References 1. Breuninger H et al. J Dtsch Dermatol Ges. 2013;11 Suppl 3:37–45, 39–47. 2. Stratigos AJ et al. Eur J Cancer. 2015;51:1989–2007. 3. Porceddu SV et al. J Clin Oncol. 2018;36:1275–1283. 4. Regeneron Pharmaceuticals, Inc. LIBTAYO® (cemiplimab-rwlc) injection, for intravenous use [US prescribing information]; 2021. Available at: https://www. accessdata.fda.gov/drugsatfda_docs/label/2021/761097s007lbl.pdf. Accessed January 28, 2022. 5. Health Canada. LIBTAYO® – Notice of compliance with conditions – qualifying notice; 2019. Available at: https://www.canada.ca/en/health-canada/services/ drugs-health-products/drug-products/notice-compliance/conditions/libtayo- notice-compliance-conditions-218718.html. Accessed January 28, 2022. 6. Brazilian Health Authority – ANVISA. Libtayo (Cemiplimab): new indication; 2021. Available at: https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/ novos-medicamentos-e-indicacoes/libtayo-cemiplimabe-nova-indicacao. Accessed January 28, 2022. 7. Ministry of Health Israel. The Israeli Drug Registry – LIBTAYO; 2019. Available at: https://israeldrugs.health.gov.il/#!/medDetails/164%2099%20 36023%2000. Accessed January 28, 2022. 8. Regeneron Pharmaceuticals, Inc. Libtayo® (cemiplimab) approved by the European Commission as the first immunotherapy indicated for patients with advanced basal cell carcinoma; 2021. Available at: https://www.prnewswire.com/news-releases/libtayo-cemiplimab- approved-by-the-european-commission-as-the-first-immunotherapy- indicated-for-patients-with-advanced-basal-cell-carcinoma- 301319988.html. Accessed January 28, 2022. 9. Migden MR et al. N Engl J Med. 2018;379:341–351. 10. Migden MR et al. Lancet Oncol. 2020;21:294–305. Background Cutaneous squamous cell carcinoma (CSCC) • Surgical resection is a standard treatment option for the management of CSCC with a cure rate of >95%. Some patients, however, have high risk of recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension, and prior treatment.1,2 • Postoperative radiation therapy is recommended for patients with high-risk features, but relapse with locoregional recurrence or distant metastases may still occur.3 Cemiplimab • Cemiplimab is an anti−programmed cell death-1 (PD-1) antibody approved in the US and Europe for the treatment of patients with locally advanced or metastatic CSCC who are not candidates for curative surgery or radiotherapy and is approved or under review by other health authorities.4–8 • Results from the Phase 1 (NCT02383212) and Phase 2 (NCT02760498) trials of cemiplimab generally demonstrated a clinically meaningful activity and an acceptable safety profile in patients with advanced CSCC consistent with other anti–PD-1 agents.9,10 • The C-POST study evaluates the efficacy of cemiplimab as adjuvant therapy for patients with high-risk CSCC following surgery and postoperative radiation. Here, we present the most recent study protocol amendment. Table 2. Key exclusion criteria • Squamous cell carcinoma arising from non-cutaneous sites (note: patients with parotid SCC are not excluded if impression of the investigator is that it arose from primary cutaneous lesion) • Concurrent malignancy other than localized CSCC or history of malignancy other than localized CSCC within 3 years of date of randomization, except for tumors with negligible risk of metastasis or death • Hematologic malignancies except for patients with CLL who have not required treatment within ≥6 months • History of solid organ transplant except corneal transplants CLL, chronic lymphocytic leukemia; CSCC, cutaneous squamous cell carcinoma; SCC, squamous cell carcinoma. Table 1. Key inclusion criteria • ≥18 years old (in Japan only: ≥21 years old) • Resection of pathologically confirmed CSCC, with macroscopic gross resection of all diseased area • High-risk CSCC, defined by at least one of the categories presented in Figure 2 • Completion of postoperative radiation therapy (≥50 Gy) within 2–10 weeks of randomization • ECOG performance status of 0 or 1 • Adequate hepatic, renal, and bone marrow function CSCC, cutaneous squamous cell carcinoma; ECOG, Eastern Cooperative Oncology Group. Patient eligibility Summary • Patients with high-risk CSCC often experience relapse with locoregional recurrence or distant metastases. There is an unmet need to reduce the risk of CSCC recurrence in these patients after curative surgery or radiation. • The C-POST study is evaluating the efficacy of cemiplimab as adjuvant therapy for patients with high-risk CSCC after surgery and postoperative radiotherapy. • This study is once again open for enrollment following interruptions owing to the COVID-19 pandemic. Figure 1. C-POST study design †Cemiplimab after disease recurrence permitted if protocol-specified criteria are met. Q3W, every 3 weeks; Q6W, every 6 weeks; RT, radiation therapy. Radiation therapy treatment plan analysis • Post-operative radiation therapy (RT) is delivered following complete macroscopic resection of high-risk CSCC of head and neck (HN) and non-HN sites, prior to enrollment and randomization into the study. Some patients will enter the study after having received RT at sites that are not participating centers. • A minimum set of RT details will be collected on all patients in the case report forms. Additionally, retrospective random RT treatment plan review will be performed on approximately 20% of study patients, including the first enrolled in each site whenever possible. This review will be performed by the Trans Tasman