Abstract A100: AXL Inhibitor AB801 Increases the Anti-Tumor Efficacy of KRAS Inhibition

Abstract Introduction AXL receptor tyrosine kinase (AXL) is highly expressed in a variety of tumors.High levels of AXL are correlated with poor prognosis in cancer patients and mediate resistance to multiple therapeutic modalities. In the clinic, over half of patients treated with KRAS inhibitors progress in less than 7 months. Importantly, 85% of KRAS G12C-mutant NSCLC tumors express AXL by IHC and AXL expression was shown to reduce sensitivity to a multi-RAS (ON) inhibitor.Inhibition of (K)RAS results in upregulation of AXL as well as its ligand, Gas6, to support resistance likely through activation of the PI3K-AKT pathway. Here we show that AXL inhibition by AB801, a potent and selective small molecule AXL inhibitor, in combination with adagrasib significantly reduces tumor growth and increases survival in multiple in vivo models. Methods Cancer cell lines and mice were treated with adagrasib and/or AB801.Levels of phospho-AXL, phospho-AKT, phospho-ERK and phospho-S6 were assessed by Western blot.Anti-tumor efficacy was evaluated following treatment with AB801 and adagrasib as single agents and in combination in both murine syngeneic and human xenograft KRAS G12C mutant tumor models. Results Treatment of multiple cell lines with Gas6 increased phosphorylation of AKT, which was inhibited by AB801 in vitro. At doses used for efficacy studies, adagrasib inhibited ERK and ribosomal protein S6 phosphorylation in tumors in vivo.In the syngeneic CMT-167 KRAS G12C KI lung cancer model, combining AB801 with adagrasib significantly enhanced tumor growth inhibition and increased survival, relative to single agent adagrasib treatment.In the H1373 KRAS G12C human lung cancer xenograft model, tumor growth inhibition was significantly enhanced by combining AB801 with adagrasib.These results were observed when dosing of both agents was initiated concurrently and when AB801 dosing was initiated after tumor stasis was attained with adagrasib monotherapy. Conclusion AB801 is being evaluated in ARC-27 (NCT06120075), a Phase 1/1b study in patients with advanced solid tumors with plans for an expansion cohort in 2L+ NSCLC.These data support the notion that combining AB801 with (K)RAS inhibition has the potential to overcome the resistance often observed with (K)RAS inhibitor monotherapy, leading to deeper and more durable clinical responses. Citation Format: Jhansi L. Leslie, Logan Chinn, Umida Djakbarova, Ruben Flores, Gonzalo Barajas, Ester Fernandez-Salas, Susan L. Paprcka. AXL Inhibitor AB801 Increases the Anti-Tumor Efficacy of KRAS Inhibition [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 A100.