Transcript:Jared Weiss, MD: The two major unmet needs in head and neck oncology are the big ones: efficacy and tolerability. The EXTREME study saw an advance in palliative oncology, improving survival from 7.4 to 10.1 months—but 10.1 months still isn’t that good. Similarly, in chemoradiotherapy, we don’t cure nearly enough patients, and our treatments, particularly cisplatin, are excessively toxic.

Ezra Cohen, MD: We’ve realized for a long time, for decades, that head and neck cancers profoundly influence the immune system in several ways. From The Cancer Genome Atlas (TCGA) data, we now see that there’s a substantial group of head and neck cancers, probably about a quarter of head and neck cancers, that essentially are not detected or have ways to become undetectable to the immune system by downregulating HLA—or the signaling network that allows a cell, the immune system, to detect a cell. In other words, it’s a cloaking device, if you will—if you like Star Trek. It’s a cloaking device to the immune system so the immune system doesn’t even recognize the cancer. That’s a substantial number of head and neck cancers.

In others, we’ve realized that the cancer can upregulate naturally occurring breaks in the immune system. Some of these breaks are PD-1, PD-L1, CTLA4, and many other checkpoints that are naturally occurring genes and proteins to regulate the immune response, mostly to pathogens. But, of course, cancers have utilized that to avoid, first, immune detection and then, of course, immune destruction. And those processes are active in squamous cell carcinoma of the head and neck.

Another way is recruiting immunosuppressive cell types into the tumor microenvironment, cells like T-regulatory cells, M2 macrophages, or other myeloid-derived suppressor cells. And we know that head and neck cancer is among the highest-expressing of any cancer for these types of cells, especially the M2 macrophage and the T-regulatory cells. Again, much of this derives from TCGA data, but also other data sets. So, with all that in mind, we begin to realize that, both for HPV-negative and for HPV-positive cancers, there’s a profound suppression of the immune system. We’ve known that for a long time. The problem is that we haven’t been able to take advantage of it until recently.

Recent data would suggest, in fact, that PD-1— or PD-L1–targeting drugs can be quite effective as single agents in squamous cell carcinoma of the head and neck. And we’ll see very near-term phase III data that appear to show an improvement in overall survival with these drugs compared to [the] standard of care.

Robert L. Ferris, MD, PhD, FACS: Often, we’re asked about new treatment approaches for head and neck cancer, given that we’ve had the traditional three modalities for decades. Fortunately, our biological data and scientific understanding of this disease has improved for the past 10 or 20 years. We’ve studied not only the genomic alterations in the tumor, but also this concept that the host—the patient—has an immune system that, at some point in the disease, was able to recognize the tumor cell as abnormal and was ultimately unsuccessful at preventing it, but still plays a role perhaps in keeping it at bay. As we’ve identified, some of the mechanisms that tumors use to evade the immune system—that has led to the identification of the expression of PD-1 (programmed death 1)—on infiltrating lymphocytes in cancers and its ligand, PD-L1 is expressed by the tumor cell or by immune inflammatory cells. This PD-1 pathway is part of a larger family of receptors called checkpoint immune receptors, and these can be targeted now in the clinic.

Fortunately, there are agents that were previously effective in melanoma and more recently in non—small cell lung cancer, and so they’ve begun to be tested in head and neck cancer. And, in fact, we’ve talked about the potential for immunotherapy. We’re now able to remove that word, potential, and change it for positive data that have now arisen from targeting the PD-1 pathway with a positive overall survival benefit. Data are not yet public, but there has been a press release from the company that makes nivolumab, based on a randomized phase III study suggesting an overall survival benefit—and that study was stopped early. This was similar to data that we’ve had for the past two ASCOs for a different antibody—pembrolizumab—that targets the same PD-1 receptor and disrupts the PD-1/PD-L1 interaction. And we had phase I data from two different cohorts using pembrolizumab, suggesting quite a promising response rate. We still await those data, which have been presented, to be published, but that should be soon.

And so we have at least two agents that can target the PD-1 pathway. Others may be coming down with data from trials soon, and so this is a very promising target, not only to treat as single agent, but to see how it can be integrated. And trials are underway now to combine it, either in the postoperative setting or in addition to radiation, or chemotherapy, or both, and integrating these immune checkpoint receptor—targeted therapies into standard head and neck cancer care.

