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Exploring the Impact of Cemiplimab and Pembrolizumab in Cutaneous Squamous Cell Carcinoma With Shaheer Khan, DO

Recently, Oncology Data Advisor spoke with Dr. Shaheer Khan, an Assistant Professor of Medicine at Columbia University Irving Medical Center, in honor of Skin Cancer Awareness Month. Dr. Khan shares the promising results of two recent trials of cemiplimab and pembrolizumab for cutaneous squamous cell carcinoma, explains future directions in the treatment of patients who are ineligible for immunotherapy, and offers advice for members of the multidisciplinary cancer care team who are treating patients with this disease.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, in honor of Skin Cancer Awareness Month, I'm here with Dr. Shaheer Khan, who is an Assistant Professor of Medicine at Columbia University Irving Medical Center. Dr. Khan, thank you so much for joining us today.

Shaheer Khan, DO: My name is Shaheer Khan. I'm a medical oncologist here at Columbia University, where I work within the Cutaneous Oncology and Early Phase Clinical Trial Group. We have a particular focus in trying to build our nonmelanoma skin cancer program, particularly in patients who have cutaneous squamous cell carcinoma.

Oncology Data Advisor: By way of background, what are some of the most challenging aspects of treating patients with cutaneous squamous cell carcinoma?

Dr. Khan: That's a great question, and it gets to a lot of what the overall challenges are in this disease. There are a few challenges—and there might be other challenges that others think of, as well—but I think the first is the lack of accurate epidemiologic data regarding how big of a burden this disease is. We know that cutaneous squamous cell carcinoma is extremely common. We know that in almost all cases, it can be successfully treated with local therapies. But by virtue of that, we don't have great data in terms of registries and databases as to exactly how many people are developing advanced disease, regionally advanced disease, and metastatic disease.

That can make it a little bit difficult to determine, "Okay, how bad is the burden overall in our patients?" Most of the data that we have regarding how many patients develop advanced disease or who go on to, unfortunately, pass away from their disease is based off of claims databases and estimates. We have a wide range. So that's one challenge, and I think that leads to the second point, which is that sometimes it can be difficult to determine which tumor is going to be a bad actor, especially when dermatologists or surgeons are resecting so many of these tumors. Sometimes in patients, there may be multiple tumors at the same time or multiple over the course of a year. Sometimes it can be difficult to determine, "Okay, which one of these is going to be the one that is at highest risk of developing regional or distant metastatic disease?"

We do have staging criteria which seek to standardize that, and they use very logical criteria, including size and depth of invasion and the patterns of the invasion. But we know that's inexact, and there are patients who may be lower on that risk stratification who still go on to develop aggressive disease. Then there are patients who have multiple high-risk factors but then are able to be cured with their primary resection. I think that's a secondary challenge that's been associated with the overall management, particularly in patients who develop multiple lesions or very frequent lesions: the mental and emotional burden of having to go and get repeated resections and Mohs surgeries and have continuous follow-up every few months with their dermatologists. It can be exhausting, so I think that's one burden, as well.

Then finally when it comes to treatment, because the relative rate of regional or distant metastatic disease is so uncommon, it's been difficult to conduct large randomized studies to determine what the optimal treatments are. A lot of the data, historically, that we have regarding treatment options are based on small single-arm retrospective studies or extrapolation from studies done in head and neck squamous cell carcinoma; we think there are some similarities, but they're also unique diseases. I think those are some of the biggest challenges that we have in managing patients with this illness.

Oncology Data Advisor: Can you give us an overview of cemiplimab and pembrolizumab for cutaneous squamous cell carcinoma and how they compare with other treatments for this disease?

Dr. Khan: Sure. Thankfully, with the advent of immune checkpoint agents, the treatment landscape for many cancers, including cutaneous squamous cell carcinoma, has been transformed. Cemiplimab and pembrolizumab are both monoclonal antibodies that are directed at programmed cell death protein 1 (PD-1) and interrupt the binding to programmed death ligand 1 (PD-L1), which normally results in inhibition of T-cell function. Many in the audience will be familiar with these agents and will have used them for many different indications.

Cemiplimab was the first agent to be approved, and it was based off of the results of the phase II EMPOWER study, which was performed to assess the response rate of cemiplimab in patients who had either locally advanced or metastatic cutaneous squamous cell carcinoma. There were a couple of different arms within this trial that were looking at either locally advanced or metastatic patients and also looking at two different dosing strategies, either weight-based or flat dose. Overall, when looking at the results of this study, we saw a response rate of 46% across all of the arms, with complete response rates ranging from 13% to 20% depending on the arm.

Not only that, but the proportion of patients who had durable control or durable response was very high. The most recent data has estimated that the proportion of patients who had ongoing response at one year was 88%. Although they haven't reached the median survival time point, the follow-up is still ongoing at 24 months. The estimated overall survival rate was 73%. Based off of that landmark data, cemiplimab was approved for patients who had locally advanced, unresectable, or metastatic disease.

Pembrolizumab followed shortly thereafter, and that was based off of the KEYNOTE-629 study, which included a cohort of patients with locally advanced disease and another cohort, which was the larger cohort, of patients with recurrent or metastatic disease. In the locally advanced cohort, the response rate was 50%, and approximately 17% had a complete response—very similar to the cemiplimab data. The recurrent metastatic group's response rate was a little bit lower, 35% in that cohort, with 10% having a complete response. Putting them together, the overall response rate was 40%, and about 80% continued to have a response at 12 months.

