Managing Advanced Squamous Cell Carcinoma: A Guide for the Dermatology Clinician

J Clin Aesthet Dermatol. 2025;18(8):20–26.

by Joshua Burshtein, MD, and Todd Schlesinger, MD

Dr. Burshtein is with the Department of Dermatology at the University of Illinois-Chicago in Chicago, Illinois. Dr. Schlesinger is with the Clinical Research Center of the Carolinas in Charleston, South Carolina.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Burshtein declares no conflicts of interest relevant to the content of this article. Dr. Schlesinger serves as a consultant, investigator, speaker and/or advisor for Abbvie, Almirall, Allergan, ASLAN, Arcutis, Biofrontera, Beiersdorf, Benev, Bristol-Myers Squibb, Castle Biosciences, Galderma, Eli Lilly, ExoCoBio, Incyte, Janssen, LEO, L’Oreal, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, UCB and Verrica and receives a salary from Avant Health.

Abstract: Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. Advanced cSCCs encompass locally advanced cSCC (laCSCC), including primary or recurrent tumors that are not amenable to curative surgery or radiation therapy, and metastatic (locoregional or distant) cSCCs (mCSCC). With the development of immunotherapies (eg, PD-1 inhibitors), there may be an enhanced opportunity to effectively treat advanced cSCC. We aim to review the current literature on therapeutic options and outline treatment strategies to optimize care for patients with advanced cSCC. Methods: A comprehensive literature search was completed using the keywords “advanced cutaneous squamous cell carcinoma,” “treatment,” “surgery,” “radiotherapy,” “immunotherapy,” “PD1-inhibitor,” “cemiplimab,” and “pembrolizumab”. The authors reviewed all studies and included those which addressed the topic of the review. Results: Advanced cSCCs may not be amenable to surgery or radiotherapy due to size, location, and other aggressive features. Identifying advanced cSCCs and managing patients with multiple tumors and/or those with high tumor burden can be challenging and utilizing current evidence-based guidelines and staging systems can help selection of appropriate therapeutic options. Systemic immunotherapies such as cemiplimab and pembrolizumab have growing evidence for use as a first-line treatment for advanced cSCCs. It is important to understand the adverse event profile of these immunotherapies as utility may be limited by adverse events. Limitations: This is a review article and is limited by the information available in the published literature. In addition, comparison between studies is limited as varying methodologies were used. Conclusion: Advanced cSCCs can be difficult to manage and involving a multidisciplinary team is essential. For laCSCCs and mCSCCs not amenable to surgery or radiotherapy, cemiplimab and pembrolizumab can be effective therapeutic options. Keywords: Advanced squamous cell carcinoma, locally advanced cSCC, metastatic cSCC, Mohs surgery, radiotherapy, immunotherapy, cemiplimab, pembrolizumab

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer.^1,2 In the United States, the incidence of cSCC has risen by 50 percent to 200 percent over the past three decades.^3,4 Though the majority of cSCCs can be cured with office-based treatments, advanced forms of cSCC carry substantial risks for morbidity, negative impact on quality of life, and mortality.² Advanced cSCCs encompass locally advanced cSCC (laCSCC), including primary or recurrent tumors that are not amenable to curative surgery or radiation therapy, and metastatic (locoregional or distant) cSCCs (mCSCC).^1,2,5 For those who experience metastasis of cSCC, 10-year survival rates are less than 20 percent for patients with regional metastasis to lymph nodes and less than 10 percent for distant metastasis.⁶ Identifying patients with advanced cSCCs may be difficult as the of aggressive signs may not always be clear.⁷ There are a variety of treatments available for these advanced tumors, including Mohs micrographic surgery (MMS), radiotherapy (RT), and newer therapies such as immunotherapy (ie, PD-1 inhibitors, also known as checkpoint inhibitors).^5,7–10 With the development of immunotherapies, there may be an enhanced opportunity to effectively target advanced cSCC.

Given the complexities involved in managing advanced cSCCs, it is crucial to offer clear guidance on implementing the available treatment options. This review aims to analyze the current literature on therapeutic approaches and propose strategies to optimize care for patients with advanced cSCC.

