The Challenge to the Pathologist of PD-L1 Expression in Tumor Cells of Non-Small-Cell Lung Cancer—An Overview

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Abstract

In recent years, the treatment of non-small-cell lung cancer (NSCLC) has been fundamentally changed by immunotherapy where the immune system is reactivated using anti-programmed cell death protein 1/programmed death ligand 1 (PD1/PD-L1) checkpoint inhibition. With this, the immunohistological detection of PD-L1 has become one of the most important predictive biomarkers, leading pathologists to play a central role in the immuno-oncological therapy decisions. This has brought them the challenge of requiring the knowledge of relevant checkpoint inhibitors (CI), different PD-L1 scores and cut-offs as well as the choice of the right tissues and controls. Their involvement is also required in the careful validation of both clinical trial assays (CTAs) and laboratory developed tests (LDTs), in addition to the internal and external quality assessment and the interpretation and scoring of the staining based on specialist training. After the training of tumor proportion score (TPS) scoring in NSCLC, pathologists show a high level of concordance, with some variation between different cut-offs. Since not all patients benefit from immunotherapy, further research is needed to validate new predictive markers and optimize existing ones. In this context, these studies focus on a combination of PD-L1 and molecular signatures.

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Elements of cancer immunity and the cancer–immune set point

Daniel Chen, Ira Mellman (2017)

Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is

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Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

T A Chan, M. Yarchoan, E Jaffee … (2018)

Abstract Background Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.