Dr Dumbrava on Targeting TP53 Y220C Mutations in Solid Tumors With Rezatapopt

"I believe that TP53 is becoming actionable will follow the steps of KRAS and other mutations that were previously considered to be [undruggable]."

Ecaterina Dumbrava, MD, an assistant professor in the Department of Investigational Cancer Therapeutics of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed early findings from the phase 1 PYNNACLE trial (NCT04585750) investigating rezatapopt (PC14586) in patients with solid tumors harboring TP53 Y220C mutations.

Rezatapopt is a small-molecule reactivator of mutant p53 designed to restore normal p53 function, specifically in tumors with the Y220C substitution—a conformational hotspot mutation associated with p53 protein destabilization and loss of tumor suppressor activity. The PYNNACLE trial enrolled patients with advanced solid tumors harboring this alteration, assessing the agent’s safety, pharmacodynamics, and preliminary efficacy.

In early-phase results, rezatapopt demonstrated encouraging antitumor activity, generating an overall response rate exceeding 40% among patients with TP53 Y220C–mutated tumors who did not have co-occurring RAS mutations. These outcomes suggest that TP53 Y220C may represent a clinically actionable genomic alteration when targeted with mutation-specific agents. Responses were observed across multiple tumor types, reinforcing the potential for a histology-agnostic therapeutic approach.

Dumbrava emphasized the importance of increasing clinical awareness regarding the TP53 Y220C mutation, which she said has historically been under-recognized in oncology practice. Despite its relative rarity, the presence of this mutation may guide therapeutic decision-making as targeted options such as rezatapopt become more widely studied and potentially integrated into treatment pathways.

She further noted that the development of rezatapopt parallels the evolution of other targeted therapies, such as those directed against KRAS G12C mutations, underscoring a broader shift toward drug development strategies aimed at historically “undruggable” tumor suppressor mutations. As molecular profiling becomes more comprehensive and routinely implemented in clinical care, identifying patients with TP53 Y220C mutations may enable enrollment into precision oncology trials and support individualized treatment strategies.