DNMT3A mutation to identify a subset of non-small cell lung cancers with increased sensitivity to PD-(L)1 blockade.
Authors: Ricciuti Biagio , Alessi Joao Victor Machado , Li Yvonne Y. , Lawrence Marissa N. , Gupta Hersh , Nishino Mizuki , Cherniack Andrew D. , Sholl Lynette M. , Awad Mark M. 
Published: June 2021

9113 Background: Despite significant improvements in overall survival with PD-(L)1 inhibition, the majority of patients with metastatic 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 in solid tumors. However, the genomic correlates of response and resistance to ICI in NSCLC are still largely unknown. Methods: Patients with advanced NSCLC treated with PD-(L)1 blockade whose tumors underwent comprehensive genomic profiling were included. Mutation enrichment analysis was performed to identify genomic alterations enriched in responders versus (vs) non-responders to ICI. Loss-of function mutations annotated as oncogenic by OncoKB, and missense mutations predicted to be deleterious by SIFT/Polyphen-2 were considered. Cox proportional hazards models was used to estimate hazard ratios (HRs) in univariable and multivariable models. Results: : Among 600 NSCLCs, we identified deleterious mutations in the DNA methyltransferase 3A ( DNMT3A) gene as the most significant alteration enriched in responders versus non-responders to PD-(L)1 blockade (q-Value < 0.05). DNMT3AMUT (7.3%, N = 44) and DNMT3A wild-type ( DNMT3AWT) cases (92.7%, N = 556) were well balanced in terms of baseline clinicopathologic features, including PD-L1 expression, sex, performance status, age, concurrent genomic alterations, and smoking history. DNMT3AMUT tumors had a significantly higher median TMB compared to DNMT3AWT cases (12.1 vs 9.8 mutations/megabase, P = 0.03). DNMT3A loss was associated with significantly higher objective response rate (ORR, 50% vs 20.5%, P < 0.001), longer median progression-free (mPFS, 9.2 vs 2.9 months, HR 0.60, P < 0.01) and overall survival (mOS, 23.1 s 12.1 months, HR 0.59, P = 0.01) among DNMT3AMUT compared to DNMT3AWT NSCLCs. Loss-of function mutation in DNMT3A was confirmed be an independent predictor of improved PFS (HR 0.61, P = 0.01) and OS (HR 0.62, P = 0.04) at multivariable analysis. DNMT3A mutation had no impact on OS among patients with advanced NSCLC who did not receive ICI (HR 1.18, P = 0.22), nor among those with early-stage resected NSCLC (HR 1.17, P = 0.48), suggesting that DNMT3A mutation is predictive, rather than prognostic, of ICI efficacy. Although a subset of DNMT3A mutations could have potentially arisen from tumor-associated hematopoietic cells, the DNMT3A allele fraction-to-tumor purity ratio was ≥0.5 in more than 50% of cases, suggesting that a proportion of these mutations were derived from lung cancer cells. Conclusions: Loss-of-function mutation in DNMT3A may identify a new genomically defined subset of NSCLC with increased sensitivity to PD-(L)1 blockade. Additional studies are ongoing to determine the exact source of DNMT3A mutation (clonal hematopoiesis vs tumor) and their relative contribution to ICI efficacy.