Abstract 5736: AZD9592: An EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond
Authors: Comer Frank , Mazor Yariv , Hurt Elaine , Yang Chunning , Fleming Ryan , Shandilya Harini , Vijayakrishnan Balakumar , Sterba Meghan , Chen Ruoyan , Rosfjord Edward , Floch Nicolas , Rosenbaum Anton I. , Huang Yue , Yuan Jiaqi , Beaumont Kevin , Godfrey Lisa , McGrath Lara , Arnaldez Fernanda , Sapra Puja 
Published: April 2023

Abstract
De novo and acquired drug resistance can limit the long-term efficacy of targeted cancer therapies such as tyrosine kinase inhibitors targeting key oncogenic drivers like EGFR and cMET. Mechanisms of resistance include secondary mutations of EGFR and cMET and other downstream oncogenic pathways such as KRAS and amplification of alternate growth factor receptors. MET amplification or protein overexpression has been established as the most common mechanism of clinical resistance to EGFR inhibitors such as osimertinib. AZD9592 is a first-in-class bispecific ADC designed to target EGFR and cMET, while overcoming pathway-mediated resistance mechanisms that limit other targeted agents. Here we describe the generation, characterization and preclinical evaluation of AZD9592. The ADC was constructed on the backbone of the clinically validated DuetMab monovalent bispecific IgG platform and was engineered with higher affinity for cMET compared to EGFR (&gt;15 fold), with the aim of reducing EGFR-driven toxicity in normal tissues. The antibody is conjugated via a cleavable linker to a proprietary topoisomerase 1 inhibitor (TOP1i) payload (AZ14170132). The internalization and in vitro cytotoxicity (IC50 in the low nM range) of AZD9592 were found to be optimal when both EGFR and cMET were engaged. When EGFR alone was engaged, cytotoxicity was significantly reduced, consistent with the lower affinity for EGFR. Treatment of cells with AZD9592 induced multiple DNA damage response pathway markers (like ATM, ATR, γΗ2ΑX), consistent with the proposed primary mechanism of action (MOA) of direct tumor-cell killing caused by double strand DNA breaks. AZD9592 monotherapy showed activity in vivo in patient-derived xenograft (PDX) models representing multiple EGFR and cMET expressing tumor types, including both EGFR mutant (m) and wild-type NSCLC and head and neck squamous cell carcinoma. Responses (≥30% regression from baseline tumor volume) were observed across a wide range of clinically relevant dose levels, including a 41% response rate in EGFRm NSCLC tumors treated at the lowest tested dose of 2 mg/kg. AZD9592 combined with osimertinib also showed benefit in PDX models derived from patients who progressed on osimertinib alone, as well as models representing primary resistance (EGFR ex20ins). AZD9592 was well tolerated in cynomolgus monkeys over a 6-week period (dosing every 3 weeks). The key safety findings were limited hematological effects, consistent with the MOA of the TOP1i payload. Plasma pharmacokinetics in cynomolgus monkeys showed an acceptable profile at tolerated doses, in line with other EGFR and cMET directed antibodies. These results demonstrate that AZD9592 has a promising efficacy and safety profile in preclinical models representing diverse opportunities in multiple clinical settings.
Citation Format: Frank Comer, Yariv Mazor, Elaine Hurt, Chunning Yang, Ryan Fleming, Harini Shandilya, Balakumar Vijayakrishnan, Meghan Sterba, Ruoyan Chen, Edward Rosfjord, Nicolas Floch, Anton I. Rosenbaum, Yue Huang, Jiaqi Yuan, Kevin Beaumont, Lisa Godfrey, Lara McGrath, Fernanda Arnaldez, Puja Sapra. AZD9592: An EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5736.