Herbst Tackles Key Questions in Emerging PD-1/PD-L1 Immunotherapy for NSCLC

Beth Fand Incollingo @fandincollingo
Published: Saturday, Aug 02, 2014

Dr. Roy S. Herbst

Roy S. Herbst, MD, PhD

Emerging agents and pressing research questions in immunotherapy were reviewed in depth during the 15th Annual International Lung Cancer Congress, with Roy S. Herbst, MD, PhD, of the Yale Cancer Center, leading the way.

Herbst was the recipient of the 2014 Addario Lectureship Award, which the Bonnie J. Addario Lung Cancer Foundation bestows annually at the Physicians’ Education Resource (PER) conference. 

At Yale, Herbst serves as the Ensign Professor of Medicine (Medical Oncology), professor of Pharmacology, chief of Medical Oncology, and associate director for Translational Research. He also is serving as a co-chair of the Lung-MAP trial, an innovative biomarker-driven study that is evaluating five novel therapies for the treatment of squamous cell non–small cell lung cancer (NSCLC).

As this year’s Addario honoree, Herbst delivered a keynote lecture that explored the biology of the immune system in lung cancer. In addition, he led a panel that discussed the future of immunotherapy.

He also specifically discussed four monoclonal antibodies in development that target either programmed death-1 (PD-1) or its ligand, PD-L1. The anti-PD-1 agents are nivolumab from Bristol-Myers Squibb and pembrolizumab (MK-3475) from Merck. The agents targeting PD-L1 are MPDL3280A from Genentech and MEDI4736 from MedImmune, AstraZeneca’s biologics research and development arm.

In an interview with OncLive during the conference, Herbst shared key takeaway messages about the immune system and immunotherapy in lung cancer.

OncLive: The proteins PD-1 and PD-L1 have emerged as the foremost targets for lung cancer immunotherapy. What is known about this treatment strategy so far, and what still needs to be determined?

Herbst: The exciting news is that we’re seeing response rates upward of 20% across the board with all the different antibodies in unselected patients with refractory lung cancer. We can do even better if we select the patients and enhance using biomarkers, which are still very early in development. With biomarker assays, you can bring that response rate up as high as 40% to 50% or more.

We still have to figure out what to do with patients who don’t benefit. Are there ways to enhance the immune response, combine therapies together, combine immunotherapy with targeted therapy, with standard chemotherapy? But clearly the development of this field for lung cancer, along with other tumor types, is something we should keep a close eye on. It’s very important for patients. The clinical trials are accruing quite rapidly, and many of these include tissue analysis, and old biopsies or repeat biopsies, to figure out mechanistically how this is working.

MEDI4736 is especially interesting to us because in the large lung cancer master protocol [Lung-MAP], which I co-lead, we are including an arm of immunotherapy [MEDI4736]. I’m excited about that because it gives the 40% or 50% of patients in this large NextGen-sequenced, selected protocol the option to receive immunotherapy versus chemotherapy, and also because we’ll have access to their sequencing information. Hopefully, we can begin to learn a little bit more, mechanistically, as to who responds best to some of the immune therapies.

Have PD-L1 expression levels been established as a biomarker for therapies targeting PD-1 or PD-L1? If so, is there a valid test for measuring the levels, and have thresholds been established?

It’s under development. Currently, these assays tend to be propriety to each of the groups that are developing the antibodies. But these assays are quantitative as best they can be. Most look at the PD-L1 staining on the tumor; some look at PD-L1 staining on immune infiltrate, which will include tumor but also immune cells—the entire microenvironment.

The cutoffs are picked using whatever data are available at the time you set a cutoff; then, you validate it as you treat more patients. Most groups now have locked into what they’re using as a cutoff, because you have to have your cutoff set before you start a big phase III trial. I think these cutoffs will enhance the number of patients who will benefit from immune therapy. Will they be the ultimate cutoffs that are used, the ultimate antibodies that are used, the ultimate tests? I don’t know.

I think there’s going to be a desperate need for some sort of harmonization of these tests. How can any one hospital run four different tests? Even now, as we do clinical trials, to have different tests for different drugs is quite confusing. But until something’s approved, we work with the best assay we have for any given study.

Are there any other markers that might predict which patients would be the best candidates for immunotherapy?




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