Astellas Doses First Patient in Phase 3 Trial of KRAS G12D Degrader Setidegrasib in Previously Treated NSCLC
Key Insights
Astellas has dosed the first patient in a randomized Phase 3 study of setidegrasib versus docetaxel in KRAS G12D (search)-mutated advanced NSCLC after platinum chemotherapy and checkpoint inhibitor therapy.
The open-label trial plans to enroll approximately 356 patients across multiple countries, with dual primary endpoints of progression-free survival by blinded independent central review and overall survival.
Setidegrasib is an investigational targeted protein degrader that recruits an E3 ligase (search) to eliminate the KRAS G12D (search) protein, a mutation found in roughly 5% of NSCLC cases.
Astellas Pharma has dosed the first patient in a randomized Phase 3 study of setidegrasib, an investigational KRAS G12D (search)-targeted protein degrader, compared with docetaxel in people with KRAS G12D-mutated locally advanced (unresectable) or metastatic non-small cell lung cancer (search) (NSCLC) whose disease has progressed on or after platinum-based chemotherapy and checkpoint inhibitor therapy.
The trial, registered as NCT07566052, is open-label and plans to enroll approximately 356 patients across multiple countries. Its dual primary endpoints are progression-free survival (PFS), assessed by blinded independent central review, and overall survival (OS). Both endpoints are required because PFS alone in second-line NSCLC has not reliably predicted OS benefit, and regulators increasingly want to see the harder number.
A Mutation Without a Targeted Option
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide, with NSCLC accounting for approximately 80% of cases. Around 5% of people with NSCLC carry a KRAS G12D (search) mutation. Despite advances in targeted treatment for other molecularly defined forms of NSCLC, no therapies are approved specifically for KRAS G12D-mutated disease, and patients whose disease progresses after initial treatment currently rely on standard systemic options such as chemotherapy.
Existing approved KRAS inhibitors target the G12C substitution specifically; neither sotorasib nor adagrasib covers G12D, leaving this subgroup without a targeted option. Docetaxel, the comparator in the new study, was approved by the FDA for this setting in 2000.
Degradation Rather Than Occupancy
Setidegrasib takes a different approach from binding-pocket inhibition. Rather than occupying the mutant protein's binding pocket, it is designed to work with the cancer cell's own protein degradation machinery, bringing together the KRAS G12D (search) protein and an E3 ligase (search). This triggers selective degradation of the disease-driving protein, which may disrupt cancer cell signaling and destroy cancer cells. The compound was discovered and advanced through Astellas' in-house R&D capabilities and is the company's lead investigational targeted protein degrader.
The Phase 3 study in previously treated NSCLC builds on early clinical evidence published in The New England Journal of Medicine in March 2026, which demonstrated antitumor activity and a manageable safety profile in patients with KRAS G12D (search)-mutated solid tumors, supporting the proposed mechanism of action. Efficacy and safety data in advanced NSCLC with KRAS G12D mutation were also presented at the European Lung Cancer Congress in March 2026.
Hidenori Kitai, M.D., Ph.D., of the Department of Respiratory Medicine at Hokkaido University in Japan, said: "For too long, patients with KRAS G12D (search)-mutated non-small cell lung cancer (search) have had limited treatment options after standard therapies. This Phase 3 study represents an important step forward for the field, helping to build the evidence needed to understand whether setidegrasib could offer a potential new approach for this molecularly defined patient population."
Second Phase 3 in Six Months
The NSCLC study follows the initiation of a Phase 3 trial of setidegrasib in front-line pancreatic ductal adenocarcinoma (search) (PDAC) in April 2026, registered as NCT07409272, which evaluates the degrader given with either mFOLFIRINOX or NALIRIFOX chemotherapies. Tadaaki Taniguchi, M.D., Ph.D., Chief Research and Development Officer at Astellas, said the initiation of the NSCLC study, the second Phase 3 of setidegrasib within six months, "reflects continued progress in its clinical development."
Astellas said the milestone supports its Corporate Strategic Plan, which carries an ambition to initiate five or more Phase 3 or pivotal studies by fiscal year 2027.
Translational Data at AACR
Astellas will present integrated translational analyses from the Phase 1 study of setidegrasib in patients with KRAS G12D (search)-mutated PDAC at the AACR Conference on Pancreatic Cancer, held September 25 to 28, 2026, in San Diego. The analyses cover mechanisms of response and resistance and potential rational combination approaches in pancreatic cancer, and will be featured in both a proffered oral presentation and a poster presentation. Wungki Park of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center is the lead author.
Resistance mechanisms identified in pancreatic KRAS G12D (search) disease will likely inform how the NSCLC trial interprets its own signals, particularly if the OS curve splits late or not at all.
The safety and efficacy of setidegrasib have not been established for the uses being investigated, and there is no guarantee that it will receive regulatory approval or become commercially available for those uses.