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Which PD-L1 Assay to Use With Which NSCLC Immunotherapy? There's an Atlas for That Now


NEW YORK (360Dx) – With new immunotherapies available for lung cancer, PD-L1 testing for use with the new treatments has become routine.

However, some say that confusion is rampant about how to use the assays, whether they are compatible for every immunotherapy, and if the PD-L1 tests are interchangeable.

To address this, the International Association for the Study of Lung Cancer (IASLC) last week released the Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer at the European Lung Cancer Conference, in the hopes of providing clinicians and patients clarity on which PD-L1 assays may best suit their needs.

Joanne Yi, a consultant and professor of pathology at Mayo Clinic, called the atlas a much-awaited resource "for pathologists who have been struggling in the interpretation of this very complex biomarker, PD-L1," and said that it should be a "useful reference to pathologists and clinical colleagues alike.”

Working together, pharmaceuticals and diagnostic businesses have made "encouraging progress" in developing and using immunotherapies for patients with non-small cell lung cancer, according to IASLC. However, Fred Hirsch, CEO of the association, said that confusion is common among oncologist, pathologists, and patients trying to decide which commercially available PD-L1 assay may be most appropriate for them to use.

PD-L1 protein expression detected by immunohistochemistry testing is become a widely used method to determine which patients may benefit from anti-PD-1/ PD-L1 therapies, the Atlas said.

What's needed, though, is information "regarding interpretation, assay usage for PD-L1 testing, and potential interchangeability," Hirsch said.

This "complex scenario" has arisen because each assay was codeveloped with a specific type of therapy, and until now, no publication had collectively evaluated all commercially available assays, IASLC said.

It noted that the atlas evaluated the changing landscape of laboratory testing in general, and then focused on the specifics of each assay and on the current controversies regarding PD-L1 expression testing in lung cancer.

Specific drugs in clinical development both in Europe and the US are associated with specific diagnostic assays even if the therapies are from the same family, Hirsch said, adding that not only do each of the associated diagnostic tests employ different antibodies and different training procedures, but perhaps "most important, they use different cutoff levels in defining a positive or a negative tumor."

This type of biomarker scenario is a first for lung cancer diagnostics stakeholders, he said. Therefore, a goal of the collaboration has been to create the Atlas as a new resource for understanding PD-L1 IHC assays — one that would enable patients with lung cancer to not only receive the most contemporary and well-suited treatment options based on up-to-date evidence, but also to "feel more confident and knowledgeable regarding their therapy."

Solange Peters, head of the thoracic malignancies program in the department of oncology at Lausanne University Hospital in Switzerland, said that IASLC has worked hard to get pharma companies to "sit around a table," so that they could tell them that healthcare providers "need to understand how to use each test and how to compare it with the others," so that in the end, "we have one way to describe and define PD-L1 as a biomarker."

In her role at the hospital, Peters selects patients and samples for testing by pathologists. Using the test results, she decides which type of immunotherapy a patient should receive, or if they should receive it at all.

She noted that competition in the market to develop immunotherapies and the availability of PD-L1 as a biomarker has made clinicians' decisions more complicated, which is why the release of the atlas is timely.

"Each company has been developing its own test with its own antibody; its own platform to conduct the test; its own methodology in terms of which cells to assess and which cells not to assess; its own card-scoring system; and its own definition of what is PD-L1 positive," she said.

Knowing what to do when an assay provides a positive or negative result is not simple. During testing, she said, she requests a "descriptive assessment of PD-L1. I don't want to just hear that the test is positive, because that doesn't give me enough information. I want to know about the quality of the stain and the number of cancer cells that have stained for PD-L1, and based on that, I can make a decision."

In deciding on a therapy, she looks at the percentage of tumor cells in a sample that are positive, and she evaluates the overall clinical scenario, including, for example, the patient's level of progression with cancer and the type of immunotherapy that could be prescribed, if any.

Broadly, Peters noted, clinicians need a harmonized definition of when the biomarker is presenting a positive result across different tests, clinical scenarios, and diseases. Given a clear definition, they then need "a harmonization of test quality at national and regional levels across the world," she added.

Peters noted that the atlas is particularly important because it includes "all of the characteristics of each company's PD-L1 descriptors, showing you how different they are and how different things can be studied in parallel." With the atlas, "you now know how to select a test," she added.

Leena Gandhi, director of thoracic medical oncology at NYU Langone Medical Center, said that the atlas "is critical in a fast-moving field with conflicting data and controversy regarding the utility and importance of PD-L1 as a biomarker of benefit for PD-1 inhibition and combination immunotherapy."

