The Evolving Treatment Landscape for CSCC
February 26, 2025
CSCC, immunotherapy, neoadjuvant
This is a preprint. Please see the final publication at Archives of Dermatological Research. The final version of this manuscript has substantial modifications.
Title: The Evolving Treatment Landscape for Cutaneous Squamous Cell Carcinoma
Short Title: The Evolving Treatment Landscape for CSCC
Authors: David M. Miller1,2,3* MD PhD,
1Department of Medicine, Division of Hematology/Oncology, 2Department of Dermatology, Massachusetts General Hospital, Boston, MA 3Harvard Medical School, Boston, MA
*Corresponding author: David M. Miller MD PhD
Massachusetts General Hospital
15 Parkman St. Room 132
Boston MA 02114
Email: dmiller4@mgh.harvard.edu
Funding sources: None
Manuscript word count: 2461 (3500 max)
Abstract word count: 130
References: 34
Figures: 0
Tables: 0
Keywords: Cutaneous squamous cell carcinoma, immunotherapy, immune checkpoint inhibitor
Abbreviations: CI: confidence interval, CSCC: Cutaneous squamous cell carcinoma, NMSC: Nonmelanoma skin cancer (NMSC), EFS: event-free survival, HR: hazard ratio, ICI: immune checkpoint inhibitor, NCCN: National Comprehensive Cancer Network, ORR: objective response rate, OS: overall survival, PD-1: programmed death-1, PORT: post-operative radiotherapy.
The treatment landscape for cutaneous squamous cell carcinoma (CSCC) is evolving, with immunotherapy transforming care across all stages of disease and expanding the role of dermatologists. While surgery and radiotherapy remain cornerstones for localized CSCC, immune checkpoint inhibitors (ICIs) offer durable responses and survival benefits in advanced cases. Emerging approaches, including neoadjuvant, adjuvant, and intralesional ICIs, provide dermatologists with opportunities to integrate these therapies into practice, potentially enhancing surgical outcomes and preserving function in high-risk, resectable CSCC. Preliminary data on anti-PD-1 therapy as a preventive strategy for actinic neoplasia syndrome introduces new avenues for long-term management, though further evidence is needed. As systemic immunotherapy becomes increasingly relevant in dermatology, addressing immunotherapy-related adverse events requires interdisciplinary collaboration and specialized training. These advancements emphasize the expanding responsibilities of dermatologists in CSCC management while highlighting the importance of continued research and thoughtful application of these therapies.
Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer (NMSC), with incidence rates rising worldwide, particularly among populations with significant UV exposure and an aging demographic1–3. Historically, management of CSCC has focused on localized treatments such as surgical resection, often complemented by adjuvant radiotherapy for high-risk cases. These approaches are generally effective for early-stage, localized disease but offer limited options for advanced cases, such as those with nodal involvement or distant metastasis4,5. For patients with unresectable or metastatic CSCC, systemic therapies—typically off-label chemotherapies administered by medical oncologists—provided only modest and transient benefits, underscoring the need for more effective systemic treatments tailored to CSCC’s unique profile6.
In recent years, there has been a surge of FDA approvals in cutaneous oncology, primarily driven by advancements in immunotherapy for melanoma and other high-risk skin cancers (Figure 1). Immune checkpoint inhibitors (ICIs) targeting the programmed death-1 (PD-1)/PD-L1 pathway have transformed the melanoma treatment landscape, demonstrating significant survival benefits in metastatic disease. These advancements paved the way for exploring similar strategies in other skin cancers, yet CSCC initially lagged behind in regulatory approvals despite its high prevalence and substantial unmet need7.
Despite CSCC’s highly immunogenic nature due to its high mutation burden from cumulative UV damage, the disease’s immunogenic profile had yet to be fully leveraged in systemic therapies. The FDA approval of cemiplimab in 2018 marked a significant turning point, becoming the first targeted systemic therapy specifically approved for advanced CSCC. This milestone was soon followed by the approval of pembrolizumab, underscoring the potential of ICIs in CSCC and signaling a paradigm shift in how these cases are managed4,5.
As systemic therapies are now considered for earlier stages of CSCC, the traditionally distinct roles of dermatology and medical oncology are becoming increasingly aligned. Systemic treatments for CSCC, once solely within the domain of medical oncologists, are beginning to involve dermatologists, particularly as immunotherapy becomes a viable option for high-risk, resectable disease. This evolving landscape suggests a future where dermatologists may play a larger role in managing systemic treatments, fostering a more integrated approach to treating skin cancers.
Advanced Disease
The efficacy of PD-1 inhibitors in advanced CSCC was first demonstrated in the R2810-ONC-1540 study, where cemiplimab achieved an objective response rate (ORR) of approximately 47% in patients with locally advanced or metastatic CSCC. These responses were durable and significantly improved patient outcomes over prior chemotherapy options, which had been limited by transient effects and high toxicity8.
