Abstract PR014: Integrated translational analyses of the first generation KRAS G12D degrader setidegrasib identify mechanisms of response and resistance and offers rational combination strategies in pancreatic cancer
Wungki Park, Shilpa Kadam, Anup Kasi, Teresa Macarulla, Christos Fountzilas, Makoto Ueno, Takeshi Saito, Stanley C. Gill, Erica Tong, Hui Yang, Sebastian Gloskowski, Joshua Sallin, Gustave Ronteix, Fanny Jaulin, Hisaki FujiiAbstract
Background:
KRAS G12D is a prevalent oncogenic driver in PDAC, which has a high unmet need due to few effective targeted therapies. Setidegrasib, a novel KRAS G12D-targeted protein degrader, eliminates the oncogenic driver to suppress downstream signaling and induce tumor cell death. Early clinical activity was reported in an ongoing Phase 1 study (NCT05382559). We present exploratory analyses to characterize the biological activity of setidegrasib and inform biomarker-driven combination strategies.
Methods:
Patients with locally advanced KRAS G12D-mutant PDAC and prior standard therapies received 140–800 mg setidegrasib monotherapy IV QW. Longitudinal tumor biopsies and plasma were analyzed by transcriptomic profiling to assess KRAS-MAPK signaling, tumor cell states, and the tumor microenvironment (TME). ctDNA analyses enabled real-time monitoring of tumor burden and molecular response. Target engagement was assessed by KRAS G12D IHC, downstream pharmacodynamic effects by tumor gene expression profiling, and TME by multiplex immunofluorescence. Parallel patient-derived organoid (PDO) studies and AI modeling evaluated resistance mechanisms and combination strategies.
Results:
Data cutoff was November 10, 2025. Samples from 124 patients with KRAS G12D-mutant PDAC (10–90mg=26; 140mg=5; 200mg=12; 300mg=30; 450mg=10; 600mg=31; 800mg=10) were analyzed. Setidegrasib demonstrated durable on-target activity, including robust KRAS G12D degradation (median 95.5%) and downstream MAPK suppression. Transcriptomic and proteomic analyses confirmed differential inhibition of MYC, RAS, and cell-cycle signaling in responders versus non-responders. Baseline tumors from non-responders harbored more co-mutations than responders (NR:R; TP53, 93:87%; SMAD4, 29:0%; CDKN2A, 50:20%; MTAP, 21:0%; EGFR, 7:0%). Major molecular responses were observed in 90% (9/10) of responders by C2D1, marked by a >90% reduction in KRAS G12D ctDNA VAF. Distinct ctDNA trajectories of response and resistance were observed. Progressors exhibited epithelial-mesenchymal transition programs, indicating adaptive tumor plasticity and resistance evolution. Responders demonstrated host anti-tumor immune activation characterized by apoptotic tumor cell death, GZMB+ CD8+ T-cell-mediated tumor clearance through Fas/FasL interactions, and IFN-γ signaling, followed by immune exhaustion with increased PD-L1 expression. PDO studies and AI modeling predicted clinical outcomes and biological activity, and further demonstrated improved outcomes with setidegrasib plus FOLFIRINOX, supporting a rational combination strategy.
Conclusions:
Setidegrasib demonstrated promising activity in PDAC with robust target engagement, durable pathway suppression, and TME modulation. Translational analyses identified a distinct, targetable resistance landscape, supporting continued development of setidegrasib in combination with FOLFIRINOX for PDAC (NCT07409272) to enhance clinical benefit.
Citation Format:
Wungki Park, Shilpa Kadam, Anup Kasi, Teresa Macarulla, Christos Fountzilas, Makoto Ueno, Takeshi Saito, Stanley C. Gill, Erica Tong, Hui Yang, Sebastian Gloskowski, Joshua Sallin, Gustave Ronteix, Fanny Jaulin, Hisaki Fujii. Integrated translational analyses of the first generation KRAS G12D degrader setidegrasib identify mechanisms of response and resistance and offers rational combination strategies in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr PR014.