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Big hopes, bigger questions with PD-L1

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Karen Titus

November 2016—Progress is a complicated minuet. One popular adage talks of “one step forward, two steps back,” which is not only discouraging but, in an even less-gleaming light, happens to be the title of one of Vladimir Lenin’s books, published in 1904.

Despite the excitement surrounding atezolizumab’s approval and the potential role for other agents that target PD-L1/PD-1, Dr. Donna Hansel, shown here at UCSD, urges caution. Not all antibodies correspond specifically to each therapy, she says, and screening criteria vary by antibody.

Despite the excitement surrounding atezolizumab’s approval and the potential role for other agents that target PD-L1/PD-1, Dr. Donna Hansel, shown here at UCSD, urges caution. Not all antibodies correspond specifically to each therapy, she says, and screening criteria vary by antibody.

A more optimistic version (and one less centered on the crisis facing communists in turn-of-the-century Russia) suggests advances occur with two steps forward, mitigated by only one step back.

With PD-L1 testing, matters have moved several steps ahead in recent months. But given the complexities that chaperone this marker, these advances have already been followed by steps that could make pathologists feel like they’re moving sideways, or (in proper minuet fashion) even in exasperating circles.

Most recently, results from a phase three trial of pembrolizumab (anti-PD-1) suggest that the drug is a new option for first-line treatment for patients with advanced non-small cell lung cancer and high PD-L1 expression. The study was presented at the European Society for Medical Oncology 2016 Congress in Copenhagen in early October and published online in the New England Journal of Medicine on Oct. 9 (Reck M, et al).

Earlier in the year, the FDA approved atezolizumab (anti-PD-L1) to treat urothelial carcinoma, the first immune checkpoint inhibitor approved for this disease and a decades-spanning leap in bladder cancer treatment.

In both cases, testing for PD-L1 expression has brought excitement—and perhaps mild irritation—inside the laboratory and out as physicians consider all the options.

The approval of atezolizumab was huge news.

“It was the first time in 30 years the FDA has approved a new systemic therapy for bladder cancer,” says Donna E. Hansel, MD, PhD, professor, University of California, San Diego, Department of Pathology, and chief of the Division of Anatomic Pathology. “It’s been a very big deal.”

Now the real work begins.

Antibodies that target PD-L1 or PD-1 operate similarly to other immunotherapy approaches: The goal is to interfere with the pathways that allow cancer cells to hide from the immune system. In urothelial cancers, the blockade of PD-1 or PD-L1 has been shown to reactivate immune response and unmask tumor, says Dr. Hansel, with a number of pharmaceutical companies developing their own targeted inhibitors.

The approval of atezolizumab was based on a phase two trial (Rosenberg JE, et al. Lancet. 2016;387:1909–1920) that looked at use of the drug in 310 patients with locally advanced and metastatic urothelial carcinoma who progressed after treatment with platinum-based chemotherapy. Nearly 15 (14.8) percent of patients experienced at least a partial shrinking of their tumors, lasting from 2.1 to more than 13.8 months. In patients classified as positive for PD-L1 expression, 26 percent of patients had a tumor response, versus 9.5 percent who were classified as negative for PD-L1 expression.

“PD-L1 can be expressed on immune cells and cancer cells,” says Dr. Hansel. “And in this study, the investigators thought that there was an association between immune cell PD-L1 expression and the ability to respond to this antibody.”

(At the time of the drug’s approval, the FDA also approved the Ventana PD-L1 [SP142] assay [Roche] to detect PD-L1 protein expression on tumor-infiltrating immune cells.)

Other agents look promising as well and are being studied, including nivolumab (a PD-1 inhibitor) and durvalumab (a PD-L1 inhibitor). This includes multiple phase three trials underway in first-line, refractory, and adjuvant studies, with and without chemotherapy, as well as phase two single-agent and combination trials. Dr. Hansel says the data look promising so far.

Now might be a good place to cue the complications. Despite the excitement surrounding atezolizumab’s approval and the potential role for other agents that target PD-L1/PD-1, Dr. Hansel urges caution, noting that not all antibodies correspond specifically to each therapy, and that screening criteria vary by antibody. “Tissue testing will range in the cutoffs anywhere from one percent or more, to five percent or more, to 25 percent or more. Each antibody has different cutoffs.” Anti-PD-L1 antibodies include two from Ventana (the aforementioned SP142, as well as SP263), two from Dako (28-8 and 2230), and others.

There are considerable complications when using archived material, Dr. Hansel continues, since the epitope may not be stable. Sampling is another issue; pathologists need to ensure adequate material is available, depending on the cutoff. “It’s been very difficult to try to say it’s only one percent, versus two percent, versus five percent on a limited number of cells.”

Even larger questions loom. PD-L1 is expressed on tumor as well as immune infiltrating cells; in general, expression by immunostaining on either type of cells appears to positively indicate response, but not all trials have shown clinical value, she says.

With each new study, more questions roll in like so many waves: How many antibodies should be tested on the sample? How variable are the results? Does impact differ for patients who have received chemotherapy versus those who have not? Does the therapy indicate a need for testing? How should labs quantify immune cells versus tumor cells? Do immune cells need to be in the center or in the periphery? What is the possible impact of molecular diversity on PD-L1 expression?

“It’s clear that there are many factors that are important,” Dr. Hansel continues.

Early data suggested that even a small amount of expression could be targeted by antibodies and instigate a better response to treatment. “We know now that’s not necessarily the case,” Dr. Hansel says, explaining that in some cases, good clinical response to immunotherapy has been seen even when PD-L1 or PD-1 expression has been shown to be negative by immunohistochemistry.

That has left laboratories with new questions. “Where are we now, for immunohistochemistry, with using these antibodies, which are proliferating at a remarkable rate?” Dr. Hansel asks. “Or do we find alternative methods to see if someone would be responsive to immunotherapy?”

Dr. Hansel points to a few possibilities. One is looking at mutational burden. Mutated proteins differ in appearance from normal proteins and, as neoantigens, can be recognized and targeted by the immune system. “The more you have in your cancer, the more likely your immune system will find something.” One study, the IMvigor-­
210 trial, has linked better response to higher mutational burden in urothelial carcinoma.

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