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CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
REPORTING FROM THE ACMS ANNUAL MEETING
Key clinical point:
Major finding: Disease control was achieved in 11 of 16 patients (69%).
Study details: The open-label, phase 1 study included seven patients with distant metastatic cutaneous squamous cell carcinoma and nine with locally and/or regionally advanced disease.
Disclosures: The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. Dr. Migden reported receiving honoraria from Regeneron and Sanofi as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.