Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations
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.
Authors
- Federico Cappuzzo (ORCID: https://orcid.org/0000-0002-6295-6767)
- Aditi Qamra (ORCID: https://orcid.org/0000-0003-2977-0087)
- Barzin Y. Nabet (ORCID: https://orcid.org/0000-0002-4824-3533)
- M. Ballinger (ORCID: https://orcid.org/0009-0009-9006-5433)
- Sören Müller (ORCID: https://orcid.org/0000-0001-9490-5270)
- Eloisa Fuentes
- Tianshi Lu (ORCID: https://orcid.org/0000-0002-6458-1217)
- Hartmut Koeppen (ORCID: https://orcid.org/0000-0003-0923-3110)
- Martin Reck (ORCID: https://orcid.org/0000-0002-5348-4462)
- David S. Shames (ORCID: https://orcid.org/0000-0002-5900-1177)
- Robert M. Jotte (ORCID: https://orcid.org/0000-0003-3920-0731)
- Jennifer M. Giltnane (ORCID: https://orcid.org/0000-0002-8333-9995)
- Habib Hamidi (ORCID: https://orcid.org/0000-0003-0196-9852)
- Minu K. Srivastava (ORCID: https://orcid.org/0009-0000-3827-9180)
- Mark A. Socinski (ORCID: https://orcid.org/0000-0003-2915-9325)
- Assaf Amitai (ORCID: https://orcid.org/0000-0002-8594-6529)
- Fabrice Barlési (ORCID: https://orcid.org/0000-0001-5793-3539)
- Xiangnan Guan
- Yulei Wang (ORCID: https://orcid.org/0000-0002-9057-9786)
- Meng He (ORCID: https://orcid.org/0000-0003-2464-9309)
Institutions
- Aix-Marseille Université (FR)
- Université Paris-Saclay (FR)
- AdventHealth Orlando (US)
- Institut Gustave Roussy (FR)
- Genesys (United States) (US)
- Roche (Canada) (CA)
- German Center for Lung Research (DE)
- Rocky Mountain Cancer Centers (US)
- LungenClinic Grosshansdorf (DE)
- Tumori Foundation (US)
- Genvac Aerospace (United States) (US)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s41467-025-66803-8
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- F. Hoffmann-La Roche
- Genentech