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Nivolumab-Related Efficacy and Toxicity in HNSCC Patients

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
Published: Monday, Feb 27, 2017


Transcript:

Ezra Cohen, MD:
When we think about patients with squamous cell carcinoma of the head and neck and applying immunotherapy, we have to realize that there are some differences in that setting compared to, let’s say, melanoma, non–small cell lung cancer, bladder cancer, and some of the other diseases where these agents have been approved. The mechanism of action, of course, is exactly the same. We’re relying on inhibition of a checkpoint that appears to be critical to the biology of these cancers. But we have come to recognize that there are differences in efficacy, likely, and in toxicity. Let’s talk about the efficacy issue first.

Without a doubt, the cancer that appears to respond best to immunotherapeutic interventions is melanoma. And for drugs like pembrolizumab and nivolumab, the same holds true: the response rates for single-agent PD-1 blockade in melanoma are almost double what you’d expect to see for squamous cell carcinoma of the head and neck. For head and neck cancer, we’re talking about response rates of somewhere around 15% to maybe 20%, depending on the study and the setting. Interestingly, the response rates in non–small cell lung cancer are probably also a little bit higher than for squamous cell carcinoma of the head and neck, and maybe that has something to do with a higher mutational burden for non–small cell lung cancer, maybe a greater dependence on the PD-1, PD-L1 pathway. We don’t know completely why that is, but arguably, if we compare trials with all the caveats involved, we do fairly consistently have a little bit of higher response rate in non–small cell lung cancer.

The other thing that’s clear is that head and neck cancer patients have 2 adverse events that are more common in that population than we’ve seen in the other disease types that these agents have been applied to. The first is facial swelling, and that is likely related to inflammatory response being generated by these drugs and the fact that many of these patients have had interventions that disrupt the lymphatic flow of the head and neck area. So, we have come to recognize that we see more facial edema with anti-PD-1 agents in head and neck cancer patients than we do with other cancers.

The other is hypothyroidism or, in some patients, hyperthyroidism. And, again, I think that probably relates to the fact that many of these patients have had a prior toxic intervention to their thyroid, namely radiation. And they may be a set up for hypothyroidism in the face of an agent that activates the immune system. So, there are 2 things to remember with respect to toxicity in head and neck cancer patients: a little bit higher rate of facial edema and a little bit higher rate of hypothyroidism.

Nabil F. Saba, MD: We are still learning about toxicities from these immune checkpoints and other immune therapeutic approaches in treatment of head and neck cancer in comparison to what we’ve seen with chemotherapy. This is a class of agent that has a completely different side effect profile than what we have been using for a long time when we treat patients with chemotherapy. And the take-home message is we need to educate ourselves. And when I say “we,” it means medical oncologists, but also nursing staff, people from other expertise, radiation oncologists, and surgical oncologists. We really need to learn more about the toxicity profiles of these drugs.

The severe toxicities that could result from these agents can affect different organ systems, including skin toxicities, gastrointestinal toxicities, liver toxicities, endocrine toxicities, and other types of toxicities as well. And the different agents may have different toxicity profiles. For example, diarrhea seems to be a much more common toxicity seen with CTLA4 inhibitors compared to PD-1 or PD-L1 inhibitors. And so, familiarizing ourselves with these patterns of toxicities is going to be crucial for the future treatment of these patients. So, education is going to be essential in understanding because we are going to use these agents frequently in the treatment of cancer patients—not just head and neck cancer, but different types of cancers.

So far, the immune biomarkers that predict response to treatment seem to be a combination of markers, and those markers seem to be related to PD-L1 expression, but also to other factors that have to do with the inflammatory cells that surround the actual tumor. We still have not mastered this very well, but subsequent data from CheckMate-141 and from KEYNOTE-012 and KEYNOTE-055 are currently very actively being analyzed to better understand what the key biomarkers are that may be used to predict responses.

