Pembrolizumab for the Treatment of Locally Advanced Cutaneous Squamous Cell Carcinoma: Patient Selection and Special Considerations

Introduction

Cutaneous squamous cell carcinoma (cSCC), a keratinocyte carcinoma, composes the second most common type of nonmelanoma skin cancer after basal cell carcinoma, together with Merkel cell carcinoma, comprising non-melanoma skin cancers (NMSC). Although NMSCs are not tracked by the Centers for Disease Control (CDC), cSCC is estimated to account for at least 33% of cases, with approximately 1.8 million cases diagnosed annually in the United States.¹

The most significant risk factor for cSCC is chronic exposure to ultraviolet radiation from the sun. Frequent and prolonged exposures place patients at higher risk, as do fair skin and older age. The immune system is a clear regulator in the cSCC disease process: immunosuppression is a well-established and significant risk factor for developing cSCC.^2–4 Immunos-suppressed individuals, particularly solid organ transplant recipients, face a significantly higher risk of developing cSCC, with studies indicating a 5- to 113-fold increased risk in these patients.⁵ In addition, immunosuppression from lymphoma, leukemia, HIV, and chronic immunosuppressive therapies also increase the risk of developing cSCC. Immunosuppression is generally associated with a more aggressive clinical course, including faster tumor growth, deeper invasion, higher recurrence rates, greater metastatic potential, and poorer prognosis.⁵

While the majority of cases of cSCC can be eradicated by surgical excision alone and feature cure rates >90%,⁶ there are some cases that have features that put them at higher risk for recurrence, metastasis, and death. Advanced cSCC is typically stratified into two categories: locally advanced and metastatic. Locally advanced disease comprises cases where the tumor has invaded deeper tissues and invaded nearby structures, without metastasizing to distant organs. Metastatic cSCC, on the other hand, includes cases where disease involves distant organs, but also notably includes when disease spreads to regional lymph nodes. Regional nodal metastases, the most common form of metastatic cSCC, are a significant prognostic factor, with worse outcomes compared to locally advanced disease.⁷

cSCC Treatment Approaches

Treatment for advanced cSCC is often multidisciplinary, and the modalities commonly employed include surgical resection, radiation therapy, and systemic therapy. In cases where surgical resection with curative intent is feasible for locally advanced disease, the first-line treatment and standard of care is surgical excision with clear margins. In some cases, where function, cosmesis, and patient preference are of concern, an alternative primary treatment can be radiotherapy.^8,9 Adjuvant radiation is often recommended following surgery, particularly in cases with high-risk features such as positive surgical margins, perineural invasion, lymphovascular invasion, extracapsular spread, and poor differentiation. For patients with locally advanced disease not amenable to curative surgery due to factors such as proximity to major nerves, organs, or blood vessels, large tumor size, concerns over functional deficits, age, frailty, or other patient-related factors, radiotherapy with or without systemic therapy becomes the standard of care.^9,10 Notably, in advanced disease, a combination of both surgery and post-operative radiation (PORT) is often recommended to improve locoregional control and survival outcomes. PORT is recommended for perineural spread, positive margins that cannot reasonably be further corrected by surgery, and recurrence in the setting of a prior margin-negative resection.¹⁰

For patients where surgical excision is not an option, the NCCN guidelines list definitive chemoradiotherapy (CRT) as a treatment option. Cisplatin is the preferred systemic agent of choice, with carboplatin as an alternative for those who cannot tolerate cisplatin. These chemotherapy options have shown limited efficacy in treating locally advanced disease, with both reduced response rates and limited response durability. Additionally, the toxicity profiles of these agents can often limit their use, particularly in the case of elderly or frail patients. Notably, however, definitive CRT is controversial due to limited high-quality evidence (available studies are often small, retrospective, or lack randomization), mixed clinical outcomes, as well as toxicity concerns as previously mentioned.^11,12

