Squamous cell carcinoma of the skin is a clinical challenge, affecting both the well-being and survival of patients. Our study explores the real-world effectiveness of cemiplimab, a monoclonal antibody targeting the PD-1 receptor, in the treatment of advanced SCC. Through a retrospective analysis of a dataset encompassing 50 patients with SCC, we aimed to shed light on the practical application and effectiveness of cemiplimab within diverse clinical contexts. Our patient cohort consisted of 50 individuals, primarily elderly with a median age of around 83 years, and predominantly male (66%). Importantly, almost all patients (96%) were aged 65 years or older at the initiation of cemiplimab therapy. This demographic distribution underscores the relevance of our study in the context of a patient population often underrepresented in clinical trials. Encouragingly, our findings demonstrated that 42% of the patients who received at least one cycle of cemiplimab exhibited a clinical partial or complete response, with a median PFS of approximately 20 months and a median OS that was not reached. A central aspect of our analysis involved conducting univariate analyses to better understand the interplay of multiple factors in predicting treatment outcomes. When considering the influence of tumor location, age, and distant metastasis on clinical response, we found that the absence of distant metastasis was a significant predictor of a clinical response even after adjusting for other significant variables. Patients without distant metastasis had significantly higher odds of responding to cemiplimab treatment. This multivariate analysis reaffirms the importance of distant metastasis as a critical predictor of cemiplimab response in advanced SCC. Importantly, our analysis revealed that age, whether analyzed using arbitrary or median cutoffs, was not associated with either PFS or OS. This observation suggests that cemiplimab demonstrates effectiveness and tolerability across a wide age range, including the elderly. The lack of an association with age implies that the primary determinant of progression and mortality is not age itself but rather the underlying disease.

Overall, our results align with the growing body of evidence supporting the effectiveness of cemiplimab in the treatment of advanced SCC [7, 8]. Furthermore, the toxicity profile of cemiplimab in our study was notably favorable, with a low incidence of adverse events, suggesting its tolerability and safety in this patient population. In a pivotal phase 2, single-arm trial [9] conducted across 25 outpatient clinics in Australia, Germany, and the USA, cemiplimab demonstrated significant antitumor activity and an acceptable safety profile in patients diagnosed with locally advanced SCC of the skin. A total of 78 eligible patients aged 18 years or older, with histologically confirmed locally advanced cutaneous squamous cell carcinoma (cSCC) and an Eastern Cooperative Oncology Group performance status of 0–1, received cemiplimab intravenously at a dose of 3 mg/kg every 2 weeks for a maximum of 96 weeks. Findings from this study revealed a notable objective response in 44% (34 of 78) of the enrolled patients. Within this responsive group, 13% achieved a complete response, while 31% exhibited a partial response. Notably, grade 3–4 treatment-emergent adverse events were documented in 44% of patients, with hypertension affecting 8% and pneumonia occurring in 5% of cases. Furthermore, serious treatment-emergent adverse events were noted in 29% of patients. Importantly, one treatment-related death was reported, which was attributed to aspiration pneumonia. Importantly, the final analysis of the study [7] confirmed consistent and durable responses. The results displayed a remarkable OS rate at 48 months, with 61.8% (95% CI 54.0–68.7), underscoring the long-term effectiveness of cemiplimab in treating advanced cSCC. The median duration of response (DOR) was also substantial, with an overall median of 41.3 months.

Conversely, in a retrospective observational study [10], Baggi and colleagues examined the real-world data of cemiplimab in the treatment of locally advanced and metastatic SCC of the skin. The study encompassed patient records from 17 referral Italian centers, covering the period between May 2019 and February 2020. A total of 131 patients, with a median age of 79 years, were included in the analysis. Among them, 9.2% had concurrent chronic lymphoproliferative diseases, and 8.5% had concomitant autoimmune diseases. The safety profile was assessed on the basis of Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), with 42.7% of patients experiencing at least one treatment-related adverse event (AE). Notably, 9.2% of patients encountered grade 3–4 adverse events, and two fatal adverse events were reported. The study revealed an overall response rate (ORR) of 58% and a disease control rate (DCR) of 71.7% among the patients. In another recent study, Denaro et al. [8] investigated the use of cemiplimab in ultra-octogenarian patients with cSCC at a tertiary referral center. The study included 20 patients, with a median age of 86.9 years, and assessed the efficacy and safety of cemiplimab treatment. Despite advanced age and comorbidities, the results indicated that cemiplimab was effective in this patient population, with a 65% response rate, including partial responses and long-lasting stable disease. The median duration of response was 14 months, and no treatment-related adverse events of grade 3 or higher were reported [8].

Importantly, in a phase 2 study exploring the neoadjuvant use of cemiplimab in resectable stage II–IV SCC of the skin [11], Gross and colleagues observed a substantial pathological complete response rate of 51%, indicating the potential effectiveness of cemiplimab in this context. In another study, multivariate analysis revealed a notable correlation between elevated serum interleukin (IL)-6 levels and shorter PFS, establishing IL-6 as an independent predictive factor for cemiplimab response [12]. Another clinical trial examining first-line pembrolizumab monotherapy for unresectable SCC of the skin suggested that PD-L1 positivity might serve as a predictive factor for a positive response to anti-PD-1 agents, such as cemiplimab. Specifically, the trial demonstrated that patients who were PD-L1-positive exhibited a significantly higher response rate (55%) compared to their PD-L1-negative counterparts (17%) [13].

It is crucial to recognize and address the limitations of our study. First, the retrospective nature of our research introduces inherent biases and prevents the establishment of causal relationships. Notably, the retrospective design may have led to an underestimation of toxicity. Furthermore, it is important to emphasize that this retrospective study lacked the availability of biomarkers for investigation. However, despite these limitations, the study’s strengths, including the sample size for a rare condition and the reflection of a real-world scenario, provide valuable insights into the practical application of cemiplimab.