Radiation Oncology Group (TROG) Radiation Therapy Treatment Plan Review Committee (RTTPRC). • A checklist of the source data required for each selected case will be provided by the RTTPRC. This checklist can also be accessed via the TROG website (www.trog.com.au). • Intensity-modulated radiotherapy is preferable, particularly for HN sites, but all forms of RT including three-dimensional conformal radiotherapy and electron beam therapy are acceptable. Acknowledgments Editorial writing support was provided by Sameen Yousaf, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Disclosure Danny Rischin reports institutional research grant and funding from Regeneron Pharmaceuticals, Inc., Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Merck KGaA, Bristol-Myers Squibb, and GlaxoSmithKline; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; and travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. Presented at Winter Clinical Derm 2023, January 13–18, 2023 (encore of previous presentation at the European Association of Dermato Oncology [EADO] Congress, April 21–23, 2022, Rischin D et al.). Reused with permission. C-POST protocol update: A Phase 3, randomized, double-blind study of adjuvant cemiplimab versus placebo post surgery and radiation therapy in patients with high-risk cutaneous squamous cell carcinoma Danny Rischin,1 Daniel Brungs,2 Fiona Day,3 Hayden Christie,4 Vishal A Patel,5 Gerard Adams,6 James Estes Jackson,7 Maite De Liz Vassen Schurmann,8 Dmitry Kirtbaya,9 Thuzar M Shin,10 Christopher D Hart,11 Elizabeth Stankevich,12 Siyu Li,12 Israel Lowy,12 Hyunsil Han,12 Priscila Gonçalves,12 Matthew G Fury,12 Sandro V Porceddu13 1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; 2Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, Australia; 3Department of Medical Oncology, Calvary Mater Newcastle, Waratah, Australia; 4Cancer Care Centre Hervey Bay, Urraween, Australia; 5Institute for Patient-Centered Initiatives and Health Equity, George Washington University School of Medicine & Health Science, Washington, DC, USA; 6Genesis Cancer Care, Bundaberg, Australia; 7Radiation Oncology Centers, Gold Coast, Australia; 8Animi Oncology Treatment Unit, University Planalto Catarinense (UNIPLAC), Centro, Lages, Brazil; 9State Budgetary Institution of Health Oncology Dispensary No. 2, Krasnodar, Russia; 10Department of Dermatology, Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, PA, USA; 11St Vincent’s Hospital Melbourne, Fitzroy, Australia; 12Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 13School of Medicine, University of Queensland, Herston, Australia, and the Department of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Australia Methods Study design • C-POST is a randomized, placebo-controlled, double-blind, multicenter Phase 3 study comparing cemiplimab versus placebo as adjuvant therapy for patients with high-risk CSCC after surgery and postoperative radiation (NCT03969004). The revised study design is shown in Figure 1. Treatment The study consists of two parts: • Part 1: Randomized (1:1), double-blind, placebo-controlled. • Part 2: Optional open-label cemiplimab treatment (for patients who experience disease recurrence). Outcome measures • Primary endpoint: Disease-free survival (DFS). • Secondary endpoints: Overall survival (OS), freedom from locoregional and distant recurrence, cumulative occurrence of secondary primary tumors, and safety. • Exploratory endpoints: Pattern of failures, geographic variations in administration of postoperative radiation, health-related quality of life, molecular characterization of pretreatment tumor samples, and circulating tumor DNA detection. Surgery, with high-risk features on surgical pathology report Completion of post-operative RT Patient information cards Informed consent and screening Completion of RT within 2–10 weeks N=412 Randomize 1:1 Cemiplimab for up to 48 weeks: 350 mg Q3W for 12 weeks, followed by 700 mg Q6W for 36 additional weeks Placebo for up to 48 weeks: Q3W for 12 weeks, followed by Q6W for 36 additional weeks Primary endpoint: disease-free survival† Figure 2. High-risk CSCC features †Defined as extension through the lymph node capsule into the surrounding connective tissue with or without associated stromal reaction. CSCC, cutaneous squamous cell carcinoma; ECE, extracapsular extension; HN, head and neck. High-risk CSCC features *Additional features: • ≥N2b disease associated with the recurrent lesion • Nominal ≥T3 (recurrent lesion ≥4 cm in diameter or minor bone erosion or deep invasion >6 mm measured from the granular layer of normal adjacent epithelium) • Poorly differentiated histology and ≥20 mm diameter of recurrent lesion. The recurrent lesion must be documented to be within the area of the previously resected CSCC by radial measurement of the greatest radius of the final defect, measured from the estimated center of the original surgical wound Recurrent CSCC • CSCC that arises within the area of the previously resected tumor, plus ≥1 additional feature* Inclusion 3e Perineural invasion • Clinical and/or radiologic involvement of named nerves Inclusion 3d T4 lesion • Including HN and non-HN lesions Inclusion 3c In-transit metastases • Skin or subcutaneous metastases that are >2 cm from the primary lesion but are not beyond the regional nodal basin Inclusion 3b Nodal disease with ECE† and ≥1 node ≥20 mm and/or ≥3 lymph nodes regardless of ECE • Per surgical pathology report Inclusion 3a Scan the QR code for co-author disclosures.