Abstract 2133: Next-generation sequencing-based MET focal amplification can predict treatment efficacy of MET inhibitors in lung cancer
Authors: Xiang Chan , Guo Lianying , Zhao Ruiying , Teng Haohua , Zhang Zhou , Kuang Ting , Lv Xinze , Hou Ting , Liu Chenglin , Sun Wenjie , Du Haiwei , Han Yuchen 
Published: April 2023

Abstract
Background: MET amplification (METamp) occurs in 1-5% of treatment-naïve or 5-20% of epidermal growth factor receptor tyrosine kinase inhibitors-treated lung cancers (LC). It is a promising therapeutic target in LC. Although fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemical staining (IHC) are available for METamp detection, but the most appropriate detection method and criteria for defining METamp are uncertain. Here, we explored the concordance of these three methods in informing METamp status and identified patients likely to benefit from MET inhibitors.
Methods: Tissue samples from LC patients who underwent MET detection by FISH, NGS, and IHC tests at Shanghai Chest Hospital were retrospectively collected. MET focal amplification and polysomy by FISH were determined as MET/CEP7 ratio ≥ 2, and &lt; 2 with the average MET signals per cell ≥ 5, respectively. NGS-based MET focal amplification and polysomy were determined with in-house scripts (Burning Rock Biotech). Focal amplification and polysomy were defined as METamp-positive. IHC-based MET positive was determined with H-score ≥ 200. FISH was used as a reference.
Results: A total of 231 patients with a median age of 65 years were enrolled. With FISH as reference testing, NGS detection for METamp showed 66.9% (87/130) sensitivity and 95.1% sensitivity (96/101), and IHC had 71.5% (93/130) sensitivity and 91.1% (92/101) specificity. Furthermore, NGS detection for MET focal amplification achieved 87.2% (75/86) sensitivity and 96.6% (140/145) specificity, while MET polysomy detection showed 20.5% (9/44) sensitivity and 98.4% (184/187) specificity. Of 153 treatment-naïve patients, patients with focal amplification (FISH: 16.7%; NGS: 16.3%) had a significantly lower frequency of classic LC oncogene alterations than those with polysomy (FISH: 51.6%, p = 0.001; NGS: 58.3%, p = 0.006) and METamp-negative patients (METneg; FISH: 72.1%, p &lt; 0.001; NGS: 64.1%, p &lt; 0.001). A total of 27 patients had follow-up data. The disease control rate (DCR) to MET inhibitors was 73.1% (19/26) for overall METamp, 81.0% (17/21) for focal amplification, and 40.0% (2/5) for polysomy using FISH results. In contrast, corresponding DCRs using NGS results were 84.2% (16/19), 88.9% (16/18), and 0% (0/1), respectively. Moreover, patients with NGS-based focal amplification had a significantly longer progression-free survival (PFS) than those with polysomy or METneg. Of note, 1 patient with METneg by FISH was determined to harbor focal amplification by NGS and achieved partial response to crizotinib with a PFS of 314 days.
Conclusion: Our results suggest that MET focal amplification leads to oncogenic MET addiction and is associated with promising efficacy of MET inhibitors. MET focal amplification by NGS tests might be a feasible and powerful biomarker to identify LC patients who benefit from MET inhibitors.
Citation Format: Chan Xiang, Lianying Guo, Ruiying Zhao, Haohua Teng, Zhou Zhang, Ting Kuang, Xinze Lv, Ting Hou, Chenglin Liu, Wenjie Sun, Haiwei Du, Yuchen Han. Next-generation sequencing-based MET focal amplification can predict treatment efficacy of MET inhibitors in lung cancer [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 2133.