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Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations #MMPMID41339316
Lu T; Hamidi H; Socinski MA; Reck M; Cappuzzo F; Barlesi F; Jotte RM; Muller S; Qamra A; Amitai A; Guan X; Fuentes E; Koeppen H; Giltnane JM; Shames DS; Ballinger M; He MX; Wang Y; Srivastava MK; Nabet BY
Nat Commun 2025[Dec]; ? (?): ? PMID41339316show ga
The phase 3 IMpower150 trial in treatment-naive 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.
Nat+Commun 2025 ; ? (?): ?
