The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity.
针对无可靶向驱动基因突变的转移性非小细胞肺癌（NSCLC）一线治疗格局正在快速演变，目前以帕博利珠单抗为基础的方案占据主导地位。本文探讨了新型抗PD-1抗体西米普利单抗独特的分子特征，并明确了其在现有标准治疗中的最优定位。西米普利单抗是一种全人源IgG4单克隆抗体，具有两大关键特性：一是通过工程化铰链区突变防止Fab臂交换，确保卓越的分子稳定性，从而最大程度降低由分子不稳定引发的抗药物抗体（ADA）风险；二是与PD-1糖基化位点的独特相互作用，可能增强结合效力。这些结构优势在鳞状NSCLC等组织学类型中尤为重要——该类肿瘤因体细胞突变累积产生高肿瘤新抗原负荷及强免疫应答，形成了历史上易产生ADA的微环境。基于关键性EMPOWER-Lung研究项目的数据，我们特别关注西米普利单抗在特定人群中的突出潜力：首先，在EMPOWER-Lung 1试验预设的独特"超高"PD-L1表达亚组（TPS≥90%）分析中，西米普利单抗单药治疗显示出超越历史基准的卓越生存获益；其次，无论是用于高PD-L1表达患者的单药治疗，还是联合化疗用于PD-L1表达<50%的患者，西米普利单抗在难治性鳞状组织学类型中均表现出持续而强劲的疗效。综上，西米普利单抗凭借其独特的结构稳定性和低免疫原性，为鳞状组织学类型伴超高PD-L1表达患者确立了独特的治疗定位。
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