In cancer immunotherapy, one PD-L1 test to rule them all?

December 01, 2016

Clinical trials have proven the power of immunotherapies targeting PD-L1 or PD-1 in a range of cancers. However, these same trials show that only some patients benefit - tumors must depend on PD-L1 to be affected when medicines block its action. In response, the companies Merck, AstraZeneca, Genentech/Roche, and Bristol-Myers Squibb together with the diagnostic companies Ventana and Dako have developed four tests to predict which tumors do and do not express on PD-L1 and thus which tumors will respond to the therapies. An ambitious collaboration between these companies and research organizations including the International Association for the Study of Lung Cancer, the American Association for Cancer Research, and academic medical centers including the University of Colorado Cancer Center, results in a study published online today in the Journal of Thoracic Oncology comparing these four tests.

The study, called the "Blueprint PD-L1 IHC Assay Comparison Project," used all four tests to evaluate 38 samples of human non-small cell lung cancer. In all four tests, half of the tumors were positive for PD-L1 and 5 of the tumors were negative. However, in 14 of 38 cases (37 percent), some tests considered the sample positive while others considered it negative. The disagreement implies that the choice of test used to determine a tumor's PD-L1 dependence may influence whether or not a patient is offered anti-PD-L1 therapy.

"Immunotherapy is evolving very fast and with very encouraging results in lung cancer as well as other cancers. However, a main issue is how to select patients for these therapies. Each company is pursuing their own predictive PD-L1 assay in order to select patients. However, the PD-L1 assays are all different in terms of antibody used and cut-off values for positive/negative results," says Fred R. Hirsch MD, PhD, investigator at the University of Colorado Cancer Center and CEO of the International Association for the Study of Lung Cancer.

With support from the U.S. Food and Drug Administration, Hirsch brought together the four pharmaceutical companies and the two diagnostic companies with leading PD-L1 assays to explore their agreements and discrepancies.

Importantly, each test is paired with a drug - the drug pembrolizumab, developed by Merck, is prescribed based on results from the assay called 22C3; the drug nivolumab, developed by Bristol-Myers Squibb, is paired with an assay called 28-8; likewise, atezolizumab by Genentech/Roche and durvalumab by AstraZeneca are both paired with assays specific to the compound. In fact, this mimics the way in which targeted therapies generally earn FDA approval - a drug and a test determining which patients will benefit from the drug tend to be approved in tandem.

However, all four of these drugs target a tumor's ability to hide from the immune system by the expression of PD-L1, which interacts with the protein PD-1 expressed on immune cells in a way that deactivates these immune cells against tumor tissue. However, by blocking the interaction between PD-L1 and PD-1 the immune cells (T-lymphocytes) remain activated against tumor tissue. In theory, any of these four tests should be able to predict the benefit of any of these four drugs. Critically, each measures how much PD-L1 protein is expressed on the membranes of tumor cells and, based on clinical trial data, how much PD-L1 must be expressed in order for the drug to show benefit.

"Rather than black and white, this can be a grey area. It is not that some tumors express PD-L1 and others do not, but rather that tumors express PD-L1 across a gradient and at some cutoff point in that gradient, the expression becomes clinically relevant," Hirsch says.

Results show that three of the four tests tend to cluster together in their results. Also, differences in these tests meant that there was no absolute cutoff in the amount of PD-L1 that made a sample positive or negative - the different tests must be evaluated by their own scales.

Now with results in hand for the first phase of this study, the comparison will continue into a second phase by comparing these test results to patient outcomes. Basically, the goal is to determine which test allowed doctors to prescribe PD-L1 inhibitors to the patients who benefit, while avoiding the use of these drugs with patients who went on to see little or no benefit.

"This is a unique study based on a unique partnership meant to solve a very important clinical problem," Hirsch says. It might not be long before the field of anti-PD-L1 cancer immunotherapies receives a peer-reviewed recommendation for the one test that will rule them all.

University of Colorado Anschutz Medical Campus

Related Lung Cancer Articles from Brightsurf:

State-level lung cancer screening rates not aligned with lung cancer burden in the US
A new study reports that state-level lung cancer screening rates were not aligned with lung cancer burden.

The lung microbiome may affect lung cancer pathogenesis and prognosis
Enrichment of the lungs with oral commensal microbes was associated with advanced stage disease, worse prognosis, and tumor progression in patients with lung cancer, according to results from a study published in Cancer Discovery, a journal of the American Association for Cancer Research.

New analysis finds lung cancer screening reduces rates of lung cancer-specific death
Low-dose CT screening methods may prevent one death per 250 at-risk adults screened, according to a meta-analysis of eight randomized controlled clinical trials of lung cancer screening.

'Social smokers' face disproportionate risk of death from lung disease and lung cancer
'Social smokers' are more than twice as likely to die of lung disease and more than eight times as likely to die of lung cancer than non-smokers, according to research presented at the European Respiratory Society International Congress.

Lung cancer therapy may improve outcomes of metastatic brain cancer
A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Lung transplant patients face elevated lung cancer risk
In an American Journal of Transplantation study, lung cancer risk was increased after lung transplantation, especially in the native (non-transplanted) lung of single lung transplant recipients.

Proposed cancer treatment may boost lung cancer stem cells, study warns
Epigenetic therapies -- targeting enzymes that alter what genes are turned on or off in a cell -- are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant.

Are you at risk for lung cancer?
This question isn't only for people who've smoked a lot.

Read More: Lung Cancer News and Lung Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to