Neoadjuvant Immunotherapy in the Management of Cutaneous Squamous Cell Carcinoma

Christopher Guirguis, DMD¹; Lauren Ching, BS¹; Mariana Phillips, MD^2,3

¹Georgetown University School of Medicine, Washington, DC, USA
²Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
³Carilion Clinic Dermatology and Mohs Surgery, Roanoke, VA, USA

Disclosure: The authors indicate no conflicts of interest related to this manuscript and have not received any compensation for this manuscript.

Abstract

Immunotherapy has shown promise in treating locally advanced, recurrent, and metastatic cutaneous squamous cell carcinoma. More recently, studies have shown the role of immunotherapy as neoadjuvant treatment in advanced disease for which surgery may not be curative or would be expected to result in functional or cosmetic morbidity. This paper reviews data showing the safety and efficacy of cemiplimab as neoadjuvant treatment in cutaneous squamous cell carcinoma. Early findings suggest that neoadjuvant immunotherapy may help improve surgical outcomes by reducing tumor burden before resection.

Keywords: neoadjuvant, immunotherapy, cutaneous squamous cell carcinoma, cemiplimab

Introduction

Neoadjuvant immunotherapy involves administration of a systemic agent, given before definitive surgery or radiation treatment of the primary cancer, with the intent of boosting the anti-cancer immune response. The treatment not only targets the primary cancer, but may reach cancer cells present in the circulation or at distant sites.^1,2 Cemiplimab, an anti-programmed cell death 1 (PD-1) monoclonal antibody, has been approved for treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) for patients who are not candidates for curative surgery or radiation. Some CSCC tumors are resectable, but due to the location or extent of the tumor, surgery may produce significant functional and cosmetic impairment. More recently, studies have shown favorable outcomes of resectable stage II to IV CSCC treated with neoadjuvant cemiplimab.^3-5 Given the known response of advanced CSCC to immunotherapy, this paper serves to review the literature relating to cemiplimab as neoadjuvant treatment in resectable CSCC.

Discussion

Supporting Evidence for Anti-PD-1 Checkpoint Inhibitors as Neoadjuvant Treatment for Resectable Cutaneous Squamous Cell Carcinoma

In a pilot, phase 2, single institution study, the safety and efficacy of neoadjuvant PD-1 inhibition in locoregionally advanced, resectable CSCC was assessed.⁴ Patients with newly diagnosed or recurrent stage III-IVA CSCC on the head and neck (n=20) were recruited to undergo treatment with two cycles of intravenous cemiplimab 350 mg every 3 weeks prior to surgery. All patients underwent definitive surgery, based on the original extent of the tumor, at least 21 days after the final dose of neoadjuvant therapy. All patients were planned for post-operative radiotherapy. Patients were enrolled in the study from July 2018 to February 2019 and followed for a median period of 22.6 months.

The primary endpoint studied was the overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1. The ORR was assessed using baseline and post treatment imaging after two rounds of cemiplimab. The ORR among participants was 30% and all imaging responses were considered partial.

Secondary endpoints studied included pathologic response, disease-specific survival (DSS), disease free survival (DFS), overall survival (OS), time to recurrence, and patterns of failure. Pathological complete response (PCR) was defined by absence of viable tumor in the post-treatment surgical specimens and major pathological response (MPR) was defined as 10% or less viable tumor in the resection specimen. Interestingly, pathological response did not correlate with imaging and 70% (n=14) of patients achieved either PCR or MPR. Over half of the patients (n=11) were recommended to forgo the adjuvant radiotherapy that was previously planned based on their pathological response.

Interestingly, in patients achieving complete and MPR, analysis of pretreatment biological specimens revealed an inflamed tumor immune microenvironment, based on gene expression profiles, indicating higher infiltration of T cells and immune related genes. In contrast, an immunosuppressive tumor microenvironment was noted in patients with stable or progressive disease.