Advanced cSCC

Understanding how to identify and classify advanced cSCCs is necessary in order for clinicians to implement adequate treatment. Due to their aggressive features, advanced cSCC can result in significant morbidity and greater mortality rate compared to other forms of SCC.^1,11 Advanced cSCC is classified as either laCSCC or mCSCC.⁵ Specifically, laCSCCs are cSCCs that are not amenable to surgery or RT due to either considerable size, location, recurrence, bone erosion/invasion, or infiltration beyond subcutaneous tissue into muscle and/or nerves such that excision would incur considerable complications, morbidity, or deformity.⁵ A cSCC may also be classified as laCSCC in the event that the patient is unwilling to pursue surgery due to high tumor burden rendering surgery a less favorable option. The incidence of laCSCC is not well defined in the literature.¹

Identifying Aggressive cSCC

Aggressive and high-risk cSCCs can be identified using clinical and histopathological characteristics. High risk tumor locations include non-sun exposed areas, scars, burns, previously radiated regions, or within or adjacent to chronic inflammatory conditions, and these can be prognostic risk factors for aggressive cSCC.^12–14 Size greater than 2cm is also a high-risk clinical risk factor.^12–14 Histologically, high-risk features include greater than 6mm invasion beyond subcutaneous fat, moderately or poorly differentiated, and subtypes desmoplastic, acantholytic, and spindle.^12–14 As shave biopsies are commonly performed for lesions suspected to be cSCC, superficial biopsy specimens may fail to show presence of deeper, more aggressive growth patterns and therefore adequate depth is recommended.¹⁵ When feasible, a quality tissue biopsy should include the base of the tumor.¹⁶ An expert steering committee recommends the use of synoptic pathology reports to specify the specific histological features for advanced cSCC to aid in clinical staging and decision-making for additional therapy after surgery.¹⁶ Further, patients who have history of immunosuppression following organ transplant or chronic immunosuppressive disease are at higher risk of aggressive cSCCs.^12–14

cSCC is stratified into three anatomic regions:

• Area H (highest risk): Central face, eyelids, eyebrows, periorbital area, nose, lips, chin, mandible, preauricular and postauricular regions, temple, and ear (collectively known as the “mask area” of the face), genitalia, hands, and feet^17,18
• Area L: Trunk and extremities (excluding pretibia, hands, feet, nail units, and ankles)^17,18
• Area M: Cheeks, forehead, scalp, neck, and pretibial^17,18

Currently, there is no universally accepted staging system for cSCC.² The National Comprehensive Cancer Network (NCCN) has been recommended for use in differentiating between high- and low-risk localized cSCC, whereas the American Joint Committee on cancer (AJCC 8th edition) and the Brigham and Women’s Hospital (BWH) tumor classification system can be used more for prognostication.^2,19

Per the NCCN guidelines, high risk cSCC location and size includes any cSCC in area H, cSCC greater than or equal to 10mm in area M, and cSCC greater than or equal to 20mm in area L.¹⁹ These guidelines further include clinical risk factors for aggressive cSCC as those with poorly-defined borders, recurrent tumors, patients having immunosuppression, cSCC in a site of prior radiation or chronic inflammatory process, rapidly growing, and presence of neurologic symptoms.¹⁹ Histologic risk factors for aggressive cSCC include poorly differentiated, subtypes adenoid, adenosquamous, desmoplastic, or metaplastic, depth of greater than or equal to 2mm or Clark Level IV or V, and presence of perineural, lymphatic, or vascular involvement.¹⁹

The AJCC8 classification divides cSCC as T0 (no primary tumor), Tis (in situ), T1 (diameter ≤2cm), T2 (diameter >2cm and ≤4cm), T3 (diameter >4cm, minor bone invasion, perineural invasion, or deep invasion), and T4 (T4a [extensive cortical or medullary bone involvement] and T4b [invasion of the base of the cranium or invasion through the foramen of the base of the cranium]).¹³ Further, the BWH system places cSCC in a category based on number of risk factors: T0 (in situ), T1 (0 risk factors), T2a (1 risk factors), T2b (2–3 risk factors), or T3 (4 risk factors or bone invasion).²⁰ For this classification system, risk factors include tumor diameter greater than or equal to 2cm, poorly differentiated histology, perineural invasion, and tumor invasion beyond the subcutaneous fat.²⁰ Though the AJCC8 system was developed for head and neck cSCC, the BWH system permits classifications of cSCC across the entire body.

