Optimizing CSCC Management Requires a Multifaceted Approach to Care

Sunandana Chandra, MD, MS

Typically presenting in geriatric populations, cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer, and despite its tendency not to metastasize, it can result in local disfigurement because it usually involves soft tissue, cartilage, and bone.¹

“CSCC can spread to regional lymph nodes, and in rare instances, it can in fact metastasize to distant organs,” Sunandana Chandra, MD, MS, explained during a recent OncLive Insights^® program. “The mainstay of therapy is local therapy that includes excision. However, when patients have unresectable or metastatic disease, that is when they are presented to medical oncology.”

Joining Chandra, who is an associate professor of medicine (hematology and oncology) at Northwestern Feinberg School of Medicine in Chicago, Illinois, were melanoma experts Anna C. Pavlick, DO, MSc, MBA, BSN, a professor of medicine in the Division of Hematology & Medical Oncology at Weill Cornell Medicine and founding director of the Cutaneous Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian, and Nikhil Khushalani, MD, vice chair of the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, Florida. The panel discussed the importance of multidisciplinary care in CSCC and patient counseling regarding available therapies.

Chandra: Dr Pavlick, given that you see these patients daily in your clinic, what would you say are the biggest unmet needs in each of these histologies respectively, both CSCC and melanoma?

Pavlick: One of the largest unmet needs [in CSCC] is in the immunocompromised patients, those who have organ transplants, those who have CLL [chronic lymphocytic leukemia] or low-grade lymphomas because they don’t respond as well. And we have a big problem when it comes to the solid organ transplant patients who are at risk of organ rejection with the use of some of our newer immunotherapies, namely the anti–PD-1 therapies. We really need to look at controlling the disease in patients who have these underlying issues [and] a locally advanced CSCC. How can we best treat those in a way that we’re not going to compromise the transplant? When it comes to melanoma, one of the greatest unmet needs is [managing] patients who get immunotherapy as a first-line therapy, do not have a BRAF mutation, but don’t respond or progress after PD-1 therapy. The PD-1–refractory patients are a big focus of our research.

Chandra: Why is a multidisciplinary approach needed in CSCC and how can we leverage the expertise of colleagues to provide the best recommendations for their patients?

Khushalani: [Multidisciplinary management is] critically important for the optimal care of our patients, particularly those with CSCC. Most have localized disease; almost 95% to 97% of them can be addressed right there in the dermatology office. This is a disease of UV light exposure over time. The epidemiologic insult, if I may call it that, has occurred over a span of decades. Therefore, these patients don’t necessarily present with 1 tumor, they often will have multifocal disease or recurrent cutaneous squamous cells or carotenoid carcinomas. Three to 5% of patients are truly considered high risk. [This is] based on the size of the tumor, the location of the tumor, certain histologic characteristics such as poorly differentiated tumors or perineural invasion that have a higher risk for lymph node metastases, as well as distant metastases.

Locally advanced tumors are the vast majority of CSCC that we see as medical oncologists, tumors that have already exhausted standard surgical or radiotherapy options. A minority are truly metastatic tumors such as, metastases to the lung lymph nodes, bone, and other visceral organs. Surgery was the mainstay of treatment, but in high-risk cases, we have to consider involvement of the radiation oncologist because many [cases] are prone to local or locoregional recurrence. Radiation can potentially reduce that risk of recurrence.

Our systemic options, specifically with anti–PD-1 immunotherapy, have changed treatment paradigms for advanced disease. These regimens are now being tested in the adjuvant setting for high-risk patients and, more importantly, in patients who present with nodal disease or clear, locally advanced disease that is borderline resectable. We are now even considering immunotherapy upfront. Therefore, crosstalk between the surgeon, the dermatologist, the radiation oncologist, the medical oncologist, is important, and even within surgery [because] the vast majority of these [patients] are seen by our head and neck surgeons who traditionally will take care of mucosal tumors of the head and neck but will often address cutaneous tumors as well.

