PD-L1 in Cancer: ESMO Biomarker Factsheet

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Hendrik-Tobias Arkenau
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Author: Hendrik Tobias Arkenau 
Sarah Cannon Research Institute
UK

Definition of PD-1/PD-L1

PD-1 or ‘programmed-death 1’ (CD279) is a cell surface receptor that is part of the immunoglobulin superfamily. It is expressed primarily on the surface of activated T-cells 1,2. PD-L1 or ‘programmed-death ligand 1’ (CD274) is one of two PD-1 ligands. It is a transmembrane protein expressed on a variety of cell types, including antigen presenting cells, mainly Dendritic cells and macrophages 1. PD-L1 is also expressed constitutively by non-lymphoid tissue including heart, lung and others 3. Binding of PD-L1 inhibits the proliferation of activated T-cells, which is an important mechanism for negative feedback control of inflammation and autoimmunity in the peripheral effector phase of T-cell activation 1. This identifies the PD-1/PD-L1 pathway as an important immune response checkpoint.

Tumour cells can co-opt this PD-1/PD-L1 regulatory mechanism. Tumour cells may express PD-L1, with subsequent PD-1 binding and inhibition of T-cell activation allowing cancer cells to evade immune attack. PD-L1 expression can be driven by both adaptive immune resistance as well as oncogenic mechanisms 4. A range of solid and haematological malignancies have been shown to over-express PD-L1 1. Preclinical studies that found decreased tumour growth and improved survival with PD-1/PD-L1 pathway blockade provided the rationale for immune checkpoint inhibition as a novel approach in cancer treatment.

Drugs Targeting the PD-1/PD-L1 Pathway

Blockade of the PD-1/PD-L1 pathway has emerged as a promising cancer therapy preventing evasion of tumour cells from the immune system with restoration of host immunity against the tumour. Several monoclonal antibodies have been developed and licensed, and many more are in pre-clinical and clinical development that can disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T-cells, with resultant tumour recognition by cytotoxic T-cells. Remarkable clinical responses have been seen in some patients in various cancer types, including melanoma, lung, kidney, bladder cancer and others. Clinical trials are investigating immune checkpoint blockade therapies both alone, in combination with chemotherapy, small molecules, or other immune targeting agents to treat a variety of cancers. There are now several hundreds of ongoing immunotherapy combination trials 4.

Currently, two PD-1 inhibitors are approved for clinical use in both Europe and the US. Nivolumab and pembrolizumab are both human IgG4 monoclonal antibodies that block PD-1. In both Europe and the US, nivolumab is indicated for the treatment of unresectable or metastatic melanoma, alone or in combination with the anti-CTLA4 Monoclonal antibody, ipilimumab; for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior therapy; and as monotherapy for the treatment of advanced renal cell carcinoma after prior therapy 5,6. In the US, nivolumab has a wider indication and in addition, is approved for classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin 6. In the US, the Food and Drug Administration (FDA) approved the complimentary diagnostic test, PD-L1 IHC 28-8 pharmDx, for the detection of PD-L1 expression in NSCLC and melanoma tissue, to assist physicians with their treatment decisions 7.

Pembrolizumab is indicated in Europe and the US for the treatment of advanced (unresectable or metastatic) melanoma, and locally advanced (only in Europe) or metastatic NSCLC after prior therapy in patients whose tumours express PD-L18,9. In the US, the pembrolizumab licence is broader and is also indicated as first-line treatment in patients with metastatic NSCLC whose tumours express a high level of PD-L1 with no EGFR or ALK genomic tumour aberrations, and in patients with recurrent or metastatic head and neck Squamous cell carcinoma (HNSCC) after prior platinum-based chemotherapy 8.  For use of pembrolizumab in metastatic NSCLC, the US licence specifies that PD-L1 status must be determined using an FDA-approved test 8. For first-line treatment of metastatic NSCLC without EGFR or ALK genomic tumour aberrations, PD-L1 must be expressed in ≥ 50% of tumour cells, and for treatment after prior therapy, it must be expressed in ≥ 1% of tumour cells 8. The FDA have approved the immunohistochemical assay, PD-L1 IHC 22C3 pharmDx, as a companion diagnostic for the detection of PD-L1 protein in NSCLC tissue 10.

