Gedatolisib (PF-05212384): A Comprehensive Profile of a First-in-Class Pan-PI3K/mTOR Inhibitor Poised to Redefine Treatment Paradigms in Advanced Solid Tumors

Executive Summary

Gedatolisib (PF-05212384, PKI-587) is an investigational, intravenously administered, small molecule therapeutic poised to become a first-in-class dual inhibitor of the phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling pathways. Developed by Celcuity Inc., this agent is distinguished by its unique mechanism of action, which involves the potent, comprehensive, and simultaneous inhibition of all four Class I PI3K isoforms (p110α, β, γ, δ) and both critical mTOR complexes (mTORC1 and mTORC2). This complete blockade of the PI3K/AKT/mTOR (PAM) signaling cascade is designed to overcome the adaptive resistance mechanisms that have limited the efficacy of previous single-node pathway inhibitors.

The clinical development of Gedatolisib is anchored by the pivotal Phase 3 VIKTORIA-1 trial, which has yielded practice-changing results in a population with a profound unmet medical need: patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC) whose disease has progressed following treatment with a CDK4/6 inhibitor. In the PIK3CA wild-type cohort, a population with historically poor outcomes, Gedatolisib in combination with palbociclib and fulvestrant demonstrated an unprecedented 76% reduction in the risk of disease progression or death, extending median progression-free survival (PFS) to 9.3 months compared to 2.0 months with fulvestrant alone.