Abstract A015: AB801, a potent and selective clinical-stage AXL inhibitor, enhances the anti-tumor efficacy and duration of response of KRAS inhibitors

Abstract Introduction Novel combination therapies are needed to enhance clinical responses to RAS inhibitors. AXL expression in tumors correlates with poor prognosis and resistance to multiple therapeutics by activating survival bypass signaling. In KRASG12C NSCLC, 85% of tumors express AXL by IHC and high AXL expression reduces sensitivity to a multi-RAS(ON) inhibitor in preclinical models. AB801 is a potent and highly selective AXL inhibitor with minimal off-target activity. It exhibits low clearance, excellent oral bioavailability, and a low potential for drug-drug interactions. AB801 is being evaluated in patients with advanced solid tumors (NCT06120075). Methods The potency, selectivity, metabolism, CYP mediated drug-drug interaction potential, and pharmacokinetic properties of AB801 were assessed in relevant models. AXL and Gas6 expression were analyzed in clinical datasets of patients treated with KRAS inhibitors. Anti-tumor efficacy was evaluated following treatment with AB801 and the KRASG12C inhibitor adagrasib, as single agents and in combination in both murine syngeneic and human xenograft KRASG12C models. PD markers were assessed in xenograft tumors to confirm target engagement. Results Treatment with KRAS inhibitors in the clinic results in rapid upregulation of AXL and its ligand Gas6, supporting bypass survival signaling through the PI3K-AKT pathway. AB801 treatment inhibits phosphorylation of AKT mediated by Gas6. In the syngeneic CMT-167 KRASG12C KI model, AB801 combined with adagrasib, was superior to adagrasib monotherapy, providing significant and durable tumor control and increased survival. Tumor growth inhibition was significantly improved by combining AB801 with adagrasib in the human H1373 KRASG12C xenograft model as well. After treatment withdrawal, significantly better tumor control was maintained in the combination group. Furthermore, treatment with AB801 and adagrasib, after tumor stasis was attained with adagrasib monotherapy, resulted in tumor regression. Conclusion Our data indicates that AXL signaling may limit the efficacy of KRAS inhibitors in the clinic. AB801 demonstrates excellent potency, AXL selectivity, and in vitro and preclinical DMPK properties. AB801, in combination with adagrasib significantly reduces tumor growth and increases survival in mice. The data presented here support the hypothesis that targeting AXL with AB801 in combination with (K)RAS inhibition will produce deeper and longer responses through blockade of survival pathway activation in cancer cells. AB801 is the only potent and selective AXL inhibitor in the clinic and has completed a healthy volunteer study and is undergoing Phase 1 dose escalation in patients. AB801 is well tolerated and demonstrated excellent human PK consistent with a once daily dosing regimen (ARC-27; NCT06120075). Citation Format: Ester Fernandez-Salas, Susan L. Paprcka, Jhansi L. Leslie, Tiffany Huang, Logan Chinn, Jenna Pappalardo, Umida Djakbarova, Dillon H. Miles, Ruben Flores, Gonzalo Barajas, Matt Wright. AB801, a potent and selective clinical-stage AXL inhibitor, enhances the anti-tumor efficacy and duration of response of KRAS inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A015.