Dr. Brown on EV plus cabozantinib in metastatic urothelial carcinoma

Commentary
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"We could have had our expansion doses [at] 40 mg, but we made the clinical decision to go with 20 mg in expansion based on a hope for future clinical tolerability and longevity," says Jacqueline T. Brown, MD.

In this video, Jacqueline T. Brown, MD, shares the background and key findings from the study, “Interim analysis of a phase I/Ib study of enfortumab vedotin plus cabozantinib in patients with metastatic urothelial carcinoma,” which was presented at the 2024 ASCO Genitourinary Cancers Symposium in San Francisco, California. Brown is a genitourinary medical oncologist at the Winship Cancer Institute and an assistant professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta, Georgia.

Video Transcript:

Could you describe the background for this study?

We're presenting data from our phase 1/1b study of enfortumab vedotin combined with cabozantinib in patients who have metastatic urothelial carcinoma. The idea behind this study is that all of us know that enfortumab vedotin is a really effective drug in urothelial carcinoma, something we've used in third-line for a long time and more recently, something we're using in the first-line with pembrolizumab. So, very active agent. We know that targeted therapy in the form of a TKI, like cabozantinib, has the potential to have some synergy with enfortumab vedotin. Specifically, there was some preclinical data that [suggested] targeted therapy like cabo could lead to increased delivery of an antibody drug conjugate to tumor cells. Then also, we know that there's some immunologic cell kill with EV, or enfortumab. So, [we asked], "can we augment that with a cabozantinib?" That was really the rationale for combining these 2 agents in a phase 1 trial.

What were the key findings from this study?

Our primary end point is safety, as a phase 1/1b study. There was a preliminary signal for efficacy, which we're really excited about, but I'll start by telling you a little bit about the safety. So, this is just 6 patients who are enrolled in the dose escalation phase of our study. There is an ongoing dose expansion phase. I'll set up what the study looked like. There were 2 dose levels in dose escalation. Three patients were enrolled taking cabo 20 mg, and then 3 more patients were enrolled taking cabo 40 mg. All of them received EV starting at the standard dose of 1.25 mg/kg. Within those 6 patients, the combination seems well-tolerated. We were able to dose escalate to 40 mg. The main side effects that we were seeing, that occurred in 4 out of 6 patients, were rash, which was generally grade 1 and manageable, as well as fatigue. Those were the 2 most prevalent side effects we saw. There were 4 serious adverse events in these patients. In the 20 mg cohort, there was an SAE for dehydration. In the 40 mg cohort, there were 3 SAEs, 1 for an acute kidney injury, 1 for neutropenia, and 1 for superior vena cava syndrome. The only grade 4 and the only dose-limiting toxicity of the entire study was the neutropenia. We could have had our expansion doses [at] 40 mg, but we made the clinical decision to go with 20 mg in expansion based on a hope for future clinical tolerability and longevity. That was in terms of the safety. We're very happy about that so far. In terms of preliminary signal for efficacy, of those 6 patients, 100% had a partial response. We're very happy about that. One patient had 100% tumor shrinkage. The only reason that's not classified as a complete response is that patient still had non-measurable disease present on their scans, so they classified as a PR. So, a really nice signal of efficacy. [It] seems pretty tolerable, and we're excited to share more tomorrow.

This transcription has been edited for clarity.

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