Hussain M. et al. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 2002;20(4):937–40. DOI: 10.1200/JCO.2002.20.4.937

23. Sridhar S.S., Blais N., Tran B. et al. Efficacy and safety of nab-paclitaxel vs paclitaxel on survival in patients with platinum-refractory metastatic urothelial cancer: the Canadian Cancer Trials Group BL.12 randomized clinical trial. JAMA Oncol 2020;6(11):1–8. DOI: 10.1001/jamaoncol.2020.3927

24. Meric-Bernstam F., Makker V., Oaknin A. et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol 2024;42(1):47–58. DOI: 10.1200/JCO.23.02005

25. Challita-Eid P.M., Satpayev D., Yang P. et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76:3003–13. DOI: 10.1158/0008-5472.CAN-15-1313

26. Hoffman-Censits J.H., Lombardo K.A., Parimi V. et al. Expression of nectin-4 in bladder urothelial carcinoma, in morphologic variants, and nonurothelial histotypes. Appl Immunohistochem Mol Morphol 2021;29(8):619–25. DOI: 10.1097/PAI.0000000000000938

27. Zhang Y., Liu S., Wang L. et al. A novel PI3K/AKT signaling axis mediates nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. Cancer Lett 2016;375:179–89. DOI: 10.1016/j.canlet.2016.02.049

28. Zhang Y., Zhang J., Shen Q. et al. High expression of nectin-4 is associated with unfavorable prognosis in gastric cancer. Oncol Lett 2018;15:8789–95. DOI: 10.3892/ol.2018.8365

29. Tomiyama E., Fujita K., Rodriguez Pena M.D.C. et al. Expression of nectin-4 and PD-L1 in upper tract urothelial carcinoma. Int J Mol Sci 2020;21(15):5390. DOI: 10.3390/ijms21155390

30. Mantia C.M., Sonpavde G. Enfortumab vedotin-ejfv for the treatment of advanced urothelial carcinoma. Expert Rev Anticancer Ther 2022;22(5):449–55. DOI: 10.1080/14737140.2022.2069563

31. Instructions for the drug Padtsev Onco. Available at: https://www.vidal.ru/drugs/padtsev-onko (In Russ.).

32. Rosenberg J., Sridhar S.S., Zhang J. et al. EV-101: a phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol 2020;38:1041–9. DOI: 10.1200/JCO.19.02044

33. Rosenberg J.E., O’Donnell P.H., Balar A.V. et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37:2592–600. DOI: 10.1200/JCO.19.01140

34. Yu E.Y., Petrylak D.P., O’Donnell P.H. et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2021;22:872–82. DOI: 10.1016/S1470-2045(21)00094-2

35. Balar A.V., McGregor B.A., Rosenberg J.E. et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-i neligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol 2021;39(suppl):394.

36. Powles T., Rosenberg J.E., Sonpavde G.P. et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384(12):1125–1135. DOI: 10.1056/NEJMoa2035807

37. Rosenberg J.E., Powles T., Sonpavde G.P. et al. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol 2023;34(11):1047–54. DOI: 10.1016/j.annonc.2023.08.016

38. Rosenberg J.E., Mamtani R., Sonpavde G.P. et al. Health-related quality of life in patients with previously treated advanced urothelial carcinoma from EV-301: a phase 3 trial of enfortumab vedotin versus chemotherapy. Eur Urol 2024;85(6):574–85. DOI: 10.1016/j.eururo.2024.01.007

39. Koshkin V.S., Henderson N., James M. et al. Efficacy of enfortumab vedotin in advanced urothelial cancer: analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study. Cancer 2022;128(6):1145–345. DOI: 10.1002/cncr.34057