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Historic Perspective on Systemic Therapy for Advanced HNSCC

Insights From: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Robert L. Ferris, MD, PhD, University of Pittsburgh Cancer Institute
Published: Thursday, Jan 05, 2017


Transcript:

Ezra Cohen, MD:
When we think about the application of systemic therapy in patients with head and neck cancer, we really think about it as a function of disease setting. For early-stage disease, stage I and stage II patients, we really don’t think about systemic therapy. Those patients are often cured with single modality therapy, surgery, or radiation. Remember, for head and neck cancer, you can have stage IV disease, IVa and IVb, and not have metastatic disease. Those are still considered locally-advanced patients. And it’s in those patients, stage III and stage IV, where we begin to think about the application of systemic therapy. Of course, we have a few options that had been validated with phase III data. The first and probably the most common standard is cisplatin. That’s usually delivered every 3 weeks in a high dose, 100 mg/m2, concurrent with radiation. Depending on the radiation scheme, we’ll usually plan on giving 2 or 3 doses of cisplatin. The other option, of course, is cetuximab—phase III data supporting its use, usually started a week before the radiation starts as a loading dose, and then continued on a weekly basis through radiation.

There are also some other options. For instance, a European trial demonstrated that carboplatin 5-FU provides a superior overall survival compared to radiation therapy alone, and some, let’s say, much less frequently used regimens that either don’t have phase III data behind them or are somewhat idiosyncratic. So, in North America, I think the 2 most common uses of systemic chemotherapy would be cisplatin or cetuximab. Let’s talk about cisplatin for just a moment because there are 2 ways now that are commonly used that deliver cisplatin. I talked about the high-dose regimen, but there are also data—although much more limited data—for the weekly application of cisplatin, usually at a dose of about 40 mg/m2. The reality is that we actually don’t have a comparative trial that looked at high dose versus weekly dose of cisplatin. We have some data in other cancers, some data in nasopharynx cancer, showing that weekly is superior to radiation therapy alone, but we don’t have anything comparing the high dose versus the weekly.

Unfortunately, for those individuals or those practitioners who favored the weekly regimen, we’re beginning to see retrospective and registry data that are beginning to suggest that the weekly a) may not be better tolerated than the every-3-week and b) may not be as effective as the every-3-week, which is the most concerning. And so, in my practice, I usually am using the every-3-week high-dose cisplatin because most of the data continue to support that.

Now, shifting gears a little bit from locally advanced disease to the recurrent metastatic setting, we really begin to think about different goals of therapy. Unfortunately, for patients with recurrent metastatic disease, usually they can’t be cured. Some of them can be with either surgery or perhaps re-radiation, but for most patients we’re talking about the palliative systemic therapy. And there, we think about lines of therapy. So, first line, second line, and even in some patients, third line. For first-line therapy, we do have an approved and validated regimen in phase III trial, and that is the EXTREME trial regimen. That’s a triplet regimen combining platinum, either cisplatin or carboplatin, with 5-FU and cetuximab. And that demonstrated an improvement in overall survival versus platinum 5-FU alone of about 10 months versus 7.5 months. As I said, that is an approved regimen for first-line recurrent metastatic head and neck cancer. The reality though is that’s, at least in the United States, a regimen that’s not often used. And I would estimate probably somewhere in the range about 20% of patients end up getting the EXTREME trial regimen for first line. In the United States, the more commonly applied chemotherapy is a doublet regimen, often consisting of a platinum and a taxane. And the reason behind that is, first of all, the feeling is that this is a palliative setting, and we really want to preserve quality of life as much as possible. Secondly, platinum taxane combinations are clearly effective, with good response rates, at least in phase II trials; evidence of good overall survival and progression-free survival; evidence of symptom control or quality of life, at least management; and, that it may be wise to preserve some of the agents for second- or third-line. And so, the common practice in the United States is to use a doublet in that first line. In the second line, most patients are usually being treated with single-agent cytotoxic chemotherapy or cetuximab.

Now, of course, in 2016 that changed completely, and it changed because of immunotherapy and the anti-PD-1 antibodies. We saw data first with pembrolizumab and its efficacy in usually second-line or third-line patients, patients who were refractory to platinum. And in some cases, patients were refractory to both platinum and cetuximab, demonstrating response rates, good progression-free survival, and good overall survival, in non-randomized trials. And then, later in 2016 we saw the first randomized study in squamous cell carcinoma of the head and neck using nivolumab, demonstrating an improvement in overall survival versus single-agent therapy. That was investigator’s choice of either methotrexate, docetaxel and cetuximab. Nivolumab in patients who were refractory to platinum. This doubled overall survival, going from about 17% to 36%; unprecedented in patients who are platinum refractory with squamous cell carcinoma of the head and neck. And now, for many patients, if not most patients, in the second line for a current metastatic disease, we would be using an anti-PD-1 antibody.