Although the literature on treatment options for advanced cSCC is expanding, clinicians still face challenges in determining the optimal therapy for patients and deciding when to advance to the next treatment step.

Treatment Options

Mohs micrographic surgery. MMS is recommended by the NCCN as a primary treatment option for cSCC.¹⁹ Low-risk cSCC can undergo standard surgical excision with 4- to 6-mm clinical margins, and if margins are positive, continue to MMS.¹⁹ These tumors are recommended to be excised to the depth of subcutaneous adipose tissue.² For high-risk, recurrent cSCC and those on particular anatomic areas such as the head and neck, MMS is the standard of care.^7,8,19 The MMS Appropriate Use Criteria describes the specific criteria of cSCCs that qualify for MMS.^17,18

One systematic review found that five-year local recurrence rate for primary cSCC treated with MMS was 3.1 percent (vs. 10.0 percent for standard excision).²¹ This study also reported that recurrence rate for recurrent cSCC treated with MMS was 10.9 percent (vs. 23.3 percent for standard excision).²¹ Further, a retrospective review of high-risk primary cSCC treated with MMS reported a disease-specific survival of 95.7 percent, the five-year local recurrence-free survival was 96.9 percent.²² For those with metastatic disease, the five- and 10-year progression-free survival rates were 92.6 percent and 90.0 percent, respectively, demonstrating that MMS may result in a survival benefit for these patients.²²

Despite the utility of surgery for cSCC, some tumors may not be candidates for surgical intervention due to location, size, and other aggressive features such that complete resection is not feasible or would result in substantial functional or cosmetic damage to the patient.⁷ For these cases, other therapeutic options need to be considered.

Radiotherapy. Radiotherapy is recommended by the American Society for Radiation Oncology (ASTRO) as primary treatment for patients with cSCC who are not surgical candidates.²³ Per the NCCN guidelines, RT is recommended as a primary and adjuvant treatment for high-risk cSCC.¹⁹ Though there is a paucity of prospective randomized studies for RT in the treatment of cSCC, literature has described that it can be an efficacious therapy while also preserving function and cosmesis.^23–25 RT can be used for both low and high-risk cSCC in the definitive, adjuvant, and palliative settings.^24,26,27

In a systematic review of RT for cSCC, pooled local control (LC) and local recurrence (LR) rates for all tumors was 87.3 percent and 8.6 percent, respectively.²⁸ Specifically, using RT as monotherapy had LC of 87.2 percent and LR of 8.6 percent, while adjuvant RT had LC of 88.5 percent and LR of 16.7 percent.²⁸ Rate of LR rose for each increasing tumor stage and tumors with stage T3 and T4 had LR rates above 25.9 percent.²⁸ Further, the rate of nodal metastases for all tumors was reported to be 4.8 percent and the rate for distant metastasis rate was 3.5 percent.²⁸ RT can also be used along with chemotherapy and a meta-analysis of cSCC of the head and neck found that the combination of RT and chemotherapy (cisplatin) is an effective therapy and is superior to altered fractionation RT.²⁹

In a study of patients with laCSCC, adjuvant RT resulted in five-year Kaplan-Meier estimates of 59.4 percent for disease-free survival and 47.4 percent for overall survival.³⁰ It also improved disease-free survival, particularly for tumors with perineural invasion and regional spread.³⁰ Another study reported that laCSCC treated with adjuvant RT had lower recurrence rates compared to surgery alone (23% vs. 55%, respectively).³¹ RT also significantly improved survival outcomes, with disease-free survival and overall survival being significantly higher for adjuvant RT versus surgery alone.³¹ Further, a study found that four-year locoregional control for advanced cSCC was 58 percent after treatment with radical RT, though the median time to recurrence was five months and 65 percent of patients with locoregional recurrent cSCC died from the disease.³² Studies demonstrating a significant survival benefit with adjuvant RT describe that a common risk factor was mCSCC involving the parotid gland (the main metastatic site for facial cSCC) or regional lymph nodes.²⁷ Studies have found that mCSCC treated with adjuvant RT may have worse survival outcomes.^26,27

RT should not be administered to patients with ataxia telangiectasia, nevoid basal cell carcinoma syndrome, or Li-Fraumeni syndrome as these genetic conditions increase risk of radiosensitivity, as well as those with connective tissue diseases.²³ Further, RT is not typically recommended for patients less than 60 years of age unless there are special circumstances.³³ RT has demonstrated to be a feasible therapy for advanced cSCCs particularly in the adjuvant setting, though many patients are not amenable to this treatment option.

