“Interchangeability” of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy

Abstract

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using “PD-L1” as a search term for 01/01/2015 to 31/08/2018, with limitations “English” and “human”. 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

“…PD-L1 expression in tumor cells and TILs using immunostaining-scoring methods have been associated with response to blockade of the PD-1/PD-L1 axis (Dolled-Filhart et al, 2016;Torlakovic et al, 2020). However, there is no clear-cut between separation of responders and non-responders patients.…”

Fit-For-Purpose PD-L1 Biomarker Testing For Patient Selection in Immuno-Oncology: Guidelines For Clinical Laboratories From the Canadian Association of Pathologists-Association Canadienne Des Pathologistes (CAP-ACP)

“…Strong recommendation-Health Canadaapproved, FDA-approved, and CE-marked PD-L1 IHC Kits that are validated in clinical trials for specific purposes must be used for those specific purposes. [76][77][78][86][87][88][89][90] Explanatory note: "PD-L1 IHC Kit" is a commercially manufactured and marketed Diagnostic assay that uses IHC to detect certain expression patterns of PD-L1 protein and that was clinically validated (see GS01) with biospecimens from responders and nonresponders of a clinical trial for a specific drug in a specific disease population.…”

“…Strong recommendation-Health Canadaapproved, FDA-approved, and CE-marked PD-L1 IHC Kits that are validated in clinical trials for specific purposes, when not used for these specific purposes, but used for a different purpose (ie, in accordance with the 3D approach for a different disease and/or different drug), must be considered as LDTs and are not to be considered as Health Canada-approved, FDA-approved, or CE-marked for this new purpose. [86][87][88][90][91][92][93] Explanatory note: If Diagnostic assay #1, which was clinically validated with results from its clinical trial (ie, clinical trial #1) that assessed the efficacy of Drug #1 in Disease #1, is used to predict potential response to Drug #2 in Disease #2, then Diagnostic assay #1 is considered a LDT in the context of Drug #2 in Disease #2. In the context of Drug #1 in Disease #1 though, Diagnostic assay #1 is a fit-for-purpose companion/complementary diagnostic assay (eg, PD-L1 IHC Kit #1).…”

“…Strong recommendation-Published results of properly conducted studies of direct or indirect clinical validation and/or meta-analyses of such studies, that address diagnostic accuracy of candidate assays, must guide selection of potential "replacement assays" for any specific purpose (eg, both Dako PD-L1 IHC 28-8 pharmDx and VENTANA PD-L1 (SP263) showed acceptable diagnostic accuracy for the 50% TPS cut-off for PD-L1 IHC 22C3, but not for the 1% cut-off). 90 Explanatory note: A systematic review and meta-analysis for PD-L1 replacement assays indicated that the evidence does not support interchangeability of the assays when based on diagnostic accuracy. 90 GS07.…”

Lessons learned at SABCS 2019 and to-dos from immunotherapy in breast cancer

“…18 In fact, the most accurate method for PD-L1 assessment is yet to be elucidated, since most anti-PD-(L)1 drug manufacturers have validated their own companion immunohistochemistry assay, with variations between antibodies, methods of PD-L1 positivity scoring and predictive values for anti-PD(L)1 efficacy, which can change according to disease and stage. 19 As of today, therefore, patients with metastatic disease can expect to derive a considerable benefit of immunotherapy if they have PD-L1-positive TNBC and are treated upfront with immunotherapy plus chemotherapy. New strategies to further prime the immune system are being tested to extend the benefit of anti-PD-(L)1 drugs to patients with ER-positive BC, such as combined checkpoint inhibition, CDK4/6 inhibition, anti-angiogenic agents and other targeted therapies, radiation and manipulation of the tumour microenvironment, among others.…”