Robert L. Ferris, MD, PhD: Since 2006, cetuximab has been an FDA-approved regimen when combined with radiation therapy for locally advanced head and neck cancers. We have experience with a large number of patients receiving cetuximab and radiation for upfront curative disease in the locally advanced previously untreated setting. Very commonly, we use cetuximab as a replacement or a substitute when a patient is not eligible to receive cisplatin—in somebody with kidney disease, renal toxicity, and neurologic symptoms, or an older person, older than 70 years of age. So, an appropriate candidate to receive cetuximab would be somebody who is not eligible to receive chemotherapy like cisplatin. Now, people often ask whether HPV-positive patients or HPV-negative patients should receive cetuximab.

It turns out that although not prospectively determined, retrospective analyses of large numbers of patients who have received cetuximab demonstrate that both HPV-positive and HPV-negative patients benefit by adding cetuximab to radiation therapy alone. It turns out that HPV-positive patients benefit more, but that may be because HPV-positive patients benefit more no matter what treatment we give them. So far, HPV-positive patients benefit dramatically with survival rates in the high 80s at 2 years. HPV-negative patients, although they benefit some, their overall outcome is not quite as good. And so, most clinicians would try as best as they could to use cytotoxic chemotherapy, since it may be more effective than cetuximab for HPV-negative patients.

Cetuximab is also approved in the recurrent and metastatic setting. The regimen combining cetuximab with platinum and 5-FU chemotherapy is called the EXTREME regimen. And the EXTREME regimen was FDA approved in the United States in 2011, combining cetuximab with platinum/5-FU where it showed a survival advantage over the chemotherapy alone. It also permitted months and months of maintenance. And so, probably the best population for maintenance cetuximab therapy is those who have received the EXTREME regimen for recurrent metastatic disease, combining cetuximab with platinum/5-FU chemotherapy, then continuing with an adjuvant maintenance phase of weekly cetuximab until disease progression.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
When we think about the application of systemic therapy in patients with head and neck cancer, we really think about it as a function of disease setting. For early-stage disease, stage I and stage II patients, we really don’t think about systemic therapy. Those patients are often cured with single modality therapy, surgery, or radiation. Remember, for head and neck cancer, you can have stage IV disease, IVa and IVb, and not have metastatic disease. Those are still considered locally-advanced patients. And it’s in those patients, stage III and stage IV, where we begin to think about the application of systemic therapy. Of course, we have a few options that had been validated with phase III data. The first and probably the most common standard is cisplatin. That’s usually delivered every 3 weeks in a high dose, 100 mg/m2, concurrent with radiation. Depending on the radiation scheme, we’ll usually plan on giving 2 or 3 doses of cisplatin. The other option, of course, is cetuximab—phase III data supporting its use, usually started a week before the radiation starts as a loading dose, and then continued on a weekly basis through radiation.

There are also some other options. For instance, a European trial demonstrated that carboplatin 5-FU provides a superior overall survival compared to radiation therapy alone, and some, let’s say, much less frequently used regimens that either don’t have phase III data behind them or are somewhat idiosyncratic. So, in North America, I think the 2 most common uses of systemic chemotherapy would be cisplatin or cetuximab. Let’s talk about cisplatin for just a moment because there are 2 ways now that are commonly used that deliver cisplatin. I talked about the high-dose regimen, but there are also data—although much more limited data—for the weekly application of cisplatin, usually at a dose of about 40 mg/m2. The reality is that we actually don’t have a comparative trial that looked at high dose versus weekly dose of cisplatin. We have some data in other cancers, some data in nasopharynx cancer, showing that weekly is superior to radiation therapy alone, but we don’t have anything comparing the high dose versus the weekly.

Unfortunately, for those individuals or those practitioners who favored the weekly regimen, we’re beginning to see retrospective and registry data that are beginning to suggest that the weekly a) may not be better tolerated than the every-3-week and b) may not be as effective as the every-3-week, which is the most concerning. And so, in my practice, I usually am using the every-3-week high-dose cisplatin because most of the data continue to support that.

