Panelists:Ezra Cohen, MD, FRCPSC, FASCO, UC San Diego; Joshua M. Bauml, MD, University of Pennsylvania; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Barbara A. Burtness, MD, Yale University School of Medicine
Ezra Cohen, MD: Of course, we’re now moving into a new era of immunotherapy, something that we’ve all been excited about, first with preliminary phase I data and now with larger data sets. Barbara, we’ve got, for the first time in a little while, new indications in head and neck squamous cell carcinoma. Tell us a little bit about those.
Barbara A. Burtness, MD: There are 2 PD-1 inhibitors. They’re both monoclonal antibodies, and they target the PD-1 receptor. They have been approved by the FDA for use in platinum-refractory disease, and this has been defined in 2 ways. One is that the patient who has recurrent metastatic disease goes on a standard first-line regimen that’s platinum-containing—the EXTREME regimen or something like that—and then progresses. The other is the person whose recurrence happens so quickly within the window after platinum and radiation definitive therapy that the expectation is they are de novo platinum refractory. So, both pembrolizumab and nivolumab are approved for monotherapy intravenously in that setting: pembrolizumab every 3 weeks with flat dosing and nivolumab every 2 weeks. Obviously, many studies are ongoing to try to build on these first observations of response and durable response to figure out how best to incorporate these into treatment.
Ezra Cohen, MD: We have to really remember that these are truly different therapies that are targeting a different system than what we’ve been used to with cytotoxic chemotherapy or with targeted therapies. It’s really a physiologic system that happens to be upregulated in cancer, and it puts a brake on the immune system that we’re now taking off. And so, with that in mind, Jared, we’ve got these approved agents. Has that changed your approach in patients with recurrent or metastatic disease?
Jared Weiss, MD: I think it’s important to remember as we talk about palliative care, but that’s not the dominant conversation that we’re having in our offices and our tumor boards. As medical oncologists focused on head and neck cancer, our default—most of our patient encounters—is aimed at cure. And so, when the patient reaches an incurable context in head and neck cancer, I think there has been something like a therapeutic nihilism in the realm of palliative care, for a long time, of whether or not our agents work well enough to be worth it and for which patients they’re worth it—maybe not amongst this panel, but certainly amongst colleagues from other disciplines that purely do cure.
And I think now, as a theme, we’ve entered an era where our palliative therapies are actually palliative. While these agents have very real toxicities, and toxicities that are very different than what we saw before with the cytotoxics, I think it would also be fair to say that they are, for the most part, gentler than our cytotoxic and combined options. And while we don’t really talk about them as aimed at cure, it is clear that we are offering a meaningful, if minority, number of our patients the opportunity at durable control of their cancer. We’re counting survival in years instead of in weeks or months, which I think fundamentally changes the conversation.
Barbara A. Burtness, MD: There are clearly patients from the first single-arm study with pembrolizumab who finished 2 years of exposure, are now in observation, and have not recurred. The whole question of how long does the immune system stay jazzed up and how well does it continue to recognize any microscopic residual disease, I think is unanswered. But it’s looking like we see some things that are as good as curative, but they’re not curative.
Ezra Cohen, MD: It’s certainly interesting when we begin to look at the duration of response in some of those patients. Let’s look at those data and dissect them. Josh, take us through the data sets specifically for pembrolizumab and studies that have shown us the activity in these patients.
Joshua M. Bauml, MD: There are 2 studies of pembrolizumab in head and neck cancer that have been presented at this time, 2 large studies. The first was KEYNOTE-012. This was a multicohort phase I study. So, we’ve got the standard phase I group: it’s all the kids in the pool. Everyone is allowed to come and get treatment, regardless of their prior treatments, and so, as a result, it’s a bit of a mixed picture. But what was impressive is that, even for this mixed group—and the phase I patients tend to be relatively heavily pretreated—there was an 18% response rate. Now, this is really impressive when you consider patients who are heavily pretreated, patients who have previously been treated with platinum or cetuximab, the classic historical comparator is methotrexate. I don’t think any of us are jumping to treat our patients with methotrexate. It has a response rate at, or under, 5%. And so, it is exciting that we can give this agent.
KEYNOTE-055 was a follow-up study based on the fact that methotrexate has such a low response rate in terms of comparator. It was a single-arm study specifically focused on those patients who were refractory or had failed both platinum and cetuximab. Now, many of the patients in KEYNOTE-012 were similarly refractory to both, but KEYNOTE-055 specified it with rigor. And in that study, they found a 16% response rate. It’s really interesting to think about that. If we consider patients with cancer after multiple rounds of treatment, we would expect the response rates of subsequent treatments to go down.
Here we have a more heavily pretreated patient population, and the response rate is pretty much the same with a median duration of response of around 8 months, with some patients having more durable responses than that. And this is really, really exciting. The other nice part about these studies was that within them, PD-L1 staining, which is traditionally thought of as a biomarker that increases the chance for a response to these agents, on the tumor was not associated with the response. And so, as a result, pembrolizumab’s FDA approval is agnostic of PD-L1 status.