When it comes to adjuvant CRT in locally advanced, resected cSCC, the NCCN guidelines do not routinely recommended it based on evidence from the TROG 05.01 trial. However, this is controversial as there are concerns over study design. The TROG 05.01 trial concluded that concurrent carboplatin with postoperative radiotherapy did not improve locoregional recurrence, disease-free survival, or overall survival.¹³ However, it is important to note that the study’s design limits the generalizability of these conclusions. The trial included the use of carboplatin over the widely considered more efficacious cisplatin, which has been suggested to improve outcomes when added to radiotherapy in patients with high risk resected cSCC.¹⁴ Patient eligibility is another important limitation of the study, as evidenced by the favorable outcomes in the control arm of the study. Those patients excluded had the highest-risk disease features, including chronic immunosuppression, more advanced tumor stage and nodal staging, and other histologic markers known to confer high-risk disease such as lymphovascular invasion and satellitosis.^15,16 Including these patients, in addition to using cisplatin, may have afforded different results in favor of a concurrent chemoradiotherapy approach.

Given the limited efficacy and toxicity concerns associated with CRT, newer systemic therapies, such as immune checkpoint inhibitors, have garnered attention for advanced cSCC treatment. In a study by Pickering et al, they identify a high mutation rate as being characteristic of aggressive cSCC, as is the case with advanced cSCC.¹⁷ Given that a high mutational burden, which correlates with an increased number of neoantigens, has been associated with better responses to immune checkpoint inhibitors in other cancers, it goes on to follow that the same principle would apply to cSCC.¹⁸ In recent years, this understanding has significantly altered the landscape of systemic therapy for the treatment of advanced cSCC that is unresectable or not amenable to radiotherapy. Programmed cell death protein 1 inhibitors (PD-1), such as cemiplimab and pembrolizumab, are immune checkpoint inhibitors that have distinct indications for treatment of cSCC. Cemiplimab was approved by the FDA in 2018 for the treatment of patients with metastatic cSCC or locally advanced cSCC who are not candidates for curative surgery or curative radiation. Pembrolizumab, on the other hand, was approved by the FDA in 2020 for the treatment of patients with recurrent or metastatic cSCC that is not curable by surgery or radiation, with locally advanced disease a notable exception.

Immunotherapy in cSCC: Efficacy and Safety

Several studies have demonstrated cemiplimab as a highly effective and safe treatment for patients with locally advanced cSCC. A pivotal study by Migden et al published in the New England Journal of Medicine in 2018 demonstrated that cemiplimab was able to achieve an objective response rate (ORR) of 47% in patients with metastatic disease and 57% of responding patients maintained their response for over 6 months.¹⁹ For locally advanced disease specifically, Migden et al published a study in 2020 that demonstrated an ORR of 44%; 13% of whom achieved a complete response (CR).²⁰ The safety profile demonstrated limited side effects and good tolerability, especially when compared to EGFR inhibitors and cytotoxic chemotherapy.

While cemiplimab has demonstrated impressive response rates, pembrolizumab has also shown promising efficacy, as seen in the KEYNOTE-629 trial. At the time of initial publication, KEYNOTE-629 demonstrated a 34% ORR, with a 10% CR.²¹ The duration of response was not reached at the time of initial data cut off, suggesting that a significant proportion of patients who responded continued to do so for an extended period. However, preliminary 5-year follow-up data from 2024 updated the ORR to 52% in patients with locally advanced disease, with 22% achieving CR.²²

Incorporating Immunotherapy in Locally Advanced Disease

Adjuvant

Historically, 40–50% of patients with high-risk, locally advanced cSCC experience local recurrence and regional metastasis despite receiving standard-of-care surgical resection and adjuvant radiation.¹³ The use of immunotherapy as an adjuvant treatment in patients in this setting is an area of active investigation, with the aim of improving these outcomes. Patient selection, particularly for high-risk, locally advanced disease, is critical; it includes characteristics such as tumor size >2 cm, poor differentiation, perineural invasion, lymphovascular invasion, depth of invasion >6 mm or beyond subcutaneous fat, and tumors located in high-risk areas like the ear, lip, or temple.^23–25 In a study by Kus et al, lymphovascular invasion (LVI) in particular was shown to be an independent predictor of poor outcomes; the study found that tumors with LVI had significantly higher rates of metastasis and disease-specific death as compared to cSCC without LVI.¹⁵ Furthermore, satellitosis or in-transit metastasis, which is not currently part of the staging system of cSCC, was associated with a significantly higher risk of recurrence, similar to the prognosis for patients with nodal involvement.¹⁶ Two ongoing trials, NCT03969004 and NCT03833167, are currently evaluating the addition of immunotherapy following resection and post-operative radiotherapy. Both trials are nearing completion of accrual, and results are eagerly anticipated.

