AstraZeneca has initiated clinical development of AZD0022, a novel oral KRASG12D-selective inhibitor designed to target one of the most challenging oncogenes in cancer treatment. The drug is currently being evaluated in the ALAFOSS-01 study (NCT06599502), a first-in-human, open-label, multicenter Phase I/IIa trial for patients with KRASG12D-mutated solid tumors.
Preclinical Efficacy and Selectivity
Preclinical studies demonstrate that AZD0022 delivers robust pathway inhibition and anti-tumor activity specifically in KRASG12D models. The compound exhibits oral bioavailability and effectively suppresses KRAS pathway activity in xenograft models, supporting its potential as an oral therapeutic option for patients with KRASG12D mutations.
The therapeutic responses observed in KRASG12D colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) models were significantly enhanced when AZD0022 was combined with cetuximab. This combination treatment resulted in sustained tumor regressions in both cancer types, suggesting potential synergistic effects between the KRASG12D inhibitor and the EGFR-targeting monoclonal antibody.
Clinical Trial Design and Structure
The ALAFOSS-01 study is structured in two main modules, each designed to evaluate different treatment approaches. Module 1 focuses on AZD0022 monotherapy and includes multiple parts: dose escalation (Part A), dose optimization (Part B), potential efficacy expansion (Part C), and a food effect cohort to assess the impact of food on drug absorption.
Module 2 investigates the combination of AZD0022 with cetuximab, incorporating both dose escalation (Part A) and dose optimization (Part B) phases. Cetuximab, marketed as Erbitux®, is a recombinant chimeric human/mouse immunoglobulin G monoclonal antibody that binds to EGFR and competitively inhibits the binding of EGFR and other ligands.
Target Patient Population
The trial targets patients with KRASG12D-mutated solid tumors, including colorectal cancer, lung cancer, non-small cell lung cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. KRASG12D mutations represent a significant subset of KRAS mutations, which are among the most common oncogenic drivers in human cancers.
Mechanism of Action
AZD0022 functions as an oral KRASG12D inhibitor that specifically blocks KRASG12D function in patients carrying this mutation. The drug's selectivity for the G12D variant of KRAS represents a targeted approach to addressing this historically "undruggable" oncogene, potentially offering improved therapeutic outcomes with reduced off-target effects.
The preclinical pharmacology profile of AZD0022 supports its development as both a monotherapy and in combination with other agents, positioning it as a versatile treatment option for patients with KRASG12D-mutated cancers across multiple tumor types.
