Disease Stabilization Reflects Clinical Value of Brenetasfusp in Melanoma

Daniel Olson, MD, assistant professor of medicine at the University of Chicago, presents an update on a phase 1 study (NCT04262466) evaluating brenetasfusp, an innovative Immune Mobilizing Monoclonal T-Cell Receptor Against Cancer (ImmTAC) construct designed for patients with advanced melanoma. Brenetasfusp is structurally similar to its predecessor, tebentafusp (Kimmtrak), which is approved for uveal melanoma. The soluble T-cell receptor construct binds specifically to PRAME (Preferentially Expressed Antigen in Melanoma) on tumor cells, while its CD3 binding domain recruits and activates peripheral T cells directly into the tumor microenvironment to drive disease control.

A critical takeaway from this class of ImmTAC therapies is that intermediate clinical end points, such as progression-free survival (PFS) or objective response rates, do not accurately predict long-term overall survival (OS) benefit. Although traditional melanoma therapies like immune checkpoint inhibitors and TIL therapy rely on robust tumor shrinkage to indicate durable success, ImmTACs primarily function through long-term disease stabilization. In this study, brenetasfusp demonstrated a modest objective response rate of 12% and a modest PFS of around 4 months. However, the true clinical value is reflected in a disease control rate exceeding 50% and a clear, decoupled survival signal.

Safety data indicates that brenetasfusp is highly tolerable over the long term. It exhibits a unique phenomenon of tachyphylaxis, where cytokine release syndrome (CRS) is initially observed but rapidly mitigates over time. Utilizing a step-up dosing schedule requires extra monitoring during the initial weeks, but once patients reach their maintenance dose, the treatment becomes routine and well-tolerated. These promising phase 1 results have provided the impetus for an upcoming randomized phase 3 trial (PRISM-MEL; NCT06112314) evaluating brenetasfusp in the frontline setting. By targeting PRAME-positive tumors via a mechanism completely distinct from checkpoint inhibitors, this therapy offers a valuable, non-overlapping frontline option to achieve disease stability.