EQA for PD-L1 IHC staining: is it a conundrum? Keith Miller

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1 EQA for PD-L1 IHC staining: is it a conundrum? Keith Miller Director UK National External Quality Assessment Scheme for Immunohistochemistry & In-situ Hybridisation

2 The dangers of using laboratory developed tests as a CDx and especially in an NSCLC setting Keith Miller Director UK National External Quality Assessment Scheme for Immunohistochemistry & In-situ Hybridisation

3 New Host for the UKNEQAS-ICC&ISH Bart s HEALTH NHS Trust External Quality Assessment Services for Cancer Diagnostics - Community Interest Company not for profit

4 Professor Peter Isaacson Fellow of the Royal Society of Medicine 2009 Others who are Fellows of the Royal Society in London include Charles Darwin, Louis Pasteur

5 The UK National External Quality Assessment Scheme for Immunocytochemistry and ISH Fully Accredited under ISO UKNEQAS.org.uk

6 Strict Code of Practice Not for Profit Commercially neutral Monitor poor performance and assisting laboratories UK NEQAS central services are a registered charity

7 Breast HER2 IHC

8 Yesterday s Immunohistochemistry Laboratory k.miller@ucl.ac.uk

9 Range of HER2 immunostaining Negative Equivocal Positive FISH analysis

10 HER2 FISH Chr 17 centromere,, HER2. Ratio HER2:Chr is considered positive (20 60 non-overlapping nuclei assessed) 1.8 < 2.0 borderline negative 2.0 < 2.2 borderline positive

11 Breast Cancer Module: HER-2 Two diagnostic techniques AND two UK NEQAS EQA modules: IHC: Cell surface HER-2 protein expression Subjective scoring criteria 0 No staining / very slight partial membrane staining, < 10% of tumour cells 1+ Faint barely perceptible partial membrane staining, >10% of tumour cells 2+ Weak - moderate complete membrane staining, > 10% of tumour cells 3+ Strong complete membrane staining, > 10% of tumour cells FISH: Gene expression

12 Each of the cell lines for HER-2 have different levels of expression They are grown and processed to paraffinwax under very strict conditions The thickness of each section is measured with an interferometer UKNEQAS.org.uk

13 External EQA helps improve procedures over time HER2 IHC example UK laboratory Pass Rates:

14 The IHC Instruments available today All can also support either FISH or Chromogenic ISH protocols too

15 100% 90% 80% 70% Breast HER2 IHC: Kit v Laboratory Developed Test (HB) OS & UK ( combined data) % Users % Pass rate 92% UK 70% OS P< % P< % 100% 90% 80% 70% 60% 50% 53% 47% 60% 50% 40% 38% 40% 30% 20% Users of Approved CDx Users of LDTs Users of Approved CDx 30% 20% 10% 0% Kit-OS (n=2,483) HB-OS (n=1,574) Kit-UK (n=1,297) HB-UK (n=130) 8% Users of LDTs 10% 0%

16 ALK in NSCLC Detected in tumour specimens using: Immunohistochemistry (IHC) With positive cases confirmed by Fluorescence in situ hybridization (FISH) Reverse transcription polymerase chain reaction of cdna (RT-PCR) or NGS

17 UK NEQAS EQA for ALK includes cell lines and patient cancers

18 ALK Immunohistochemistry in Non-Small Cell Lung Carcinoma (NSCLC): A. Lessons Learned From External Quality Control OR B. Discordant Staining and Potential Impact On Patient Treatment Regimen C. Discordant Staining Can Impact Patient Treatment Regimen Merdol Ibrahim 1*, Suzanne Parry 1, Dawn Wilkinson 1, Neil Bilbe 1, David Allen 2, Steven Forrest 3, Perry Maxwell 5, Anthony O Grady 6, Jane Starczynski 7, Phillipe Taniere 1, John Gosney 3, Keith Kerr 1, Keith Miller 1 & Erik Thunnissen 9 1 UK NEQAS ICC & SH, Research Department of Pathology, University College London, London UK 2 UCLAD, Research Department of Pathology, University College London, London UK 3 Royal Liverpool University Hospital, Liverpool, UK 4 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 5 Royal Victoria Hospital, Northern Ireland, UK 6 Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland 7 Birmingham Heartlands Hospital, Birmingham, UK 8 Queen Elizabeth Hospital, Birmingham, UK 9 Aberdeen Royal Infirmary, Aberdeen, Scotland Journal of Thoracic Oncology: July 2016

19 Average Pass Rates for ALK IHC

20 Dochotomous ALK-IHC is a better Predictor for ALK inhibition outcome than traditional ALK-FISH in advanced non-small cell lung cancer van der Wekken A, Pelgrim R, 't Hart N, et al. Clinical Cancer Research 2017 Feb 9. Main points: Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine needle aspirations (FNA) were treated with ALK inhibitors (Crizotinib). All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients This was confirmed in an external cohort of 16 patients. ROC curves for ALK- IHC and ALK-FISH compared to treatment outcome, showed that dichotomous ALK- IHC outperforms ALK-FISH