Jared Weiss, MD: I think that immunotherapy is the most promising new answer to these problems. The checkpoint inhibitors, PD-1 and PD-L1 inhibitors, and perhaps even the CTLA4 inhibitors in combination, are extraordinarily promising. We’ve seen really promising results with multiple agents in the pre-treated patient population. We’ve seen data with nivolumab, we’ve seen data with pembrolizumab, and we’ve seen data with durvalumab, formerly MEDI4736. And now all of those agents are being studied in the first-line. They’re being studied alone, or sometimes in combination with CTLA4 inhibitors, as compared to the EXTREME regimen. And I think this is incredibly promising for getting our palliative patients something that every patient wants. No patient cares about a 4-month improvement in survival. I mean, they’ll take it because it’s better than not having it. What patients really want is some chance at being alive a few years down the road, and these agents—with those tails to the curve that we’re always talking about—offer a legitimate chance of that. And their combinations with other agents may offer that chance to a greater proportion of patients. I think it’s only a matter of time until these agents are moved into the curative intent population.

In fact, we have a phase II trial opening at UNC any day now combining pembrolizumab with definitive radiation therapy. And I think these agents are going to be integrated in all sorts of ways into curative therapy, into neoadjuvant approaches, into adjuvant approaches. I do think that, in both the curative and the palliative context, they are going to lead us to greater efficacy, including some patients getting durable control. And they certainly do so with much greater tolerability than the standard agents that we’re used to. I’m hoping that this is just the opening salvo in a much more impressive world, where we get many more immunotherapeutics with various mechanisms of actions in combinations that can really revolutionize our field.

There are typical patterns of response in progression that we’re used to seeing in oncology. Response looks like a shrinkage of cancer usually followed by a valleying of that, stable disease for a time. Progression looks like growth, and if you’re foolish enough to keep going with something that’s not working, it keeps growing. We’re seeing different patterns with the immuno-oncologic drugs. We’re seeing patients with really deep, long responses; some with stable disease that lasts a very long time. And, of course, there are patients for whom it just doesn’t work. I want to pay particular attention to one unusual pattern called pseudoprogression. This was first recorded in the melanoma literature with ipilimumab, where patients achieved what looked like progressive disease. Only later, the cancer started shrinking dramatically. The dominant explanations for this are either that immunotherapy takes time to work or—my preferred explanation—that immune infiltration takes up space and that can look like progression until good things happen later. In melanoma, this is a relatively common phenomenon, and so it’s very important not to discontinue patients too early.

In head and neck cancer, as with lung cancer data that we’ve seen already, pseudoprogression is a relatively rare event. It certainly happens in head and neck cancer, but the vast majority—perhaps 90%, 95% of apparent progression—is, in fact, real. In lung cancer, we’ve seen patients not be eligible for third-line therapy because they’ve received immunotherapy too far past progression. And, as their cancer keeps growing, they get more and more sick and less and less able to get a third-line therapy that might help them. In head and neck cancer, I’m even more afraid of this because, anatomically, progressive disease can be very harmful in the neck. And so I think the key lesson here is that if you have a patient on immunotherapy when these agents do become available, who’s feeling wonderful with apparent progression, they say, “Doctor, I feel way better than I started,” and the cancer is nowhere near anything scary—it’s not sitting on the carotid artery, pressing on it, on a major airway in the lung—there’s nothing wrong with continuing a few more cycles, re-imaging, and giving them a shot that’s just pseudoprogression. But for the progression that looks typical, the patient isn’t feeling wonderful, or the cancer is near something scary, there needs to be a low threshold to just keep practice similar to what was done with the cytotoxic agents, and just switch to something else.

Unambiguously, the most exciting thing coming to head and neck cancer in the near-term future are the checkpoint inhibitors. I predict that one or more of these agents will be FDA-approved in the spring of 2016, and I think they’re going to make a big impact. Where we have these much gentler agents that offer a real chance of durable cancer control, that’s going to make a very big deal. Down the road, we’re seeing these agents being compared to chemotherapy in the first-line. That’s an additional attempt to improve therapy, and we’re going to see them integrated into all kinds of curative intent approaches. This is a revolution in our world, and hopefully, it’s only the beginning of the study of other immunologic agents that might make a big difference as well.

Transcript Edited for Clarity