TY - JOUR
T1 - Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade
T2 - A Systematic Review and Meta-analysis
AU - Lu, Steve
AU - Stein, Julie E.
AU - Rimm, David L.
AU - Wang, Daphne W.
AU - Bell, J. Michael
AU - Johnson, Douglas B.
AU - Sosman, Jeffrey A.
AU - Schalper, Kurt A.
AU - Anders, Robert A.
AU - Wang, Hao
AU - Hoyt, Clifford
AU - Pardoll, Drew M.
AU - Danilova, Ludmila
AU - Taube, Janis M.
N1 - Funding Information:
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 Information:
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.
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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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U2 - 10.1001/jamaoncol.2019.1549
DO - 10.1001/jamaoncol.2019.1549
M3 - Review article
C2 - 31318407
AN - SCOPUS:85069467444
VL - 5
SP - 1195
EP - 1204
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 8
ER -