IHC of PD-L1-positive Tumour

IHC of PD-L1-positive Tumour. Credit: Hendrik Tobias Arkenau

Atezolizumab is an engineered IgG1 antibody that inhibits the PD-1/PD-L1 checkpoint by interacting directly with PD-L1 and preventing its binding to PD-1, and is currently the only licensed PD-L1 inhibitor in the US. Atezolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma after prior platinum-based chemotherapy, and for metastatic NSCLC after prior therapy 11. The FDA have approved the VENTANA PD-L1 (SP142) Assay as a complimentary diagnostic, to determine the proportion of PD-L1 expressing tumour-infiltrating immune cells in urothelial carcinoma tissue, to help physicians decide which patients are most likely to respond to atezolizumab 12.

PD-L1 as a Predictive Biomarker  

Defining biomarkers that predict therapeutic response to PD-1/PD-L1 blockade is an important goal 13. There is increasing evidence that PD-L1 measured by levels of Immunohistochemistry (IHC) expression is a relevant marker to predict response to treatment. The first study that provided evidence of a link between PD-L1 protein expression by tumour cells detected by IHC and response to anti-PD-1 therapy, was the first-in-human phase I nivolumab trial conducted in patients with a variety of different solid tumour types 14. Subsequently, a number of trials validated that PD-L1 expression correlates with an increased response to PD-1 and PD-L1 immune checkpoint inhibitors, but the response rate was lower than the early studies. 

IHC of PD-L1-negative Tumour

IHC of PD-L1-negative Tumour. Credit: Hendrik Tobias Arkenau

Thus, while PD-L1 expression has been associated with more favourable response rates to PD-1/PD-L1 checkpoint inhibitors, PD-L1 does not appear to be a static Biomarker and does not offer binary discrimination of responsiveness. 

The wording of the licences for pembrolizumab, nivolumab and atezolizumab, have different recommendations regarding PD-L1 expression that reflect the clinical trial evidence. Only pembrolizumab has an indication restricted to tumours expressing PD-L1, whereas nivolumab and atezolizumab have been approved regardless of tumour PD-L1 expression 5,6,8,9,11. Patients without PD-L1 expression can also derive benefit from these agents, with studies across multiple cancer types demonstrating a pooled response rate of 48% in patients with PD-L1-positive tumours compared with 15% in PD-L1-negative tumours 15.

Both pembrolizumab and nivolumab are licensed by the European Medicines Agency (EMA) and FDA for treatment of advanced melanoma independent of PD-L1 expression. The combination of nivolumab with ipilimumab in advanced melanoma improved progression-free survival (PFS) over nivolumab alone, in patients with low tumour PD-L1 expression measured by the PD-L1 IHC 28-8 pharmDx assay 16, and this finding is reflected in the wording of the nivolumab melanoma indication in the EU 5.

PD-L1 positivity is also associated with improved survival from nivolumab treatment in non-squamous NSCLC 17. The predictive value of PD-L1, using the PD-L1 IHC 28-8 pharmDx assay, was seen across all the efficacy end points of the CheckMate 057 study at an expression level ≥1% 7. Despite these findings, a companion diagnostic is not required for nivolumab treatment in melanoma or NSCLC 5,6. The FDA has instead approved the PD-L1 IHC 28-8 pharmDx test as a complementary test that may provide physicians more information and inform patient dialogue when deciding treatment for melanoma or NSCLC. This decision was likely influenced by limitations of the clinical data to support the assay, for example, findings from clinical trials that demonstrated similar outcomes irrespective of PD-L1 expression status 18,19,20. Furthermore, testing for PD-L1 expression in the CheckMate 057 study was retrospective and was not performed on all patient specimens but rather a subset of 78% of cases, with the potential risk of selection bias 18.

Currently, PD-L1 IHC 22C3 pharmDx (Dako) is the only FDA-approved companion diagnostic for selecting NSCLC patients for treatment with pembrolizumab. This approval was based on results of two randomised, controlled trials that demonstrated statistically significant improvements in PFS and overall survival (OS) for patients randomised to pembrolizumab compared with chemotherapy. In a trial of 305 patients with metastatic NSCLC, whose tumours had high PD-L1 expression (expressed in ≥ 50% tumour cells), had not received prior chemotherapy and did not have EGFR or ALK genomic tumour aberrations, those who received pembrolizumab had a significant improvement in PFS for patients receiving pembrolizumab versus chemotherapy. Additionally, a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomised to pembrolizumab as compared with chemotherapy 8. In a trial of 1033 patients who were previously treated for metastatic NSCLC and expressed PD-L1 in greater than or equal to 1% tumour cells, those randomised to pembrolizumab had an improved OS compared with patients receiving docetaxel.

