A phase I trial looked at other potential treatment options for urothelial cancer. For this cancer, first-line treatment is platinum-based chemotherapy and immunotherapy; however, after those options, there are no alternatives. This leaves a wide array of research opportunities in urothelial cancer. One area of research that could be beneficial is targeted therapy, the modality examined in this study.

Specifically, the phase I trial looked at a targeted therapy option called enfortumab vedotin, which is first in its class and targets nectin-4. In 2,394 tissue samples of different tumor types, it was found that 69% expressed nectin-4, with the highest amount present in bladder cancer followed by other tumor types. It also showed activity in cell lines of mouse models, which led to an examination of cancer cells in humans.

Initially, to be included in the trial, patients had to be tested for nectin-4; however, since 97% of samples expressed it, this requirement for study participation was eliminated. There have been 81 patients with urothelial cancer who have been treated with enfortumab vedotin. The objective response rate was 41%, including three patients who had a complete response. In the past, patients who had relapsed after immunotherapy and did not show a response were given enfortumab, and 44% of those patients responded. For patients with metastatic urothelial cancer, especially to the liver, the objective response rate was 47%. The main adverse effects of the drug were nausea, pruritus, alopecia, hair loss, and fatigue. The antibody had rare ophthalmologic effects, which are common with these types of antibody drugs, indicating that the drug is safe to administer.

In March 2018, the FDA granted breakthrough-therapy designation for the medication in patients with locally advanced or metastatic urothelial cancer that had progressed during or following checkpoint-inhibitor therapy. This led to phase II trials, which enrolled urothelial patients who had been treated in the past with platinum-based chemotherapy or checkpoint inhibitors.

These patients were divided into two groups: those who had been treated with both types of therapy and those who had not received platinum therapy. Results are still being determined, but preliminary results of the group that was previously treated with chemotherapy and immunotherapy are available: 70% of patients in the enfortumab group were male with a median age of 69 years, and 44% of them responded to enfortumab, showing shrinkage of the tumor, and 12% had a complete response with no signs of cancer. The median overall survival time was 11.7 months.

Currently, a phase III study is being conducted to validate these findings through ongoing patient enrollment. The trial is assessing efortumab in combination with pembrolizumab, as well as in combination with platinum-based chemotherapy. If results from the phase III trial mirror the phase I and II trials, targeted therapy could offer more options for patients with urothelial carcinoma.

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