CEACAM5是一种表达在某些固体肿瘤上皮细胞表面的糖蛋白。Tusamitamab ravtansine（SAR408701）是一个靶向CEACAM5的人源化抗体药物结合物，正在临床开发中，用于CEACAM5高表达的非鳞状非小细胞肺癌（NSQ-NSCLC）（定义为在≥50％的肿瘤细胞中，膜状CEACAM5免疫组织化学染色强度为≥2+）。我们研究了NSQ-NSCLC患者源自异体移植模型（PDX）的CEACAM5免疫组织化学表达、ELISA检测的CEACAM5蛋白表达和RNA-seq检测的CEACAM5 RNA表达之间的相关性，并研究了这些模型对tusamitamab ravtansine的肿瘤反应。我们评估了CEACAM5高表达的流行病学特征和临床队列中非鳞状非小细胞肺癌患者的分子标记物。在一个包含10个NSQ-NSCLC样本的肺PDX集中，CEACAM5的免疫组织化学、ELISA和RNA-seq之间的相关性范围在0.72至0.88之间。在一个更大的肺PDX集中，NSQ-（n = 93）与SQ-NSCLC（n = 128）模型中出现了更高的H分数，并且在这些NSQ-NSCLC模型中的12例中，tusamitamab ravtansine对CEACAM5高表达的肿瘤有更多的肿瘤反应（5/8；62.5％），相比之下，对CEACAM5中等或阴性表达的肿瘤的肿瘤反应较少（1/4；25％），其中6个应答者中有3个患有KRAS突变。在临床NSQ-NSCLC样本中，CEACAM5高表达的患病率分别为原发肿瘤为(52/214；24.3％)，转移灶为(6/17；35.3％)。在NSQ-NSCLC原发肿瘤中，与野生型相比，KRAS变异体（35.0％vs19.5％；P = 0.028）和程序性细胞死亡配体1（PD-L1）阴性（肿瘤细胞0％）/低（1-49％）和高（≥50％）（33.3％，26.1％，5.0％；P = 0.031）中CEACAM5高表达的患病率显著较高，但EGFR突变与野生型（20.0％vs25.7％；P = 0.626）之间无显著差异。在NSQ-NSCLC肿瘤中，CEACAM5高表达的患病率总体为24.3％，KRAS变异和PD-L1阴性/低的患病率较高，而EGFR突变与否无论如何患病率都接近。这些研究结果支持以CEACAM5为靶点，并且支持tusamitamab ravtansine在CEACAM5高表达的NSQ-NSCLC患者中进行临床开发。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。

CEACAM5 is a cell-surface glycoprotein expressed on epithelial cells of some solid tumors. Tusamitamab ravtansine (SAR408701), a humanized antibody-drug conjugate targeting CEACAM5, is in clinical development for nonsquamous non-small cell lung cancer (NSQ-NSCLC) with CEACAM5 high expression (HE), defined as membranous CEACAM5 immunohistochemistry staining at ≥ 2+ intensity in ≥ 50% of tumor cells.We investigated correlations between CEACAM5 expression by immunohistochemistry, CEACAM5 protein expression by ELISA, and CEACAM5 RNA expression by RNA-seq in NSQ-NSCLC patient-derived xenograft (PDX) models, and tumor responses to tusamitamab ravtansine in these models. We assessed prevalence of CEACAM5 HE, clinicopathologic characteristics and molecular markers in patients with NSQ-NSCLC in clinical cohorts.In a lung PDX set of 10 NSQ-NSCLC specimens, correlations between CEACAM5 by IHC, ELISA and RNA-seq ranged from 0.72 to 0.88. In a larger lung PDX set, higher H-scores were present in NSQ- (n = 93) vs SQ-NSCLC (n = 128) models, and in 12 of these NSQ-NSCLC models, more tumor responses to tusamitamab ravtansine occurred in CEACAM5 HE (5/8; 62.5%) versus moderate or negative expression (1/4; 25%), including 3 with KRAS mutations among the 6 responders. In clinical NSQ-NSCLC samples, CEACAM5 HE prevalence was (52/214; 24.3%) in primary tumors and (6/17; 35.3%) in metastases. In NSQ-NSCLC primary tumors, CEACAM5 HE prevalence was significantly higher in KRAS-altered versus wild-type (35.0% vs 19.5%; P = 0.028) and in programmed cell death ligand 1 (PD-L1) negative (tumor cells 0%)/low (1-49%) versus high (≥50%) (33.3%, 26.1%, 5.0%; P = 0.031), but not significantly different in EGFR-mutated versus wild-type (20.0% vs 25.7%, P = 0.626).In NSQ-NSCLC tumors, CEACAM5 HE prevalence was 24.3% overall and was higher with KRAS altered and with PD-L1 negative/low tumors but similar regardless of EGFR mutation status. These findings support targeting CEACAM5 and the clinical development of tusamitamab ravtansine for patients with NSQ-NSCLC with CEACAM5 HE.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.