Now, shifting gears a little bit from locally advanced disease to the recurrent metastatic setting, we really begin to think about different goals of therapy. Unfortunately, for patients with recurrent metastatic disease, usually they can’t be cured. Some of them can be with either surgery or perhaps re-radiation, but for most patients we’re talking about the palliative systemic therapy. And there, we think about lines of therapy. So, first line, second line, and even in some patients, third line. For first-line therapy, we do have an approved and validated regimen in phase III trial, and that is the EXTREME trial regimen. That’s a triplet regimen combining platinum, either cisplatin or carboplatin, with 5-FU and cetuximab. And that demonstrated an improvement in overall survival versus platinum 5-FU alone of about 10 months versus 7.5 months. As I said, that is an approved regimen for first-line recurrent metastatic head and neck cancer. The reality though is that’s, at least in the United States, a regimen that’s not often used. And I would estimate probably somewhere in the range about 20% of patients end up getting the EXTREME trial regimen for first line. In the United States, the more commonly applied chemotherapy is a doublet regimen, often consisting of a platinum and a taxane. And the reason behind that is, first of all, the feeling is that this is a palliative setting, and we really want to preserve quality of life as much as possible. Secondly, platinum taxane combinations are clearly effective, with good response rates, at least in phase II trials; evidence of good overall survival and progression-free survival; evidence of symptom control or quality of life, at least management; and, that it may be wise to preserve some of the agents for second- or third-line. And so, the common practice in the United States is to use a doublet in that first line. In the second line, most patients are usually being treated with single-agent cytotoxic chemotherapy or cetuximab.

Now, of course, in 2016 that changed completely, and it changed because of immunotherapy and the anti-PD-1 antibodies. We saw data first with pembrolizumab and its efficacy in usually second-line or third-line patients, patients who were refractory to platinum. And in some cases, patients were refractory to both platinum and cetuximab, demonstrating response rates, good progression-free survival, and good overall survival, in non-randomized trials. And then, later in 2016 we saw the first randomized study in squamous cell carcinoma of the head and neck using nivolumab, demonstrating an improvement in overall survival versus single-agent therapy. That was investigator’s choice of either methotrexate, docetaxel and cetuximab. Nivolumab in patients who were refractory to platinum. This doubled overall survival, going from about 17% to 36%; unprecedented in patients who are platinum refractory with squamous cell carcinoma of the head and neck. And now, for many patients, if not most patients, in the second line for a current metastatic disease, we would be using an anti-PD-1 antibody.

Robert L. Ferris, MD, PhD: Since 2006, cetuximab has been an FDA-approved regimen when combined with radiation therapy for locally advanced head and neck cancers. We have experience with a large number of patients receiving cetuximab and radiation for upfront curative disease in the locally advanced previously untreated setting. Very commonly, we use cetuximab as a replacement or a substitute when a patient is not eligible to receive cisplatin—in somebody with kidney disease, renal toxicity, and neurologic symptoms, or an older person, older than 70 years of age. So, an appropriate candidate to receive cetuximab would be somebody who is not eligible to receive chemotherapy like cisplatin. Now, people often ask whether HPV-positive patients or HPV-negative patients should receive cetuximab.

It turns out that although not prospectively determined, retrospective analyses of large numbers of patients who have received cetuximab demonstrate that both HPV-positive and HPV-negative patients benefit by adding cetuximab to radiation therapy alone. It turns out that HPV-positive patients benefit more, but that may be because HPV-positive patients benefit more no matter what treatment we give them. So far, HPV-positive patients benefit dramatically with survival rates in the high 80s at 2 years. HPV-negative patients, although they benefit some, their overall outcome is not quite as good. And so, most clinicians would try as best as they could to use cytotoxic chemotherapy, since it may be more effective than cetuximab for HPV-negative patients.

Cetuximab is also approved in the recurrent and metastatic setting. The regimen combining cetuximab with platinum and 5-FU chemotherapy is called the EXTREME regimen. And the EXTREME regimen was FDA approved in the United States in 2011, combining cetuximab with platinum/5-FU where it showed a survival advantage over the chemotherapy alone. It also permitted months and months of maintenance. And so, probably the best population for maintenance cetuximab therapy is those who have received the EXTREME regimen for recurrent metastatic disease, combining cetuximab with platinum/5-FU chemotherapy, then continuing with an adjuvant maintenance phase of weekly cetuximab until disease progression.

Transcript Edited for Clarity
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