Assessment of OS, DFS, and DSS was greater than 90% at 12 months. The survival data is summarized in Table 1. Safety was also assessed with monitoring for adverse effects for 30 days after the final injection of cemiplimab, with no significant adverse events noted.⁴

Table 1:

The results of this early pilot study showing efficacy of neoadjuvant cemiplimab were supported in a phase 2, multicenter, single-arm study.⁵ In this phase 2 study, patients with resectable stage II, III, or IV CSCC were recruited (n=79) and given intravenous cemiplimab 350 mg every 3 weeks (for a maximum of up to four doses) prior to surgery with curative intent. Sixty percent of the patients presented with nodal metastasis but patients with distant metastasis were not included and there was no control arm. All four doses of neoadjuvant cemiplimab were given to 78% (n=62) of the patients with a median follow-up of 9.7 months. Most of the patients had tumors on the head and neck (91%). Seventy of the 79 enrolled patients proceeded to surgery.

The primary endpoint studied was PCR, defined as the absence of viable tumor cells in the surgical specimen upon review from an independent laboratory. Secondary endpoints studied included MPR, defined as 10% or less viable tumor in the resection specimen, response on imaging, and safety. The PCR and MPR rates among participants were 51% (n=40) and 13% (n=10), respectively. Complete or partial response on imaging was seen in 68% (n=54). A PCR was noted in 51% of patients while only 5% of patients showed complete response on imaging. Of note, while some discrepancy existed between response on imaging and laboratory assessments, the response noted on imaging spared two patients orbital exenteration. An adverse event of any grade attributed to the treatment was observed in 72% (n=57), with fatigue, maculopapular rash, and diarrhea being the most common. Grade 3 immune related events occurred in 4% (n=3). Four fatal events were observed in the study, with one event (exacerbation of heart failure) considered to be possibly related to the treatment.⁵

This study also investigated the pathological response as it relates to PD-L1 (programmed death ligand 1) expression on tumor cells. Although pathological response was observed in both PD-L1 negative and positive patients, patients with PD-L1 expression on less than 1% of tumor cells showed a lower PCR (20% response compared to 54% response in PD-L1 positive patients).⁵

A follow-up to the aforementioned multicenter study reported further significant data including event-free survival (EFS), DFS, OS, and adverse events.³ The median follow-up period for the enrolled cohort was 18.7 months. At the discretion of the investigator, patients received adjuvant cemiplimab for up to 48 weeks (23%), radiotherapy (24%), or observation (46%) following curative intent surgery. Post-surgical management data was not available for 7% of subjects. Of patients with PCR, none had a recurrence, and of patients that achieved MPR, 10% (n=1) had a recurrence. EFS was defined as time to progressive disease that precluded surgery, inability to undergo complete resection, disease recurrence, or death due to any cause. The Kaplan-Meier analysis estimated EFS for the entire enrolled cohort (n=79) was 89% and 85% at 12- and 24-months, respectively. Furthermore, the Kaplan-Meier estimated 12-month DFS and OS for those patients who underwent surgery with curative intent following enrollment (n=70) was 92% and 92%, respectively. Four of the 16 patients receiving adjuvant cemiplimab (following curative intent surgery) had grade 3 adverse events, however no grade 4 or treatment-related deaths occurred.³ The results of this study are summarized in Table 1.

Conclusion

Neoadjuvant cemiplimab has been shown to be both safe and effective in the management of resectable CSCC, with trials reporting encouraging rates of pathologic response and survival outcomes. These results highlight the utility of neoadjuvant cemiplimab in achieving disease control and potentially facilitating function-preserving surgical interventions. Neoadjuvant cemiplimab should be considered in cases where surgery carries a high morbidity or where surgery may not be curative. Although some patients may be cured by immunotherapy alone, based on observed pathological complete response rates, the current standard of care remains surgery followed by the consideration of adjuvant radiotherapy. The data also emphasize the importance of tissue-based assessments in evaluating treatment responses, given the observed discordance between imaging-based and pathologic response rates. Such discordance may be attributed to the unreliability of imaging to distinguish between viable tumor and immune-related changes, making pathologic assessment the continued gold-standard for evaluating treatment response in neoadjuvant immunotherapy trials.

Further research investigating the influence of neoadjuvant therapy on improving postsurgical outcomes and patterns of recurrence will aid in refining its application. Absence of a control group is a limitation of both studies reviewed above. These studies provide a foundation for the role of neoadjuvant cemiplimab in CSCC and underscore the need for continued research.

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