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Cemiplimab Phase I Trial

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 20, 2019



Transcript:

Robert L. Ferris, MD, PhD:
The cemiplimab trial with the Regeneron antibody, which many of us remember as 2810 before it got its fancy new name, was used to look in different subgroups, initially as a safety trial, but then as safety parameters were met, there were expansion cohorts for locally advanced unresectable disease, or expansion populations for metastatic disease, up-front metastatic. And so this was a dose escalation and safety evaluation. Once the dose of 3 mg/kg every 2 weeks was reached, then expansion continued to a large enough extent to assess the response estimates, which was the primary clinical parameter, complete response, partial response, and then in combination the overall response rate.

So as a single-arm phase I expansion cohort with 2 different cohorts—locally advanced disease or metastatic—we have these 2 cohorts that led to the approval of cemiplimab. In both cohorts, the overall response rate approximated 50%. In the metastatic disease, although the numbers are small, there was a slightly elevated rate of complete responders, about 7% complete responders, but the numbers are quite small, just 25 to 35 patients. But in both groups impressive partial responses were seen, as was a longer duration of therapy, and so stabilization of disease and partial responses were the dominant clinical feature of patient benefit. But in the metastatic expansion cohort, there was a complete response rate of 6% or 7%, indicating that this could potentially be curative for a small subset of patients. But at minimum, durability and a partial response with stable disease in long-term benefit was seen.

As I mentioned earlier, aggressive skin cancer is dramatically increased in patients or individuals who have chronic immunosuppression, either through chronic lymphocytic leukemia or through organ transplantation and other immunosuppressive anti-inflammatories. So given that history, it was clear that the immune system plays an important role in controlling skin cancer premalignancy and progression on to invasive cancer. So it made sense in this population, which is rapidly increasing over the past few decades, to try to do something new.

The PD-1 inhibitors, [programmed cell] death protein 1], is a receptor. It’s an inhibitory receptor on the immune system, and it’s a way that the immune system dampens the immune responses, particularly to avoid autoimmune attack against our own tissues. And so the PD-1 inhibitors have been effective in a number of different cancers because the T lymphocytes, the primary cell type in the immune system that controls against cancer progression and recurrence, expressed a high level of the PD-1 receptor. And the tumor cells then express the ligate.

So you have the T cells in these cancer patients expressing PD-1. You have the tumor cell expressing the programmed death-ligand 1, PD-L1, and that inactivates or suppresses, turns off, those T cells. So the rationale for the PD-1 inhibitors, like cemiplimab, is to disrupt and block the PD-L1 and PD-1 interaction. That permits the T cells to be reactivated and then be much more competent, functional, and able to reject the cancer cells—in a way turning back the clock and reversing immune escape. So cemiplimab blocks PD-1 and prevents the negative inhibitory signal being transmitted to it by the tumor cell and allows those T cells then to recognize and lyse and kill the cancer cells.

Anna C. Pavlick, DO: We know that tumors that have a high mutational burden really respond nicely to immunotherapy. We learned this from all the studies that we did with metastatic melanoma, that melanoma has a very high mutational burden, and we know that patients who had more mutations had better responses to immunotherapy. Interestingly, cutaneous squamous cell carcinoma has an even higher mutational burden than melanoma, and so intuitively knowing what we know in melanoma, we can extrapolate that over to squamous cell cancer and say, these are patients whose tumors are chock-full of mutations, and so they should have an exceptionally good response rate to immunotherapy.

Robert L. Ferris, MD, PhD: The approval of cemiplimab for advanced cutaneous squamous cell carcinoma has provided a new tool that we’ve been able to use here in our multidisciplinary team. Prior to that, we had experience with relatively ineffective therapies in these advanced recurrent and metastatic patients. And so our experience has been quite impressive. The tolerability of the adverse-effect profile is very manageable. We have a lot of experience with PD-1 inhibitors in other diseases, particularly because head and neck squamous cell carcinoma of the mucosa has been approved for 2 years now, since the fall of 2016. So we were primed as an oncologic community when we had the PD-1 inhibitor cemiplimab now available for advanced cutaneous squamous cell carcinomas to integrate this, and it’s lived up to the hype and certainly been a great new addition to our toolkit.

Anna C. Pavlick, DO: My experience with cemiplimab is quite extensive because I participated in the registrational trial, or actually my patients participated in the registrational trial, and we saw very amazing things that happened. We have a very large dermatology department at New York University that provides me with an enormous amount of patients, and many of my patients who came to me with locally advanced or metastatic squamous cell cancer were very excited about participating in a trial that offered them the potential for a long-term durable control of their disease.