She said that the report serves as the foundation for a larger IASLC project on "harmonization" of the different assays to better understand "how we can clinically use PD-L1 testing in real practice and to better personalize care for patients by using immunotherapy drugs where they are most likely to be helpful."

The IASLC project has two phases. Phase one, the Blueprint stage, was initiated about two years ago with a goal to compare four assays. It involved participation by "an interesting and unique partnership involving four pharmaceutical companies," and two diagnostic businesses that agreed to conduct the study with IASLC, Hirsch said.

Specifically, the Blueprint phase provides information on the analytical and clinical comparability of four PD-L1 IHC assays used in clinical trials, Hirsch added.

Investigators collected patient specimens and conducted tests to provide comparisons among four of the five US Food and Drug Administration-cleared assays — two from Agilent's Dako cancer diagnostics business, the PD-L1 IHC 28-8 pharmDx and PD-L1 IHC 22C3 pharmDx assays; and two from Roche Diagnostics, the Ventana PD-L1 (SP142) and Ventana PD-L1 (SP263) assays. The pharmaceuticals companies were Bristol-Myers Squibb, AstraZeneca, Genentech Roche, and Merck.

In February, the team published the results of phase one in the Journal of Thoracic Oncology.

The study, comparing assays and cutoffs, indicated that "despite similar analytical performance of PD-L1 expression for three [of the four] assays, interchanging assays and cutoffs would lead to 'misclassification' of PD-L1 status for some patients." More data are required, the study concluded, "to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs."

Phase two of the project is ongoing, and the collaborators have added the fifth FDA-approved diagnostic test, the Dako PD-L1 IHC 73-10 Assay, which is used as a clinical decision-making tool to support the use of the immunotherapeutic drug Bavencio (avelumab), codeveloped and co-commercialized by Pfizer and MSD, the name for Merck outside the US and Canada. Pfizer and MSD have joined the collaboration for this phase of the project.

"The objective of phase two is to obtain validation," Hirsch said. "It evaluates how assays perform using larger tissue specimens versus a smaller biopsy and versus cytology."  

In October, the collaborators plan to present results of this phase at the World Lung Cancer Conference in Japan.

Overall, although the atlas primarily aims to be a guide or resource for physicians and others involved in lung cancer diagnosis and treatment, it is hoped that it may also eventually give patients a more comprehensive understanding of their current biomarker treatment options, Hirsch said.

The authors noted in the atlas that updates will "almost certainly be needed, sooner rather than later, due to the rapidly evolving nature of the field." Other biomarkers relating to the immune response itself or to tumor mutational burden are being investigated, they added. 

These emerging assays could in the future alter the landscape for diagnostic testing used as a guide for therapeutic selection, Hirish said, adding that they "might be better than the existing assays, but we don't know that yet, as the data are not conclusive." 

It seems likely that the PD-L1 biomarker and its associated analytic tools it will be part of the profile required for administration of anti–PD-1/PD-L1 drugs "for the foreseeable future," the atlas reported.

It noted that the FDA has approved a variety of companion and complementary diagnostics for PD-L1 expression testing to help determine an appropriate PD-1/PD-L1 axis blockade therapy for a variety of cancer types. However, "the proliferation of these diagnostic assays poses special challenges for pathology laboratories because most laboratories do not use all of the staining platforms required by the different assay manufacturers, and the use of companion diagnostic kits often increase the cost of each individual test."

Therefore, laboratories seeking to offer PD-L1 testing services "face significant capital and operating expenditures to acquire the equipment and reagents necessary to offer a full range of companion and complementary PD-L1 diagnostics," the report added.

Just last week, Roche said that its PD-L1 assay had received CE-label expansion to identify untreated and previously treated patients with metastatic non-small cell lung cancer that are eligible for Merck's Keytruda (pembrolizumab) immunotherapy.

Also last week, Roche said that its PD-L1 assay had been approved by the FDA as a complementary diagnostic for patients with locally advanced or metastatic urothelial carcinoma who are being considered for treatment with AstraZeneca's immunotherapy Imfinzi (durvalumab).

The FDA previously approved the PD-L1 test as a complementary diagnostic test for the lung cancer and bladder cancer drug Tecentriqu.

Hans Christian Pedersen, global director of scientific affairs in the Agilent pathology division, said that the firm "welcomes the development of the [atlas]…as an educational resource for immuno-oncology and PD-L1 testing in lung cancer."

He added that Agilent has two FDA approved PD-L1 kits in lung cancer, available "in many countries around the world," and that it has provided comprehensive training materials, including interpretation guidelines and interactive e-learning services to help pathologists achieve confidence in scoring of PD-L1 stained slides. He said that the firm encourages use of its educational resources and standardized pharmDx kits when considering treatment of lung cancer patients with either Keytruda or Opdico.