Targeting Trop-2 in Advanced Urothelial Carcinoma - Episode 9

Antibody-Drug Conjugates in Advanced Urothelial Carcinoma

Reactions to the availability of antibody-drug conjugates as later-line therapy for patients with metastatic urothelial carcinoma, and potential considerations for adopting enfortumab vedotin into clinical practice.

Neeraj Agarwal, MD: Regarding your question on antibody-drug conjugates, I haven’t been more excited about any drug for patients with metastatic bladder cancer since we saw immune checkpoint inhibitors approved. In the last 2 or 3 years, the most exciting drugs I’m seeing, which are already resulting in very impressive response rates, are the antibody-drug conjugates. I remain very excited with enfortumab vedotin and sacituzumab govitecan. What do you think about these 2 agents? Before we talk about sacituzumab govitecan, what do you think about the enfortumab vedotin data?

Petros Grivas, MD, PhD: I agree with you, Neeraj. We’re very excited about the advent of these agents. We talked about erdafitinib, the first target therapy approved, and obviously, antibody-drug conjugates. Enfortumab vedotin has phase 2 and phase 3 data. To briefly summarize for the audience, the phase 2 trial, EV-201, had 2 cohorts. Cohort 1 was the basis for the accelerated approval by the FDA as of December 2019. This saw a very high overall response rate with enfortumab vedotin as a single agent in patients in the third-line space and beyond after prior platinum-based chemotherapy and checkpoint inhibitor. The response rate was about 44%. That led to the accelerated approval by the FDA.

Now we have the phase 3 trial that compared enfortumab vedotin, this antibody-drug conjugate, vs salvage chemotherapy, a single-agent taxane in the United States, or vinflunine in Europe. It’s an important take-home point that we’ll now have level 1 evidence based on the 2021 ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] presentation, with a hazard ratio of 0.70 favoring enfortumab vedotin vs salvage chemotherapy.

Obviously, in all the agents that we discussed, we have to think about efficacy and toxicity. There are certain things in the toxicity profile of all those agents to keep in mind. For example, in enfortumab vedotin, peripheral neuropathy has been highlighted in those presentations, especially with prior platinum-based chemotherapy. This can be more of an issue. Skin rash has been seen. A small proportion of patients, less than 10%, experienced hyperglycemia, but that can potentially be life-threatening, so it needs attention. There are other adverse effects, including fatigue, alopecia, and nausea. Obviously, this discussion applies to all the agents. But based on the EV-301 trial, it’s possible that enfortumab vedotin may get FDA full approval down the road. We haven’t compared it with other antibody-drug conjugates or erdafitinib, so the optimal sequence has to be defined down the road. Do you have any comments on that?

Neeraj Agarwal, MD: No, you summarized it very well. It’s very nice to know the level 1 evidence now backing the use of enfortumab vedotin in the third-line setting. As we saw from the results of the EV-301 trial, there was a 4-month absolute improvement in overall survival compared with taxane-based chemotherapy in the United States and vinflunine chemotherapy in Europe, and a 30% reduction in risk of death. It’s fantastic news for our patients.

Transcript edited for clarity.