Transcript edited for clarity.
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Transcript:

Robert L. Ferris, MD, PhD:
The cemiplimab trial with the Regeneron antibody, which many of us remember as 2810 before it got its fancy new name, was used to look in different subgroups, initially as a safety trial, but then as safety parameters were met, there were expansion cohorts for locally advanced unresectable disease, or expansion populations for metastatic disease, up-front metastatic. And so this was a dose escalation and safety evaluation. Once the dose of 3 mg/kg every 2 weeks was reached, then expansion continued to a large enough extent to assess the response estimates, which was the primary clinical parameter, complete response, partial response, and then in combination the overall response rate.

So as a single-arm phase I expansion cohort with 2 different cohorts—locally advanced disease or metastatic—we have these 2 cohorts that led to the approval of cemiplimab. In both cohorts, the overall response rate approximated 50%. In the metastatic disease, although the numbers are small, there was a slightly elevated rate of complete responders, about 7% complete responders, but the numbers are quite small, just 25 to 35 patients. But in both groups impressive partial responses were seen, as was a longer duration of therapy, and so stabilization of disease and partial responses were the dominant clinical feature of patient benefit. But in the metastatic expansion cohort, there was a complete response rate of 6% or 7%, indicating that this could potentially be curative for a small subset of patients. But at minimum, durability and a partial response with stable disease in long-term benefit was seen.

As I mentioned earlier, aggressive skin cancer is dramatically increased in patients or individuals who have chronic immunosuppression, either through chronic lymphocytic leukemia or through organ transplantation and other immunosuppressive anti-inflammatories. So given that history, it was clear that the immune system plays an important role in controlling skin cancer premalignancy and progression on to invasive cancer. So it made sense in this population, which is rapidly increasing over the past few decades, to try to do something new.

The PD-1 inhibitors, [programmed cell] death protein 1], is a receptor. It’s an inhibitory receptor on the immune system, and it’s a way that the immune system dampens the immune responses, particularly to avoid autoimmune attack against our own tissues. And so the PD-1 inhibitors have been effective in a number of different cancers because the T lymphocytes, the primary cell type in the immune system that controls against cancer progression and recurrence, expressed a high level of the PD-1 receptor. And the tumor cells then express the ligate.

So you have the T cells in these cancer patients expressing PD-1. You have the tumor cell expressing the programmed death-ligand 1, PD-L1, and that inactivates or suppresses, turns off, those T cells. So the rationale for the PD-1 inhibitors, like cemiplimab, is to disrupt and block the PD-L1 and PD-1 interaction. That permits the T cells to be reactivated and then be much more competent, functional, and able to reject the cancer cells—in a way turning back the clock and reversing immune escape. So cemiplimab blocks PD-1 and prevents the negative inhibitory signal being transmitted to it by the tumor cell and allows those T cells then to recognize and lyse and kill the cancer cells.

Anna C. Pavlick, DO: We know that tumors that have a high mutational burden really respond nicely to immunotherapy. We learned this from all the studies that we did with metastatic melanoma, that melanoma has a very high mutational burden, and we know that patients who had more mutations had better responses to immunotherapy. Interestingly, cutaneous squamous cell carcinoma has an even higher mutational burden than melanoma, and so intuitively knowing what we know in melanoma, we can extrapolate that over to squamous cell cancer and say, these are patients whose tumors are chock-full of mutations, and so they should have an exceptionally good response rate to immunotherapy.

Robert L. Ferris, MD, PhD: The approval of cemiplimab for advanced cutaneous squamous cell carcinoma has provided a new tool that we’ve been able to use here in our multidisciplinary team. Prior to that, we had experience with relatively ineffective therapies in these advanced recurrent and metastatic patients. And so our experience has been quite impressive. The tolerability of the adverse-effect profile is very manageable. We have a lot of experience with PD-1 inhibitors in other diseases, particularly because head and neck squamous cell carcinoma of the mucosa has been approved for 2 years now, since the fall of 2016. So we were primed as an oncologic community when we had the PD-1 inhibitor cemiplimab now available for advanced cutaneous squamous cell carcinomas to integrate this, and it’s lived up to the hype and certainly been a great new addition to our toolkit.

Anna C. Pavlick, DO: My experience with cemiplimab is quite extensive because I participated in the registrational trial, or actually my patients participated in the registrational trial, and we saw very amazing things that happened. We have a very large dermatology department at New York University that provides me with an enormous amount of patients, and many of my patients who came to me with locally advanced or metastatic squamous cell cancer were very excited about participating in a trial that offered them the potential for a long-term durable control of their disease.

Transcript edited for clarity.
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