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Multicenter Study
. 2022 Aug 1;8(8):1160-1168.
doi: 10.1001/jamaoncol.2022.1981.

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

Biagio Ricciuti  1 , Xinan Wang  2 , Joao V Alessi  1 , Hira Rizvi  3 , Navin R Mahadevan  4 , Yvonne Y Li  5   6 , Andrew Polio  1 , James Lindsay  7 , Renato Umeton  8 , Rileen Sinha  8 , Natalie I Vokes  9 , Gonzalo Recondo  1 , Giuseppe Lamberti  1 , Marissa Lawrence  1 , Victor R Vaz  1 , Giulia C Leonardi  1 , Andrew J Plodkowski  10 , Hersh Gupta  5   6 , Andrew D Cherniack  6 , Michael Y Tolstorukov  8 , Bijaya Sharma  11 , Kristen D Felt  11 , Justin F Gainor  12 , Arvind Ravi  13 , Gad Getz  13 , Kurt A Schalper  14 , Brian Henick  15 , Patrick Forde  16 , Valsamo Anagnostou  16 , Pasi A Jänne  1   17 , Eliezer M Van Allen  18 , Mizuki Nishino  19 , Lynette M Sholl  5 , David C Christiani  2 , Xihong Lin  20 , Scott J Rodig  21 , Matthew D Hellmann  3 , Mark M Awad  1
Affiliations
Multicenter Study

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

Biagio Ricciuti et al. JAMA Oncol. .

Erratum in

  • Error in Figure Axis Label.
    [No authors listed] [No authors listed] JAMA Oncol. 2022 Nov 1;8(11):1702. doi: 10.1001/jamaoncol.2022.5957. JAMA Oncol. 2022. PMID: 36394573 Free PMC article. No abstract available.

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mahadevan reported owning stock in AstraZeneca and Roche outside the submitted work. Dr Li reported holding equity in Root Biomedical Services. Dr Vokes reported receiving personal fees from Sanofi/Genzyme and Oncocyte outside the submitted work. Dr Recondo reported receiving grants from Amgen and Janssen and receiving personal fees from Roche, Bayer, Bristol-Myers Squibb, Pfizer, Merck Sharpe & Dohme, and Takeda outside the submitted work. Dr Cherniack reported receiving research support from Bayer outside the submitted work. Dr Gainor reported receiving grants from Mark Foundation and Stand Up To Cancer during the conduct of the study; receiving research support from Novartis, Genentech/Roche, Ariad/Takeda, Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; receiving personal fees from Ariad/Takeda, Oncorus, Regeneron, Gilead, GlydeBio, Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, Moderna, Blueprint, Loxo/Lilly, Mirati, Pfizer, EMD Serono, iTeos, Novartis, Amgen, Beigene, Nuvalent, Karyopharm, and Silverback Therapeutics outside the submitted work; and having an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. Dr Ravi reported receiving personal fees from Tyra Biosciences and Halo Solutions outside the submitted work. Dr Getz reported receiving grants from Stand Up To Cancer, the Mark Foundation, IBM, and Pharmacyclics outside the submitted work; receiving personal fees from Scorpion Therapeutics; and holding a patent for Polysolver with royalties paid from Neon Therapeutics, a patent pending for predicting response to checkpoint blockade in melanoma, and a patent pending for lung cancer subtypes. Dr Schalper reported receiving personal fees from Moderna Inc, Pierre-Fabre Research Institute, Ono Pharmaceuticals, Dynamo Therapeutics, PeerView, AbbVie, Shattuck Labs, EMD Serono, Clinica Alemana de Santiago, Genmab, Fluidigm, Takeda, Merck Sharpe & Dohme, Bristol-Myers Squibb, AstraZeneca, Agenus, Torque Therapeutics, Repertoire Therapeutics, OnCusp, and Ariagen; and receiving grants from Navigate Biopharma, Tesaro/GlaxoSmithKline, Moderna Inc, Takeda, Surface Oncology, Pierre-Fabre Research Institute, Merck Sharpe & Dohme, Bristol-Myers Squibb, AstraZeneca, Ribon Therapeutics, Akoya Biosciences, Boehringer-Ingelheim, and Eli Lilly outside the submitted work. Dr Henick reported serving on the advisory boards of AstraZeneca and Ideaya and having a patent pending (63/232,549). Dr Forde reported receiving grants from Stand Up To Cancer and Kyowa during the conduct of the study; receiving research funding to Johns Hopkins University from Corvus and Kyowa; receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, Novartis, Daiichi, Iteos, Surface Oncology, Merck, Janssen, Genentech, Mirati, Sanofi, and F Star; and serving on data safety monitoring boards for Flame Therapeutics and Polaris. Dr Anagnostou reported receiving grants from AstraZeneca and Bristol-Myers Squibb outside the submitted work. Dr Jänne reported receiving personal fees from Boehringer Ingelheim, Pfizer, AstraZeneca, Roche/Genentech, Ignyta, Chugai Pharmaceutical, Eli Lilly, LOXO Oncology, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion, Accutar Biotech, AbbVie, and Revolution Medicines; and grants from the Mark Foundation for Cancer Research, the American Cancer Society, PUMA, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Takeda Oncology, Revolution Medicines, Eli Lilly, and Daiichi Sankyo outside the submitted work. Dr Van Allen reported receiving personal fees from Tango Therapeutics, Roche, Genentech, Microsoft, Genome Medical, Syapse, Invitae, Monte Rosa Therapeutics, Manifold Bio, Illumina, Enara Bio, Janssen, and Foaley & Hoag; receiving grants from Novartis and Bristol-Myers Squibb; and filing institutional patents for chromatin mutations, immunotherapy response, and methods for clinical interpretation. Dr Nishino reported receiving grants from Daiichi Sankyo, AstraZeneca, and Canon Medical Systems Research; and personal fees from Daiichi Sankyo and AstraZeneca outside the submitted work. Dr Sholl reported serving as a consultant for Foghorn Therapeutics, receiving personal fees from EMD Serono, and receiving grants from Genentech outside the submitted work. Dr Rodig reported receiving research funding from Brisol-Myers Squibb, Merck, KITE/Gilead, and Affimed and holding equity in Immunitas Therapeutics. Dr Hellmann reported receiving personal fees from Bristol-Myers Squibb, Achilles, Adagene, Adicet, Arcus, AstraZeneca, Blueprint, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs, and Regeneron; holding equity in Factorial, Avail, and Immunai; owning options in Shattuck Labs and Arcus Options; and having a patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208; pending and licensed by PGDx). Dr Awad reported serving as a consultant for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui; receiving grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly; and receiving personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Objective Response Rate, Progression-Free Survival, and Overall Survival in Patients With a High vs Low Harmonized Tumor Mutation Burden (TMB)
Data are from the pooled cohort of 1552 patients with non–small cell lung cancer treated with programmed death ligand–1 blockade from the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Stand Up To Cancer/Mark Foundation data sets. HR indicates hazard ratio; NR, not reached.
Figure 2.
Figure 2.. Multiplexed Immunofluorescence (ImmunoProfile) Showing Intratumoral, Tumor-Stroma Interface, and Total CD8+ Cells, PD1+ Cells, CD8+ PD1+ Cells, and Foxp3+ Cells in Patients With Non–Small Cell Lung Cancer
Data are from patients in the Dana-Farber Cancer Institute cohort, including 384 patients with low tumor mutation burden (TMB) and 44 patients with high TMB.
See this image and copyright information in PMC

Comment in

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