Wungki Park, Assistant Attending at Memorial Sloan Kettering Cancer Center and Assistant Professor of Medicine at Weill Cornell Medicine shared a post on LinkedIn.
“We are entering a new phase in targeting one of the most important drivers in cancer. I am proud of our collaborators and study team for this narrative.
Medicinal chemistry – Preclinical science – First human translation.
Our first-in-human phase 1 study of a KRAS G12D-targeted protein degrader TPD (setidegrasib) has now been published in the NEJM Group New England Journal of Medicine with a simultaneous presentation at ELCC 2026.
KRAS mutations have been historically difficult to target. KRAS G12D is particularly important, present in ~40% of pancreatic cancers and ~5% of lung cancers and more in cholangiocarcinoma and gynecologic cancers. This study represents the first clinical demonstration that a degrader strategy can directly degrade this oncogenic protein and translate into meaningful clinical activity.
In previously treated patients:
- NSCLC (2L+ in metastatic setting) showed response rates ~36% with encouraging durability of 12-months survival rate of 59%.
- PDAC (2/3L in metastatic setting, most [14/21] were in 3L) showed response rates ~24% with median overall survival ~10 months.
Importantly, we observed a consistent pharmacologic and biologic signal: drug exposure – KRAS protein reduction – ctDNA suppression – clinical response
The safety profile was favorable, with most treatment-related adverse events limited to transient infusion-related reactions, supporting further development and combination strategies.
This work reflects a global effort and highlights what is possible when translational science and early clinical development are closely integrated.
We are now building on this foundation with ongoing registrational studies, earlier-line combinations, and next-generation KRAS-targeting approaches.
Incredibly grateful to the patients who participated, our collaborators across institutions, and the outstanding team at MSK.”
Title: Setidegrasib in Advanced Non–Small-Cell Lung Cancer and Pancreatic Cancer
Authors: Wungki Park, Anup Kasi, Alexander I. Spira, Luis Paz-Ares Rodríguez, Benjamin O. Herzberg, Meredith S. Pelster, Anthony W. Tolcher, Yasutoshi Kuboki, Shigehisa Kitano, Hirokazu Shoji, Judy S. Wang, Jordan D. Berlin, Antoine Hollebecque, Patricia LoRusso, Christos Fountzilas, Philippe A. Cassier, Tomohiro Nishina, Daisuke Sakai, Chiaki Inagaki, Daniel Morgensztern, Makoto Ueno, Minkyu Jung, Sang-We Kim, Pasi A. Jänne, Antoine Italiano, Benoît You, T. Macarulla, Hisaki Fujii, Aditya Shetty, Ying Lu, Daniel Cui, Shilpa Kadam, Stanley C. Gill, Junko Toyoshima, Takeshi Saito, Jonathan W. Goldman
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