AZD4625 / AstraZeneca - LARVOL DELTA

Comparative profiling of TEAD palmitoylation and YAP-TEAD protein-protein interaction inhibitors as combination agents with KRAS inhibitors (AACR 2026) - "Additionally, the PPI re-sensitized KRASG12C-mutant NCI-H2122 cells resistant to AZD4625, a KRASG12C-selective inhibitor...In contrast to the in vitro results, CPI and PPIs drove equivalent regression of NCI-H2122 NSCLC xenografts when combined with the KRASG12C inhibitor sotorasib, followed by similar outgrowth once dosing was stopped...Collectively, these findings suggest that while differential activity was observed between TEAD CPI and PPIs in vitro, the two modalities drove similar therapeutic benefit in vivo when combined with KRAS inhibitors. Careful exploration of the long-term benefit of TEAD and KRAS inhibitor combinations is warranted due to the disconnect between in vitro and in vivo data."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KRASG12C inhibitor resistance in patient-derived non-small cell lung cancer models (AACR 2024) - "We leveraged our patient-derived xenograft (PDX) and xenograft-derived organoid (XDO) development programs to study primary resistance to the novel G12Ci, AZD4625. Twelve KRASG12C PDX models were established which recapitulated patient tumor histology, and genomic, transcriptomic, and methylome profiles... PDX and XDO are useful models to study resistance to this novel class of inhibitor, with the KRASG12C NSCLC PDX models exhibiting a treatment response rate that is similar to those observed in clinical trials. Global proteomics suggests uniqueness of each model in our cohort, hinting that a universal combination of specific targeted agents to treat KRASG12C LUAD tumors may be insufficient."

Clinical • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DUSP6 • KRAS

Modeling response to the KRAS-G12C inhibitor AZD4625 in KRASG12C NSCLC patient-derived xenografts reveals insights into primary resistance mechanisms. (PubMed, Br J Cancer) - "Our findings confirm AZD4625 as a highly active KRASG12C inhibitor. This data also supports the use of PDX models in understanding resistance mechanisms that may be leveraged to develop more active combination therapies."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DUSP6 • KRAS

AstraZeneca pays $24M to join race for next big KRAS opportunity, bagging Chinese rival to Mirati asset (FierceBiotech) - "The deal furthers AstraZeneca’s long-standing interest in KRAS. In 2012, the drug developer licensed an anti-KRAS antisense oligonucleotide, AZD4785, from Ionis. That candidate never progressed past phase 1, with AstraZeneca pulling the plug after wrapping up a trial in 2019, but the company’s research teams continued to work on the target...After discovering the KRAS G12C inhibitor AZD4625, AstraZeneca tweaked the molecule to generate the clinical candidate AZD4747...the potential for its molecule to penetrate the central nervous system could offer a point of differentiation."

Pipeline update • Solid Tumor