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This is an excerpt from an article that appeared on Medscape.com. Read the full story here.

Two immunotherapies that target the cell programmed death (PD) pathway are now available, and both nivolumab (Opdivo, Bristol-Myers Squibb Company) and pembrolizumab (Keytruda, Merck Sharp & Dohme Corp) are approved for treating advanced, refractory, non–small cell lung cancer (NSCLC). Across several studies in patients with NSCLC, response to these agents has been correlated with PD-L1 staining, which determines PD-L1 levels in the tumor tissue. How do the available assays for PD-L1 compare?

The linear correlation between three commercially available assays is good across a range of cutoff points, concluded a presentation at the 2016 American Association for Clinical Research Annual Meeting.

Cutoffs are defined as the percentage of cells expressing PD-L1 when analyzed histochemically. "The dataset builds confidence that the assays may be used according to the cutoff clinically validated for the drug in question," Marianne J. Radcliffe, M.D., diagnostic associate director at AstraZeneca, told Medscape Medical News.

"The correlation is good between the assays across the range examined," she added.

However, a recently published study showed a high rate of discordance between another set of PD-L1 assays that were tested.

"Different diagnostic tests yield different results, depending on the cutoff for each assay. We need to harmonize the assays so clinicians are talking about the same thing," Brendon Stiles, M.D., associate professor of cardiothoracic surgery at Weill Cornell Medicine and New York-Presbyterian Hospital, New York City, told Medscape Medical News.

For Dr Stiles, these studies raise the issue that it is difficult to compare results of diagnostic testing across the different drugs and even with the same drug that are derived from different assays. "More importantly, it raises confusion in clinical practice when a patient's sample stains positive for PD-L1 with one assay and negative with another," he said.

"The commercial strategy for developing companion diagnostics for each drug is not in the best interests of the patients. It generates confusion among both clinicians and patients," Dr Stiles commented. "We need to know if these assays can be used interchangeably," he said.

As new agents come into the clinic, Dr Stiles believes there should be a universal yes-or-no answer, so that clinicians can use the assay to help decide on the use of immunotherapy.

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Why Correlations Are Needed

Pembrolizumab is approved for use only in patients with PD-L1-positive, previously treated NSCLC. A similar patient profile is being considered for nivolumab, for which testing for PD-L1 expression is not required.

For new PD-immunotherapy agents in clinical development, it is not clear whether PD-L1 testing will be mandated.

However, in clinical practice, it is clear that some patients respond to therapy, even if they are PD-L1 negative, as defined from the study. "Is it a failure of the assay, tumor heterogeneity, or is there another time point when PD-L1 expression is turned on?" Dr Stiles asked.

Dr Stiles also pointed out that a recent publication from Yale researchers showed a high a rate of discordance. In this study, PD-L1 expression was determined using two rabbit monoclonal antibodies. Both of these were different from the ones used in the Ventana SP263 and Dako 28-8 assays.

In this study, whole-tissue sections from 49 NSCLC samples were used, and a corresponding tissue microarray was also used with the same 49 samples. Researchers showed that in 49 NSCLC tissue samples, there was intra-assay variability, with results showing fair to poor concordance with the two antibodies. "Assessment of 588 serial section fields of view from whole tissue showed discordant expression at a frequency of 25%.

"Objective determination of PD-L1 protein levels in NSCLC reveals heterogeneity within tumors and prominent interassay variability or discordance. This could be due to different antibody affinities, limited specificity, or distinct target epitopes. Efforts to determine the clinical value of these observations are under way," the study authors conclude.

Coincidentally, a blueprint proposal was announced at the AACR meeting at a workshop entitled FDA-AACR-ASCO Complexities in Personalized Medicine: Harmonizing Companion Diagnostics across a Class of Targeted Therapies.

The blueprint proposal was developed by four pharmaceutical giants (Bristol-Myers Squibb Company, Merck & Co, Inc, AstraZeneca PLC, and Genentech, Inc) and two diagnostic companies (Agilent Technologies, Inc/Dako Corp and Roche/Ventana Medical Systems, Inc).

In this proposal, the development of an evidence base for PD-1/PD-L1 companion diagnostic characterization for NSCLC would be built into studies conducted in the preapproval stage. Once the tests are approved, the information will lay the foundation for postapproval studies to inform stakeholders (eg, patients, physicians, pathologists) on how the test results can best be used to make treatment decisions.

The blueprint proposal is available online.