FLEX November 2023

The new england journal of medicine

C utaneous squamous-cell carcino ma is the second most common form of skin cancer worldwide, with approxi mately 2.4 million new cases and 56,000 deaths in 2019. 1 From 1990 through 2019, the overall incidence increased by more than 200%. 1 Most patients with cutaneous squamous-cell carcinoma present with early-stage disease that can be successfully treated with surgery alone. 2 A small percentage of patients present with loco regionally advanced disease or disease with ad verse histopathological features, which may be treated with adjuvant radiation therapy and pos sibly systemic therapy, in addition to surgery. 3 Cutaneous squamous-cell carcinoma most com monly develops in sun-exposed areas, such as the head and neck, where surgical extirpation may lead to disfiguration. 4-7 Thus, treatment can have a profound effect on psychosocial function ing and quality of life. 8-10 Cemiplimab, an anti–programmed cell death 1 (PD-1) monoclonal antibody, has been approved for the treatment of metastatic or locally ad vanced cutaneous squamous-cell carcinoma for which no curative local treatment options are available. In studies involving patients with advanced cutaneous squamous-cell carcinoma, cemiplimab was associated with an objective response in 44 to 50% of patients, along with durable disease control and improved patient reported quality of life. 11-13 Other PD-1 inhibitors have also been shown to have activity in patients with advanced cutaneous squamous-cell carci noma. 14,15 A potential reason for the exceptional responsiveness of cutaneous squamous-cell car cinoma to immunotherapy is a high tumor mu tational burden due to sun-related ultraviolet mutagenesis. 16 Currently, no role has been estab lished for any systemic therapy as a curative treatment option for cutaneous squamous-cell carcinoma. The promising results associated with the use of immunotherapy for advanced cutaneous squa mous-cell carcinoma prompted interest in assess ing the use of neoadjuvant immunotherapy for resectable cutaneous squamous-cell carcinoma. In a single-institution pilot study involving the administration of two doses of neoadjuvant ce miplimab in 20 patients with resectable stage III or IV (M0) cutaneous squamous-cell carcinoma, a pathological complete response was observed

in 55% of the patients. 17 The current phase 2, multicenter study was designed to provide con firmatory data and formally assess the efficacy of up to four doses of neoadjuvant therapy with cemiplimab for resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma.

A Quick Take is available at NEJM.org

Methods

Study Oversight The study protocol (available with the full text of this article at NEJM.org) was approved by the appropriate institutional review board or inde pendent ethics committee at each participating study site. The study was conducted in accor dance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent. The study sponsors were Regeneron Pharma ceuticals and Sanofi. The study was designed by employees of Regeneron Pharmaceuticals in col laboration with the authors. The data were col lected by investigators, analyzed by statisticians who were employed by the sponsors, and inter preted by the authors, including employees of Regeneron Pharmaceuticals. The authors had unrestricted access to the data and were respon sible for all content. The first draft of the manu script was prepared by a medical writer who was paid by Regeneron Pharmaceuticals. Thereafter, the first draft was critically reviewed and exten sively revised by the authors. The authors vouch for the accuracy and completeness of the data and the fidelity of the study to the protocol. Study Population Patients 18 years of age or older were eligible for inclusion in the study if they had resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma for which primary surgery would be recommended in routine clinical practice. Tumor– node–metastasis (TNM) staging of cutaneous squamous-cell carcinoma with involvement of the head and neck was based on the eighth edi tion of the American Joint Committee on Cancer Stag ing Manual , 18 and TNM staging of cutaneous squamous-cell carcinoma without involvement of the head and neck was based on the ninth edition of the Union for International Cancer Control Manual of Clinical Oncology . 19 The metastasis stage

1558

n engl j med 387;17 nejm.org october 27, 2022

The New England Journal of Medicine Downloaded from nejm.org on October 30, 2023. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved.