Insights From: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Robert L. Ferris, MD, PhD, University of Pittsburgh Cancer Institute; Nabil F Saba, MD, FACP, Emory University
Robert L. Ferris, MD, PhD: Now that we have positive clinical data from the checkpoint immunotherapeutic agents, like nivolumab and pembrolizumab, we think about when is the best time to use those agents and what are the patients that are most likely to benefit. In particular, if a patient is symptomatic, has a large growing tumor, and an early response rate is needed, sometimes a chemotherapeutic combination will be used at first. Pembrolizumab or nivolumab are beneficial. They may not provide as fast a tumor shrinkage, but they’re much more tolerable than combinations of chemotherapeutic agents. Therefore, if the patient can tolerate a little bit more time for the clinical benefit to occur, many clinicians would like to use an immunotherapeutic agent because it has a better long-term chance of the tail of durability.
In addition, we should recognize that the toxicities of immunotherapy are quite different. I mentioned that grade 3 and 4 adverse events with nivolumab were only one-third the rate of the single-agent chemotherapeutic agents, but, in fact, they’re different. They’re not just lower; the toxicities and adverse events of immunotherapies are much more immune- or inflammatory-mediated. Pneumonitis, lung inflammation, hypophysitis—such as pituitary inflammation—dermatitis, rashes on the skin, and liver inflammation are just a list of toxicities and side effects that we see with immunotherapies that are unique. We don’t really see those as often with the chemotherapies, where we see more bone marrow suppression or neurologic side effects. So, the immune toxicities, like thyroiditis or pneumonitis, are much more autoimmune and inflammatory-mediated.
Nabil F. Saba, MD: I think a better question here is, is there a patient who we would not give checkpoint inhibitors to? I think, clearly, there are some clinical scenarios where we would not give them because of toxicities. Those include, for example, patients who have known liver failure, who have known hepatitis B or C active infections, and who have known autoimmune colitis, like ulcerative colitis or Crohn’s Disease. But I think the question is more complex than that. The question is, should all these patients be automatically excluded? Does the exclusion of patients with hepatitis B or C do this for every patient or does it depend, perhaps, on the viral titers, the status of the viral infection? Similarly, if you have a patient with, for example, ulcerative colitis who has not had any flare for their disease for the past 10 years and has not been on immune suppression, can we give checkpoint inhibitors to this patient and expect not to have significant side effects? We don’t know the accurate answer to this question. So, I think it’s important, with the next generation of trials, to try to explore what the actual true indications and contraindications to giving these agents are.
I think, as far as the disease response and disease activity or antitumor activity of these agents, one question that is worth raising is, would we give it, for example, to a patient who has a rapidly progressing, rapidly growing cancer and where it is imperative to produce a quick response? In a patient with a rapidly growing neck mass that may impede certain vital functions, would it make sense to use a single-agent checkpoint inhibitor on this patient? I think those decisions have to be individualized based on the patient we’re seeing, but perhaps such a patient should be treated with cytotoxic chemotherapy to produce a rapid response rather than immune therapy.