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Historic and Ongoing Unmet Needs in cSCC

Insights From: Robert L. Ferris, MD, PhD, UPMC Hillman Cancer Center; Anna C. Pavlick, DO, NYU Langone Hospitals; Todd E. Schlesinger, MD, FAAD, FASMS, Dermatology & Laser Center of Charleston
Published: Wednesday, Feb 13, 2019



Transcript: 

Todd E. Schlesinger, MD, FAAD, FASMS: The unmet needs in cutaneous squamous cell carcinoma surgery are the challenges that we’ve faced for a long time. So, the biggest challenge that we face is dealing with tumors that result in morbidity to the patient. So if there is going to be a functional deficit to the patient, if they’re going to be losing a structure of their skin, they’re going to be losing significant function, that’s a tumor that we’ve always struggled with—whether we should perform surgery or another modality such as radiation; we’ve never really had a lot of good options for those poorly differentiated tumors, tumors in, that affect nerves. For example, perineural invasion. Perineural invasion is another risk factor that I didn’t mention earlier that’s very important to consider when it comes to metastatic rate. And so, you know these are the things that we consider when we’re looking at the squamous cell carcinoma.

Robert L. Ferris, MD, PhD: We’ve had good surgical technique for years. We’ve had good radiation technique, but when you think about what have been the real advances, it’s been in those aggressive metastatic, multiply recurrent skin cancers that the surgeon or the radiation therapist has been unable to remove and get around. And so in that setting, using cetuximab over the past 6 to 8 years, the EGFR inhibitor, and now most recently, a bona fide immunotherapeutic, cemiplimab, to harness the immune system which of course we know has failed since aggressive skin cancer is so much more of a clinical problem in the immunosuppressed populations, it makes sense that even in individuals who are not overtly immunosuppressed, that the immune system defect is prevalent, is present when their aggressive skin cancer begins to metastasize.

So, a major benefit is having a new tool and really just a proof of principle. Cemiplimab monotherapy is just, I think, scratching the surface of the type of therapies that are immune-based that will begin integrating. And now we can take the anti–PD-1, cemiplimab, and the successors. And then as we optimize and add combinations and begin to integrate PD-1 inhibitors in the preoperative setting and the postoperative setting, with radiation and potentially combine with chemotherapy. So, it’s opened up a whole new vista in treatment options available for this population.

For poor surgical candidates, the question was whether to do any surgery at all in former days, whether debulking mattered, and I think that depended in part on the surgeon’s preference, experience, and goals of surgery, particularly if the tumor resection was going to be disfiguring or debilitating. At that point, in the past when we had a nonoperative case, we really had radiation therapy that tended to be a 1-way street, because if it didn’t work, then you have a nonhealing wound or a big ulcer, and they’re very difficult then to resect or do much of anything with. So, we try to use radiation therapy judiciously.

And then 6 to 8 years ago we began integrating cetuximab, which was available for squamous carcinomas of the mouth and throat, the mucosa, and because the treating teams were similar because you know half to two-thirds of advanced cutaneous squamous cell carcinomas occur in the head and neck. Where we were using cetuximab for the other type of squamous cell carcinoma, we began using cetuximab in the palliative situation with or without radiation.

Now we have a different modality. You know the approval is for monotherapy with cemiplimab, but I would suggest we’re going to begin seeing integration back with cetuximab, or to try to make a nonsurgical candidate potentially surgically resectable we’re still really limited by if the patient is frail and infirm, not a surgical candidate. But if, in fact, preoperative therapy with cemiplimab could shrink the tumor down to where the surgery is not disfiguring, there are many lines of therapy and we’re going to have to re-evaluate all of them into where this new modality will fit.

Anna C. Pavlick, DO: Prior to the FDA approval of cemiplimab we had radiation as an option. We had recurrent surgeries as an option, which many times posed deforming surgeries for patients.

We had EGFR receptor inhibitors such as cetuximab that we gave patients, which did work but was not a durable response. Patients would have recurrent disease 6 or 8 months later. And in some cases, we even gave patients chemotherapy with a platinum-based chemotherapy agent, which was also responsive, the tumor was responsive; however, again, the durability and the toxicity was pretty significant. So, you really had to think about to be able to tolerate it. Because keeping in mind, many of these squamous cell cancers happen in the elderly.

Prior to the approval of cemiplimab the goals were essentially palliative—try and control it; try and control a tumor that has the potential to fungate, become infected, become painful. Especially the cSCCs that had perineural invasion, those could cause patients an exorbitant of pain. And so, our goal was really symptom management and palliation to manage their cancer for as long as we could, which, again, was usually less than a year.

My experience with agents such as cetuximab or chemotherapy in the management of locally advanced or metastatic cSCC has really been not the best for the simple reason that many of these patients are older. You’re providing them with palliation, but as a consequence you’re also providing them with a significant amount of toxicity. Many of these patients, because they’re older, have impaired kidney function, and now you’re talking about giving them a platinum-based agent that requires good renal function. Many older patients don’t have a voracious appetite and now you’re going to give them chemotherapy that makes their mouth taste like metal, gives them anorexia, and so you’re going to take a thin, frail patient and make them even thinner and even frail. So sometimes by trying to do good you may actually impose harm.

The EGFR receptor inhibitors like cetuximab, a little bit easier in my book to use in this population. However, you know that getting a rash as a consequence of this therapy is usually indicative of a response so you really actually want your patients to get the rash, but the rash can also be very disfiguring because it’s generalized, it’s a very pustular painful acne type of rash that really impacts whether patients want to even leave the house because they feel like they’ve got all of these lesions over their face, and it makes them self-conscious, where you’ve got someone who may not get out of the house very often and now you’re essentially making them more homebound. So, options were there but options weren’t great.

