Spatial biomarkers outperform PD-L1 IHC and TMB in predicting response to PD-1/PD-L1 immunotherapy

An in-depth comparison of immuno-oncology biomarker modalities determined that multiplex immunohistochemistry (mIHC)/multiplex immunofluorescence (mIF) with spatial characterization significantly outperformed other biomarker testing approaches — such as gene expression profiling (GEP), tumor mutational burden (TMB) assessment, and PD-L1 immunohistochemistry (IHC) — for predicting patient response to treatments targeting PD-1/PD-L1. The study was conducted by scientists at Johns Hopkins University, Yale University, Vanderbilt University, and Northwestern University and was published in JAMA Oncology.

Immunotherapies targeting PD-1 or PD-L1 have proven remarkably effective for treating cancer in some patients, but there remains a paucity of accurate biomarkers that can differentiate responders from non-responders. Identifying the patients most likely to respond to these therapies is an important step in ensuring optimal outcomes for all patients. To date, several assays have been developed with the potential to predict response based on genetic signatures, gene expression profiles, and immunohistochemistry. Although these assays are helpful in limited situations, there is a need for options that are better at predicting response across a larger percentage of cases.

The study reviewed published data from more than 50 studies covering more than 10 types of cancer and over 8,000 patients. Data came from abstracts from the annual meetings of the American Association for Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Immunotherapy of Cancer.

Statistical analyses were performed to assess the performance and predictive value of each type of biomarker. While TMB, GEP, and PD-L1 IHC had comparable performance to each other for differentiating between responders and non-responders, mIHC/mIF had considerably better performance metrics. Specifically, it had fewer false positives, meaning it was less likely to predict positive response in a patient who would not ultimately respond to therapy.

Spatially resolved multiplex immunofluorescence, a new type of biomarker assay, allows investigators to simultaneously analyze the expression of many proteins in individual cells within the tumor microenvironment, preserving critical information about which cells are influencing treatment response and how they are spatially distributed relative to each other.

By performing an sROC curve evaluation, the authors of the JAMA Oncology publication cited mIF and mIHC (AUC of 0.79) as having significantly higher diagnostic predictive accuracy when compared to PD-L1 IHC (AUC of 0.65, P<.001). Additionally, it outperformed both gene expression profiling (AUC of 0.65, P=.003) and tumor mutational burden (AUC of 0.69, P=.049).

The mIHC/mIF studies featured in this publication cite the use of the Phenoptics™ next-generation biomarker multiplexing platform for clinical and translational research from Akoya Biosciences. To learn more about this platform and the use of mIF technology for generating spatially resolved biomarker data, please visit https://www.akoyabio.com/phenopticstm/.

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