Astellas Pharma Inc. has dosed the first patient in a Phase 3 study evaluating setidegrasib, an investigational KRAS G12D-targeted protein degrader, against docetaxel in patients with KRAS G12D-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC).

The randomised, open-label study will enrol approximately 356 patients whose disease has progressed following initial platinum-based chemotherapy and Checkpoint Inhibitor Therapy (CPI). The trial will assess whether setidegrasib can provide a new treatment option for patients with this molecularly defined form of NSCLC.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths worldwide. NSCLC accounts for approximately 80 percent of lung cancer cases, while KRAS G12D mutations are found in around 5 percent of people with NSCLC. Currently, no therapies are specifically approved for KRAS G12D-mutated NSCLC, leaving patients whose disease progresses after initial treatment with standard systemic therapies such as chemotherapy.

Setidegrasib is designed to selectively degrade and eliminate the KRAS G12D protein that drives cancer cell signalling. The investigational therapy works by engaging the cancer cell’s natural protein degradation machinery, bringing the KRAS G12D protein together with an E3 ligase to trigger its selective degradation.

The Phase 3 study follows early clinical findings published in The New England Journal of Medicine in March 2026. Those findings demonstrated antitumour activity and a manageable safety profile in patients with KRAS G12D-mutated solid tumours, providing clinical support for further evaluation of setidegrasib.

The trial will compare setidegrasib with docetaxel in patients with KRAS G12D-mutated locally advanced, unresectable or metastatic NSCLC. Its dual primary endpoints are Progression-Free Survival (PFS), assessed through blinded independent central review, and Overall Survival (OS).

Hidenori Kitai, MD, PhD, Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, said patients with KRAS G12D-mutated NSCLC have had limited treatment options following standard therapies. He said the Phase 3 study will help establish whether setidegrasib could offer a new approach for this patient population.

Tadaaki Taniguchi, MD, PhD, Chief Research and Development Officer at Astellas, said the initiation of the NSCLC trial represents continued progress in the clinical development of setidegrasib. He added that the study will evaluate whether the drug’s protein-degradation mechanism can address unmet treatment needs in KRAS G12D-mutated NSCLC.

The latest trial is Astellas’ second Phase 3 study of setidegrasib initiated within six months. The company began a Phase 3 study of the drug in first-line pancreatic ductal adenocarcinoma (PDAC) in April 2026.

Astellas will also present translational analyses from its Phase 1 study of setidegrasib in patients with KRAS G12D-mutated PDAC at the AACR Conference on Pancreatic Cancer, scheduled for September 25–28, 2026. The analyses are expected to provide additional insights into treatment response, resistance mechanisms and potential combination strategies in pancreatic cancer.

The Phase 3 NSCLC study is part of Astellas’ broader clinical development strategy for setidegrasib. The company aims to initiate five or more Phase 3 or pivotal studies by fiscal year 2027.

Setidegrasib is Astellas’ lead investigational targeted protein degrader and was discovered and developed through the company’s internal research and development programmes. Astellas is evaluating the compound as a potential treatment for cancers driven by the KRAS G12D mutation.