The FDA granted cemiplimab regular approval in 2018 based on this durable tumor shrinkage and compelling photographic evidence from Study 1540, which documented marked improvements in disfiguring lesions on visible areas like the face and neck. The near-complete resolution of previously unresponsive tumors offered both survival and quality-of-life benefits, fulfilling the FDA’s criteria for a direct clinical benefit8.
Subsequently, the KEYNOTE-629 trial evaluated pembrolizumab in metastatic CSCC, achieving a 34% ORR with a favorable safety profile, further establishing PD-1 inhibitors as a transformative option in CSCC. Together, these approvals represent a paradigm shift, providing effective systemic treatment options where few had previously existed4,5.
Neoadjuvant and Adjuvant Immunotherapy in High-Risk, Resectable CSCC
Building on the success of ICIs in advanced cases, these therapies are increasingly being explored as neoadjuvant and adjuvant treatments for high-risk, resectable CSCC. Neoadjuvant ICIs aim to shrink tumors preoperatively, potentially improving surgical outcomes, minimizing the extent of surgery required, and reducing the risk of recurrence. Although neoadjuvant ICI strategies are not yet FDA-approved, they have been endorsed in recent National Comprehensive Cancer Network (NCCN) guidelines, reflecting a growing consensus around their clinical utility in carefully selected patients9.
An initial pilot trial laid the groundwork for using neoadjuvant ICIs in CSCC, achieving a 75% (15/20) pathologic response rate and a complete response (pCR) in 55% of patients, highlighting its feasibility in high-risk cases10. Building on this, a larger multicenter phase II trial of cemiplimab reported a 63% pathologic response rate, with only one recurrence among patients who achieved a major or complete response, demonstrating the potential for durable disease-free survival benefits11,12.
Real-world studies, like that of Kim et al., have reinforced the applicability of neoadjuvant ICIs, especially for patients with comorbidities. This study observed a 37% pCR rate and 50% radiologic response rate in patients treated with cemiplimab and pembrolizumab, with some able to forgo planned surgery, indicating potential to reduce surgical morbidity13.
Recent trials, such as NEO-CESQ and MATISSE, have further investigated neoadjuvant combinations in high-risk CSCC. NEO-CESQ reported a 52% (12/23) pathologic response rate with combined neoadjuvant and adjuvant cemiplimab, while MATISSE achieved deep clinical responses in 50% (13/26) with nivolumab alone and 61% (14/23) with nivolumab plus ipilimumab. These preliminary findings suggest ICIs may enable organ preservation for selected patients14,15.
The De-Squamate trial, introduced an innovative, risk-adapted approach to managing high-risk, locally advanced CSCC with neoadjuvant pembrolizumab16. This phase II trial enrolled patients with stage II–IV CSCC, administering neoadjuvant pembrolizumab followed by interval staging. Based on response, patients either proceeded to resection or continued with adjuvant pembrolizumab, with or without post-operative radiotherapy (PORT) as needed. Early results indicated encouraging response rates, with a substantial proportion of patients achieving a pCR or significant tumor downstaging (17/27, 62.9%), allowing for more conservative surgical and post-operative interventions. While neoadjuvant ICIs demonstrate promising results, the De-Squamate study also underscores the need to carefully monitor for adverse events, as two patients experienced grade 3 or higher immune-related adverse events during the trial, although no treatment discontinuations were reported. These findings highlight the emerging role of personalized, risk-adapted neoadjuvant strategies for CSCC, which could provide effective tumor control while minimizing morbidity for selected patients.
Adjuvant-Only Approaches and Comparisons with Melanoma Studies
An evidence gap remains for adjuvant-only ICI use in CSCC. Two large trials have investigated ICIs as adjuvant therapy, though no published data are yet available. Notably, Merck recently halted the KEYNOTE-630 trial on pembrolizumab in the adjuvant setting due to lack of efficacy, underscoring challenges in determining optimal timing for immunotherapy in CSCC17.
The exploration of neoadjuvant versus adjuvant approaches in CSCC mirrors insights gained from melanoma studies, where recent trials have demonstrated the potential superiority of preoperative over postoperative immunotherapy. Evidence from melanoma research suggests that neoadjuvant immunotherapy could enhance immune response efficacy due to preserved lymphatic architecture and exposure to a broader array of neoantigens prior to surgical tumor removal, which may not be as robust in adjuvant-only approaches18,19. For instance, in a recent phase 3 study, neoadjuvant pembrolizumab combined with adjuvant therapy showed significantly longer event-free survival (EFS) compared to adjuvant-only pembrolizumab (72% 2-year EFS vs. 49%, p = 0.004), highlighting how early immunologic priming can lead to improved outcomes20.
