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An Overview of Immunotherapy in Head and Neck Cancer
Dr. Shah: Welcome to PracticeUpdate. I'm here with Dr. Barbara Burtness, a PracticeUpdate oncology advisor, and Dr. Burtness, I wanted to talk to you about immunotherapy in recurrent head and neck cancer. Could you tell us what are the options available right now and where they stand?
Dr. Burtness: Yes. In the United States, there are two drugs that are approved for use as immune checkpoint inhibitors in recurrent metastatic disease. Those are nivolumab and pembrolizumab. They were approved first for use in platinum-refractory patients, and each of them had demonstrated in a randomized phase 3 trial that if you got the immune checkpoint inhibitor as opposed to getting one of a menu of standard agents, methotrexate, docetaxel, or cetuximab, that survival was superior for the patients who received an immune checkpoint inhibitor at that time point.
And we then moved to the first-line setting, and there was a randomized trial, the KEYNOTE-048, and this compared a standard chemo regimen of platinating agent 5-fluorouracil and cetuximab with either pembrolizumab alone or with pembrolizumab plus the same chemo backbone but leaving the cetuximab out.
Dr. Shah: Okay.
Dr. Burtness: And the way the study was designed, there were numerous hypotheses that centered on pembrolizumab alone or pembrolizumab plus chemotherapy either in the overall population or in biomarker-selected populations, and the biomarker that was used was the combined positive score. So, that allows you to look at PD-L1 expression not only in the tumor cell but also in the immune cells that are associated with the tumor.
Dr. Shah: And are there any other markers that you use to guide your therapy decisions with immunotherapy?
Dr. Burtness: So, at present, in head and neck cancer, it's just PD-L1. There are hints that a gene expression signature for inflammation has utility, and we are still trying to figure out whether or not tumor mutational burden does, as you know, that story's been going back and forth in other cancers, as well, and so what the KEYNOTE-048 showed was that pembrolizumab was highly active. And if you had a tumor that expressed PD-L1, pembrolizumab monotherapy was actually superior to that three-drug regimen of platinum 5-FU, and cetuximab that we'd been using for years, and if you looked at the overall population, pembrolizumab plus chemotherapy was superior to the extreme regimen.
There's been a lot of curiosity about how are we going to figure out who should get pembrolizumab alone and who should get pembrolizumab plus chemotherapy, and biomarkers are clearly going to have a big role to play there because the higher your PD-L1 expression is, the higher your response rate is, the less likely you are to have early progression.
However, the highest response rates were seen for pembrolizumab plus chemotherapy, and in head and neck cancer, some of our patients have very bulky local recurrences. They deal with pain and risk of aspiration and difficult swallowing and risk to the airway. So, I think that it may end up being both looking at the intensity of PD-L1 expression as well as how badly does the patient who's sitting in front of you just need some relief from their symptoms?
And so, I can anticipate that anybody who's PD-L1 expressing, even if it's only in the 1-to-19 range, if they're asymptomatic, would do well starting with pembrolizumab alone, and then the patients who are more symptomatic, we'd be more likely to look at pembro plus chemo.
At this meeting, at ESMO today, Ezra Cohen presented the biomarker results from that second-line study I mentioned of pembrolizumab versus chemotherapy, and he showed that the older score, where you just look at PD-L1 on the tumor cells, and the combined positive score, where you're looking both at tumor cells and immune cells, converge as you get up to about the 50% range, but at the lower level of expression, the CPS definitely adds something. So, there are patients who don't express PD-L1 on tumor cells but do express PD-L1 on immune cells, who still are going to be benefitting from pembrolizumab.
Dr. Shah: Well, that, at least, is very positive because PD-L1 does not always correlate that well in other tumor types. So, that is promising.
Dr. Burtness: I think that it's the best biomarker that we have for immune checkpoint inhibition in head and neck cancer at the moment.
Dr. Shah: And where would you see immunotherapy featuring in the treatment of head and neck cancer, moving forward?
Dr. Burtness: Well, we're very hopeful that it will also eventually have a role in curative therapy for locally advanced disease, and there are a number of strategies that are being approached there. So, there are completed studies looking at nivolumab with chemoradiation. There's a completed study looking at pembrolizumab incorporated with chemoradiation and then given afterwards.
There are some very intriguing suggestions that giving an immune checkpoint inhibitor, either nivolumab or pembrolizumab, in the preoperative setting can lead to very dramatic histologic regression. So, I think there's great interest in whether or not everybody who's going to surgery for a large head and neck cancer would be eligible for that kind of approach, and so some of those studies are completed. We don't have the data yet. We don't have a firm sense of exactly what the toxicity profile will look like, although small studies appear to show that there's no increase in high-grade toxicity.
Within the ECOG-ACRIN cooperative group, we have a trial for intermediate-risk HPV-associated disease, where patients are randomized up front. They get treated with their definitive chemo/radiation and then either get nivolumab or observation afterwards, and the thinking there was this is a group of patients who already have a pretty decent shot at cure. You don't want to take any risks during the chemo/radiation, but given the activity of these agents in head and neck cancer, this might be a way of reducing the risk of recurrence, so, a number of different strategies, and we're just waiting for the data to come out.
Dr. Shah: Sounds very promising. Thank you so much.
Dr. Burtness: Thank you.
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