Abstract 3044: The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling

Abstract

Abstract Development of drug resistance is one of the main causes of poor prognosis and therapeutic failure in NSCLC. Mutual synergism between cMET and EGFR is known to promote acquired drug resistance. In NSCLC, cMET gene amplification is reported in 2-4% previously untreated patients and in 5-20% of patients with EGFR mutation and acquired resistance to EGFR TKIs. Because of this crosstalk between cMET and EGFR pathways, dual inhibition of these targets holds promise as a treatment for NSCLC patients, especially those with acquired cMET activation. CKD-702 is a bispecific antibody designed to dually target cMET and EGFR. It is tetravalent IgG1-like bispecific antibody, in which single-chain variable fragment specific to EGFR is genetically fused to the c-terminus of a conventional IgG1 of a cMET. The antibody binds to extracellular domains of cMET and EGFR with high affinity and inhibits signaling by blocking ligand binding. CKD-702 also induces internalization and degradation of both receptors. There are various types of cMET activation in NSCLC patients, including point mutations and amplification. An emerging aberrant cMET activation is through a splice site mutation of cMET that leads to skipping of exon 14, inducing prolonged signaling and oncogenic activity. In this study, we carried out genetic analysis of cMET activation in cancer cell line as well as PDX model with or without EGFR mutation, and the efficacy of CKD-702 in each model for NSCLC was determined. CKD-702 showed complete tumor regression as monotherapy in tumor models that have primary/secondary activating EGFR mutations and cMET amplification. Also, CKD-702 resulted in complete tumor regression in models where cMET is activated by either skipping of exon 14 or amplification. Interestingly, unlike other previously developed EGFR-targeting agents, CKD-702 showed limited skin rash in GLP toxicity study. In summary, CKD-702 is confirmed to inhibit tumors with activated cMET pathway such as cMET amplification and exon 14 skipping as well as with EGFR-activating mutations. This profile of preclinical data supports the clinical trial of CKD-702 as monotherapy in selected lung cancer patients with aberrant cMET and EGFR signaling. A Phase I study of CKD-702 is planned to initiate in 2020. Citation Format: kyu jin park, Eun-Ju Jeon, Ji-Hye Choi, Kwan-Woo Lee, Kyung-Woo Lee, Gun-Woo Park, Hae-Jin Hong, In-Chang Hwang, Seung-Kee Moon, Yeo-Wook Koh. The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3044.