This document discusses PD-L1 testing and its role in immune checkpoint inhibition. It covers the historical context of PD-L1's role in immune escape and checkpoints. It notes that PD-L1 testing has nuances regarding sample type, preanalytic conditions, assay methods, scoring, and the dynamic nature of PD-L1 expression over time and with treatment. Issues include tumor heterogeneity, the interval between biopsy and treatment, and how previous treatments can affect expression levels.

1. PD-L1 testing:
why and why not?
Karine Darbinyan
November 2018
Montefiore Medical Center

2. Contents
• Historical aspect
• PD-L1 role in immune escape
• Nuances of PD-L1 testing
• Future prospective

3. Nobel Prize in Medicine, 2018

4. From mice to men
November 1999
• Evidence indicates that
receptor PD-1 is an immune
checkpoint
November 2012
• Anti-PD-1 antibody shows
dramatic results in phase I
trial
Topalian, NEJM, 2012Nishimura, Immunity 1999

5. PD-L1 among multiple other check points
Pardoll Nat Rev Cancer 2012

6. Escape from immune surveillance
Pardoll Nat Rev Cancer 2012

7. Checkpoint inhibitors
Ribas, Science, 2018

8. Approved checkpoint inhibitors (March 2018)
Ribas, Science, 2018

9. 2012 - PD-L1 expression in tumors is a candidate molecular marker
Topalian, NEJM, 2012

10. PD-L1 Testing
Histology or
cytology
Preanalytic
conditions
Analytic
conditions
Postanalytic
phase
-Different Ab clones
-Signal enhancement
SCORING AND REPORTING

11. Histology versus Cytology (NSCLC)
• At least 30% to 40% of all patients with advanced NSCLC are
diagnosed by cytology alone
• However, use of cytology samples for determination of PD-L1 is not
advocated because none of the assays are validated for this purpose
• Paired comparisons of PD-L1 expression on cytologic and histologic
specimens found high degree of agreement (Skov, 2017)

12. Preanalytic
conditions may
affect staining
outcome
Fading With Time of PD-L1
Immunoreactivity in Non-Small Cells
Lung Cancer Tissues:
A Methodological Study.
PMID 27801735

13. PD-L1 IHC assays
Will there be a universal
PD-L1 IHC test that will
be equivalent to all
clinically validated tests?

15. Interobserver variability
In majority of clinical trials PD-L1 status was evaluated by
two independent pathologists

16. Blueprint study led by IASLC

17. Issues with PD-L1 as a biomarker
- Heterogeneity – multiple tumors and
multiple passes within a tumor
- Interval between biopsy and treatment
- Primary versus metastatic disease
- Different antibody and staining conditions
McLaughlin JAMA Oncology 2016

18. Effect of previous treatment
Neoadjuvant
chemotherapy
Sheng, J Sci Rep, 2016
Immune cells
• Positivity of PD-L1 on
tumor cells (TCs) changed
from 75% to 37.5% after
NACT (p = 0.003)
• Moreover, patients with
response to NACT
presented significantly
reduced PD-L1 expression
on TCs (p = 0.004)
Tumor cells
IIIA
and
IIIB

19. Dynamism of PD-L1 expression
• Biology of PD-L1 expression is dynamic, depending on the patient’s
status relative to the disease continuum
• Patient’s previous treatment and response to treatment can interfere
with PD-L1 expression levels
Should PD-L1 expression be measured once on static biopsy or
continuously throughout the course of disease (example: ctDNA) ?

20. Meta-analysis 2018: Primary end point - OS
Shen, BMJ, 2018
ICI better Chemotherapy better

21. PD-L1 testing in clinical trials: 2016