21 SP142 22C off-label use of Pharm-Dx! SP263 SP142 Pharm-Dx SP C3 CD, Poundbury Cancer Inst. Blueprint studies German harmonisation studies LDTs (laboratory developed tests)

22 PD-L1 CDx Landscape Ventana (SP142) Ventana (SP263) Dako (28-8) Dako (22C3) Type Rabbit Monoclonal Rabbit Monoclonal Rabbit Monoclonal Rabbit Monoclonal Commercial Availability CE IVD analytical claim CE-IVD predictive claim CE IVD predictive claim CE IVD predictive claim, CDx Pharma Partner Roche / Genentech AstraZeneca / MedImmune BMS Merck Pharma Drug name Atezolizumab Durvalumab Nivolumab Nivolumab Pembrolizumab CDx Configuration BenchMark Series RTU Antibody OptiView Detection OptiView Amp Complementary Dx BenchMark Series RTU Antibody OptiView Detection Complementary Dx Dako Autostainer Dako Link RTU antibody Complementary Dx Dako Autostainer Dako Link RTU antibody Companion Dx PD-1/PD-L1: the target of many drug

23 EQA for PD-L1 Technical PD-L1 Interpretive A mixture of appropriate tissues and cell lines that cover the main decision points within each of the respective assays.

24 PD-L1: Some of our assessors

25 PD-L1 Protocols/Antibodies employed by our participants At least 50% of participants are using laboratory developed tests

26 PD-L1 EQA on lung cancer & cell lines PD-L1 IHC -Dako Approved 22C3/28.8 CDx PD-L1 IHC - Ventana Approved SP263 CDx

27 Differences between the different assays for PD-L1 Roche-Ventana SP142 Roche-Ventana SP263 Dako 28-8 Dako 22C3

28 Scores for Clones SP263/22C3/28.8

29 Scores for Clones SP263/22C3/28.8

30 PD-L1 Laboratory Developed Test where there was a significant reduction of positive cells in all samples Seen with both SP263 and 22C3 antibodies

31 PD-L1: Approved v LDT Approved PD-L1 IHC CDx using SP263 on strong expressing cell line. 80%-100% of cells are positive Laboratory Developed Test using SP263 on strong expressing cell line. <20% of cells are positive

32 PD-L1: Approved v LDT Approved CDx using SP263 on Tonsil Laboratory developed test for SP263 on Tonsil

33 RTD Multiplexing Capabilities in Lung Esteban Roberts, Adrian Murillo, Teresa Ruffalo and Larry Morrison All images shown in this presentation are meant to serve as examples of the capability of the technology and are not to be interpreted as a medical claim or source of medical information

34 Interpretive EQA for PD-L1 PD1/PD-L1 An online service is being planned

35 PD-L1 Creating a digital slide resource for all EQA s across the world to access for their local Educational EQA activities

36 PD-L1 Digital Education Resource Pilot EQA provider Academia Academia EQA provider EQA provider IQN-Path Digital Resource +Ad Board Journal Publication Industry Industry

37 IQN-Path Digital Education Resource Working Group Keith Miller UK-NEQAS Chair Colin Tristram - Histiocyte John Garratt ciqc Jacqueline Hall (IQN Path) Working Group Committee Members Hans Juergen Grote (Merck), Els Dequeker (ESP EQA), Erik Thunissen (ESP EQA), Julia Pagliuso (RCPAQAP), Rudy Hovelinck (Astra Zeneca), Mogens Vyberg (NordiQC), Soren Nielsen (NordiQC), Robert Lott (Roche), Beth Sheppard (Roche), Zenobia Haffajee (RCPAQAP), Jessica Whiteley (RCPAQAP), Helle Fisker (Visiopharm), Daniel Martinez (SEAP). Manfred Dietel (QUIP), Colin Tristram (Histocyte), Xueying Shi s (CCP)

38 Digital Education Resource from IQN-Path STAGE 1 DEVELOPMENT STAGE 2 PD-L1 PILOT STAGE 3 FULL IMPLEMENTATION

39 Is this slide positive for Red Marbles?

40 What is the Percentage of Red Marbles?

41 Teaching and Training A unique combination in a single building: A dedicated independent slide-based Cancer Testing Laboratory An Education Centre for the pathology community Based at: The Poundbury Cancer Institute, Newborough House, Queen Mother Square, Poundbury, Dorset, UK

42 Advanced Course for Pathologists and Scientists at Poundbury Professor Keith Kerr giving a seminar on Lung Cancer Is this something for IQNPath to get Involved in?

43 And finally to our PD-L1/PD1 IHC Trainer!

44 Another successful PD-L1 trainee!

45 ACKNOWLEDGEMENTS Dr Merdol Ibrahim Suzanne Parry Neil Bilbe Ailin Rhodes Clara Lynch Dawn Wilkinson Seema Dhanjal Professor Bharat Jasani Dr Corrado D Arrigo Dr Sarah Wedden & John Garratt from CIQC David Allen Josep Linares Numerous assessors Roche-Ventana Menarini Visiopharm and many more k.miller@ucl.ac.uk