Abstract 490: A very high tumor mutational burden (TMB) is associated with improved efficacy of PD-(L)1 inhibition across different PD-L1 expression subgroups and a distinct immunophenotype in NSCLC
Authors: Ricciuti Biagio , Arbour Kathryn C. , Mahadevan Navin R. , Alessi Joao V. , Lindsay James , Umeton Renato , Sinha Rileen , Hoojghan Amir , Vokes Natalie , Recondo Gonzalo , Lamberti Giuseppe , Polio1 Andrew , Rizvi Hira , Leonardi Giulia , Plodkowski Andrew J. , Felt Kristen , Sharma Bijaya , Tolstorukov Michael Y. , Janne Pasi A. , Van Allen Eliezer M. , Sholl Lynette M. , Rodig Scott J. , Hellmann Matthew D. , Awad Mark M. 
Published: July 2021

Abstract
Background: Although high TMB correlates with improved outcomes to immune checkpoint inhibitors (ICI) in patients (pts) with non-small cell lung cancer (NSCLC), an optimal TMB cut-off to discriminate cancers most likely to respond to ICI has not been identified. Whether TMB impacts outcomes to ICI in different PD-L1 levels subgroups is also unclear.
Methods: Unbiased recursive partitioning (URP) was used to identify an optimal TMB cut-off for objective response rate (ORR) in two independent cohorts (DFCI and MSKCC) of pts with NSCLC treated with ICI. TCGA was interrogated to find differences in tumor immune cell subsets according to the TMB cut-off identified. Multiplexed immunofluorescence (IP) was also performed on NSCLC samples.
Results: In the DFCI (N=686) and MSKCC (N=672) cohorts, URP found an optimal cut-off of TMB for ORR at 19 mutations/megabase (mut/Mb), corresponding to the 90th percentile in each cohort. Median progression-free (PFS) and overall survival (OS) were significantly longer in NSCLCs with TMB ≥19 mut/Mb vs &lt;19 mut/Mb, in both cohorts (Table). After harmonizing TMB between DFCI OncoPanel and MSK-IMPACT NGS platforms, URP confirmed an optimal TMB cut-off for ORR at the 90th percentile in the combined cohort, which also associated with longer PFS/OS (Table). A TMB ≥90th percentile correlated with longer PFS/OS among NSCLCs with PD-L1 levels ≥50% and 1-49%, and longer PFS among those with PD-L1 &lt;1% (Table). Cell subset transcriptome analysis from the TCGA showed higher proportions of CD8+ T cells (P=0.02) and M1 macrophages (P&lt;0.01), among NSCLCs with a TMB ≥ vs &lt;90th percentile. IP confirmed increased CD8+ and CD8+/PD1+ T-cell infiltration (P&lt;0.01) in NSCLC with very high TMB.
Conclusion: A very high TMB is associated with better outcomes to ICI and a distinct immunophenotype in NSCLC. Rational integration of TMB and PD-L1 expression may identify NSCLCs most likely to respond to ICI.
CohortPD-L1 expressionPFS TMB ≥ vs &lt;90th percentile HR [95%CI],POS TMB ≥ vs &lt;90th percentile HR [95%CI],PDFCI N=6860-1000.48 [0.36-0.65],P&lt;0.010.57 [0.41-0.78],P&lt;0.01MSKCC N=6720-1000.38 [0.28-0.52],P&lt;0.010.46 [0.33-0.65],P&lt;0.01DFCI+MSKCC0-1000.44 [0.35-0.54],P&lt;0.010.50 [0.39-0.64],P&lt;0.01DFCI+MSKCC≥50%0.52 [0.34-0.81], P&lt;0.010.54 [0.32-0.94],P=0.031-49%0.33 [0.19-0.57],P&lt;0.010.36 [0.19-0.69], P&lt;0.01&lt;1%0.40 [0.25-0.65], P&lt;0.010.72 [0.34-1.18],P=0.19
Citation Format: Biagio Ricciuti, Kathryn C. Arbour, Navin R. Mahadevan, Joao V. Alessi, James Lindsay, Renato Umeton, Rileen Sinha, Amir Hoojghan, Natalie Vokes, Gonzalo Recondo, Giuseppe Lamberti, Andrew Polio1, Hira Rizvi, Giulia Leonardi, Andrew J. Plodkowski, Kristen Felt, Bijaya Sharma, Michael Y. Tolstorukov, Pasi A. Janne, Eliezer M. Van Allen, Lynette M. Sholl, Scott J. Rodig, Matthew D. Hellmann, Mark M. Awad. A very high tumor mutational burden (TMB) is associated with improved efficacy of PD-(L)1 inhibition across different PD-L1 expression subgroups and a distinct immunophenotype in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 490.