Targeting Trop-2 in Advanced Urothelial Carcinoma - Episode 10

Trop-2–Targeting ADC Therapy for Advanced Urothelial Carcinoma

The rationale for treating patients with advanced urothelial carcinoma with sacituzumab govitecan, a novel antibody-drug conjugate now approved that targets Trop-2.

Neeraj Agarwal, MD: I would like to ask you about sacituzumab govitecan. You are leading these trials, so please tell us about the mechanism of action. Obviously, this is a much newer and somewhat lesser-known drug than enfortumab vedotin. What do you think about the novelty of the mechanism of action of sacituzumab govitecan compared with enfortumab vedotin?

Petros Grivas, MD, PhD: Thanks, Neeraj. It’s a very good question. Just for context, the 2 different antibody-drug conjugates are very distinct in their mechanisms of action. Obviously, they have different targets, Nectin-4 for enfortumab vedotin, and Trop-2 for the sacituzumab govitecan. You also have a different linker and different toxin payload chemotherapy drug. Enfortumab vedotin uses Nectin-4 as a target and MMAE, monomethyl auristatin E, as a chemotherapy microtubule disruptor. This is different. Sacituzumab govitecan has Trop-2 as the target, and the toxin payload is SN-38, which is a metabolite of irinotecan, a topoisomerase 1 inhibitor. I want to make the point that antibody-drug conjugates are not one-size-fits-all. They’re very different drugs. They’re under the umbrella category of antibody-drug conjugates, but they’re very different because of the different structure. Nectin-4 is conjugated with MMAE for enfortumab vedotin, and Trop-2 is conjugated with SN-38 for sacituzumab govitecan.

The data from sacituzumab govitecan comes from the TROPHY-U-01 trial. Neeraj, you’re a big part of that trial. You’re a part of the study and the prominent author in the paper published in the JCO [Journal of Clinical Oncology] just a couple of months ago. The TROPHY-U-01 trial had different cohorts. Cohort 1 seems similar to the EV-201 cohort 1. It evaluated sacituzumab govitecan, this antibody-drug conjugate against Trop-2, in patients with prior progression on chemotherapy and immune checkpoint inhibitor, so in the third line and beyond. A significant proportion of patients had more than 3 prior lines of therapy. This is a heavily pretreated population of patients and a high proportion of patients with a high Bellmunt risk score. They’re heavily pretreated and a population with poor prognosis.

Sacituzumab govitecan, the antibody-drug conjugate against Trop-2, saw a very impressive response rate of 27% in patients who were heavily pretreated. This led to the accelerated approval of sacituzumab govitecan by the FDA as of April 13, 2021. This response rate was also corroborated by the promising signal of PFS [progression-free survival] and OS [overall survival]. However, I always have great caution in how you interpret the signal of PFS and OS in the context of a single-arm phase 2 study like TROPHY-U-01 cohort 1.

The toxicity profile is different from enfortumab vedotin. We can briefly comment on that. Neutropenia can be an issue with sacituzumab govitecan. However, neutropenia is usually well managed by either dose hold, dose reduction, or use of growth factor support. It’s irrelevant because only about 10% of patients had febrile neutropenia. It’s usually managed by dose reductions or growth factor. Diarrhea can happen in about two-thirds of the patients, usually grade 1 or 2, and is usually managed well with antidiarrheal medications, hydration, electrolytes, and education of patients. Despite the high frequency, the grade 3 diarrhea is rare. It’s less than 10%. Other adverse effects, like alopecia, fatigue, nausea, skin changes, and nail changes, appear to be manageable. Overall, I would say it has a manageable safety profile and is another important tool we have.

Transcript edited for clarity.