There needs to be that crosstalk. Dr Pavlick has used the term disease of neglect, which is critically important, and that’s where our social work teams and nursing education becomes important because some of our patients, unfortunately, do have psychosocial issues that led them to neglecting their tumor. A true multidisciplinary approach is critically important here.

Chandra: Can you run through the rationale and the patient and disease characteristics that help you decide on a systemic therapy in cases of unresectable or metastatic CSCC?

Pavlick: [Here] we’re talking about patients who have been referred because they’ve either been radiated and they have a recurrence, or radiation is not an option, or surgery can be done but may be disfiguring…. Knowing why patients are in our office is the biggest thing. We have to look at their medical history.

One of the other things we need to consider is that some of our therapies will include capsules. If patients cannot swallow capsules, these medicines [may not be an option because they] are not things that we can open or crush or put through a feeding tube.

We also need to talk to them about anti–PD-1 agents. We have several therapies that are approved for locally advanced or metastatic squamous cell carcinoma. The 2 agents that we most commonly use in this disease are cemiplimab-rwlc [Libtayo] and pembrolizumab [Keytruda],^2,3 both anti–PD-1 agents that have the potential for rash pruritus. For some patients, if they have underlying gastrointestinal disorders such as Crohn’s disease or ulcerative colitis, they may be more prone to developing inflammatory diarrhea from these agents. You can also see pneumonitis, hepatitis, or autoimmune-induced hepatitis from the drugs.

One of the things that we don’t often tell patients is that they need to report visual changes because these drugs can also cause uveitis that needs to be assessed by an ophthalmologist. We are familiar now with how to manage these toxicities. And so, we need to be very honest with patients that although the risk of toxicity is low, they need to be very well-versed on reporting to us and telling us the effects…because the sooner we intervene, the easier it is to manage these toxicities and allow patients to continue therapy.

I stress to patients that there is a low but very real risk of endocrinopathies for the simple reason that most of the toxicities that are incurred with immunotherapy are very easily manageable and reversible with corticosteroid intervention. When it comes to endocrinopathies, however, if the patient develops hypothyroidism because of an autoimmune response to immunotherapy, in the majority of cases that hypothyroidism is permanent [and] patients would then be committed to taking thyroid replacement medicine for the rest of their life…. The same thing happens if they develop adrenal insufficiency and, likewise, insulin-requiring diabetes, [which as a] very low incidence. But if it does happen, you now have to manage that issue with medications for the rest of the patient’s life.

Chandra: Are you worried about patient age or ability to tolerate these immunotherapies?

Pavlick: Usually not. I think these are exceedingly well-tolerated medications. I have a 98-year-old patient getting immunotherapy right now for locally advanced CSCC because his performance status is good. He has, essentially, no concurrent medical issues. You can’t discriminate among patients based on a chronologic age because many times you can have younger patients, in their 50s and 60s, with so many chronic medical issues that they are at a much higher risk of toxicity.

Khushalani: I completely agree. This is not the era of chemotherapy, when we were always a little bit concerned about individuals who are about age 70 or 75 years, and so the definition of a geriatric population keeps increasing in our lifetime, which is a good thing.

Chandra: Can you comment on cemiplimab and pembrolizumab, the trials that led to their approval, and whether there are any data to support switching from one to the other if there’s no response?

Khushalani: They’re virtually identical, targeting the same pathway. If you look at an equivalent population from the 2 trials that led to their respective approvals, the EMPOWER-CSCC-1 study [NCT02760498] for cemiplimab and KEYNOTE-629 [NCT03284424] for pembrolizumab, the response rates on average in the frontline setting for immunotherapy-naïve patients were both approximately 50%.^2,3

Cemiplimab certainly has a longer duration of follow-up since it was the first to be approved and tested…and approximately 20% of patients treated with cemiplimab for locally advanced or distant metastatic disease go on to develop a complete response [CR]. In many cases, these responses, at least in our anecdotal experience, have been durable. The duration of response for patients who have experienced a partial or CR has not been reached. In the most recent [EMPOWER] update that was presented at the European Society for Medical Oncology [ESMO] Annual Congress 2022,⁴ we were able to identify the median progression-free survival [PFS] and overall survival [OS] in the 2 metastatic arms, which were arms 1 and 3 on that trial [Table 1⁴]. On average, the median PFS is approximately 18 months, and the median OS is reaching close to 5 years. These patients are doing very well. The problem is that almost half of patients either don’t respond or eventually develop a secondary resistance. I don’t think we have a clear winner in the second-line setting.

