Dr Garmezy on the Rationale for Developing Zelenectide Pevedotin in Urothelial Cancer

"The concept of this drug is [to ask]: How do we learn from targeting NECTIN-4 and perhaps provide not just another option to patients, but also provide a drug with a different toxicity profile as well?"

Benjamin Garmezy, MD, assistant director, Genitourinary Research, Sarah Cannon Research Institute, discusses the rationale for developing zelenectide pevedotin (BT8009) for patients with metastatic urothelial carcinoma who are enfortumab vedotin-ejfv (Padcev)–naive in the phase 1/2 Duravelo-1 trial (NCT04561362)

NECTIN-4 is a validated target in metastatic urothelial carcinoma, with enfortumab vedotin demonstrating significant activity against this target, Garmezy begins. Although enfortumab vedotin has proven effective, drug development should not stop with a single approved therapy, he states. In diseases like kidney cancer, multiple TKI combinations have been approved over time, with each new generation offering improved outcomes due to advances in medicinal chemistry, Garmezy details. The development of BT8009 builds on this concept, aiming to provide not only another treatment option but also a potentially different toxicity profile, he explains.

The continued development of BT8009 is supported by the validated nature of both the NECTIN-4 target and its payload, which has shown success in patients with urothelial carcinoma, Garmezy continues. However, there are gaps in the treatment landscape for patients who cannot receive enfortumab vedotin due to toxicity or intolerance, such as skin rash, neuropathy, and eye toxicity, he notes. BT8009 may offer a more favorable balance of efficacy and adverse effects (AEs) compared with enfortumab vedotin, making it a promising alternative for these patients, Garmezy explains.

The goal is to continually improve therapies for metastatic urothelial carcinoma, addressing both treatment durability and quality of life, Garmezy reiterates. By testing novel therapies like BT8009, there is an opportunity to enhance treatment outcomes while minimizing AEs for patients, he concludes.

The ongoing phase 2/3 Duravelo-2 trial (NCT06225596) is assessing zelenectide pevedotin alone or in combination with pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer who are either treatment naive or have received at least 1 prior systemic therapy.