Fulzerasib (GFH-925): A Comprehensive Analysis of a Next-Generation KRAS G12C Inhibitor

Executive Summary

Fulzerasib (GFH-925) is a potent, selective, orally active, and irreversible covalent inhibitor of the KRAS G12C oncoprotein, a therapeutic target that has historically presented significant challenges in drug development.[1] Developed from a novel chemical scaffold, fulzerasib has demonstrated a highly compelling clinical profile that positions it as a formidable agent in the treatment of KRAS G12C-mutated solid tumors. This report provides a comprehensive analysis of its molecular characteristics, mechanism of action, extensive clinical trial data, regulatory trajectory, and strategic positioning within the competitive landscape.

The clinical efficacy of fulzerasib is a standout feature of its profile. In the first-line treatment of Non-Small Cell Lung Cancer (NSCLC), a combination of fulzerasib with the EGFR inhibitor cetuximab yielded an exceptional Objective Response Rate (ORR) of approximately 80% and a median Progression-Free Survival (PFS) of 12.5 months in the KROCUS study, setting a new benchmark for chemo- and immune-free regimens.[4] As a monotherapy in heavily pre-treated patient populations, fulzerasib has shown robust and durable activity. In second-line and later NSCLC, it achieved a confirmed ORR of 49.1% and a median PFS of 9.7 months, leading to its regulatory approval in China.[6] Furthermore, it has demonstrated remarkable efficacy in metastatic Colorectal Cancer (CRC), a setting where other inhibitors have shown modest single-agent activity, with a confirmed ORR of 44.6% and a median PFS of 8.1 months.[8] A critical differentiator is its significant activity against intracranial tumors, addressing the challenging issue of brain metastases.[4]