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Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective.

ABSTRACT: Checkpoint inhibitors targeting the programmed cell death 1 protein (PD-1) and programmed cell death ligand 1 (PD-L1) are demonstrating promising efficacy and appear to be well tolerated in a number of tumour types. In non-small-cell lung cancer, head-and-neck squamous cell carcinoma, and urothelial carcinoma, outcomes appear particularly favourable in patients with high PD-L1 expression. However, assays for PD-L1 have been developed for individual agents, and they use different antibody clones, immunohistochemistry staining protocols, scoring algorithms, and cut-offs. Given that laboratories are unlikely to use multiple testing platforms, use of one PD-L1 assay in conjunction with a specific therapy will become impractical and could compromise treatment options. Methods to harmonize testing methods are therefore crucial to ensuring appropriate treatment selection. This paper focuses on lung, bladder, and head-and-neck cancer. It reviews and compares available PD-L1 testing methodologies, summarizes the literature about comparability studies to date, discusses future directions in personalized diagnostics, and provides a pathologist's perspective on PD-L1 testing in the Canadian laboratory setting.

SUBMITTER: Ionescu DN

PROVIDER: S-EPMC6023555 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective.

Ionescu D N DN Downes M R MR Christofides A A Tsao M S MS

Current oncology (Toronto, Ont.) 20180628 3

Checkpoint inhibitors targeting the programmed cell death 1 protein (PD-1) and programmed cell death ligand 1 (PD-L1) are demonstrating promising efficacy and appear to be well tolerated in a number of tumour types. In non-small-cell lung cancer, head-and-neck squamous cell carcinoma, and urothelial carcinoma, outcomes appear particularly favourable in patients with high PD-L1 expression. However, assays for PD-L1 have been developed for individual agents, and they use different antibody clones, ...[more]

PMID: 29962847

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Project description:A meeting among expert pathologists was held in 2019 in Rome to verify the results of the previous harmonization efforts on the PD-L1 immunohistochemical testing by scoring a representative series of non-small cell lung cancer (NSCLC) digital slides. The current paper shows the results of this digital experimental meeting and the expertise achieved by the community of Italian pathologists. PD-L1 protein expression was determined using tumor proportion score (TPS), i.e., the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The gold standard was defined as the final PD-L1 score formulated by a panel of seven lung committed pathologists. PD-L1 status was clustered in three categories, namely negative (TPS < 1), low (TPS 1-49%), and high (TPS ≥ 50%). In 23 cases (71.9%) PD-L1 staining was performed using the companion diagnostic 22C3 pharmDx kit on Dako Autostainer, while in nine (28.1%) cases it was performed using the SP263 Ventana kit on BenchMark platform. A complete PD-L1 scoring agreement between the panel of experts and the participants was reached in 57.1% of cases, whereas a minor disagreement in 16.1% of cases was recorded. Italian pathologists performed best in strong positive cases (i.e., tumor proportion score TPS > 50%), whereas only 10.8% of disagreement with the gold standard was observed, and 55.6% regarded a single challenging case. The worst performance was achieved in the negative cases, with 32.0% disagreement. A significant difference resulted from the analysis of the data separated by the different clones used: 22.3% and 38.1% disagreement (p = 0.01) was found in the group of cases analyzed by 22C3 and SP263 antibody clones, respectively. In conclusion, this workshop record proposed the application of a digital pathology platform to share controversial cases in educational meetings as an alternative possibility for improving the interpretation and reporting of specific histological tools. Due to the crucial role of PD-L1 TPS for the selection of patients for immunotherapy, the identification of unconventional approaches as virtual slides to focus experiences and give more detailed practical verifications of the standard quality reached may be a considerable option.

Project description:BackgroundTo review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)-1 and PD-ligand 1 blocking antibodies (collectively referred to as PD-[L]1 inhibitors) over a 6-year period and corresponding companion/complementary diagnostic assays.Materials and methodsTo determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD-[L]1 inhibitors to identify all new indications granted from the first approval of a PD-[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type.ResultsOf 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression-free survival, 2 (3%) on recurrence-free survival, and 1 (1%) on complete response rate. Most ORR-based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed.ConclusionPD-[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available.Implications for practiceThe number of PD-[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD-L1 immunohistochemical assays between PD-1/PD-L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD-L1 expression have limited the use of PD-L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development.

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Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective.

Publications

Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective.

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