Abstract 1708: CKD-702, a novel bispecific antibody, enhances anti-tumor effect of combination with EGFR TKIs in NSCLC preclinical model

Abstract The development of drug resistance is a major cause of poor prognosis and therapeutic failure in NSCLC. The mutual synergism between cMET and EGFR is known to promote acquired drug resistance, which complicates effective treatment strategies. In NSCLC, cMET gene amplification is reported in 2-4% of previously untreated patients and in 5-20% of patients with EGFR mutations and acquired resistance to EGFR TKIs. This crosstalk between the cMET and EGFR pathways underscores the need for dual inhibition as a promising treatment for NSCLC patients, especially those with acquired cMET activation. cMET, a proto-oncogene encoding the RTK HGFR, plays a crucial role in cell proliferation, motility, and survival. Aberrant activation of cMET through gene amplification, mutation, or overexpression has been implicated in the development of various cancers, including NSCLC. EGFR, another critical RTK, is frequently mutated in NSCLC, leading to uncontrolled cell growth and survival. The interplay between cMET and EGFR signaling pathways facilitates the emergence of resistance to EGFR TKIs, a common occurrence in NSCLC patients undergoing treatment. This resistance often results from secondary mutations in the EGFR gene, such as T790M and C797S, or from activation of alternative signaling pathways, including cMET amplification. CKD-702 is a bispecific antibody specifically designed to target both cMET and EGFR. It is a tetravalent IgG1-like bispecific antibody, in which a single-chain variable fragment specific to EGFR is genetically fused to the C-terminus of a conventional IgG1 of cMET. This innovative design allows CKD-702 to bind with high affinity to the extracellular domains of both cMET and EGFR, effectively inhibiting their signaling by blocking ligand binding. Additionally, CKD-702 induces the internalization and degradation of both receptors, thereby further inhibiting their activity and downstream signaling pathways. This study aims to evaluate the efficacy of combination therapy with EGFR TKIs and CKD-702 for overcoming resistance in NSCLC, particularly in EGFR exon 20 insertion mutant models and triple mutant models, including the C797S mutation. The combination therapy demonstrates superior efficacy compared to monotherapy in both cellular and animal models, effectively inhibiting signaling pathways and tumor growth. These findings are promising for addressing the significant challenge posed by the development of resistance to EGFR TKIs in the treatment of NSCLC. A Phase I study of CKD-702, which began in 2020, is currently ongoing. Current clinical trials of CKD-702 monotherapy show promising results, with combination therapy being considered to address resistance mechanisms in NSCLC. Citation Format: Mi Jin Yoon, Soon-Ki Hong, Gun-Woo Park, Kyung-Woo Lee, Sunhong Kim, Young-Shin Kwak, Ju-Hee Lee. CKD-702, a novel bispecific antibody, enhances anti-tumor effect of combination with EGFR TKIs in NSCLC preclinical model [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 1708.