A first-in-human trial testing setidegrasib against KRAS G12D–driven lung and pancreatic cancers reported early clinical success, published by an international consortium in the New England Journal of Medicine. Setidegrasib is designed as a targeted therapy aimed at the KRAS G12D mutation, a common driver across aggressive tumor types. The report highlights the initial clinical proof-of-concept for a mutation-specific strategy in KRAS-driven disease, including enrollment of patients with pancreatic ductal adenocarcinoma and non–small-cell lung cancer. The study supports continued development in a field still searching for durable, broadly effective KRAS mutation coverage. Clinicians and drug developers will now focus on the durability of responses, safety signals, and whether the approach meaningfully expands benefit over existing KRAS-targeted programs that have been more narrowly mutation-defined.