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Examining the Use of Cetuximab for HNSCC

Insights From: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Robert L. Ferris, MD, PhD, FACS, University of Pittsburgh Cancer Institute; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Wednesday, Jun 08, 2016


Transcript:

Ezra Cohen, MD:
Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. And, in terms of how it works or its mechanism of action, we’ve come to realize it’s actually a dual mechanism. First, it’s a mechanism against the target that we know is important in head and neck cancer; it’s important to its biology. It has prognostic implication, and we’ve targeted it. In fact, cetuximab is the only approved targeted agent for head and neck cancer. When we inhibit EGFR with a drug like cetuximab, what we see is a reduction in proliferation, a reduction in metastatic potential, a reduction in angiogenesis—really all the things we want to reverse in the cancer phenotype.

But we also have to realize that there’s another end to the monoclonal antibody, and that’s the end that interacts with immune cells. That can actually activate a part of the immune system called antibody-dependent cytotoxicity, and that involves primarily natural killer cells. So, studies for the last several years have really born this out, that cetuximab has a dramatic effect on activating this immune system. In fact, there are some investigators and some researchers that think that that’s, in fact, the more important mechanism of action for cetuximab. Whether that’s true is still debated, but I think without a doubt, there is an immune component to its mechanism of action. We published a study with the University of Maryland just last year that had patients who were treated with cetuximab. And we were able to demonstrate that those patients in an ex vivo assay—who could form an immune response based on ADCC, based on natural killer cell activation, and who could form this immune response to cetuximab—actually did significantly better with cetuximab therapy than their counterparts that could not. This suggests that, in fact, the immune component is quite an important part of the mechanism of action.

The use of cetuximab for patients with head and neck cancer has really had dramatic effect, and certainly significant effect, on the outcome of these patients. Let’s talk about, first, the patients with locally advanced disease. What we know about cetuximab is that it is a radiosensitizer, and a good radiosensitizer, that improves survival when added to radiation in patients with locally advanced head and neck cancer. That survival was first seen at 3 years, about a 10% difference in survival, and then a later publication at 5 years maintaining that same 10% improvement in overall survival. Although that number, I agree, is modest, we also have to remember that that means we’re curing 10% more patients with the disease—so really a difference in those patients between life and death. Of course, that garnered approval for cetuximab in patients with locally advanced disease.

Interestingly, in that same setting—locally advanced—when we combined cetuximab with chemotherapy and radiation, specifically with cisplatin and radiation, we didn’t see a beneficial effect. The reason behind that is still unknown, but what we do know is that cetuximab is best used as a single agent with radiation and now should not be combined with chemotherapy radiation. In fact, that only leads to more toxicity and no benefit in terms of efficacy.

Jared Weiss, MD: I think that cetuximab may actually be a fairly underused drug in combination with radiotherapy. When the Bonner study came out, I think the absence of extreme toxicity led some to consider the regimen to have a little less effect. The failure to do a study comparing against cisplatin with radiotherapy left many practitioners wondering which was the better regimen. And I think the subgroup analysis on that trial was a little bit confusing. Preclinically, there’s reason to believe that cetuximab might work a little less well for the HPV-positive patient. And yet in Bonner, they seem to be describing the HPV-positive patient in the forest plots of who benefitted more. We now have that HPV subgroup data. It’s fairly agnostic, the efficacy of cetuximab. In my practice, I’ve actually had a very good experience with the agent. I found it very well tolerated, almost as well tolerated as radiation alone. It is certainly, quite a bit better tolerated than bolus cisplatin with radiotherapy, and it has a positive phase III study behind it. So, in my practice, I’ve seen it as a very viable option.

Ezra Cohen, MD: Conversely, when we look at patients with recurrent metastatic disease, we can see that cetuximab is effective in really two ways, or adds to our efficacy. First of all, as a single agent, it has a response rate of about 10% to15%, and is approved as a single agent for second-line recurrent metastatic head and neck cancer. Perhaps more importantly, it improves survival in patients in the first-line recurrent metastatic setting when combined with chemotherapy. So, this is the so-called EXTREME regimen that combined cetuximab with platinum and 5-FU compared to cisplatin or platinum and 5-FU alone. And what the investigators saw was an improvement in overall survival from median 7.5 months with chemotherapy alone to a median of about 10 months with the addition of cetuximab. And, of course, the EXTREME regimen is approved for the treatment of first-line recurrent metastatic head and neck cancer in the United States and in Europe.

