Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels Journal Article

   

Authors:	Ricciuti, B.; Wang, X.; Alessi, J. V.; Rizvi, H.; Mahadevan, N. R.; Li, Y. Y.; Polio, A.; Lindsay, J.; Umeton, R.; Sinha, R.; Vokes, N. I.; Recondo, G.; Lamberti, G.; Lawrence, M.; Vaz, V. R.; Leonardi, G. C.; Plodkowski, A. J.; Gupta, H.; Cherniack, A. D.; Tolstorukov, M. Y.; Sharma, B.; Felt, K. D.; Gainor, J. F.; Ravi, A.; Getz, G.; Schalper, K. A.; Henick, B.; Forde, P.; Anagnostou, V.; Jänne, P. A.; Van Allen, E. M.; Nishino, M.; Sholl, L. M.; Christiani, D. C.; Lin, X.; Rodig, S. J.; Hellmann, M. D.; Awad, M. M.
Article Title:	Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels
Abstract:	Key Points: Question: Is tumor mutation burden (TMB) associated with improved outcomes of programmed cell death–1 (PD-1)/programmed death ligand–1 (PD-L1) inhibition across PD-L1 expression levels in non–small cell lung cancer (NSCLC)? Findings: In this cohort study of 1552 patients with NSCLC, the group with high TMB had improved response rates and survival after receiving PD-1/PD-L1 inhibition therapy across PD-L1 expression subgroups compared with the group with low TMB. High TMB levels were associated with increased CD8-positive T-cell infiltration and distinct immune response gene expression signatures. Meaning: These findings suggest that in NSCLC, a high number of nonsynonymous tumor mutations is associated with immune cell infiltration and inflammatory T-cell expression signatures, leading to increased sensitivity to PD-1/PD-L1 inhibition across PD-L1 expression subgroups. This cohort study examines the association between increasing tumor mutation burden (TMB) levels and immunotherapy efficacy across clinically relevant programmed death ligand–1 (PD-L1) levels in patients with non–small cell lung cancer (NSCLC). Importance: Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non–small cell lung cancer (NSCLC). Objectives: To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand–1 (PD-L1) levels in patients with NSCLC. Design, Setting, and Participants: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death–1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022. Exposures: Treatment with PD-1/PD-L1 inhibition without chemotherapy. Main Outcomes and Measures: Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1–positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures. Conclusions and Relevance: These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell–mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.
Keywords:	adult; aged; aged, 80 and over; mutation; prospective studies; carcinoma, non-small-cell lung; tumor burden; immunity; data analysis software; descriptive statistics; middle age; treatment outcomes; mann-whitney u test; cox proportional hazards model; fisher's exact test; spearman's rank correlation coefficient; kruskal-wallis test; human; male; female; programmed cell death ligand 1
Journal Title:	JAMA Oncology
Volume:	8
Issue:	8
ISSN:	2374-2437
Publisher:	American Medical Association
Date Published:	2022-08-01
Start Page:	1160
End Page:	1168
Language:	English
DOI:	10.1001/jamaoncol.2022.1981
PROVIDER:	EBSCOhost
PROVIDER:	cinahl
PMCID:	PMC9204620
PUBMED:	35708671
DOI/URL:	https://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,shib&db=cin20&AN=158627771&site=ehost-live&scope=site&custid=s2915669
Notes:	Accession Number: 158627771 -- Entry Date: 20220830 -- Revision Date: 20220830 -- Publication Type: Article; research; tables/charts -- Journal Subset: Peer Reviewed; USA. -- Source: Cinahl

https://synapse.mskcc.org/synapse/works/has_related_data_chk/197638