Transcript Edited for Clarity
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Transcript: 

Todd E. Schlesinger, MD, FAAD, FASMS: The unmet needs in cutaneous squamous cell carcinoma surgery are the challenges that we’ve faced for a long time. So, the biggest challenge that we face is dealing with tumors that result in morbidity to the patient. So if there is going to be a functional deficit to the patient, if they’re going to be losing a structure of their skin, they’re going to be losing significant function, that’s a tumor that we’ve always struggled with—whether we should perform surgery or another modality such as radiation; we’ve never really had a lot of good options for those poorly differentiated tumors, tumors in, that affect nerves. For example, perineural invasion. Perineural invasion is another risk factor that I didn’t mention earlier that’s very important to consider when it comes to metastatic rate. And so, you know these are the things that we consider when we’re looking at the squamous cell carcinoma.

Robert L. Ferris, MD, PhD: We’ve had good surgical technique for years. We’ve had good radiation technique, but when you think about what have been the real advances, it’s been in those aggressive metastatic, multiply recurrent skin cancers that the surgeon or the radiation therapist has been unable to remove and get around. And so in that setting, using cetuximab over the past 6 to 8 years, the EGFR inhibitor, and now most recently, a bona fide immunotherapeutic, cemiplimab, to harness the immune system which of course we know has failed since aggressive skin cancer is so much more of a clinical problem in the immunosuppressed populations, it makes sense that even in individuals who are not overtly immunosuppressed, that the immune system defect is prevalent, is present when their aggressive skin cancer begins to metastasize.

So, a major benefit is having a new tool and really just a proof of principle. Cemiplimab monotherapy is just, I think, scratching the surface of the type of therapies that are immune-based that will begin integrating. And now we can take the anti–PD-1, cemiplimab, and the successors. And then as we optimize and add combinations and begin to integrate PD-1 inhibitors in the preoperative setting and the postoperative setting, with radiation and potentially combine with chemotherapy. So, it’s opened up a whole new vista in treatment options available for this population.

For poor surgical candidates, the question was whether to do any surgery at all in former days, whether debulking mattered, and I think that depended in part on the surgeon’s preference, experience, and goals of surgery, particularly if the tumor resection was going to be disfiguring or debilitating. At that point, in the past when we had a nonoperative case, we really had radiation therapy that tended to be a 1-way street, because if it didn’t work, then you have a nonhealing wound or a big ulcer, and they’re very difficult then to resect or do much of anything with. So, we try to use radiation therapy judiciously.

And then 6 to 8 years ago we began integrating cetuximab, which was available for squamous carcinomas of the mouth and throat, the mucosa, and because the treating teams were similar because you know half to two-thirds of advanced cutaneous squamous cell carcinomas occur in the head and neck. Where we were using cetuximab for the other type of squamous cell carcinoma, we began using cetuximab in the palliative situation with or without radiation.

Now we have a different modality. You know the approval is for monotherapy with cemiplimab, but I would suggest we’re going to begin seeing integration back with cetuximab, or to try to make a nonsurgical candidate potentially surgically resectable we’re still really limited by if the patient is frail and infirm, not a surgical candidate. But if, in fact, preoperative therapy with cemiplimab could shrink the tumor down to where the surgery is not disfiguring, there are many lines of therapy and we’re going to have to re-evaluate all of them into where this new modality will fit.

Anna C. Pavlick, DO: Prior to the FDA approval of cemiplimab we had radiation as an option. We had recurrent surgeries as an option, which many times posed deforming surgeries for patients.

We had EGFR receptor inhibitors such as cetuximab that we gave patients, which did work but was not a durable response. Patients would have recurrent disease 6 or 8 months later. And in some cases, we even gave patients chemotherapy with a platinum-based chemotherapy agent, which was also responsive, the tumor was responsive; however, again, the durability and the toxicity was pretty significant. So, you really had to think about to be able to tolerate it. Because keeping in mind, many of these squamous cell cancers happen in the elderly.

Prior to the approval of cemiplimab the goals were essentially palliative—try and control it; try and control a tumor that has the potential to fungate, become infected, become painful. Especially the cSCCs that had perineural invasion, those could cause patients an exorbitant of pain. And so, our goal was really symptom management and palliation to manage their cancer for as long as we could, which, again, was usually less than a year.

My experience with agents such as cetuximab or chemotherapy in the management of locally advanced or metastatic cSCC has really been not the best for the simple reason that many of these patients are older. You’re providing them with palliation, but as a consequence you’re also providing them with a significant amount of toxicity. Many of these patients, because they’re older, have impaired kidney function, and now you’re talking about giving them a platinum-based agent that requires good renal function. Many older patients don’t have a voracious appetite and now you’re going to give them chemotherapy that makes their mouth taste like metal, gives them anorexia, and so you’re going to take a thin, frail patient and make them even thinner and even frail. So sometimes by trying to do good you may actually impose harm.

The EGFR receptor inhibitors like cetuximab, a little bit easier in my book to use in this population. However, you know that getting a rash as a consequence of this therapy is usually indicative of a response so you really actually want your patients to get the rash, but the rash can also be very disfiguring because it’s generalized, it’s a very pustular painful acne type of rash that really impacts whether patients want to even leave the house because they feel like they’ve got all of these lesions over their face, and it makes them self-conscious, where you’ve got someone who may not get out of the house very often and now you’re essentially making them more homebound. So, options were there but options weren’t great.

Transcript Edited for Clarity
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