Jared Weiss, MD: In my practice, I do frequently use cetuximab for palliative care. For the patient with very-low-bulk disease that’s not imminently threatening their well-being, I like single-agent cetuximab as a very well-tolerated regimen to try to control disease in such patients. The other way I use it is for [a] more aggressive palliative regimen. I will graft it on to chemotherapy, just not the very toxic cisplatin 5-FU backbone shown in the EXTREME study. In my personal practice for the patient that has a great need of response, I like to graft it on to weekly carboplatin and paclitaxel, kind of employing the Kies neoadjuvant regimen as a palliative approach.

We happen to be filming in the Southeast of the United States where there’s a 20% anaphylaxis rate. I will say that there is an Alpha-Gal assay that can be used to predict against these. Negative predictive value is excellent, 100%. That’s about to be published in the journal, Cancer. Positive predictive value, we really don’t know. But in my practice, I will get an Alpha-Gal. If it’s negative, I’m very comfortable treating the patient with cetuximab. If it’s positive, we use Benadryl pre-meds, we use steroid pre-meds. And because just about all these reactions happen in the first 15 minutes of the first infusion, I personally supervise the infusion of the first 15 minutes.

Ezra Cohen, MD: With respect to trying to manage the radiation dermatitis, what we’ve realized is that if we begin to manage it very early, we’re much more successful. And that includes tetracycline antibiotics, topical therapies. Of course, we have to be careful with topical therapies when using radiation because they cannot be applied during the radiation administration. Good skin hygiene and good skin hydration is important. And if we do that, we’ve really learned that we can avoid the more serious grade 4 radiation dermatitis that can be associated with cetuximab, and even sometimes avoid the grade 3 dermatitis that can be associated. So, really the key is to begin management very early.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. And, in terms of how it works or its mechanism of action, we’ve come to realize it’s actually a dual mechanism. First, it’s a mechanism against the target that we know is important in head and neck cancer; it’s important to its biology. It has prognostic implication, and we’ve targeted it. In fact, cetuximab is the only approved targeted agent for head and neck cancer. When we inhibit EGFR with a drug like cetuximab, what we see is a reduction in proliferation, a reduction in metastatic potential, a reduction in angiogenesis—really all the things we want to reverse in the cancer phenotype.

But we also have to realize that there’s another end to the monoclonal antibody, and that’s the end that interacts with immune cells. That can actually activate a part of the immune system called antibody-dependent cytotoxicity, and that involves primarily natural killer cells. So, studies for the last several years have really born this out, that cetuximab has a dramatic effect on activating this immune system. In fact, there are some investigators and some researchers that think that that’s, in fact, the more important mechanism of action for cetuximab. Whether that’s true is still debated, but I think without a doubt, there is an immune component to its mechanism of action. We published a study with the University of Maryland just last year that had patients who were treated with cetuximab. And we were able to demonstrate that those patients in an ex vivo assay—who could form an immune response based on ADCC, based on natural killer cell activation, and who could form this immune response to cetuximab—actually did significantly better with cetuximab therapy than their counterparts that could not. This suggests that, in fact, the immune component is quite an important part of the mechanism of action.

The use of cetuximab for patients with head and neck cancer has really had dramatic effect, and certainly significant effect, on the outcome of these patients. Let’s talk about, first, the patients with locally advanced disease. What we know about cetuximab is that it is a radiosensitizer, and a good radiosensitizer, that improves survival when added to radiation in patients with locally advanced head and neck cancer. That survival was first seen at 3 years, about a 10% difference in survival, and then a later publication at 5 years maintaining that same 10% improvement in overall survival. Although that number, I agree, is modest, we also have to remember that that means we’re curing 10% more patients with the disease—so really a difference in those patients between life and death. Of course, that garnered approval for cetuximab in patients with locally advanced disease.

