Abstract
Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Surgery is the standard of care with curative intent of localized disease; however, for large head and neck cSCCs, it is associated with high morbidity. Cemiplimab, an antibody anti programmed cell death-1 (PD-1) protein, is effective in locally advanced unresectable or metastatic cSCC. A pilot study demonstrated a high rate of pathologic complete response using cemiplimab in the neoadjuvant setting. Case Presentation: Here, we report the case of an 84-year-old man with two locally advanced unresectable cSCCs (a nasolabial lesion and a retroauricular lesion) treated with cemiplimab, for whom closer follow-up revealed a complete response of the retroauricular lesion and a partial response of the nasolabial lesion after 4 cycles. Patient will be submitted to nasolabial lesion resection. Conclusion: This illustrates the efficacy of the use of cemiplimab as preoperative therapy in advanced unresectable cSCC, facilitating a definitive surgical treatment.
Introduction
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence has been increasing. Risk factors include chronic sun exposure, advanced age, and immunosuppression. These lesions typically affect photoexposed areas, such as the head and neck [1]. In localized disease, which corresponds to 95% of cases, surgery is the gold standard of curative treatment, with a disease-free survival at 5 years greater than 90%. Radiotherapy (RT) is an alternative as definitive treatment if surgical therapy is not feasible, contraindicated, or not preferred by the patient [2]. However, surgery of large lesions in the head and neck area is associated with high morbidity, with esthetic and functional consequences and an important impact on the quality of life [1]. The use of cemiplimab – an anti-PD-1 monoclonal antibody – is approved by European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) as palliative treatment for locally advanced and metastatic cSCC treatment in patients who are not candidates for curative surgery or radiation [3]. Considering the effectiveness of cemiplimab in advanced or metastatic disease, the use of this therapy in the neoadjuvant setting was tested in patients with resectable disease stage II, III, or IV (M0) in which a complete response was seen in 51% of patients, with a maximum of 4 administrations, reporting manageable toxicity [4].
There are several ongoing trials to access the potential of PD-1 inhibitors in the neoadjuvant setting. The MATISSE trial, which included patients with cSCC with an indication for extensive surgery with or without adjuvant RT, reported a major pathological response or clinical response of 50% and 61% upon two cycles of neoadjuvant nivolumab and two cycles of nivolumab plus ipilimumab, respectively [5]. The NEO-CESQ study reported a pathological response of 52% and a major pathological response of 48% with the use of neoadjuvant plus adjuvant cemiplimab in surgically resectable high-risk stage III/IV (M0) cSCC [6]. A similar study with neoadjuvant and adjuvant pembrolizumab in locally advanced resectable cSCC showed a 57% rate of pathologic complete response but reported one possible grade 5 cardiac immune-related adverse event [7]. Here, we describe a case of an 84-year-old man with two unresectable advanced cSCCs treated with cemiplimab for four cycles with an exceptional response leading to conversion of one lesion to resectable and a complete response of the other, turning a palliative treatment into a perioperative strategy.
Case Presentation
An 84-year-old male was referred to our center because of two lesions with fast growth, one on the nasolabial right region with 50 mm and other on the retroauricular left region with 40 mm (Fig. 1a). A fine needle aspiration cytology of the two lesions was performed and confirmed the diagnosis of cSCC. Patient had a previous history of several excisions of basal cell carcinomas and cSCCs of the head and neck region, namely, two cSCCs in the nasal pyramid in 2008 and 2013, both well-differentiated, without lymphovascular or perineural invasion, and with negative margins; he received adjuvant RT in this location in 2013. In 2020, two right anterior cervical lesions were excised with a diagnosis of cSCC with low-risk profile. He had numerous medical comorbidities, including coronary artery disease, hypertension, pacemaker carrier, diabetes mellitus type II, hyperlipidemia, and hyperuricemia. The head and neck computed tomography scan confirmed a nasolabial lesion with 57 × 54 × 16 mm and a retroauricular lesion with 40 × 16 × 46 mm and excluded lymph node involvement and bone invasion – cT3N0 – stage III disease. The patient was evaluated at the multidisciplinary team meeting, and 3 weeks after the initial evaluation, the nasolabial tumor and the retroauricular tumor measured 60 mm and 70 mm, respectively. Due to the extension and localization of the lesions, it was considered that upfront resection would compromise the nose, mouth, and eye function, and given the unresectability and location in a previously irradiated area, an anti-PD-1 monoclonal antibody trial was proposed as a palliative strategy. The patient was treated with 4 cycles of cemiplimab 350 mg every 3 weeks (Fig. 1b–d). The only toxicity reported was generalized pruritus that was controlled with bilastine. After four cycles, the patient exhibited a complete response of the retroauricular lesion and a partial response of the nasolabial lesion and he was proposed for surgery of the nasolabial lesion (Fig. 1d). A brief illustrative timeline of the clinical case is included (Fig. 2). The CARE Checklist has been completed by the authors for this case report and it is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540842).
