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The Impact of Systemic Therapy and KEYNOTE-048 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: Tuesday, Feb 26, 2019



Transcript:

Todd E. Schlesinger, MD, FAAD, FASMS:
Now that we have an approved medication for a cutaneous squamous cell carcinoma, we do bring in other specialties more readily than we might have before. Of course, for anyone who, you know, for being a dermatologist and Mohs surgeon, you know, especially being community-based, I’m going to be looking to lean on my colleagues in the other specialties: oncology, radiation oncology, and other surgical specialties as well. But now there’s an approved option. If you know one is not able to infuse their medication themselves and completely follow that patient and do everything that needs to be done, medical oncology is a great resource for us. Those who are infusing medications in their offices or are using infusion centers, it allows us another option for these patients to explain to them that there’s something else they could do besides having surgery, or besides having radiation.

So in medicine, as we see the advancements and these new drugs that were able to be approved more quickly than ever before, it’s nice they’ll offer something to our patients. At least they have choices, and so they’re able to make an informed decision about how they want to approach their tumor.

Robert L. Ferris, MD, PhD: A multidisciplinary treatment team should include at most oncologic surgeon; a head and neck surgeon to manage lymph nodes, which is an important area of metastasis and failure; the medical oncologist; and the radiation oncologist. So I think in the community setting earlier involvement of those individuals is key. Once advanced, an aggressive cutaneous squamous cell carcinoma is recognized, and that patient tends to now emerge and move away from the dermatologic oncologic surgeon and more toward the head and neck surgeon and more toward the medical or radiation oncologist.

So although the most successful surgeon is often the one who brings the case to the treatment team because they were referred a patient by 1 of their general dermatology colleagues, and the hope was tissue preservation for Mohs surgery. But then they begin to see high-risk features, because most surgeons are also pathology trained, and they analyze their own pathology. And if they’re concerned about their margins, or they see perineural invasion, 1 of the risk features is greater than 0.1-mm nerve involvement, and as the dermatologic surgeon, the most surgeons see under the microscope, then they’re the ones who should be triggering referral to a head and neck surgeon or a plastic surgeon, the medical and the radiation oncologist really as early as possible, because cemiplimab may begin to play a role earlier in therapy, particularly in combinations where that might make both work better than either 1 alone.

The KEYNOTE-048 clinical trial was a phase III trial moving anti–PD-1 [anti-programmed cell death protein 1], in this case pembrolizumab, earlier into therapy in disease stage. So FDA approval in 2016 for nivolumab and pembrolizumab was for so-called second line, or platinum refractory head and neck cancer patients. So it made sense to move it into first line, and this population has a single standard of care called the EXTREME regimen that’s platinum, 5-FU [5-fluorouracil], and cetuximab.

Now that’s a pretty aggressive regimen, and it’s somewhat difficult to tolerate. And so the KEYNOTE-048 trial was a 3-arm trial of over 800 patients. The 3 different arms were of course extreme as the control arm, compared with monotherapy with anti–PD-1 pembrolizumab, or compared with a combination of pembrolizumab with platinum and 5-FU. So replacing the cetuximab with pembrolizumab.

The results of this have only been announced by press release. The actual data are being presented orally in Munich, Germany, at the ESMO 2018 [European Society for Medical Oncology 2018 Congress], almost as we speak. The press release indicated that monotherapy with pembrolizumab beat the 3-drug extreme regimen of platinum 5-FU cetuximab. All the press release indicated was that monotherapy with pembrolizumab was better in the population who had higher than 20% PD-L1 [programmed death-ligand 1] ligand expression. This is with the composite score, the CPS [combined positive score]. That looks at and scores PD-L1 expression on either the tumor cell or the inflammatory cell. So that composite score of greater than 20% positivity was the population that the press release indicated monotherapy with pembrolizumab had better overall survival, significantly better, and met its primary endpoint versus 3 drugs of chemotherapy.

What we’re waiting to hear is what was the up-front response rate of the extreme 3-drug chemotherapy versus pembrolizumab monotherapy was. We’d like to see data on the lower than 20% intent-to-treat population, the whole group. And then, missing from the press release was what pembro plus chemotherapy, that third arm, and whether that was as good or better than the 3-drug chemotherapy, either in response or overall survival.

