Biomarkers: PD-L1

ESMO Preceptorship, Immuno-Oncology

November 26, 2018 Singapore

Teh-Ying Chou, MD, PhD, MBA

Chair, Department of Pathology & Lab Medicine

Taipei Veterans General Hospital, TAIWAN

Professor, Institute of Clinical Medicine

National Yang-Ming University, TAIWAN

Relationships with commercial interests:Advisory Board : Astra Zeneca, Merck Sharp & Dohme, Novartis, RocheHonoraria : Astra Zeneca, Merck Sharp & Dohme, Novartis, Roche

DISCLOSURE

Cancer Immunotherapy

Standard of Care for Advanced NSCLC

Immune Checkpoint Inhibitor anti-PD-1/PD-L1

ICPI

Biomarkers

• Prognostic Marker

– Single trait or signature of traits that identifies

different groups of patients with respect to the

risk of an outcome of interest in the absence of

treatment

• Predictive Marker

– Single trait or signature of traits that identifies

different groups of patients with respect to the

risk of an outcome of interest in response to a

specific treatment

Peters S et al

WCLC 2016

ICPI

PD-L1

PD-L1 immunohistochemistry as a biomarker

Presented By Keith Kerr at 2015 ASCO Annual Meeting

Immune Biomarker Considerations

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• Epitope stability• Distribution (patchy vs diffuse)• Different antibodies and platforms• Different thresholds for expression• Inter-observer readability

Technical: Assay 1,2

• Inter- and intra-tumour heterogeneity• Inducible and dynamic• Cell type (immune cell vs tumour vs

both)• Location (membrane vs cytoplasm)

Biological: Biomarkers 2,5-8

Immune Biomarker

Considerations

• Interval between tissue and treatment (archived vs fresh)

• Biopsy obtained from primary vs metastatic disease site

• Some circumstances not favorable to obtaining any tissue

• Certain biopsy methods result in poor tissue quality/quantity

• Core needle biopsy • Fine needle aspiration biopsy• Liquid biopsy

Logistical: Tissue 3,4

PD-L1 Tumor Heterogeneity

McLaughlin et al, JAMA Oncol., 2016.

H&E PD-L1 (SP142)

PD-L1 Tumor Heterogeneity

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PD-L1 (SP142)

Atezolizumab Nivolumab Pembrolizumab

Detectionantibody*

SP142 28-8 22C3

IHC platform Ventana Dako Dako

Tested cellsNSCLC (IC and TC)

UC (IC)Lung (TC)

NSCLC (TC)UC (TC and stroma)

Estimated PD-L1prevalence in NSCLC

Predictive value?

TC1/2/3 & IC1/2/3‡

26%

IC1/2/3 & TC0*

30%

TC1/2/3 & IC0*

11%

PD-L1+ as ≥50% of TCs

~46%1

PD-L1+ as ≥5% of TCs

~25%1

*TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1+; TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1+; TC1/2/3 or IC1/2/3 = TC or IC ≥ 1% PD-L1+; TC0 and IC0 = TC and IC < 1% PD-L1+, respectively.‡POPLAR (Spira, et al. ASCO 2015); Study-003 (Brahmer, et al. ASCO 2014; KEYNOTE-001 (Garon, et al. AACR 2015)1. Kerr KM, et al. J Thorac Oncol 2015

PD-L1 expression correlates with efficacy

Approved and Investigational PD-L1 Diagnostics in NSCLC

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Nivolumab 1: BMS

Pembrolizumab 2: Merck

Atezolizumab 3: Roche

Durvalumab 4: AstraZeneca

Ab Clone 28-8 SP263 22C3 SP142 SP263

Diagnostic Partner Dako5 Ventana6 Dako7 Ventana8 Ventana4

Scoring Method † % of PD-L1–expressing tumour cells

% of PD-L1–expressing tumour

cells

% of PD-L1–expressing tumour

cells or immune cells

% of PD-L1–expressing tumour

cells

Diagnostic Status

Complementary:

testing not required

Companion:

testing required

US/EU: SQ and NSQ

NSCLC

Dx not approved for

NSCLC setting

Dx not approved for

durvalumab in any

settingUS/EU:

NSQ NSCLC

EU:

NSQ NSCLC

Approved IVD

PD-L1 Threshold

US/EU:

All patients

eligible

EU:

All patients eligible

US: ≥50%

EU: ≥1%NA NA

Validated PD-L1

Thresholds≥1%, ≥5%, or ≥10% ≥1%, ≥50% NA NA

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Different Classes of In Vitro Diagnostics

IVDs vs LDTs

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Practical Considerations for PD-L1 Testing

• Formal HTA Assessment of PD-L1 Dx Test Is Not Required in Most Markets

Class III In Vitro Diagnostics 1,2

Developed in the form of a kit for general use

FDA approval of kits

requiredCE marking required

Highly regulated PMA

process before being

marketed

Clinical safety or

performance evaluation

required

Laboratory-Developed Tests 1,2

Created by local laboratories, at which use

is restricted

Created by local laboratories

No requirement for

premarket review, plans

in place for future

No requirement for

premarket review,

manufacturer self-

declares

Clinical validation is not

required for their use

Clinical safety or

performance evaluation

required

CE = Conformité Européene (European Conformity); Dx = diagnostic; HER2 = human epidermal growth factor receptor 2; HTA = health technology assessment; IVDs = in vitro diagnostics; LDTs = laboratory-developed tests; PMA = premarket approval.