Immunotherapies. Cemiplimab. Systemic immunotherapies have evolved the therapeutic landscape for advanced cSCCs. Due to the high mutation burden in cSCC and the known strong link between immunosuppression and risk of cSCC, blockade of immune checkpoints prevents the negative regulation of T cells thereby upregulating the immune response to cSCC cancer cells.^34–36 These immunotherapies target the programmed cell death-1 (PD-1) pathway and clinical trials have demonstrated sustained efficacy for both laCSCC and mCSCC.^34–36

Cemiplimab is a high-affinity PD-1 antibody that was the first FDA-approved treatment for mCSCC and laCSCC who are not candidates for curative surgery or curative RT.³⁷ In the Phase I expansion cohort for cemiplimab 3mg/kg (weight-based dosing) every two weeks for the treatment of mCSCC, 50 percent of patients experienced response and the median observed time to response was 2.3 months.⁹ Further, response rate in the Phase II analysis for mCSCC was 47 percent by independent central review (ICR) with a 61 percent rate of durable disease control.⁹ In this group, median observed time to response was 1.9 months and the duration of response exceeded six months in 57 percent of those who had a response.⁹

For patients with laCSCC treated with cemiplimab weight-based dosing every two weeks, the objective response rate (ORR) was 44 percent based on ICR and 53 percent based on investigator’s assessment.³⁸ There was a complete response in 13 percent of patients and 31 percent had a partial response.³⁸ Further, 79 percent of patients obtained disease control, which was either complete response, partial response, or stable disease after about 56 days of treatment (first response assessment).³⁸ Durable disease control was seen in 63 percent of patients, which was the best overall response for at least 105 days.³⁸ There were 87.8 percent of patients who were estimated to remain in response at 12 months.³⁸

Additionally, patients with mCSCC treated with cemiplimab 350mg IV every three weeks (fixed-dosing) had an ORR of 41.1 percent per ICR and those treated with weight-based dosing evaluated at longer timeframes (up to 26 months) had ORR of 49.2 percent per ICR.³⁹ The combined ORR for mCSCC with both forms of treatment was 45.3 percent per ICR.³⁹ The estimate for duration of response was 95 percent for fixed dosing at eight months and 88.9 percent for weight-based dosing at 12 months.³⁹

In a pooled longer-term analysis, the Phase II study of cemiplimab for advanced cSCC, overall ORR was 46.1 percent per ICR.⁴⁰ Complete response was achieved by 20.3 percent of patients receiving weight-based dosing for mCSCC, 12.8 percent for those with laCSCC receiving weight-based dosing, and 16.1 percent for those with mCSCC receiving fixed dosing.⁴⁰ For these patients, the median time to complete response was 11.2 months.⁴⁰ Additionally, of all patients who had either partial or complete response, 87.8 percent were estimated to have an ongoing response after 12 months from the first objective response.⁴⁰ The overall survival at 24 months was estimated to be 73.3 percent.⁴⁰

The final analysis of the Phase II study for cemiplimab included patients receiving both weight-based and fixed-dosing of cemiplimab. For patients who received weight-based dosing for laCSCC and mCSCC and those with mCSCC treated with fixed-dosing, the ORR at 42.5 months was 47.2 percent.³⁵ For these groups, the median duration of follow-up was 42.5 months, the estimated 12-month duration of response was 88.3 percent, and the median progression-free survival (PFS) was 26.0 months.³⁵ The median time to complete response was 11.3 months.³⁵ Further, for patients treated with fixed-dosing of cemiplimab for laCSCC/mCSCC, ORR at 8.7 months was 44.8 percent.³⁵ The median time to complete response in this group was 4.17 months and the median duration of response and PFS were not reached.³⁵