Similarly, another study with neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma found enhanced event-free survival in the neoadjuvant arm compared to adjuvant nivolumab alone. Patients receiving neoadjuvant treatment experienced a superior 12 month recurrence-free survival (83.7%, 99.9% confidence interval [CI], 73.8 to 94.) compared with post-operative only treatment (57.2%, 99.9% CI, 45.1 to 72.7)21. These findings reinforce the potential advantages of initiating immune-based treatments before surgery, though it remains to be determined if the same benefits will apply to CSCC.
Future Directions and Emerging Therapies in CSCC
Intralesional Therapy
Following the success of systemic ICIs in advanced and high-risk resectable CSCC, researchers are now exploring intralesional approaches as a localized method of targeting tumors directly22. The ongoing intralesional trial (NCT03889912) investigates the safety and efficacy of cemiplimab, an anti-PD-1 antibody, delivered directly into early-stage, recurrent CSCC lesions. This study employs a dose-escalation approach, with weekly injections over a 12-week treatment period, to evaluate both safety and response rates23.
Preliminary findings suggest that intralesional cemiplimab is generally well-tolerated. Grade III–IV adverse events were observed in 17.6% (3/17) of patients, with no treatment-related deaths reported23. Most adverse events were low-grade, and serious events were relatively rare, indicating that the localized administration of cemiplimab minimizes systemic exposure and associated risks. Efficacy data from the study are promising, with an complete response rate of 76.5% (13/17). This high rate of tumor control suggests that intralesional cemiplimab could be an effective and practical option for dermatologists to manage certain CSCC cases in-office, potentially reducing the need for more invasive or systemic treatments.
Building on promising early results, the phase III CLEAR trial (NCT06585410) has been initiated to evaluate intralesional cemiplimab in a larger cohort of patients with early-stage CSCC. This randomized study compares the efficacy of intralesional cemiplimab versus surgical resection in achieving EFS and composite complete response rate. CLEAR’s inclusion criteria focus on patients with non-metastatic CSCC tumors measuring 1 to 2 cm in diameter. For those eligible for surgical resection, only patients scheduled for procedures with precise margin control—such as Mohs surgery or other methods with Complete Margin Assessment—are included, while patients slated for excision without margin control are excluded.
The results of the CLEAR trial are anticipated to offer deeper insights into the role of intralesional therapy in CSCC management. Should the trial validate the efficacy and safety of intralesional cemiplimab, it may support regulatory approval and broaden therapeutic options within dermatology practices for managing early-stage CSCC.
Immunoprophylaxis in CSCC: Exploring Systemic and Emerging Approaches
Given the significant recurrence risk in high-risk CSCC patients, various chemopreventive agents—capecitabine, nicotinamide, and retinoids—have been investigated. While each offers unique mechanisms, their efficacy and tolerability vary, leaving an unmet need for patients with extensive field cancerization.
Capecitabine, an oral prodrug of 5-fluorouracil, has shown promise in reducing new CSCC occurrences, particularly in solid-organ transplant recipients and those with a history of multiple NMSCs. Although retrospective studies suggest it may lower CSCC incidence in high-risk populations, side effects like gastrointestinal distress and hand-foot syndrome necessitate careful management. Additional studies are needed to determine its broader applicability and long-term tolerability24.
Nicotinamide, a form of vitamin B3, has demonstrated effectiveness in reducing new NMSCs in high-risk individuals with minimal adverse effects, making it an accessible option for chemoprevention25. However, recent trials in immunosuppressed patients, including transplant recipients, have shown limited benefit, suggesting the need for tailored approaches in this population26,27.
Retinoids, such as acitretin and etretinate, have shown efficacy in reducing SCCs and actinic keratoses among transplant recipients with extensive UV exposure. However, side effects—including mucocutaneous symptoms, hyperlipidemia, and a rebound effect upon discontinuation—limit their long-term utility.28–31.
These limitations underscore the need for novel, effective, and well-tolerated chemopreventive strategies for patients with field cancerization and high risk for recurrent CSCC.
Emerging Interest in Anti-PD-1 Prophylaxis
Following the success of PD-1 inhibitors in managing advanced and high-risk CSCC, there is increasing interest in their potential use as immunopreventive agents. Emerging clinical observations32 and preliminary studies33 suggest that anti-PD-1 therapy may reduce the incidence of new CSCCs in patients treated for other malignancies. Findings from melanoma studies, where patients under anti-PD-1 therapy demonstrated fewer new primary cutaneous malignancies, offer a promising rationale for exploring these agents as a prophylactic approach for high-risk CSCC populations33.
While promising, the prophylactic use of PD-1 inhibitors warrants careful evaluation, as future studies will need to address optimal dosing, administration, and patient selection criteria, alongside managing the adverse effects associated with this therapeutic class. Early evidence provides a compelling rationale for this approach, although additional investigations are required to fully establish the role of PD-1 inhibitors in CSCC immunoprophylaxis.