In a non-randomised, prospective, single-arm study of atezolizumab, PD-L1 expression in ≥ 5% tumour infiltrating immune cells, determined by the VENTANA PD-L1 (SP142) Assay, in urothelial carcinoma tissue was associated with increased objective response rate 21. In patients who were classified as positive for PD-L1 expression (5% tumour infiltrating immune cells), 26% of participants experienced a tumour response compared to 9.5% of participants who were classified as negative for PD-L1 expression (< 5% tumour infiltrating immune cells). Therefore, patients experienced a tumour response across the study; however, the greater effect in those who were classified as positive for PD-L1 expression suggests that the level of PD-L1 expression in tumour-infiltrating immune cells may help identify patients whose tumours are more likely to respond 12. Hence, the VENTANA PD-L1 (SP142) Assay has been approved by the FDA, as a complimentary diagnostic to help physicians decide which patients with urothelial cancer are most likely to respond to atezolizumab 12.

Quality Testing Results

The conflicting observations regarding PD-L1 as a predictive biomarker of tumour response likely reflects a number of issues, both IHC-test specific and tumour-biology-related. These include the limitations inherent in tumour sampling, with focal expression potentially missed in small biopsies, and differential PD-L1 expression apparent over time and by anatomical site in individual patients. Different IHC detection methods and antibodies, quality of samples, methods used to acquire material, and positivity thresholds may also be a factor 4. Recognising this, a Blueprint Working Group has been established with cooperation from the Pharmaceutical Industry to provide a comparison of different IHC tests and cell scoring methods for PD-L1 expression, reflecting that each drug is developed in the context of a unique biological scientific hypothesis and registration strategy. In terms of the tumour microenvironment, PD-L1 can be expressed across a wide range of cell types, creating challenges in individual cell identification 4. The impact on the tumour microenvironment that may have occurred through multiple previous cancer treatments remains undefined 4.

Patient Selection

As a result and highlighted here PD-L1 IHC positivity is an imperfect biomarker of response and currently not suitable as a definite biomarker for selection for therapy 4,18. It is likely that a more complex, multicomponent predictive biomarker system will be required to refine appropriate patient selection for PD-1/PD-L1 blockade 4,22.

References

  1. Patel SP, Kurzrock R PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther. 2015 Apr;14(4):847-56
  2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 2015; 373:123-135.
  3. Suarez ER, Chang de K, Sun J, et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2016; 7(23):34341-55. doi: 10.18632/oncotarget.9114.
  4. Topalian SL, Taube JM, Anders RA, et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016; (5):275-87.
  5. Opdivo Summary of Product Characteristics, 2016.
  6. Opdivo prescribing information, 2016.
  7. PD-L1 IHC 28-8 pharmDx Summary of Safety and Effectiveness Data, 2016.
  8. Keytruda prescribing information, 2016.
  9. Keytruda Summary of Product Characteristics, 2016.
  10. PD-L1 IHC 22C3 pharmDx Summary of Safety and Effectiveness Data, 2016.
  11. Tecentriq Prescribing Information, 2016.
  12. VENTANA PD-L1 (SP142) Assay Summary of Safety and Effectiveness Data, 2016.
  13. Bhaijee F, Anders RA. PD-L1 Expression as a Predictive Biomarker: Is Absence of Proof the Same as Proof of Absence? JAMA Oncol 2016; 2(1):54-5.
  14. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28(19):3167-75.
  15. Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015; 23:32-8.
  16. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373:23-34.
  17. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. N Engl JMed 2015; 373:1627–1639.
  18. Jørgensen JT. Companion diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC. Expert Rev Mol Diagn 2016 Feb;16(2):131-3.
  19. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372:320–330.
  20. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372:2521–2532.
  21. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387:1909-1920.
  22. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med 2016; 375:1767-78.
Last update: 21 November 2016