Interestingly, in that same setting—locally advanced—when we combined cetuximab with chemotherapy and radiation, specifically with cisplatin and radiation, we didn’t see a beneficial effect. The reason behind that is still unknown, but what we do know is that cetuximab is best used as a single agent with radiation and now should not be combined with chemotherapy radiation. In fact, that only leads to more toxicity and no benefit in terms of efficacy.

Jared Weiss, MD: I think that cetuximab may actually be a fairly underused drug in combination with radiotherapy. When the Bonner study came out, I think the absence of extreme toxicity led some to consider the regimen to have a little less effect. The failure to do a study comparing against cisplatin with radiotherapy left many practitioners wondering which was the better regimen. And I think the subgroup analysis on that trial was a little bit confusing. Preclinically, there’s reason to believe that cetuximab might work a little less well for the HPV-positive patient. And yet in Bonner, they seem to be describing the HPV-positive patient in the forest plots of who benefitted more. We now have that HPV subgroup data. It’s fairly agnostic, the efficacy of cetuximab. In my practice, I’ve actually had a very good experience with the agent. I found it very well tolerated, almost as well tolerated as radiation alone. It is certainly, quite a bit better tolerated than bolus cisplatin with radiotherapy, and it has a positive phase III study behind it. So, in my practice, I’ve seen it as a very viable option.

Ezra Cohen, MD: Conversely, when we look at patients with recurrent metastatic disease, we can see that cetuximab is effective in really two ways, or adds to our efficacy. First of all, as a single agent, it has a response rate of about 10% to15%, and is approved as a single agent for second-line recurrent metastatic head and neck cancer. Perhaps more importantly, it improves survival in patients in the first-line recurrent metastatic setting when combined with chemotherapy. So, this is the so-called EXTREME regimen that combined cetuximab with platinum and 5-FU compared to cisplatin or platinum and 5-FU alone. And what the investigators saw was an improvement in overall survival from median 7.5 months with chemotherapy alone to a median of about 10 months with the addition of cetuximab. And, of course, the EXTREME regimen is approved for the treatment of first-line recurrent metastatic head and neck cancer in the United States and in Europe.

Jared Weiss, MD: In my practice, I do frequently use cetuximab for palliative care. For the patient with very-low-bulk disease that’s not imminently threatening their well-being, I like single-agent cetuximab as a very well-tolerated regimen to try to control disease in such patients. The other way I use it is for [a] more aggressive palliative regimen. I will graft it on to chemotherapy, just not the very toxic cisplatin 5-FU backbone shown in the EXTREME study. In my personal practice for the patient that has a great need of response, I like to graft it on to weekly carboplatin and paclitaxel, kind of employing the Kies neoadjuvant regimen as a palliative approach.

We happen to be filming in the Southeast of the United States where there’s a 20% anaphylaxis rate. I will say that there is an Alpha-Gal assay that can be used to predict against these. Negative predictive value is excellent, 100%. That’s about to be published in the journal, Cancer. Positive predictive value, we really don’t know. But in my practice, I will get an Alpha-Gal. If it’s negative, I’m very comfortable treating the patient with cetuximab. If it’s positive, we use Benadryl pre-meds, we use steroid pre-meds. And because just about all these reactions happen in the first 15 minutes of the first infusion, I personally supervise the infusion of the first 15 minutes.

Ezra Cohen, MD: With respect to trying to manage the radiation dermatitis, what we’ve realized is that if we begin to manage it very early, we’re much more successful. And that includes tetracycline antibiotics, topical therapies. Of course, we have to be careful with topical therapies when using radiation because they cannot be applied during the radiation administration. Good skin hygiene and good skin hydration is important. And if we do that, we’ve really learned that we can avoid the more serious grade 4 radiation dermatitis that can be associated with cetuximab, and even sometimes avoid the grade 3 dermatitis that can be associated. So, really the key is to begin management very early.

Transcript Edited for Clarity
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