New capabilities of 2<sup>nd</sup> and subsequent therapy lines in metastatic urothelial cancer

According to the World Health Organization data, in 2022 bladder cancer (BC) was the 9th (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 2nd 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.