The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers in breast cancer clinical trials and daily practice

Abstract

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a riskmanagement framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC.

Understanding PD-L1 Testing in Breast Cancer: A Practical Approach

“…As already mentioned, using a particular score and cut-off, each has been specifically implemented in these studies in relation to the clinical testing of 1 specific ICI. Furthermore [18].…”

“…However, various commercially available assays and numerous antibody clones for PD-L1 detection as well as multiple expression scores and cut-offs exist. Since these different IHC staining and scoring methods have each been specifically used to evaluate the clinical efficacy of a particular ICI in clinical studies, (i) the approval of ICI is often linked to a certain PD-L1 IHC assay (given that an assessment of the PD-L1 status is required), and (ii) direct comparison of the predictive value of various IHC antibody clones and PD-L1 scores/cut-offs is hampered [18]. Harmonization studies have been performed to address this issue and investigate the most reliable assays and antibody clones [19][20][21][22][23].…”

“…Harmonization studies have been performed to address this issue and investigate the most reliable assays and antibody clones [19][20][21][22][23]. However, there is still a need to compare the different staining and counting methods and their predictive values for ICI response, especially in breast cancer [18].…”

“…Prevalence of TNBC with any IC score ≥1% fluctuates between 32 and 86%, depending on the assay used (e.g., 41% for SP142). The review by Gonzalez-Ericsson et al [18] provides a comprehensive overview of published prevalences. Varying IC score (%) in triple-negative breast cancer.…”

“…− Therefore, each country/union has different admission requirements depending on the decision of the respective agency evaluating the medicinal products. − If the approval of each ICI is linked to one specific CIVD and there is no permission to use an LDT, we should be aware that smaller community hospital-associated pathological laboratories, in particular, cannot afford to provide each test for reasons mentioned in the section "PD-L1 IHC Assays and Antibody Clones" [18]. • There are increasing insights into immuno-oncology, PD-L1, and ICI with the frequently changing approval of ICI.…”