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Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint BlockadeA Systematic Review and Meta-analysis

Educational Objective
To learn the diagnostic accuracy of biomarker assays for predicting clinical response to anti–PD-1/PD-L1 therapy
1 Credit CME
Key Points

Question  What is the relative diagnostic accuracy of different biomarker assay modalities in predicting clinical response to anti–PD-1/PD-L1 (programmed cell death 1/programmed cell death ligand 1) therapy?

Findings  In this systematic review and meta-analysis involving tumor specimens from 8135 patients, multiplex immunohistochemistry/immunofluorescence (mIHC/IF) had significantly higher diagnostic accuracy than PD-L1 IHC, tumor mutational burden, or gene expression profiling in predicting clinical response to anti–PD-1/PD-L1 therapy and was similar to multimodality cross-platform composite approaches, such as PD-L1 IHC + tumor mutational burden.

Meaning  Multiplex immunohistochemistry/IF facilitates quantification of protein coexpression on immune cell subsets and assessment of their spatial arrangements; initial findings suggest that mIHC/IF has diagnostic accuracy comparable to multimodality cross-platform composite approaches in predicting response to anti–PD-1/PD-L1.


Importance  PD-L1 (programmed cell death ligand 1) immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) assays have been used to assess pretreatment tumor tissue to predict response to anti–PD-1/PD-L1 therapies. However, the relative diagnostic performance of these modalities has yet to be established.

Objective  To compare studies that assessed the diagnostic accuracy of PD-L1 IHC, TMB, GEP, and mIHC/IF in predicting response to anti–PD-1/PD-L1 therapy.

Evidence Review  A search of PubMed (from inception to June 2018) and 2013 to 2018 annual meeting abstracts from the American Association for Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Immunotherapy of Cancer was conducted to identify studies that examined the use of PD-L1 IHC, TMB, GEP, and mIHC/IF assays to determine objective response to anti–PD-1/PD-L1 therapy. For PD-L1 IHC, only clinical trials that resulted in US Food and Drug Administration approval of indications for anti–PD-1/PD-L1 were included. Studies combining more than 1 modality were also included. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. Two reviewers independently extracted the clinical outcomes and test results for each individual study.

Main Outcomes and Measures  Summary receiver operating characteristic (sROC) curves; their associated area under the curve (AUC); and pooled sensitivity, specificity, positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (LR+ and LR−) for each assay modality.

Results  Tumor specimens representing over 10 different solid tumor types in 8135 patients were assayed, and the results were correlated with anti–PD-1/PD-L1 response. When each modality was evaluated with sROC curves, mIHC/IF had a significantly higher AUC (0.79) compared with PD-L1 IHC (AUC, 0.65, P < .001), GEP (AUC, 0.65, P = .003), and TMB (AUC, 0.69, P = .049). When multiple different modalities were combined such as PD-L1 IHC and/or GEP + TMB, the AUC drew nearer to that of mIHC/IF (0.74). All modalities demonstrated comparable NPV and LR−, whereas mIHC/IF demonstrated higher PPV (0.63) and LR+ (2.86) than the other approaches.

Conclusions and Relevance  In this meta-analysis, tumor mutational burden, PD-L1 IHC, and GEP demonstrated comparable AUCs in predicting response to anti–PD-1/PD-L1 treatment. Multiplex immunohistochemistry/IF and multimodality biomarker strategies appear to be associated with improved performance over PD-L1 IHC, TMB, or GEP alone. Further studies with mIHC/IF and composite approaches with a larger number of patients will be required to confirm these findings. Additional study is also required to determine the most predictive analyte combinations and to determine whether biomarker modality performance varies by tumor type.

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Article Information

Accepted for Publication: March 15, 2019.

Corresponding Author: Janis M. Taube, MD, Division of Dermatopathology Johns Hopkins University, 600 N Wolfe St, Blalock Building Room 907, Baltimore, MD 21287 (

Published Online: July 18, 2019. doi:10.1001/jamaoncol.2019.1549

Author Contributions: Dr Taube and Mr Lu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lu, Rimm, Hoyt, Pardoll, Taube.

