Abstract 5615: ALRN-0192519 is a potent and selective EGFR L858R mutation inhibitor that demonstrates anti-cancer activity in preclinical cancer models as monotherapy or in combination with osimertinib

Epidermal growth factor receptor (EGFR) therapy with small-molecule tyrosine kinase inhibitors (TKIs) is initially effective in patients with EGFR-mutant lung cancer, but resistance to the treatment typically emerges over time. EGFR allosteric inhibitors bind to a distinct site on the EGFR protein, separate from the ATP-binding site targeted by existing EGFR TKIs, offering a potential strategy to overcome resistance associated with EGFR mutations. Here we report the development and preclinical characterization of ALRN-0192519, a novel, orally bioavailable small molecule mutant-selective allosteric EGFR inhibitor. In an enzymatic assay, ALRN-0192519 potently inhibits the activity of EGFR carrying L858R mutation with 50% inhibitory concentration (IC50) in the sub-nanomolar range. A very low hit rate is observed when ALRN-0192519 is assessed in kinome profiling, further revealing the selectivity of this compound. ALRN-0192519 exhibits single-digit nanomolar potency against the proliferation of BaF3 cells carrying different EGFR mutations and is more than 400× fold selective against BaF3 EGFR WT cells. In addition, X-ray crystal structure analysis revealed ALRN-0192519 as an EGFR allosteric binder. ALRN-0192519 led to tumor regression in multiple EGFR dependent CDX and PDX tumor models with daily oral dosing, while showing no effects on tumor growth in the EGFR WT xenograft tumor model at comparable dosing levels. When combined with osimertinib, ALRN-0192519 delayed the tumor regrowth much longer than osimertinib alone, demonstrating the potential advantage of combination therapy. Taken together, these results support that ALRN-0192519 is a promising EGFR allosteric inhibitor for treating lung cancer patients with the EGFR L858R mutation as either monotherapy or in combination with osimertinib. Citation Format: Jiaqi Liang, Yezhen Zhang, Lisha Xie, Jihong Chen, Xipan Liu, Wenheng Liang, Tingru Zhou, Xiaobin Zhang, Tao Ji, David Pirovich, Xiang Zhai, Yipin Lu, Ming Yu, John Campbell, Fang Li, Yaoyu Chen, Lina Gu. ALRN-0192519 is a potent and selective EGFR L858R mutation inhibitor that demonstrates anti-cancer activity in preclinical cancer models as monotherapy or in combination with osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5615.