Neoadjuvant

Gross et al published Phase II results of neoadjuvant cemiplimab in patients with resectable stage II to IV cSCC.²⁶ Patients received cemiplimab every three weeks for up to four doses before undergoing surgery with curative intent. The study’s primary end point was a pathological complete response (absence of viable tumor cells in the surgical specimen), and a notable secondary endpoint was pathological major response (presence of viable tumor cells that constitute ≤10% of the surgical specimen). Following the surgery, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone, at the investigator’s discretion.²⁷ Of the 79 patients included in the study, 51% (n=40) showed a pathologic complete response, with long-term follow-up data demonstrating no recurrences at data cut off (approximately 18 months following the conclusion of study enrollment). Thirteen percent (n=10) had a major pathologic response, with long-term data showing that only one patient experienced recurrence.^26,27 To further underscore Gross et al’s findings, another study by Kim et al conducted a cohort study involving 27 patients, investigating the use of neoadjuvant cemiplimab or pembrolizumab in patients with advanced but resectable cSCC. The study found that 47.4% of patients had a pathologic complete response or near complete response.²⁸ Table 1 lists ongoing and upcoming clinical trials registered through ClinicalTrials.gov that are exploring the usage of pembrolizumab in the neoadjuvant setting.

Table 1 Clinical Trials Listed on ClinicalTrials.gov Exploring the Usage of Pembrolizumab in the Neoadjuvant Setting

The RAMPART trial (NCT05574101) is an actively recruiting study that aims to use cemiplimab as a neoadjuvant treatment in unresectable disease, followed by radiotherapy. The study hypothesizes that combining immune checkpoint inhibitors with radiotherapy may lead to synergistic effects through immune modulation, potentially enhancing tumor control and improving outcomes over radiotherapy alone.¹⁸

Discussion

Pembrolizumab was initially approved by the FDA in 2020 for the treatment of recurrent or metastatic cSCC that is not amenable to curative surgery or radiation. This approval was based on the results of the KEYNOTE-629 study which demonstrated an ORR of 50% in the local advanced cohort and durable responses in patients with advanced cSCC overall. Following its initial approval, pembrolizumab has been further evaluated in various settings, including adjuvant therapy after surgical resection and in combination with other modalities like radiation therapy. KEYNOTE-630 is exploring pembrolizumab’s efficacy in the adjuvant setting for patients with locally advanced cSCC, aiming to prevent recurrence in high-risk individuals. Further, there are numerous studies that are exploring pembrolizumab’s possible role as a neoadjuvant treatment for locally advanced cSCC. These trials continue to expand the understanding of pembrolizumab’s role in managing cSCC, with the potential to improve outcomes across different stages of the disease. However, despite its established efficacy, safety, and promising upcoming trial data, patient selection remains critically important for treatment success.

Despite the promising results of the KEYNOTE-629’s study, approximately half of the patients did not respond, and this underscores the importance of patient selection and exploring possible reasons that limit efficacy in select patients.²¹ Factors influencing how a patient may respond to ICI therapy are numerous, but notably include PD-L1 expression, tumor mutational burden (TMB), and variability within the tumor microenvironment. As noted above, high tumor mutational burden (TMB) has been associated with better responses to ICIs – in cancers on a broader scale, but also specifically in cSCC.^18,19,21 What is notable, however, is that early cemiplimab studies, as well as KEYNOTE-629, demonstrated that virtually all cSCC tumors exhibit high TMB, even those that do not respond to immunotherapy.^19,21 One plausible theory is that cancer cell plasticity and the tumor microenvironment (TME) play a critical role in resistance to ICIs. In a study by Lorenzo-Sanz et al, cancer cells can acquire epithelial/mesenchymal plasticity which can thereby alter their immune checkpoint ligand profiles.²⁹ This is important because although epithelial cells primarily utilize the PD-1/PD-L1 pathway for immune evasion, mesenchymal cancer cells utilize the CTLA-4/CD80 and TIGIT/CD155 pathways.³⁰ Thus, different expression of the checkpoints could theoretically lead to partial responses to PD-1 inhibitors. In other words, some patients may need treatments that target different ligands beyond PD-1/PD-L1.