So, the clinical trials per se are designed to collect more information, for sure, and for a good reason because we want to learn from what the trials are telling us. I would not test for a PD-L1 for a patient with head and neck cancer at the moment. But I’m not sure this will last for very long. I think we’re hoping that a certain panel of biomarkers will allow us to basically be making clinical decisions based on these biomarkers in the near future.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
When we think about patients with squamous cell carcinoma of the head and neck and applying immunotherapy, we have to realize that there are some differences in that setting compared to, let’s say, melanoma, non–small cell lung cancer, bladder cancer, and some of the other diseases where these agents have been approved. The mechanism of action, of course, is exactly the same. We’re relying on inhibition of a checkpoint that appears to be critical to the biology of these cancers. But we have come to recognize that there are differences in efficacy, likely, and in toxicity. Let’s talk about the efficacy issue first.

Without a doubt, the cancer that appears to respond best to immunotherapeutic interventions is melanoma. And for drugs like pembrolizumab and nivolumab, the same holds true: the response rates for single-agent PD-1 blockade in melanoma are almost double what you’d expect to see for squamous cell carcinoma of the head and neck. For head and neck cancer, we’re talking about response rates of somewhere around 15% to maybe 20%, depending on the study and the setting. Interestingly, the response rates in non–small cell lung cancer are probably also a little bit higher than for squamous cell carcinoma of the head and neck, and maybe that has something to do with a higher mutational burden for non–small cell lung cancer, maybe a greater dependence on the PD-1, PD-L1 pathway. We don’t know completely why that is, but arguably, if we compare trials with all the caveats involved, we do fairly consistently have a little bit of higher response rate in non–small cell lung cancer.

The other thing that’s clear is that head and neck cancer patients have 2 adverse events that are more common in that population than we’ve seen in the other disease types that these agents have been applied to. The first is facial swelling, and that is likely related to inflammatory response being generated by these drugs and the fact that many of these patients have had interventions that disrupt the lymphatic flow of the head and neck area. So, we have come to recognize that we see more facial edema with anti-PD-1 agents in head and neck cancer patients than we do with other cancers.

The other is hypothyroidism or, in some patients, hyperthyroidism. And, again, I think that probably relates to the fact that many of these patients have had a prior toxic intervention to their thyroid, namely radiation. And they may be a set up for hypothyroidism in the face of an agent that activates the immune system. So, there are 2 things to remember with respect to toxicity in head and neck cancer patients: a little bit higher rate of facial edema and a little bit higher rate of hypothyroidism.

Nabil F. Saba, MD: We are still learning about toxicities from these immune checkpoints and other immune therapeutic approaches in treatment of head and neck cancer in comparison to what we’ve seen with chemotherapy. This is a class of agent that has a completely different side effect profile than what we have been using for a long time when we treat patients with chemotherapy. And the take-home message is we need to educate ourselves. And when I say “we,” it means medical oncologists, but also nursing staff, people from other expertise, radiation oncologists, and surgical oncologists. We really need to learn more about the toxicity profiles of these drugs.

The severe toxicities that could result from these agents can affect different organ systems, including skin toxicities, gastrointestinal toxicities, liver toxicities, endocrine toxicities, and other types of toxicities as well. And the different agents may have different toxicity profiles. For example, diarrhea seems to be a much more common toxicity seen with CTLA4 inhibitors compared to PD-1 or PD-L1 inhibitors. And so, familiarizing ourselves with these patterns of toxicities is going to be crucial for the future treatment of these patients. So, education is going to be essential in understanding because we are going to use these agents frequently in the treatment of cancer patients—not just head and neck cancer, but different types of cancers.

So far, the immune biomarkers that predict response to treatment seem to be a combination of markers, and those markers seem to be related to PD-L1 expression, but also to other factors that have to do with the inflammatory cells that surround the actual tumor. We still have not mastered this very well, but subsequent data from CheckMate-141 and from KEYNOTE-012 and KEYNOTE-055 are currently very actively being analyzed to better understand what the key biomarkers are that may be used to predict responses.

So, the clinical trials per se are designed to collect more information, for sure, and for a good reason because we want to learn from what the trials are telling us. I would not test for a PD-L1 for a patient with head and neck cancer at the moment. But I’m not sure this will last for very long. I think we’re hoping that a certain panel of biomarkers will allow us to basically be making clinical decisions based on these biomarkers in the near future.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: How Can We Optimize Outcomes in Head and Neck Cancers with Immunotherapeutic Strategies?Oct 31, 20191.5
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