The final long-term analysis of the Phase II trial reported that treatment-emergent adverse events (TEAEs) Grade 3 or more occurred in 45.5 to 49.2 percent of patients.³⁵ Specifically, 31.1 to 34.5 percent of TEAEs were considered serious and 7.3 percent of patients discontinued the therapy due to a TEAE.³⁵ The most common TEAEs associated with cemiplimab include fatigue (26.1–34.7%), diarrhea (21.2–27.5%), nausea (17.0–23.8%), pruritus (21.2%), arthralgia (13.3–17.6%), constipation (11.5–14.5%), non-specific rash (10.3–16.6%), and several others.³⁵ The most common Grade ≥3 TEAEs were hypertension (3.6–4.7%), pneumonia (3.6–4.1%), cellulitis (4.1%), and anemia (4.1%).³⁵

Another form of therapy for advanced SCC being investigated is intralesional immunotherapy. In an ongoing Phase I clinical trial, intralesional cemiplimab is being administrated weekly for 12 weeks for patients with advanced cSCC and basal cell carcinoma.⁴¹ Preliminary results show that intralesional cemiplimab results in a high rate of pathological response with evidence of tumor regression.

Pembrolizumab. Pembrolizumab is also a PD-1 antibody that is FDA-approved for laCSCC and recurrent or metastatic (R/M) cSCC that are not curable by surgery or RT.⁴² In the open-label non-randomized Phase II clinical trial, KEYNOTE-629, ORR for the total population (laCSCC and mCSCC) treated with pembrolizumab was 40.3 percent.³⁶ For patients with laCSCC, ORR was 50.0 percent with 16.7 percent having a complete response and 33.3 percent having a partial response.³⁶ The median time to response was 2.6 months for laCSCC and 84.1 percent of responses were estimated to last greater than or equal to 12 months.³⁶ For those with R/M cSCC, ORR was 35.2 percent with 10.5 percent achieving complete response and 24.8 percent achieving partial response.³⁶ The median time to response for R/M cSCC was 1.6 months and 77.8 percent of responses were estimated to last at least 12 months.³⁶ Of all patients in the KEYNOTE-629 clinical trial, 69.2 percent had one or more treatment-related adverse events (TRAEs) and 11.9 percent experienced TRAEs ≥ Grade 3.³⁶ Only 8.8 percent of patients chose to discontinue therapy due to TRAEs.³⁶

A large randomized Phase III study (KEYNOTE-048) compared efficacy of pembrolizumab with and without chemotherapy agents (platinum + 5-fluorouracil, cetuximab) for R/M cSCC of the head and neck.¹⁰ Pembrolizumab monotherapy and pembrolizumab with chemotherapy each improved overall survival significantly more than cetuximab with chemotherapy.¹⁰ Pembrolizumab was also studied in the open-label Phase II trial CARSKIN for treatment of unresectable cSCC.⁴³ After 15 weeks of treatment, ORR was 41 percent, with 13 partial responders and three complete responders.⁴³ Patients in this study had a median follow-up period of 22.4 months and median progression-free survival was 6.7 months and median overall survival was 25.3 months.⁴³ Notably, ORR was significantly higher in the PD-L1 positive patients (55%) compared to PD-L1 negative patients (17%).⁴³ TRAEs occurred in 71 percent of patients with 7 percent being Grade ≥3.⁴³

Neoadjuvant therapy. Cemiplimab has also been evaluated in a Phase II clinical trial for use as neoadjuvant therapy in patients with resectable stage II–IV cSCC.⁴⁴ After receiving 350mg every three weeks for up to four doses, patients underwent surgery with intention to achieve a complete response with no tumor cells on surgical pathology.⁴⁴ Complete response per ICR occurred in 51 percent of patients and there was a 68 percent ORR.⁴⁴ Adverse events were consistent with those previously reported.⁴⁴ In the follow-up analysis, the estimated event-free survival at 12-month was 89 percent and at 24 months was 85 percent.⁴⁵ Of the 40 patients who had complete pathological response, none had recurrence, while only 10 percent of those with major pathological response had recurrence.⁴⁵ Estimated 12-month disease-free survival and overall survival were both 92 percent.⁴⁵