It's a little bit hard to compare across these trials and across these drugs. Collectively, we think that these agents are very similar, and there may be some particularly unique aspects to each of these trials which can impact the response rates and the data. One thing to note is that in the pembrolizumab study, there were a higher proportion of patients who had received prior lines of therapy, so that might impact things. But I think the overall story between both of these agents is that immune checkpoint agents appear to have excellent response rates in this disease. In patients who do respond, they can have longstanding responses, sometimes even complete response, even in the metastatic setting. Obviously, this is transformational data that's really been amazing for patients who are eligible.

Having said that, there are patients who were excluded from these studies, and the treatment for those patients continues to be an issue, including patients with solid organ transplants who are not eligible because of the risk of transplant rejection associated with these treatments. We still need to find alternative treatments for those patients and for patients who don't respond or cease to have a response to these agents. When we compare these treatments to the historical treatment options that we have, namely chemotherapies—like platinum agents, taxanes, or antimetabolites—or epidermal growth factor receptor (EGFR) antibodies like cetuximab, it's honestly hard to compare because much of the data for those agents is off such limited trial data, or it's just retrospective or extrapolated, as I mentioned.

Our best guess is that there is some portion of patients who will respond to those therapies. The estimates are probably in the 10% to 30% range, but it's unclear what impact on survival we're having with those agents. In meta-analyses that have been done, regardless of which of those agents are used, the overall survival is not great. Compared to those historical options, this is clearly the first-line treatment and a tremendous improvement upon what we have.

Oncology Data Advisor: Thank you for explaining all that. Are there any adverse events of note that are seen with cemiplimab and pembrolizumab, and how should they be managed?

Dr. Khan: I think most of the audience will be familiar with immunotherapies and the toxicity profile that can arise in associated with these agents. We know that although they don't have the same toxicities as chemotherapeutic agents, as potentially targeted agents, that doesn't mean that there aren't real toxicities associated with these therapies. In the trials that were done, most patients did really well. The treatments for both cemiplimab and pembrolizumab were both quite tolerable. The rate of treatment-related grade 3 toxicities was low, in the range of 10% in both of the studies. Similarly, the percentage of patients who had to discontinue treatment because of toxicity was also low, less than 10%. Most of the toxicities that developed were low grade, grade 1 or 2, and the overall profile was similar to that which is seen in many of the other trials that have been done in various cancers with immunotherapy agents or single-agent immunotherapy trials.

Again, that isn't to say that immune-related adverse events, which develop as a result of this, can't be serious and can't be associated with significant symptom burden and potentially permanent changes for the patient's care. But generally, these are well-tolerated agents. If they do develop immune-related adverse events, they can be alleviated with appropriate strategies, potentially including systemic steroids, and tapering over a period of time. The exception is, again, patients who have solid organ transplants—who were not studied in the trials and theoretically are not eligible to receive these therapies—in which the risk is that we could cause acute allograft rejection. It still is sometimes used because of the clear benefit that patients have demonstrated in trials and in practice, but there's that significant risk that you have to balance in regard to the potential benefit versus the risk.

Oncology Data Advisor: To wrap up, do you have any words of advice for members of the cancer care team who are treating patients with cutaneous squamous cell carcinoma?

Dr. Khan: Overall, we've learned that it's really critical to establish a strong, cohesive multidisciplinary team to manage these patients. That includes dermatology, surgery, soft tissue surgeons, general surgeons, head and neck surgeons—often these will develop in the head and neck region—radiation oncology, medical oncology, and then often social work and other members of the care team, as well. Patients with cutaneous squamous cell carcinoma frequently have significant comorbidities, whether it's lack of access to care, other social barriers, or complicated medical histories. Having a forum to discuss these cases during the diagnostic process, while decisions are being made regarding surgery, radiation therapy, or systemic therapy, can make a tremendous difference.

Thankfully, with the development and the approval of cemiplimab and pembrolizumab and these immunotherapies that have real benefit and potentially long-lasting benefit, there are patients who are doing really, really well, but there's still a lot of room for improvement. Thankfully, as a result, there's a lot of interest in improving the response rates to immunotherapy upfront and in developing alternative treatments for patients who aren't candidates for immunotherapy, as well as potentially combining different treatment strategies like immunotherapy and potentially EGFR-targeted therapy to see if we can improve the responses for patients who are in that cohort that no longer respond or don't respond to immunotherapy to begin with.

I think it's great that we have these options. It's great that most patients do well with them, but there's a lot of room to grow, and working together in a multidisciplinary team is the best way to manage these patients.

Oncology Data Advisor: Thank you so much for sharing all this advice with us.

Dr. Khan: Thank you so much.

About Dr. Khan

Shaheer Khan, DO, is an Assistant Professor of Medicine at Columbia University Irving Medical Center, where he serves as part of the Cutaneous Oncology and Early Phase Clinical Trial Group. He specializes in the treatment of patients with melanoma and cutaneous squamous cell carcinoma.

For More Information

Rischin D, Khushalani NI, Schmults CD, et al (2021). Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis. J Immunother Cancer, 9(8):e002757. DOI:10.1136/jitc-2021-002757

Hughes BGM, Munoz-Couselo E, Mortier L, et al (2021). Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. Ann Oncol, 32(10):1276-1285. DOI:10.1016/j.annonc.2021.07.008

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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