Abstract B107: Preclinical activity of ARV-806, a PROTAC KRAS G12D degrader

Abstract The KRAS gene is the most frequently mutated oncogene in cancer cells and is a leading cause of multiple cancers, including pancreatic, colorectal, and lung. There are currently no approved therapies that target the G12D mutation, the most common alteration in KRAS. We developed ARV-806, a potent and selective PROteolysis TArgeting Chimera (PROTAC) KRAS G12D degrader. ARV-806 forms a trimer complex with KRAS G12D and an E3 ubiquitin ligase, which induces ubiquitination of KRAS G12D and its subsequent degradation by the proteasome. ARV-806 engages both the ON (active GTP-bound) and OFF (inactive GDP-bound) forms of KRAS G12D. The mechanism of action of ARV-806 may have advantages compared with other therapeutic modalities (eg, small-molecule inhibitors), as it can eliminate the KRAS G12D protein instead of blocking its function, and its iterative activity may be able to overcome KRAS upregulation that is commonly observed upon inhibitor treatment. ARV-806 demonstrated picomolar degradation potency and antiproliferative activity. In preclinical models of pancreatic and colorectal cancer, ARV-806 showed >25-fold higher potency in inhibition of cell proliferation compared with clinical KRAS G12D OFF and ON inhibitors as well as other KRAS G12D degraders. Additionally, treatment of the AsPC-1 pancreatic cancer spheroid model with ARV-806 robustly suppressed oncogenic c-MYC and induced expression of the pro-apoptotic factor Bcl-2-interacting mediator of cell death (BIM) at concentrations >10-fold lower compared with other agents. Durable pharmacology was observed in vivo, where after a single intravenous dose of ARV-806, KRAS was degraded >90% for 7 days, with c-MYC suppressed and BIM induced for ≥5 days. Accordingly, low weekly or biweekly dosing of ARV-806 resulted in robust regressions (≥30% reduction from baseline in all tumors treated 3 mg/kg biweekly) in cell line–derived xenograft models of pancreatic and colorectal cancer and in a patient-derived xenograft model of lung cancer. Based on this promising preclinical activity, ARV-806 administered weekly or every 2 weeks is currently being evaluated in a phase 1 clinical trial in patients with KRAS G12D–mutated advanced solid tumors (NCT07023731). To expand the utility of PROTAC degraders to additional KRAS mutants and therefore a greater patient population, oral PROTAC pan-KRAS degraders are currently being optimized. These tool degraders display low to sub-nanomolar potencies for multiple KRAS mutants and demonstrate robust efficacy in xenograft models. Additionally, in the mutant KRAS CT26 syngeneic in vivo model, robust single-agent activity was observed as well as strong synergy with immune checkpoint blockade, all resulting in antitumor immunological memory. These combined observations suggest that PROTAC KRAS degraders may be particularly adept at attacking tumors by both eliminating the key oncogenic driver protein and by activating an antitumor immune response. Citation Format: Katie Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Samantha Andella, Jessica Kraus, Jennifer Pizzano, Mark Bookbinder, Greg Cadelina, Debbie Gordon, Noelle Strzalkowski, Ram Lingamaneni, Miklos Bekes, Jessica Teh, Christopher Kuhlberg, Dana Klug. Preclinical activity of ARV-806, a PROTAC KRAS G12D degrader [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B107.