The evolving landscape of immunotherapy presents both exciting opportunities and notable challenges for dermatologists. With their longstanding patient relationships and expertise in skin pathology, dermatologists are uniquely positioned to identify candidates for immunotherapeutic interventions. This includes preoperative and intralesional approaches and, in select high-risk patients, immunopreventive strategies aimed at reducing progression to invasive skin cancers. For patients with conditions such as actinic neoplasia syndrome, dermatologists’ role in early detection and continuous care makes them ideally suited to implement these preventive measures.
Despite this promising role, the systemic nature of immunotherapy-related adverse events (irAEs) presents challenges that extend beyond the traditional scope of dermatologic practice. While many irAEs are dermatologic, such as rash and pruritus, more serious reactions can impact multiple organ systems, including the gastrointestinal, hepatic, endocrine, and pulmonary systems. For instance, pembrolizumab and other immune checkpoint inhibitors have been associated with life-threatening side effects, such as pneumonitis, hepatitis, and colitis, which require specialized management skills that may be more familiar to medical oncology teams34. Cancer centers and medical oncologists often have multidisciplinary and interprofessional teams with experience in recognizing and managing these complex irAEs, which can ensure patient safety and optimize outcomes during immunotherapy.
To fully integrate these emerging therapies into dermatologic practice, collaboration with medical oncologists and immunotherapy specialists will be essential. Such partnerships can ensure access to multidisciplinary care and enable the timely identification and management of irAEs. As immunotherapy becomes increasingly relevant in dermatology, enhancing training to encompass systemic effects and strategies for managing immunotherapy-related side effects could further empower dermatologists to oversee these treatments safely. Educating patients about the importance of promptly reporting new or unusual symptoms will also be crucial for early detection and effective management of irAEs.
Even localized therapies like intralesional immunotherapy can occasionally elicit systemic immune responses, requiring careful observation and proactive management. Dermatologists overseeing such treatments should be prepared to recognize and address these rare but significant complications, often in collaboration with other specialists. Thus, although dermatologists play a pivotal role in the advancing field of immunotherapy, the potential for serious systemic adverse events requires a collaborative, informed, and cautious approach to ensure safe and effective patient care.
The treatment landscape for CSCC is transforming, moving beyond traditional surgical and radiotherapeutic approaches to incorporate systemic and localized immunotherapies. Immune checkpoint inhibitors, particularly for advanced and high-risk CSCC, have introduced treatments that offer durable responses and meaningful improvements in survival and quality of life. As immunotherapy extends into earlier stages of disease, approaches such as neoadjuvant, adjuvant, and intralesional therapies are broadening the scope of dermatology’s involvement, with the potential for dermatologists to play a more active role in managing systemic therapies in addition to their expertise in detection, prevention, and surgical treatment.
Chemopreventive agents like capecitabine, nicotinamide, and acitretin provide modest, though limited, options for high-risk patients. Preliminary data on anti-PD-1 therapy as a potential immunopreventive strategy offers a new avenue for managing actinic neoplasia syndrome, although robust evidence is still needed. The growing presence of systemic immunotherapy in dermatologic practice underscores the importance of vigilance in monitoring for severe, sometimes life-threatening, immunotherapy-related adverse events, which may require specialized management. To ensure safety and optimize outcomes, collaborative care models that connect dermatologists with oncology teams are essential.
While challenges remain, the evolving field of immunotherapy presents an era of unprecedented potential for improving CSCC outcomes. With ongoing research and a multidisciplinary approach to care, dermatologists are uniquely positioned to integrate immunotherapeutic advances into comprehensive strategies for managing CSCC.
This article was adapted from the Young Leadership Award session at the 144th Annual Meeting of the American Dermatological Association.
The author has received honoraria for serving as a consultant or participation on advisory boards for Almirall, Bristol Myers Squibb, Merck, EMD Serono, Regeneron, Sanofi Genzyme, Pfizer, Castle Biosciences, and Checkpoint Therapeutics. He has stock options from Checkpoint Therapeutics and Avstera Therapeutics. He has received research funding from Regeneron, Kartos Therapeutics. NeoImmune Tech, Inc, Project Data Sphere, ECOG-ACRIN and the American Skin Association.
Declaration of Generative AI and AI-assisted technologies in the writing process. During the preparation of this work the author used GPT-4o (OpenAI) in order to improve readability. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
The author expresses gratitude to Dr. Lynn Drake and the program committee of the American Dermatological Association for selecting them as a recipient of the ADA Young Leadership Award, which provided valuable support and recognition. Appreciation is also extended to Dr. Vishal Patel for his thoughtful review and constructive feedback on this manuscript, which contributed to its refinement.