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
Menée à partir de données génomiques et clinico-pathologiques portant sur 1 552 patients atteints d'un cancer du poumon non à petites cellules traité par inhibiteurs de PD-1 ou de PD-L1 (âge médian : 66 ans), cette étude évalue, en fonction du niveau d'expression intratumorale de PD-L1, l'association entre la charge mutationnelle de la tumeur et le nombre de cellules immunitaires infiltrant la tumeur ainsi que la survie des patients
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.
JAMA Oncology , article en libre accès, 2021