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Future Management of Cutaneous Squamous Cell Carcinoma

Insights From: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Dirk Schadendorf, MD, West German Cancer Center; Neil D. Gross, MD, FACS, MD Anderson Cancer Center
Published: Thursday, Jan 16, 2020



Transcript: 

Dirk Schadendorf, MD:
Obviously, it’s a challenge if we are treating patients and 50% of the patients are benefitting, which is actually great news. This benefit we are seeing is long-lasting, probably over years with cemiplimab in cutaneous squamous cell carcinoma. We have only a limited time span that we can follow at the moment, but extrapolating from melanoma and other cancers, we can expect that we’ll possibly control the tumor for years. On the other hand, we still have a subgroup of patients, roughly 50%, who are not responding to cemiplimab right from the beginning or who will escape quite early.

So here, as in other tumors like lung cancer, renal cancer, or melanoma, we are looking for mechanisms of immunotherapy [I/O] resistance. And this is tricky because this is not 1 mechanism. We are talking about different immunological phenomena that are accounting for resistance, including not enough T-cell function, exhaustion of T-cells, or that the tumor and the microenvironment surrounding the tumor are protecting the tumor against the immunological attack. There are several ideas how one could do that, which are still not operational, also not in other tumors. I think for cutaneous squamous cell carcinoma, one way could be the combination with radiation because we know that radiation is producing, for example, inflammation, which helps to bring immune cells into the tumor and possibly increases the immunological responses, an approach that needs to be tested.

Axel Hauschild, MD: We have no idea right now what to give patients who progressed after anti–programmed cell death protein 1 [anti–PD-1] therapy. It’s a very tough situation for patients. We can discuss chemotherapy, we can discuss cetuximab, or we can discuss a clinical trial like the trial from Germany, a combination of avelumab and cetuximab, which can be given to patients in second line after failure to PD-1 antibodies. Or there are other companies coming up with histone deacetylase inhibitors in combination for second-line therapy. Or we can discuss radiotherapy, conventional radiotherapy, because the tumor is radiosensitive, but there is no gold standard right now. We need to work on this, and this is going to be addressed by the next clinical trials.

Neil D. Gross, MD, FACS: In the new era of immunotherapy for cutaneous squamous cell carcinoma, there are going to be several large unmet needs. One will be patients who are resistant to first-line therapy and what combinations of treatment make sense for those patients. We’re still trying to figure out how to incorporate immunotherapy into the treatment setting for patients with resectable or borderline resectable disease. Do you give it up front in the hopes of making the surgery less morbid, or treatment more efficacious overall? Or do you give it in the adjuvant setting?

There’s also a large unmet need for these patients in the sense that they have a very high risk of second primaries. These patients are almost always destined to get more tumors. So that’s an unanswered question, what treatment with immunotherapy does to change the curve of second primary disease.

And then probably the biggest unmet needs are patients with immunosuppression. These patients traditionally are not candidates for immunotherapy, but there may be opportunities to treat them in more sophisticated ways with local delivery of drug.
 
Dirk Schadendorf, MD: For decades, patients with cutaneous squamous cell carcinoma were neglected. We had no clinical trials. We had no agents, and we were left with some old chemotherapeutic agents like platinum products, which were not suitable for a large subset of these patients. Now, we have a better biological understanding. We know that the tumor has a lot of mutations that can be tackled by the immune system. And the checkpoint inhibitor, cemiplimab, is providing for a large fraction of these patients, a new hope, a new way to control the tumor and have a good quality of life at the end of their life.


Transcript Edited for Clarity
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Transcript: 

Dirk Schadendorf, MD:
Obviously, it’s a challenge if we are treating patients and 50% of the patients are benefitting, which is actually great news. This benefit we are seeing is long-lasting, probably over years with cemiplimab in cutaneous squamous cell carcinoma. We have only a limited time span that we can follow at the moment, but extrapolating from melanoma and other cancers, we can expect that we’ll possibly control the tumor for years. On the other hand, we still have a subgroup of patients, roughly 50%, who are not responding to cemiplimab right from the beginning or who will escape quite early.

So here, as in other tumors like lung cancer, renal cancer, or melanoma, we are looking for mechanisms of immunotherapy [I/O] resistance. And this is tricky because this is not 1 mechanism. We are talking about different immunological phenomena that are accounting for resistance, including not enough T-cell function, exhaustion of T-cells, or that the tumor and the microenvironment surrounding the tumor are protecting the tumor against the immunological attack. There are several ideas how one could do that, which are still not operational, also not in other tumors. I think for cutaneous squamous cell carcinoma, one way could be the combination with radiation because we know that radiation is producing, for example, inflammation, which helps to bring immune cells into the tumor and possibly increases the immunological responses, an approach that needs to be tested.

Axel Hauschild, MD: We have no idea right now what to give patients who progressed after anti–programmed cell death protein 1 [anti–PD-1] therapy. It’s a very tough situation for patients. We can discuss chemotherapy, we can discuss cetuximab, or we can discuss a clinical trial like the trial from Germany, a combination of avelumab and cetuximab, which can be given to patients in second line after failure to PD-1 antibodies. Or there are other companies coming up with histone deacetylase inhibitors in combination for second-line therapy. Or we can discuss radiotherapy, conventional radiotherapy, because the tumor is radiosensitive, but there is no gold standard right now. We need to work on this, and this is going to be addressed by the next clinical trials.

Neil D. Gross, MD, FACS: In the new era of immunotherapy for cutaneous squamous cell carcinoma, there are going to be several large unmet needs. One will be patients who are resistant to first-line therapy and what combinations of treatment make sense for those patients. We’re still trying to figure out how to incorporate immunotherapy into the treatment setting for patients with resectable or borderline resectable disease. Do you give it up front in the hopes of making the surgery less morbid, or treatment more efficacious overall? Or do you give it in the adjuvant setting?

There’s also a large unmet need for these patients in the sense that they have a very high risk of second primaries. These patients are almost always destined to get more tumors. So that’s an unanswered question, what treatment with immunotherapy does to change the curve of second primary disease.

And then probably the biggest unmet needs are patients with immunosuppression. These patients traditionally are not candidates for immunotherapy, but there may be opportunities to treat them in more sophisticated ways with local delivery of drug.
 
Dirk Schadendorf, MD: For decades, patients with cutaneous squamous cell carcinoma were neglected. We had no clinical trials. We had no agents, and we were left with some old chemotherapeutic agents like platinum products, which were not suitable for a large subset of these patients. Now, we have a better biological understanding. We know that the tumor has a lot of mutations that can be tackled by the immune system. And the checkpoint inhibitor, cemiplimab, is providing for a large fraction of these patients, a new hope, a new way to control the tumor and have a good quality of life at the end of their life.


Transcript Edited for Clarity
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