Table 1. Final Analysis of EMPOWER-CSCC-1⁴

To answer your specific question, should we switch from cemiplimab to pembrolizumab or vice versa if a patient progresses on 1 agent? The answer is a vehement no, we should not be doing that at all. Some have considered escalating to combination immunotherapy, just like we would do in melanoma. There is no proven prospective data to support that. On an off-label basis, if other treatments have been exhausted, one would certainly consider that. In our practice, our bias is to use an anti-EGFR agent, such as cetuximab, in the second-line setting for patients who have progressed on frontline anti–PD-1 therapy.

Data from [I-Tackle; NCT03666325], which is an important study and a very innovative trial, were presented at the 2022 American Society of Clinical Oncology Annual Meeting [Table 2].⁵ Patients were treated with frontline pembrolizumab, and those who at first restaging showed clear evidence of response continued that line of therapy. But for those who had stable disease or had progression as their best response at first restaging, cetuximab was added. What [investigators] found was that the combination did have a response rate in that refractory population of approximately 38%. That is certainly an option if it can be covered.

Table 2. I-Tackle Outcomes With Immunotherapy Plus Cetuximab⁵

I will stress that the combination of anti–PD-1 plus anti-EGFR is not FDA-approved, but there are safety data [for this] in mucosal head and neck cancers as well. But in terms of whether that combination is necessarily better than single-agent anti-EGFR, I think that remains to be seen.

Then the third class of agents that one would consider for refractory disease is time-tested chemotherapy. So, we would use chemotherapy-based regimens, but as we all know, the responses are modest and durations of response, on average, are between 2 and 4 months. I use that in the more refractory patient who maintains good functional status. And certainly, a clinical trial at any of these junctures is appropriate.

Chandra: Dr Pavlick, what is your thought on duration of therapy? Is there ever a time when you think of stopping therapy monitoring?

Pavlick: There really are no guidelines for when to stop and how to stop. I think what was discussed at the 2022 [ESMO Congress] was looking at neoadjuvant therapy, giving 2 to 3 cycles, then taking these patients to the operating room.⁶ And quite remarkably, although many times there was not a big change radiographically, when these lesions were resected, they were all dead. And so, patients who have a pathologic CR are the ones that we know will go on to have these long-term, durable responses. But what do we do when it comes to patients who have locally advanced or metastatic disease?

We know that you don’t want to keep patients on immunotherapy forever. Most of the time, the most that we will treat patients is approximately 2 years. But what happens if you get someone with a very rapid response, complete resolution of their disease? Those are the patients who perplex us the most, or patients who have a very brisk response and then are left with these very small, nonspecific lesions that look like there’s still something there, but you don’t know whether that’s still active cancer. There are some data to suggest that if you can do a PET scan on these patients with locally advanced and metastatic disease and they have no FDG uptake on their imaging, then you can be confident in stopping therapy.

The other thing with the locally advanced tumors is that many times you can also do what’s called “scouting biopsies” in that area to determine if in fact there is any residual carcinoma that you’re just not able to see.

Everything is very individualized for the patient and the extent of their disease. But there are no firm rules. You’ve got to tailor your stopping to patient responses as well as tolerability.

Chandra: What are you excited about in CSCC? Where do you think management of these patients is going?

Khushalani: I think it’s almost melanoma déjà vu. With the efficacy that we’ve seen in the advanced setting, we’re now trying to move all of that to the earlier stage. What’s a little more difficult with CSCC is trying to identify who are those bad players, which tumors are the bad ones that deserve adjuvant therapy, that are considered high-risk. Because you really don’t want to run the risk of overtreating your locoregional patients. Surgery and/or radiotherapy may be more than adequate for these patients.