Transcript edited for clarity.
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Transcript:

Todd E. Schlesinger, MD, FAAD, FASMS:
Now that we have an approved medication for a cutaneous squamous cell carcinoma, we do bring in other specialties more readily than we might have before. Of course, for anyone who, you know, for being a dermatologist and Mohs surgeon, you know, especially being community-based, I’m going to be looking to lean on my colleagues in the other specialties: oncology, radiation oncology, and other surgical specialties as well. But now there’s an approved option. If you know one is not able to infuse their medication themselves and completely follow that patient and do everything that needs to be done, medical oncology is a great resource for us. Those who are infusing medications in their offices or are using infusion centers, it allows us another option for these patients to explain to them that there’s something else they could do besides having surgery, or besides having radiation.

So in medicine, as we see the advancements and these new drugs that were able to be approved more quickly than ever before, it’s nice they’ll offer something to our patients. At least they have choices, and so they’re able to make an informed decision about how they want to approach their tumor.

Robert L. Ferris, MD, PhD: A multidisciplinary treatment team should include at most oncologic surgeon; a head and neck surgeon to manage lymph nodes, which is an important area of metastasis and failure; the medical oncologist; and the radiation oncologist. So I think in the community setting earlier involvement of those individuals is key. Once advanced, an aggressive cutaneous squamous cell carcinoma is recognized, and that patient tends to now emerge and move away from the dermatologic oncologic surgeon and more toward the head and neck surgeon and more toward the medical or radiation oncologist.

So although the most successful surgeon is often the one who brings the case to the treatment team because they were referred a patient by 1 of their general dermatology colleagues, and the hope was tissue preservation for Mohs surgery. But then they begin to see high-risk features, because most surgeons are also pathology trained, and they analyze their own pathology. And if they’re concerned about their margins, or they see perineural invasion, 1 of the risk features is greater than 0.1-mm nerve involvement, and as the dermatologic surgeon, the most surgeons see under the microscope, then they’re the ones who should be triggering referral to a head and neck surgeon or a plastic surgeon, the medical and the radiation oncologist really as early as possible, because cemiplimab may begin to play a role earlier in therapy, particularly in combinations where that might make both work better than either 1 alone.

The KEYNOTE-048 clinical trial was a phase III trial moving anti–PD-1 [anti-programmed cell death protein 1], in this case pembrolizumab, earlier into therapy in disease stage. So FDA approval in 2016 for nivolumab and pembrolizumab was for so-called second line, or platinum refractory head and neck cancer patients. So it made sense to move it into first line, and this population has a single standard of care called the EXTREME regimen that’s platinum, 5-FU [5-fluorouracil], and cetuximab.

Now that’s a pretty aggressive regimen, and it’s somewhat difficult to tolerate. And so the KEYNOTE-048 trial was a 3-arm trial of over 800 patients. The 3 different arms were of course extreme as the control arm, compared with monotherapy with anti–PD-1 pembrolizumab, or compared with a combination of pembrolizumab with platinum and 5-FU. So replacing the cetuximab with pembrolizumab.

The results of this have only been announced by press release. The actual data are being presented orally in Munich, Germany, at the ESMO 2018 [European Society for Medical Oncology 2018 Congress], almost as we speak. The press release indicated that monotherapy with pembrolizumab beat the 3-drug extreme regimen of platinum 5-FU cetuximab. All the press release indicated was that monotherapy with pembrolizumab was better in the population who had higher than 20% PD-L1 [programmed death-ligand 1] ligand expression. This is with the composite score, the CPS [combined positive score]. That looks at and scores PD-L1 expression on either the tumor cell or the inflammatory cell. So that composite score of greater than 20% positivity was the population that the press release indicated monotherapy with pembrolizumab had better overall survival, significantly better, and met its primary endpoint versus 3 drugs of chemotherapy.

What we’re waiting to hear is what was the up-front response rate of the extreme 3-drug chemotherapy versus pembrolizumab monotherapy was. We’d like to see data on the lower than 20% intent-to-treat population, the whole group. And then, missing from the press release was what pembro plus chemotherapy, that third arm, and whether that was as good or better than the 3-drug chemotherapy, either in response or overall survival.

Transcript edited for clarity.
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