Discussion
cSCC is a common skin cancer with an uprising incidence, affecting older individuals and immunocompromised patients, with several comorbidities that could affect the feasibility and results of surgical treatment. In locally advanced or metastatic disease, the approval of immune checkpoint inhibitors (ICIs) has enabled pathological responses with manageable toxicity in the majority of patients, but the selection of patients who will benefit from this strategy is still a challenge, which will increase even more with the possible approval of this therapy in a neoadjuvant context. Despite the advances in immunotherapy, the development of biomarkers as predictors of response to improve patient selection is still less clear. There are tissue-based biomarkers that do not reflect the entire status of the immune system, and peripheral blood-based biomarkers, which have been the subject of greater interest because they reflect the activation of the immune system [8]. Prognostic scores related to inflammatory response have been studied as predictors of response to ICI, such as Glasgow Prognostic Score, which showed potential to predict survival in patients treated with ICI, but more trials are necessary to validate its use [9].
The results of using immunotherapy in patients with unresectable locally advanced or metastatic disease, including real life studies, demonstrate the possibility to manage cSCC with safety and effectiveness, reaching results comparable to those obtained in clinical trials with overall response rates of 45% [10]. These patients need a close surveillance of immune-related toxicity, but the rate of grade 3 or higher adverse events is low.
There is also evidence that the concomitant use of cemiplimab and RT is beneficial in advanced cSCC with earlier clinico-radiological responses and prolonged treatment response despite discontinuation of cemiplimab [11]. These promising results in the advanced disease setting have led to a trial to assess the efficacy of cemiplimab as neoadjuvant treatment, showing a pathological complete response rate of 51% and a pathological major response rate of 13%. The safety data describe a rate of grade 3 or higher adverse events of 18% [4]. The correlation between immune-mediated adverse events and the efficacy of immunotherapy is still unclear and is often disturbed by the immortal time bias [12].
We report here a clinical complete response of one lesion, which allowed the patient to avoid surgery, and a partial response of another lesion allowing a less mutilating surgery. In this case, we observed a clinical response in the first cycles of immunotherapy, but this assessment may be difficult in other patients due to the possibility of pseudoprogression, in which a transitory dimensional lesion increase secondary to tumor inflammation may be observed. This phenomenon must be distinguished from hyperprogression in which the tumor aggressiveness itself or the use of immunotherapy (with amplification of MDM2 signaling) results in permanent tumor growth and is associated with a worse prognosis [13]. To date, there is no approval for the use of cemiplimab in a neoadjuvant setting, but trial results are encouraging and would improve the results of surgical treatment.
Immunotherapy is known for its long-term response even after discontinuation [14]. A better understanding of the time to first response and maximum response is critical to evaluate treatment efficacy and may lead to optimization of treatment duration. Therefore, the duration of complete responses must be examined and the strategy for relapsed cSCC has to be defined. Will there be a role for a rechallenge with immunotherapy or is surgery mandatory? Considering that RT appears to have a synergistic effect with cemiplimab, can this combination be used in patients with high surgical risk?
Conclusion
This case illustrates a significant early clinical response to cemiplimab, which allowed the conversion of a palliative strategy with immunotherapy into a curative surgical treatment, providing new insights into the kinetics of response to this medication. Further investigations are warranted to determine whether differences in time to first response correlate with tumor burden, overall maximal response, and prognosis. For this reason, patients with multiple cSCCs or with extensive relapsed disease should be referenced to specialized centers, where treatment is tailored to each patient.
Statement of Ethics
Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. Ethical approval is not required for this case report in accordance with local or national guidelines.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Sara Cabral: manuscript preparation, data collection, and literature search. Patrícia Pereira, Hugo Nunes, and Emanuel Gouveia: manuscript revision. All authors read and approved the final manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.