9e avondsymposium: "Nieuwe ontwikkelingen in de behandeling van NSCLC" 9 november 2016, UMCG Vernieuwing en diagnostiek bij NSCLC: Immunotherapy: PD-L1 analyse: waar staan we Wim Timens Professor and Chair Dept. Pathology and Medical Biology, University Medical Center Groningen Pathology
Immunopathology in lung cancer immune checkpoint diagnostics PD-L1 testing Other immune checkpoints New/other checkpoint (companion) diagnostics? Pathology
Pathology Pardoll, Nature Rev Cancer 2012
Pathology Immune checkpoint blockade Drake, C. G. et al. (2013) Nat. Rev. Clin. Oncol.
PD-L1 testing: present state and problems From the FDA-AACR-ASCO Public Workshop, March 24, 2015, (Reena Philip, Ph.D.): Why Companion Diagnostics: Companion Diagnostics are those tests that provides information that is essential for the safe and effective use of a corresponding drug or biological product. Issues - The Case of PD-L1 Complications First results (2016) Pathology
Pathology Analytically validated assays used in clinical studies Agent Nivolumab Pembrolizumab Durvalumab Atezolizumab Antibody Dako 28-8 Ventana SP263 Dako 22C3 Ventana SP263 Ventana SP142 Cut-off(s) Tested (NSCLC) 1%, 5% or 10% (TC) 25% TC TC 50% (and 1% any stroma) 25% TC TC 1%, 5%, 50% IC 1%, 5%, 10%
Issues - The Case of PD-L1 Performance of each IHC antibody optimized for a particular protocol and platform Is the sensitivity and specificity between clones the same? Is the reactivity in tumor cells and TILs the same? Can laboratories apply one protocol to the same clone for all uses? Can laboratories adequately assess concordance with an adequate number of specimens? Rx/Dx Industry PD-L1 Blueprint Proposal FDA-AACR-ASCO Public Workshop 24 March 2015 Pathology
Complications Running a different test for every drug is impractical Limited tumor tissue Turnaround time Using one test for every drug is equally impractical All tests will not run on all platforms Each test has different performance characteristics Scoring and interpretation guidelines are not harmonized Each drug may have different clinical response based on biologic, chemistry and MOA differences There is potential for harm to patients if: FDA-approved IVD s and drugs are cross-matched by end users in the absence of FDA reviewed and approved claims of clinical and analytical concordance. Pathology Rx/Dx Industry PD-L1 Blueprint Proposal FDA-AACR-ASCO Public Workshop 24 March 2015
Pathology PD-L1 immunohistochemistry comparison and harmonisation Blueprint project (22C3, 28-8, SP142, SP263, cf validation protocol: on DAKO Link Autostainer AS- 48 and Ventana Benchmark Ultra) n=39, path=3 Ratcliffe study (SP263, 28-8, 22C3 cf validation protocol) n=500? 81? Path=? Scheel et al., Mod. Pathol 2016 (22C3, 28-8, SP142, SP263, cf validation protocol; SP142 and E1L3N lab devel. assay on Leica) n=15, path=9
Hirsch, Blueprint, AACR 2016
Pathology PD-L1 IHC variation Different PD-L1 clones on consecutive sections of one tumor Scheel et al. Modern Pathol 2016
Hirsch, Blueprint, AACR 2016
Hirsch, Blueprint, AACR 2016
Hirsch, Blueprint, AACR 2016
Hirsch, Blueprint, AACR 2016
Pathology Conclusions Astra-Zeneca study (Ratcliffe) overall percent agreement (OPA) of 96% between Dako 28-8 at the 10% cut-off and the Ventana SP263 assay (positive percent agreement [PPA]; 91%, negative percent agreement [NPA]; 98%). similar results between SP263 and 22C3 tests at the 50% cut-off mark.
Pathology Results/Conclusions Scheel-study The assays 28-8 and 22C3 stained similar proportions of carcinoma cells in 12 of 15 cases. SP142 stained fewer carcinoma cells compared to 28-8, 22C3, and SP263 in four cases, whereas SP263 stained more carcinoma cells in nine cases. SP142 and SP263 stained immune cells more intensely. The data indicate that carcinoma cells can be reproducibly scored in PD-L1 immunohistochemistry for pulmonary adenocarcinoma and squamous-cell carcinoma. No differences in interobserver concordance were noticed among the tested assays. The scoring of immune cells yielded low concordance rates and might require specific standardization. Scheel et al. Modern Pathol 2016
Key Points JAMA Oncol. doi:10.1001/jamaoncol.2016.3015 Published online August 18, 2016 Question: Do the 4 drug-matched companion diagnostic antibodies for PD-1 axis therapies all produce the same results? Findings: In this study, 3 key components of diagnostic tests were assessed: the primary antibody, assay-specific variables related to the staining platform, and immunohistochemical assessment of tissue. All antibodies tested were concordant. Meaning: Discordance of the companion diagnostic test is not attributable to the antibody but rather to inherent tumor heterogeneity or assay- or platform-specific variables Pathology
Pathology Variable expression of PD-L1 within one tumor / within one patient Cree et al, Histopathology 2016
Pitfalls of using PDL1 immunohistochemistry as a biomarker test for anti-pd1 PDL1 therapy Pathology Focal programmed cell death 1 ligand 1 (PDL1) expression in some tumours may be missed in small biopsy specimens, such as needle biopsies PDL1 expression among multiple tumour lesions from individual patients can vary over time and by anatomical site PDL1 expression in tumour biopsies collected months or years earlier might not accurately reflect PDL1 status at the time of treatment initiation; therapies given after biopsy but before administration of programmed cell death protein 1 (PD1) pathway blockade (radiation therapy, chemotherapy or kinase inhibitors) may alter PDL1 expression PDL1 epitopes detected by some antibodies are potentially unstable with prolonged specimen fixation or inadequate tissue handling before fixation (see NCI guidelines for tissue handling) Antibodies used for PDL1 detection have different affinities and specificities PDL1 protein expression can be membranous and/or cytoplasmic; however, only membranous PDL1 is functionally relevant, by contacting PD1+ T cells PDL1 can be expressed by multiple cell types within the tumour microenvironment, which poses challenges for scoring and interpretation Topalian et al. Nature Rev Cancer 2016
Immune checkpoints Pardoll, Nature Rev Cancer 2012
Kerr, USCAP 2015
Eur Respir J 2015; 46: 1762 1772
CD8 FoxP3 O Callaghan et al. Eur Respir J 2015; CD3
Pathology Conclusions: PD-L1 testing evaluation is encouraging with respect to better and simpler, reliable routine application in pathology Since PD-L1 alone is not the optimal biomarker for PD-1 therapies, considerable effort is and should be spent in examining (combination with) others such as tumorinfiltrating immune cells, mutational load, gene signatures In the future, it is likely that it will be an optimal combination of biomarkers to be used to determine, with a sufficient degree of certainty, whether a particular patient will benefit from anti-pd-1/pd-l1 therapy and future immune checkpoint blocking drugs to come
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