Increased expression of programmed death-ligand 1 (PD-L1) is one mechanism neoplastic cells employ to protect themselves from immune attack. Binding of PD-L1 to its receptor, programmed cell death protein 1 (PD-1), results in inhibition of immune cells that would otherwise attack and destroy the tumour cell. Immunomodulatory drugs include immune checkpoint inhibitors that act on the PD-1/PD-L1 axis to interrupt this protective mechanism, thereby re-exposing the tumour to the immune system. These drugs have broadened and greatly improved treatment options for a variety of cancers, including non-small-cell lung carcinoma (NSCLC).1–3 As might be expected, immunomodulatory drugs are generally more effective against tumours in which there is high expression of PD-L1 on either the tumour cells themselves or on tumour-infiltrating immune cells, hence the rationale for PD-L1 testing.1,2,4,5
Unfortunately, different immunochemical assays for detecting PD-L1 were developed for each immunomodulatory drug, resulting in a multitude of antibodies and platforms that were initially considered non-interchangeable. This, compounded by inherent heterogeneity of PD-L1 expression and the challenge of accurately quantifying its expression in tissue sections, has created a difficult environment for PD-L1 testing.1,5,6
Four anti-PD-1/anti-PD-L1 immunomodulatory drugs are currently licensed for the treatment of cancer: nivolumab, pembrolizumab, atezolizumab and avelumab. Further agents, including durvalumab, are in clinical trials but are currently unlicensed. During their clinical trials, each agent was developed with a different PD-L1 test. As shown in Table 6.1, not only do these agents employ different antibody clones but they are run on different platforms and have different cut-offs for determination of positivity.1,4,6,7
Table 6.1PD-L1 assessment in NSCLC: antibodies, platforms and interpretation. |Favorite Table|Download (.pdf) Table 6.1 PD-L1 assessment in NSCLC: antibodies, platforms and interpretation.
|Anti-PD-L1 antibody ||Immunomodulatory drug |
|Atezolizumab ||Nivolumab, pembrolizumab, durvalumaba ||Avelumab |
|Test ||Ventana SP142 ||Dako 28–8, Dako 22C3, Ventana SP263 ||Dako 73–10 |
|Platform ||Ventana ||Dako or Ventana ||Dako |
|Interpretation ||Tumour cells and immune cells ||Tumour cells ||Tumour cells |
|TPS cut-off || |
Tumour cells 0–3 (<1, 1–4, 5–49, ≥50)
Immune cells 0–3 (<1, 1–4, 5–9, ≥10)
|≥1%, ≥25%, ≥50% depending on drug and indication ||≥1% in clinical trials |
Inherent properties of PD-L1 expression
PD-L1 expression within a primary cancer, and between a primary tumour and its metastases, may be markedly heterogeneous, altering not only with time as the tumour evolves, but also spatially within the tumour.6,7 Even across a small area of a tissue section, some tumour cells might demonstrate very strong expression and others very weak or no expression (Figure 6.1). Decisions to recommend treatment are based on a percentage score, usually ...