Insights From: Ezra Cohen, MD, Moores Cancer Center; UC San Diego Health; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Ezra Cohen, MD: When a patient comes into our clinic with recurrent or metastatic disease, we now have several options that we can begin to consider—the certainly traditional options of cytotoxic chemotherapy; the more recent anti-EGFR therapy, cetuximab specifically; and now, the anti–PD-1 antibodies, nivolumab or pembrolizumab.
There are many factors that can go into the decision of which therapy, or combinations, to use. For instance, if a patient is symptomatic from their disease and a response is important, that’s a patient I would often consider treating with cytotoxic chemotherapy—usually with a doublet or the extreme regimen that adds cetuximab. We know that the response rates, especially for the extreme regimen, are going to be above 30%, maybe close to 40%. And, in a patient who’s having symptoms from their disease, a response to that individual is going to be meaningful. On the other hand, in patients who may not tolerate cytotoxic chemotherapy, where a response is not necessarily the most important thing I want to achieve—and, obviously, survival comes into play—that’s a patient where an anti–PD-1 antibody may be a better selection versus cytotoxic chemotherapy.
And then, the anti-EGFR agent, cetuximab, falls somewhere in the middle. In patients who, for instance, may not necessarily tolerate a cytotoxic chemotherapy very well and perhaps have a relative contraindication to immunotherapy, that’s where cetuximab plays an important role. This is an agent that’s clearly active, clearly has efficacy, is approved for these patients, and can be well tolerated as a single agent.
Jared Weiss, MD: There are 2 major ways that we manage patients differently on immunotherapy as compared to chemotherapy with or without targeted therapy. The first is toxicity management. The toxicities that we see with immunotherapy are radically different than those seen with chemotherapy, with or without the addition of the targeted agent. In my practice, I fear nivolumab and pembrolizumab less than I fear chemotherapy, but it’s different and it’s important for the practitioner to recognize these differences and treat them differently. In particular, it is very important with the autoimmune side effects to recognize them early and act aggressively. And when that’s done, patients can recover nicely from these adverse events and even go back on a drug and benefit.
The second major difference is evaluating progression or absence of progression. It’s much, much harder with immunotherapy as compared to chemotherapy with or without targeted agents. With cytotoxic chemotherapy with or without cetuximab, you pretty much know where you stand—the cancer is shrinking, it is growing, or it is the same. With immunotherapy, we see all kinds of patterns of response. In particular, when there is apparent early progression, we don’t always know if that is going to be real. What’s going to happen on the next scan?
In my practice, for the average patient with progression on an immunotherapy drug who is symptomatic from that progression, for the most part I stop and switch them to something else. The phenomenon of pseudoprogression, where you see clear apparent growth of tumor followed by dramatic response—we learned about that from the melanoma experience—does happen in head and neck cancer, but it’s far, far, far rarer.
In contrast, if I have a patient who’s not terribly symptomatic from their apparent progression—in particular, the patient says that they feel much better with their progression, the cancer is not pressing on a major airway or on a major blood vessel, and it is not causing major pain or other symptoms—I’ll get another scan to see what happens. Of course, I will carefully monitor the patient the whole while.
Ezra Cohen, MD: When we think about immunotherapy, what I think really gets us excited is not only the fact that patients are responding—and, if you step back a moment, what we’re talking about is interrupting a single receptor ligand system in the immune system—but also that we are seeing responses across multiple tumor types. It speaks to the importance of the PD-1, PD-L1 synapse, but it is also incredible to think that if we can just manipulate the immune system ever so slightly in a cohort of patients, we can begin to see very dramatic responses.
Going on from there, what is exciting from a clinical perspective is that these responses can be deep. They can be complete responses, and they can be durable. As the data mature, and as our clinical practices and clinical experiences with these agents mature, we’re beginning to realize that there are some patients who can have responses that last not only several months, but now we’re also getting into a few years for patients who had recurrent or metastatic disease and achieved a complete response, or near complete response, and the disease has yet to progress or return. That’s pretty incredible and, in my mind, unprecedented in our therapy for these patients.