Journal Article

Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations

Guan, Xiangnan, Hamidi, Habib, Reck, Martin, Qamra, Aditi, Wang, Yulei, He, Meng Xiao, Amitai, Assaf, Jotte, Robert M., Ballinger, Marcus, Srivastava, Minu K., Barlesi, Fabrice, Koeppen, Hartmut, Lu, Tianshi, Shames, David S., Cappuzzo, Federico, Fuentes, Eloisa, Nabet, Barzin Y., Socinski, Mark A., Müller, Sören, Giltnane, Jennifer M.

2025

Overview

The phase 3 IMpower150 trial in treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) demonstrates significantly longer progression-free (PFS) and overall survival (OS) with first-line atezolizumab (anti-PD-L1)-bevacizumab (anti-VEGF)-carboplatin-paclitaxel (ABCP) than with bevacizumab-carboplatin-paclitaxel (BCP). We characterise four molecular NSCLC subtypes identified by unsupervised clustering of transcriptomes of 564 pre-treatment primary tumour samples from IMpower150 using non-negative matrix factorization (NMF1-4). Each subtype has distinct tumour PD-L1 expression levels, epithelial characteristics, immune composition, and treatment outcomes. Both NMF2 (enriched in tumour proliferation signal, macrophages, and monocytes) and NMF4 (enriched in B cells and T cells) have elevated tumour PD-L1 expression. Of these two, only NMF4 demonstrates PFS and OS benefits with ABCP versus either BCP or atezolizumab-carboplatin-paclitaxel (ACP). Patients with NMF1 (enriched in basal and squamous-like cells) have improved outcomes on ABCP compared with ACP or BCP; those with NMF3 (enriched in adenocarcinoma signatures) show similar outcomes among treatments. These insights could help inform individualised first-line treatment for metastatic NSCLC. Standard first line therapy in patients with non-small cell lung cancer is immunotherapy but responses vary and consistent predictive biomarkers are lacking. Here, using RNA-sequencing data from a large clinical trial in NSCLC patients, the authors define four molecular subsets with distinct tumour-intrinsic and -extrinsic features with differing outcomes to immunotherapy combinations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/39 / 45 / 45/91 / 631/250/580 / 631/67/1857 / 692/4028/67/1612 / Adenocarcinoma / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Bevacizumab / Bevacizumab - administration & dosage / Bevacizumab - therapeutic use / Biology / Biomarkers / Carboplatin / Carboplatin - administration & dosage / Carboplatin - therapeutic use / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - therapy / Cell proliferation / Clustering / Datasets / Dendritic cells / Enrichment / Female / Fibroblasts / Gene expression / Gene sequencing / Genomes / Humanities and Social Sciences / Humans / Immunotherapy / Immunotherapy - methods / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Lung Neoplasms - therapy / Lymphocytes / Lymphocytes B / Lymphocytes T / Machine learning / Macrophages / Male / Metastases / Monocytes / multidisciplinary / Non-small cell lung carcinoma / Paclitaxel / Paclitaxel - administration & dosage / Paclitaxel - therapeutic use / Patients / PD-L1 protein / Plasma / Progression-Free Survival / Protein expression / Proteins / Science / Science (multidisciplinary) / Small cell lung carcinoma / Squamous cell carcinoma / Transcriptomes / Treatment Outcome / Tumors / Vascular endothelial growth factor