Suzanne L. Topalian, MD
Amid continuing excitement over the potential for immunotherapies targeting the PD-1/PD-L1 pathway, two major questions have loomed over PD-L1 expression levels as a biomarker for this emerging new class of drugs: What is the clinical utility of PD-L1 expression levels and what are the practical aspects of developing assays to measure those levels?
From the clinical standpoint, leading researchers say the significance of PD-L1 expression as a marker for recommending patients for therapy has not been established. Although patients with higher PD-L1 levels demonstrate better response rates to therapy, particularly in melanoma and non–small cell lung cancer (NSCLC), clinical trial participants with low levels also have responded to the drugs, including some patients with durable responses.
While those questions likely will be studied for years, pharmaceutical developers have a more urgent mission when it comes to developing assays that will be useful to practicing oncologists in determining which of the new immunotherapies is appropriate for a particular patient.
As it stands now, the four major companies developing anti-PD-1/PD-L1 therapies are using different assays to measure PD-L1 expression levels in the drugs they are testing.
This does not pose a problem now for oncologists who are considering the two currently approved anti-PD-L1 therapies—nivolumab (Opdivo) in melanoma and squamous NSCLC and pembrolizumab (Keytruda) in melanoma—because the indications for those agents are not linked to a biomarker or companion diagnostic.
However, oncology and industry leaders are concerned that the future will bring a confusing selection of assays that would make it difficult for oncologists to match the right patient with the right drug.
As a result, pharmaceutical companies locked in hot competition to bring the new immunotherapies to market have come together in an unusual collaboration to analyze the differing assays they have been using in NSCLC clinical trials (Table)
“Different pharmaceutical companies and diagnostic companies don’t often get together premarket and discuss their issues,” Elizabeth Mansfield, PhD, an FDA official who co-chaired a March 24 workshop1 that brought together the companies, researchers, and regulators, said in an interview with OncLive
However, she noted that “there was going to be the potential for a number of different drugs that target the same molecule to be in development at the same time and that each one of them could potentially need a companion diagnostic.”
“It could potentially get very confusing with different drugs, different tissues, different ways of measuring the biomarker,” added Mansfield, who is deputy director of personalized medicine in the Office of In Vitro Diagnostics and Radiological Health, which is part of the FDA’s Center for Devices and Radiological Health (CDRH). “We’re trying to figure out how we can out this out in a rational form so that oncologists can look at it and figure out what they need to do.”
Six Companies Cooperate on Study
PD-L1–positive lung tissue, shown in slide at left, was analyzed with an SP263 immunohistochemistry assay by Ventana Medical Systems. The tissue shown at right tested negative using the same assay.
Photos courtesy Ventana Medical Systems
The drugmakers working on the project are Bristol-Myers Squibb, Merck, Genentech, and AstraZeneca, which are developing nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (MPDL3280A), and durvalumab (MEDI4736), respectively.
Two diagnostic companies that have helped develop the assays used in clinical trials evaluating these drugs in NSCLC are conducting the analyses: Dako, which is owned by Agilent Technologies, and Ventana Medical Systems, which is a member of the Roche Group along with Genentech. Ventana already was partnering with MedImmune, the biologics research and development arm of AstraZeneca, on a PD-L1 assay for MEDI4736 clinical trials in NSCLC.
The project has been moving forward after the companies jointly announced a blueprint for the assay analysis during the workshop that the FDA, along with leaders from the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR), hosted in March.1
“The proposal is intended to establish how the tests compare to each other given the same sample,” said Mansfield. “What will come out of this will be a set of data that shows you that, if you use the same specimen from one patient and test it with all the different tests, the way [results] would read out with all the different tests.”