The TME is a dynamic environment that is composed of immune cells, stromal cells, and signaling molecules. Differences in the makeup of a patient’s TME could theoretically impact how a patient responds to ICIs. In a study by Thai et al, memory B-cell-like populations in the peritumoral stroma were associated with better prognosis and better response to ICIs.³¹ This suggests that the overall host immune response significantly impacts response to ICIs and not just the tumor’s mutational profile. Additionally, when considering the TME, there is a concept called “persistent” tumor mutational burden, or pTMB, as introduced by Niknafs et al.³² This suggests that mutations in particular regions of the genome that are unlikely to be lost may contribute to persistent anti-tumor immune responses, which can thereby increase ICI effectiveness. Niknafs et al goes to suggest that tumors with high pTMB are characterized by a more “inflamed” TME, which could be crucial for the effectiveness of ICIs.³² More study is needed here to better understand the role the TME has on ICI response; however, recognizing the TME’s impact on patient responses is crucial for making treatment decisions.

There are notable studies that demonstrate clinical outcomes of combining ICIs and other treatment modalities, namely local therapies such as radiotherapy. In particular, the RAMPART study currently underway takes into account that not all patients will have a robust response to ICI therapy alone. As described above, the study is evaluating a possible synergistic effect of radiation therapy on the increasing efficacy of ICIs. Radiation therapy induces cell death, increasing the release of tumor antigens, which may enhance the immune response. This cell death recruits immune cells within the TME, and this could theoretically “convert” an immunologically less active tumor to an immunologically very active tumor (ie, inflamed environment). This more active environment could theoretically make the tumor more responsive to ICIs. Additionally, a Phase I trial exploring the combination of cemiplimab with hypofractionated radiotherapy reported durable partial and complete responses in a subset of patients with advanced solid tumors, including CSCC.³³ Therefore, integrating radiation therapy with ICIs could be a strategic approach to improve local tumor control, but also stimulate antitumor immunity when a patient does not initially respond to ICI treatment. This may be particularly effective for patients with advanced, inoperable disease. This multimodal approach emphasizes a personalized approach that considers both the TME as well as the tumor’s genetic profile.^34–38

As for patients who are to receive ICI treatment, it must be underscored that there is a cohort of patients who are generally not able to receive PD-1 treatment for locally advanced cSCC, namely organ transplant recipients. Immune checkpoint inhibitors like pembrolizumab are contraindicated due to triggering immune responses that can lead to acute rejection of the transplanted organ. Some studies have shown allograft rejection as high as 65% in patients treated with PD-1 inhibitors.³⁹ Elderly and frail patients are also patients that need special consideration in evaluating candidacy for ICI treatment. In a study by Yakobson et al, they retrospectively studied the efficacy and safety of PD-1 inhibitors, including both cemiplimab and pembrolizumab, in patients over 75 years old. They compared outcomes in immunocompromised versus immunocompetent individuals. The median progression-free survival of the entire cohort was 8.9 months overall, with immunosuppressed patients faring better (10.6 months) as compared to immunocompetent patients (7.5 months). A complete response was achieved in 17% of patients, and a partial response was achieved in 51%. Despite its efficacy, 86% of patients experienced an immune-related adverse event (irAE), most of which were grades 1 or 2. There were no deaths reported. The most common irAEs were fatigue, rash, thrombocytopenia, and myalgias.⁴⁰ Although there was a high rate of irAEs in this population, the high antitumor activity shown was significant. Despite this, caution and extensive counseling for patients in both the elderly and immunocompromised populations is strongly advised.

The usage of ICIs like pembrolizumab has significantly improved outcomes for patients with advanced cSCC, offering many the possibility of curing disease. This is a stark change from the poor outcomes seen with traditional systemic therapy. However, despite these advances, there is a need to improve outcomes for specific patient populations, particularly those who are immunosuppressed or have tumors refractory to currently available immune checkpoint inhibitors. To address these challenges, improved patient selection is necessary to identify those who will benefit most from ICIs, which is backed by ongoing trials continuing to explore novel uses of pembrolizumab. Continued research and personalized approaches are essential to fully realize the potential of pembrolizumab in improving outcomes for patients with advanced cSCC.