As Dr Gross demonstrated at ESMO [in 2022] and then followed-up in the New England Journal of Medicine,^6,7 that 4 cycles of cemiplimab in the preoperative setting for patients with high-risk stage II or III disease, and those with resectable stage II, III, or IV disease had a pathologic complete response rate of 50%. At the time of surgery, that meant no viable tumor was identified. And, of course, we’ll still follow this trial for a longer period to determine durability of response. But if it’s similar to what we’ve seen in melanoma, that is very encouraging because it allows you to potentially de-escalate therapy, or the duration of treatment may simply then be limited to the preoperative setting, followed by surgery plus/minus radiotherapy.

These are almost entirely new paradigms that are being devised and investigated so that we can provide a comprehensive treatment map for our patients.

The other 2 trials^8,9 that are hopefully going to be completed soon are the 2 adjuvant studies. One is the C-POST study [NCT03969004] of adjuvant cemiplimab for high-risk CSCC that has been resected and has received postoperative radiation. We have the adjuvant pembrolizumab trial [KEYNOTE-630; NCT03833167] as well. That will clearly help us understand whether adjuvant anti–PD-1 immunotherapy works in this disease.

The other area that I would be particularly interested in and, quite frankly, excited about would be novel therapeutics for the difficult-totreat population, which as Dr Pavlick mentioned earlier, is the transplant population because the same treatment paradigms don’t apply to them. We certainly need some more novel therapeutics there. Finally, we need prevention strategies because these are diseases that, with adequate protection, we can actually dent. We must pay a lot of more attention to prevention strategies as well.

Pavlick: The biggest way to make the biggest impact is with prevention and education.

References

1. Farberg AS, Fitzgerald AL, Ibrahim SF, et al. Current methods and caveats to risk factor assessment in cutaneous squamous cell carcinoma (cSCC): a narrative review. Dermatol Ther (Heidelb). 2022;12(2):267-284. doi:10.1007/s13555-021-00673-y
2. FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. FDA. Updated January 18, 2019. Accessed April 15, 2023. bit.ly/41peHjQ
3. FDA approves pembrolizumab for cutaneous squamous cell carcinoma. FDA. June 24, 2020. Accessed April 15, 2023. bit.ly/3MS3fbW
4. Migden MR, Schmults C, Khushanlani N, et al. Phase II study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC): final analysis from EMPOWER-CSCC-1 groups 1, 2 and 3. Ann Oncol. 2022;33(suppl 7):S918-S919. doi:10.1016/j.annonc.2022.07.940
5. Bossi P, Alberti A, Bergamini C, et al. Immunotherapy followed by cetuximab in locally advanced/metastatic (LA/M) cutaneous squamous cell carcinomas (cSCC): the I-TACKLE trial. J Clin Oncol. 2022;40(suppl 16):9520. doi:10.1200/JCO.2022.40.16_suppl.9520
6. Gross N, Miller DM, Khushanlani N, et al. Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): primary analysis of a phase II study. Ann Oncol. 2022;33(suppl 7):S904-905. doi:10.1016/j.annonc.2022.07.915
7. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568. doi:10.1056/NEJMoa2209813
8. Rischin D, Brungs D, Day F, et al. C-POST protocol update: a phase 3, randomized, double-blind study of adjuvant cemiplimab versus placebo post-surgery and radiation therapy (RT) in patients (pts) with high-risk cutaneous squamous cell carcinoma (CSCC). J Clin Oncol. 2022;40(suppl 16):TPS9592. doi:10.1200/JCO.2022.40.16_suppl.TPS9592
9. Pembrolizumab (MK-3475) versus placebo following surgery and radiation in participants with locally advanced cutaneous squamous cell carcinoma (MK-3475-630/KEYNOTE-630). ClinicalTrials.gov. Updated April 13, 2023. Accessed April 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03833167