Translational Oncology Research Lab, Jilin Provincial Key Laboratory of Molecular Diagnostics for Lung Cancer, Jilin Cancer Hospital, Changchun, Jilin, China.
Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin, China.
J Immunother Cancer. 2024 Nov 29;12(11):e009693. doi: 10.1136/jitc-2024-009693.
The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity.
Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment.
ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8 T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1).
A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.
在肿瘤细胞程序性死亡配体 1（PD-L1）表达低于 50%的非鳞状非小细胞肺癌（nsqNSCLC）中，一线免疫治疗是否需要铂类双联化疗仍未得到充分研究。预测这种必要性的生物标志物可以指导无化疗治疗，以最大程度地减少不必要的毒性。
对 790 例低 PD-L1 表达的 nsqNSCLC 患者（内部：n=83；公共：n=707）进行了免疫检查点抑制剂单药治疗（ICI-mono）、化疗或联合治疗（ICI-chemo），分析了附加化疗交互评分（ISAC）的开发和验证。分析了转录组学（公共，n=11）和多重免疫荧光数据（内部，n=100）以评估免疫微环境。
与 ICI-mono 相比，ICI-chemo 作为一线治疗在低 PD-L1 表达的 nsqNSCLC 中更倾向于延长无进展生存期（PFS；HR=0.72，p=0.004）和总生存期（OS；HR=0.77，p=0.071）。在 ISAC 低亚组中观察到化疗的附加价值（PFS：HR=0.48，p<0.001；OS：HR=0.53，p=0.001），而不是 ISAC 高亚组（PFS：HR=1.08，p=0.65；OS：HR=1.14，p=0.56）。这种预测效用独立于肿瘤突变负担和 PD-L1 表达，亚组和多变量分析表明了这一点。高 ISAC 与适应性免疫抵抗相关，表现为更多的促炎（例如 CD8 T 细胞和 M1 巨噬细胞）而不是抗炎肿瘤浸润免疫细胞（例如 M2 巨噬细胞），以及除 PD-L1 以外的免疫检查点高表达（例如程序性细胞死亡蛋白 1）。
高 ISAC 被确定为低 PD-L1 表达 nsqNSCLC 一线 ICI 治疗中铂类双联化疗几乎没有额外价值的显著预测指标。我们的研究结果可能有助于为 nsqNSCLC 制定更精确的治疗策略，从而提高疗效并减少不必要的毒性。