Currently, cemiplimab is being evaluated in a Phase III randomized, double-blind study as an adjuvant therapy for patients with high-risk cSCC who have completed surgery and post-operative RT.⁴⁶ In the first prespecified interim analysis, patients treated with cemiplimab had a 68-percent reduction in the risk of disease recurrence or death compared to placebo (hazard ratio 0.32, p<0.0001).⁴⁷ A Phase III clinical trial (KEYNOTE-630) evaluated adjuvant therapy with pembrolizumab for patients with high-risk laCSCC who had surgery (with or without positive margins) and completed adjuvant RT compared to placebo.⁴⁸ In a pre-planned interim analysis, pembrolizumab did not produce a statistically significant recurrence-free survival.⁴⁸

Immunotherapy-related adverse events. Nonspecific blockage of immune mediators with immunotherapies (cemiplimab, pembrolizumab) can result in immune-mediated adverse events (irAEs). Any organ system can be affected by irAEs at any point during the treatment course.^49–51 Most commonly, irAEs affect the skin, gastrointestinal, endocrine, hepatic, musculoskeletal and respiratory systems and most occurrences are mild to moderate.^49,51 Regularly reported irAEs with PD-1 inhibitors are inflammatory dermatitis (itch and/or rash), fatigue, diarrhea, colitis, hepatitis, hypothyroidism, pneumonitis, and time to onset can be variable from days to weeks.^49,51,52

In a meta-analysis of adverse effects for PD-1 and PD-L1 inhibitors, 66.0 percent had at least one adverse event of any severity and 14.0 percent developed an adverse event of at least Grade 3.⁵³ Fatigue (18.26%), pruritus (10.61%), and diarrhea (9.47%) were the most common all-grade adverse events.⁵³ More severe adverse events (Grade 3 or above) were fatigue (0.89%), anemia (0.78%) and aspartate aminotransferase increase (0.75%).⁵³ For cemiplimab, irAEs and infusion reactions occurred in 22.6 percent of patients and were mostly of Grade 1–2 severity.³⁶

As irAEs can present with non-specific signs and symptoms, clinicians should educate patients and caregivers, as well as office staff, regarding reporting symptoms to prevent delays in diagnosis. Clinic staff should be informed to critically consider new symptoms in a patient receiving immuno-oncologic therapy as these could be an irAE. Early diagnosis is critical to initiating appropriate therapy. First-line treatment includes systemic corticosteroids (ie, prednisone, methylprednisolone, or equivalents) and if there is no improvement of severe irAEs within 2 to 3 days, addition of immunosuppressant or immunomodulator is recommended.^51,52,54

Literature has described efficacy of biologics (anti-TNF, anti-interleukin (IL)-6, anti-IL-4, anti-IL-17, and others), mycophenolate mofetil, and cyclophosphamide in treating toxicities related to immunotherapies.^54,55 Recently, inhibitors of the JAK-STAT pathway have emerged as a potential therapy for irAEs.⁵⁶ Tofacitinib has successfully reduced immunotherapy-induced colitis in several case reports and both tofacitinib and baricitinib treated immunotherapy-induced arthritis.^56–58 In a retrospective study of 53 patients, tofacitinib also showed clinical efficacy in treating immunotherapy-induced myositis, myocarditis, and hepatitis and only 7.5 percent experienced infectious adverse events.⁵⁹

Pausing immunotherapy can be considered for those with severe reactions or toxicity.^51,52 In addition, clinicians should be aware that mimickers of irAEs could be development of metastatic disease. Initiating appropriate workup should be considered if metastasis is suspected.

Immunocompromised populations. Caution must be applied when considering immunotherapy in immunocompromised populations such as solid organ transplant recipients (SOTRs), those with hematopoietic stem cell transplantation (HSTC), or those with HIV. SOTRs are at 65 to 250 times greater risk of cSCC compared to the general population, particularly due to these patients being on immunosuppressive regimens (ie, cyclosporine, azathioprine).^60,61 If immunotherapy is given to SOTRs, there is a risk of allograft rejection.^62,63 As such, most clinical trials for immunotherapies have excluded this population. In a systematic review of immunotherapies (ipilimumab, nivolumab, and pembrolizumab) administered to SOTRs, 37 percent experienced organ rejection with the highest rate seen in kidney (40.1%), liver (35%), and heart (20%) transplants.⁶⁴ The highest rejection rate was with nivolumab (52.2%), while pembrolizumab (26.7%) and ipilimumab (25%) were similar.⁶⁴ Notably, however, the most common cause of death was progression of metastatic disease.⁶⁴ Though this population is at risk of adverse events, evidence demonstrates potential for immunotherapy in certain circumstances.