1. In Vitro Companion Diagnostic Devices. FDA Guidance. August 6, 2014. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262327.pdf. Accessed September 2016. 2. Understanding Europe’s New Medical Devices Regulation (MDR). Key changes contained in the proposed MDR and their impact on manufacturers. EMERGO white paper: July 2016, anticipated publishing date early 2017.

PD-L1 Assay Analytic Comparability: The Blueprint Project

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Reference Area Footnotes Area

• The Blueprint project identifies four in vitro diagnostics (IVDs) for PD-L1 testing where results can be compared:

• The objective of the Blueprint project is to evaluate the analytical comparability of the four PD-L1 assays with 39 NSCLC samples

– The interchangeable use of PD-L1 assays will also be assessed

• AACR, IASLC, and four pharmaceutical companies collaborated in the design and implementation of this project

Abcam 28-8 mAb Dako 22C3 mAb Spring Bioscience

SP142 mAb

Spring Bioscience

SP263 mAb

Blueprint Project: Study Design

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• Two-phase study to gain sufficient data and rigor:

Phase 1Phase 1

Feasibility on small cohort evaluated at Dako and V entanaTo assess the four PD-L1 diagnostics on the same NSCLC cases and gather initial data in two stages:

• Step 1: Evaluate analytical comparability by quantifying and comparing PD-L1 expression on tumour and immune cells

• Step 2: Clinical agreement was assessed through comparisons of patient classification and agreement using various combinations of assays and PD-L1 staining thresholds

Feasibility on small cohort evaluated at Dako and V entanaTo assess the four PD-L1 diagnostics on the same NSCLC cases and gather initial data in two stages:

• Step 1: Evaluate analytical comparability by quantifying and comparing PD-L1 expression on tumour and immune cells

• Step 2: Clinical agreement was assessed through comparisons of patient classification and agreement using various combinations of assays and PD-L1 staining thresholds

Phase 2Phase 2 TBD: Proposed larger, statistically powered study that will be designed from the Phase 1 “information gathering”TBD: Proposed larger, statistically powered study that will be designed from the Phase 1 “information gathering”

Agreement Between Assays For PD-L1 Expression

Based on Specified Cutoffs (N=38 cases)

Nineteen (19) cases (blue circle) show agreement with all four assays above

selected cut-off regardless of which matched assay cutoff is employed

Overlapping cases < all specified cutoffs (N=5) are not shown

AGREEMENT all assays: 24/38 ( 63%)

SP142 TC1/IC1

(30/38)

28-8 1% TPS

(26/38)

22C3 1% TPS

(26/38)

SP263 25%

(20/38)

Hirsch FR et al. J Thorac Oncol 2017

Hirsch FR WCLC 2017

Reliability of Scoring PD-L1 on Tumor Cells

Take Home MessageBlue print Phase 2 study

• The feasibility of harmonizing the clinical use of 5 trial-validated PD-L1 IHC

assays (28-8, 22C3, SP263, SP142 & 73-10) are assessed by 24 international

expert pulmonary pathologists.

• Glass slides and digital images for tissue and cytology samples are applied.

• The results show highly comparable staining by 3 assays, less sensitivity by

SP142 and higher sensitivity by 73-10.

• Scoring by glass slides and digital images are highly concordant.

• Very strong reliability among pathologists in scoring TC, poor reliability in

scoring IC, and moderate agreement in sections of needle aspirate cell

blocks are observed.

• Evidence for interchangeability among 3 PD-L1 IHC assays is consolidated.

IASLC Atlas of PD-L1 IHC in Lung Cancer

Analytical versus Clinical Comparison/Compatibility !!!

Figure 1

Journal of Thoracic Oncology 2018 13, 447-453DOI: (10.1016/j.jtho.2017.10.034) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

PD-L1 Expression in CTC

Take Home Messages

• PD-L1 has been the seminal predictive marker for anti-PD-

1/PD-L1 immunotherapy

• Companion versus Complimentary PD-L1 testing is generally

based on clinical trials

• The use of IVD versus LDT depends on regional regulations

(and financial indications)

• The PD-L1 IHC of tumor cells has high scoring concordance

among 22C3, 28-8 and SP263 platforms using FFPE tissue

• The PD-L1 IHC on cytology specimens and circulating tumor

cells may be promising, as well as evaluating soluble PD-1/PD-

L1 and the post-translational modifications of PD-L1

Have a Nice Day!AcknowledgementYi-Chen Yeh, MD

Hsiang-Ling Ho, PhD