Abstract 5921: Correlation between MET amplification/overexpression status and response to MCLA-129 in advanced non-small-cell lung cancer (NSCLC): biomarker results from a phase 1 trial

Abstract Background: In this ongoing phase 1b study (NCT04930432) of the MET/EGFR bispecific antibody MCLA-129 in patients (pts) with advanced NSCLC, we aimed to gain a deeper insight into the relationship between MCLA-129 and efficacy in the MET amplification (METamp) or protein overexpression (OE) population. Methods: Eligible pts (≥18 years; ECOG PS 0-1; confirmed metastatic or unresectable NSCLC; and positive EGFR or MET alterations) received MCLA-129 (1500 mg biweekly) intravenously. MET OE was defined as IHC 2+/3+ and METamp was defined based on the gene copy number (GCN). Using a wide range of GCN cut-offs, we aimed to explore its relationship with efficacy outcomes.Results: At data cut-off (March 31, 2024), in 24 NSCLC pts, 6 with MET IHC 2+/3+ and 18 with METamp were evaluable for efficacy. Four out 6 pts with MET IHC 2+/3+ (median No. of previous lines: 1 [0-1]) achieved confirmed PRs (ORR: 66.7% [95% CI 22.3-95.7]), and all these 4 pts harbored concurrent mutations (3 METex14 skipping and 1 EGFR exon20ins). The median DOR and PFS were not reached. Eight out of 18 pts with METamp achieved confirmed PRs (median No. of previous lines: 2 [1-7]) (ORR: 44.4% [95% CI 21.5-69.2]; DOR: NR [2.8-NR]; PFS: 4.8 months [2.7-9.6]). Of 7 pts with METamp (METamp was detected prior to systemic antitumor therapy), 4 pts achieved confirmed PRs, with an ORR of 57.1% (95% CI 18.4-90.1), and all these 4 pts harbored concurrent mutations (2 EGFR exon20ins, 1 METex14 skipping and 1 L861Q). Among 9 pts that progressed on 3rd-generation EGFR-TKIs, 3 pts achieved confirmed PRs. Pts with different cut-offs of MET showed a differentiated ORR (Table). Conclusions: MCLA-129 showed clinically meaningful antitumor activity in advanced NSCLC with MET OE or METamp, particularly in pts with concurrent mutations. High GCN seemed to be associated with better efficacy in MET-amplified advanced NSCLC, suggesting its predictive properties. Citation Format: Jie Wang, Jia Zhong, Yu Yao, Di Wu, Xiujuan Qu, Guojun Zhang, Haibo Zhang, Yu Cao, Zhuang Yu, Kai Chen, Maoqiong Jiang, Zhihua Li, Jianlin Long, Xiubao Ren, Huijuan Wang, Zhehai Wang, Lin Wu, Bolin Chen, Aimin Zang, Haie Chen, Lin Ma, Kan Liu, Peiqi Li, Lieming Ding. Correlation between MET amplification/overexpression status and response to MCLA-129 in advanced non-small-cell lung cancer (NSCLC): biomarker results from a phase 1 trial [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 5921.