Another study also found a similar allograft rejection rate of 41 percent for SOTRs treated with immunotherapy for various cancers.⁶⁵ Recently, a Phase I study of cemiplimab for kidney transplant recipients with advanced cSCC reported no kidney rejection or loss and 46 percent of patients had response to treatment.⁶⁶ These patients were placed on an immunosuppressive regimen on mTOR inhibitor and corticosteroids.⁶⁶ Additionally, a case report highlighted a patient with Sezary Syndrome who underwent HSTC and developed metastatic cSCC.⁶⁷ This patient was successfully treated with pembrolizumab and demonstrated a durable response 14 months after stopping immunotherapy.⁶⁷

Similar to SOTRs and patients who have received HSTC, case reports of patients with HIV who have received immunotherapy for cancer have shown efficacy and acceptable safety profiles.^68–73 A systematic review reported that among HIV patients who received immunotherapies (ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab), 93 percent of patients had undetectable HIV load after treatment and 8.6 percent of patients experienced Grade ≥3 irAEs.⁷⁴ In a recent retrospective analysis of 390 patients with HIV who received anti-PD-1 or anti-PD-L1 therapy for a variety of cancers, 7.7 percent had Grade ≥3 irAEs.⁷⁵ Further, in an open-label nonrandomized Phase I study of pembrolizumab administered for patients with HIV with a variety of cancers, CD4 founds were not statistically different after treatment, HIV was controlled in all participants, and there was significant clinical efficacy as well.⁷⁶

Multidisciplinary Care

Due to the complexity of managing patients with advanced cSCC, a multidisciplinary team approach is essential. There are a variety of specialists who may be involved in the journey of a patient with advanced cSCC, including general practitioners, geriatricians, dermatologists, Mohs surgeons, surgical oncologists, radiation oncologists, medical oncologists, plastic surgeons, otolaryngologists, psychiatrists, and others.⁷⁷ Providing education and knowledge to specialists regarding the variety of clinicians who may be involved in the care of a patient with advanced cSCC can optimize clinical outcomes and improve communication pathways. Knowing the specialists available in a certain geographic region can streamline referrals, enable thorough discussion of management strategies, and decrease time to treatment.⁷⁷

Checklist for Clinicians in Treatment of Advanced cSCC

High-risk cSCC

• Meets criteria for high-risk features
• Based on clinical appearance, size, location, histology, depth of invasion. Patients with high tumor burden.
• If tumors may be resectable with surgery, consider neoadjuvant PD-1 inhibitor (cemiplimab, pembrolizumab) prior to surgery
• Attempt surgery with MMS if possible
• If surgery is not possible, consider radiotherapy
• If radiotherapy is not feasible, start PD-1 inhibitor (cemiplimab, pembrolizumab)

Locally advanced cSCC

• Meets criteria for locally advanced
• Tumors not amenable to surgery due to size, location, and depth of invasion. Patients with high tumor burden.
• Tumors not amenable to radiotherapy
• When surgery and/or radiotherapy are not feasible, start PD-1 inhibitor (cemiplimab, pembrolizumab)
• If tumors decrease in size due to PD-1 inhibitor, consider surgery

Metastatic/recurrent cSCC

• Distant spread to other organs or tissues
• Start PD-1 inhibitor (cemiplimab, pembrolizumab)
• If tumors decrease in size due to PD-1 inhibitor, consider surgery

Conclusion

In this review, we examine existing data to create a checklist to aid clinicians in optimizing management of advanced cSCC. Recognizing advanced cSCC and deciding on appropriate therapy can be challenging. When surgery or radiation therapy is not an option, systemic therapy may be necessary. PD-1 inhibitors, such as cemiplimab and pembrolizumab, are the first-line treatments for laCSCC and mCSCC. It is essential for clinicians to implement strategies that maximize therapeutic benefits for advanced cSCC while controlling adverse effects.

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