DNA methyltransferase 3A (DNMT3A) mutations and PD-(L)1 blockade efficacy in non-small cell lung cancer

B Ricciuti; S Scalera; X Wang; A Elkrief; M Tagliamento; E Gariazzo; F Paoloni; P G Miller; F Pecci; A Di Federico; V Santo; J V Alessi; M Aldea; E Garbo; G Lamberti; W Zrafi; J B Micol; L M Sholl; M Nishino; F Cappuzzo; N Calonaci; G Caravagna; R Ferrara; B Besse; A Schoenfeld; M Maugeri-Sacca; M M Awad

doi:10.1016/j.annonc.2025.06.003

DNA methyltransferase 3A (DNMT3A) mutations and PD-(L)1 blockade efficacy in non-small cell lung cancer

Ann Oncol. 2025 Jun 18:S0923-7534(25)00804-X. doi: 10.1016/j.annonc.2025.06.003. Online ahead of print.

Authors

B Ricciuti¹, S Scalera², X Wang³, A Elkrief⁴, M Tagliamento⁵, E Gariazzo⁶, F Paoloni⁷, P G Miller⁸, F Pecci⁶, A Di Federico⁶, V Santo⁶, J V Alessi⁶, M Aldea⁶, E Garbo⁶, G Lamberti⁶, W Zrafi⁵, J B Micol⁵, L M Sholl⁹, M Nishino¹⁰, F Cappuzzo², N Calonaci¹¹, G Caravagna¹¹, R Ferrara¹², B Besse⁵, A Schoenfeld⁴, M Maugeri-Sacca², M M Awad⁶

Affiliations

¹ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: biagio_ricciuti@dfci.harvard.edu.
² Clinical Trial Center, Biostatistics and Bioinformatics Division, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, USA.
⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
⁵ Gustave Roussy Cancer Center, Villejuif, France.
⁶ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
⁷ Department of Medical Oncology, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy.
⁸ Center for Cancer Research and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.
⁹ Department of Pathology, Brigham and Women's Hospital, Boston, MA.
¹⁰ Department of Radiology, Brigham and Women's Hospital, Boston, MA.
¹¹ Department of Mathematics and Geosciences, University of Trieste, Trieste, Italy.
¹² Medical Oncology, Università Vita-Salute San Raffaele, Milan, Italy.

PMID: 40541864
DOI: 10.1016/j.annonc.2025.06.003

Abstract

Purpose: Despite significant improvements in overall survival with PD-(L)1 inhibition, most patients with metastatic non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibition (ICI). Growing evidence suggests the importance of genomic alterations in modulating anti-cancer immune response and predicting ICI efficacy. However, the genomic correlates of response to ICI in NSCLC are largely unknown.

Experimental design: Patients with advanced NSCLC treated with ICI and comprehensive genomic profiling from multiple independent cohorts were included. Beta-binomial modelling of sequencing read counts was used to infer mutation clonality. NSCLC samples from TCGA and NSCLC cell lines from CCLE were used for transcriptomic analyses.

Results: Among 1539 NSCLCs, we identified deleterious DNA methyltransferase 3A (DNMT3A) mutations in 4.7% of cases. Patients with DNMT3A mutant NSCLC had improved response rate (41.7% vs 21.5%, P<0.001), progression-free (HR:0.61, P<0.001), and overall survival (OS: HR:0.66, P<0.01) with PD-(L)1 blockade, compared to DNMT3A wild-type cases. DNMT3A mutations had no impact on OS among patients with advanced NSCLC who did not receive ICI (HR:0.88, P=0.41). In examining the impact of DNMT3A clonality on immunotherapy outcomes to account for potential clonal hematopoiesis of indeterminate potential contamination, we confirmed that clonal DNMT3A mutations were associated with improved outcomes compared to DNMT3A wild-type cases. In NSCLC cell lines with pathogenic DNMT3A mutations DNMT3A RNA and protein expression was decreased. In the TCGA, NSCLCs with high versus low DNMT3A expression exhibited downregulation of pathways involved in innate and adaptive immune response, including INFγ, MHC-II antigen presentation, TNFα and PD-1 signaling.

Conclusion: Somatic DNMT3A mutations can be detected in a fraction of NSCLCs and are associated with a decreased DNMT3A expression, a favorable immunophenotype, and predict improved ICI efficacy.

Keywords: Comprehensive tumor genomic profiling; DNMT3A mutations; Non-small cell lung cancer (NSCLC); PD-(L)1 inhibition; Predictive biomarkers in immunotherapy response.