Quanta Therapeutics has announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for QTX3034, a multi-KRAS inhibitor with G12D-preferring activity. This clearance allows Quanta to initiate a Phase 1 clinical trial in the first quarter of 2024, evaluating QTX3034 in patients with advanced solid tumors harboring KRASG12D mutations.
The Phase 1 trial will assess QTX3034 both as a monotherapy and in combination with cetuximab, an EGFR inhibitor. The study will enroll patients with KRASG12D-mutant pancreatic, colorectal, lung, and endometrial cancers. The primary endpoints include safety and tolerability, determination of the maximum tolerated dose and recommended Phase 2 dose, pharmacokinetic properties, antitumor activity, and molecular markers.
Advancing KRAS-Targeted Therapies
In addition to QTX3034, Quanta Therapeutics is also progressing QTX3046, a KRASG12D-selective inhibitor, through IND-enabling activities, with an IND filing anticipated in the first half of 2024. Furthermore, the company has selected QTX3544, a multi-KRAS inhibitor with G12V-preferring activity, as a development candidate, marking Quanta’s third KRAS inhibitor program.
"Patients with KRASG12D-mutant cancers face a poor prognosis and no targeted therapy options," said Leonardo Faoro, MD, MBA, Chief Medical Officer of Quanta Therapeutics. "QTX3034 is the first of our two G12D-focused clinical approaches with QTX3046 following in the first half of 2024. We are confident that advancing two chemically distinct oral small molecules with differentiated mechanisms of action will enable us to achieve our goal of delivering a best-in-class treatment for G12D-mutant patients."
The Significance of KRAS Mutations
KRAS mutations are among the most prevalent oncogenic drivers, occurring in nearly one-quarter of all human cancers. These mutations impair the ability of RAS to switch from its active GTP-bound state to its inactive GDP-bound state, leading to sustained activation of the MAPK signaling pathway and promoting tumorigenesis. KRAS mutations, particularly G12D, G12V, and G12C, are frequently observed in pancreatic, colorectal, and lung cancers.
While first-generation KRAS inhibitors have shown clinical benefit, their impact is primarily limited to patients with the G12C mutation. Quanta Therapeutics aims to address the broader landscape of KRAS-driven cancers by developing inhibitors that target other common KRAS mutations, such as G12D and G12V.
Quanta's Approach to RAS Inhibition
Quanta Therapeutics is employing a unique high-throughput platform that utilizes Second Harmonic Generation (SHG) optical technology to identify allosteric modulators of protein complexes. This approach allows the company to discover novel small molecule cancer medicines that selectively target protein-protein interactions crucial for oncogenic RAS activity.
"Although RAS is one of the most clinically validated targets in oncology, the field’s understanding continues to evolve concerning the mechanisms needed to optimally target and drug KRAS-driven cancer mutations beyond G12C, including G12D and G12V," said Perry Nisen, MD, PhD, Chief Executive Officer of Quanta. "Quanta is uniquely positioned to lead further innovation in the field with our proprietary discovery platform and our RAS biology and medicinal chemistry expertise, enabling us to identify unique chemical scaffolds with functional activity that can then be optimized for best-in-class attributes."
