Astellas Pharma (TSE: 4503) dosed the first patient in a Phase III trial of setidegrasib, its investigational KRAS G12D-targeted protein degrader, in previously treated advanced non-small cell lung cancer (NSCLC) — a patient population with no approved targeted therapy.
The randomized, open-label Phase III study compares setidegrasib against docetaxel in patients with KRAS G12D-mutated locally advanced or metastatic NSCLC who have progressed on or after platinum-based chemotherapy and checkpoint inhibitor therapy (CPI). The trial carries dual primary endpoints of progression-free survival (PFS), assessed by blinded independent central review, and overall survival (OS), with approximately 356 patients planned across multiple countries.
No therapy is currently approved specifically for KRAS G12D-mutated NSCLC, leaving patients who progress on standard first-line regimens reliant on chemotherapy such as docetaxel. Around 5% of people with NSCLC harbor a KRAS G12D mutation, and NSCLC accounts for approximately 80% of all lung cancer cases, according to Astellas. Docetaxel serves as the comparator arm in this setting, where no targeted option exists for this mutation subtype.
Setidegrasib is designed to work with the cancer cell's own protein degradation machinery to bring together the KRAS G12D protein and an E3 ligase, triggering selective degradation of the disease-driving protein. Phase I data published in The New England Journal of Medicine in March 2026 demonstrated antitumor activity and a manageable safety profile in patients with KRAS G12D-mutated solid tumors, Astellas said.
The NSCLC trial is the second Phase III study of setidegrasib initiated within six months; a Phase III study in front-line KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma (PDAC) began in April 2026. Astellas has positioned the setidegrasib franchise as a central pillar of its post-Xtandi (enzalutamide) growth strategy, with the company's chief R&D officer previously arguing that setidegrasib's mutation-specific degrader approach may offer a cleaner safety profile and easier combinability with chemotherapy compared with pan-KRAS inhibitors.