Acquisition, analysis, or interpretation of data: Lu, Stein, D. Wang, Bell, Johnson, Sosman, Schalper, Anders, H. Wang, Hoyt, Danilova, Taube.

Drafting of the manuscript: Lu, Stein, D. Wang, Johnson, Sosman, Danilova, Taube.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lu, Stein, D. Wang, H. Wang, Danilova.

Administrative, technical, or material support: Lu, Stein, D. Wang, Schalper, Anders, Taube.

Study supervision: Rimm, Hoyt, Pardoll, Danilova, Taube.

Conflict of Interest Disclosures: Dr Rimm reports personal fees from and serves on the advisory board of Amgen, personal fees from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Daiichi Sankyo, Konica Minolta, personal fees from and serves on the advisory board of Cell Signaling Technology, grants and personal fees from Cepheid, AstraZeneca, NextCure, Ultivue, Ventana, Perkin Elmer, grants from Lilly, patents including AQUA software licensing and Navigate Biopharma (Yale owned patent). Dr Johnson serves on the advisory board of Array Biopharma, Bristol-Myers Squibb, Genoptix, Incyte, Merck, and Novartis; receives grant funding from Bristol-Myers Squibb and Incyte; patent pending for using MHC-II as a biomarker for immunotherapy responses. Dr Schalper reports grant funding from Navigate Biopharma, Vasculox, Tesaro, Takeda, Surface Oncology, and Bristol-Myers Squibb; receives grant funding and consulting fees from Celgene, Shattuck Labs, Pierre Fabre, Moderna Therapeutics, AstraZeneca, AbbVie, and Merck; and receives speaking fees from Merck and Fluidigm. Dr Anders receives grant funding from FLX Bio and Five Prime Therapeutics, and is a consultant for Bristol-Myers Squibb, Merck, and AstraZeneca. Mr Hoyt is employed by Akoya Biosciences and owns Akoya Biosciences stock and stock options. Dr. Pardoll reported other support from Aduro Biotech, Amgen, Bayer, Camden Partners, DNAtrix, Dracen, Dynavax, Five Prime, FLX Bio, Immunomic, Janssen, Merck, Rock Springs Capital, Potenza, Tizona, Trieza, and WindMil during the conduct of the study; grants from Astra Zeneca, Medimmune/Amplimmune, and Compugen; grants and other support from ERvaxx and Potenza. Dr Taube reports nonfinancial support from Akoya during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, Astra Zeneca, and Amgen outside the submitted work; equipment and reagents from Akoya Biosciences, and a patent pending related to image processing of mIF/IHC images. No other disclosures were reported.

Funding/Support: This work was supported by the Melanoma Research Alliance (Dr Taube); Harry J. Lloyd Trust (Dr Taube); the Emerson Collective (Dr Taube); Moving for Melanoma of Delaware (Dr Taube); Bristol-Myers Squibb (Drs Taube, Stein, Pardoll, and Ms Wang); Navigate BioPharma (Dr Rimm); Sidney Kimmel Cancer Center Core Grant P30 CA006973 (Drs Taube and Danilova); Yale Cancer Center P30 CA016359 (Dr Rimm); National Institutes of Health (NIH) Lung SPORE in Lung Cancer P50CA196530 (Drs Rimm and Schalper); Department of Defense Lung Cancer Research Program award W81XWH-16-1-0160 (Dr Schalper); Stand Up To Cancer/AACR SU2C-AACR-DT17-15 SU2C-AACR-DT22-17.ACS (Dr Schalper); Melanoma Professorship No. RP-14-246-06 (Dr Sosman); National Cancer Institute R01 CA142779 (Drs Taube and Pardoll); NIH T32 CA193145 (Dr Stein); P50 CA062924 (Dr Anders); K23 CA204726 (Dr Johnson); and The Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Role of Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication.

Additional Contributions: The authors would like to acknowledge Matthew Hellmann, MD (Memorial Sloan Kettering Cancer Center), Evan Lipson, MD, and Suzanne L. Topalian, MD (both Johns Hopkins University), and Robin Edwards, MD (Bristol-Myers Squibb), for helpful discussions. These contributions were not compensated.

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