References 1. Karia PS et al. J Am Acad Dermatol. 2013;68:957–966. 2. Stratigos AJ et al. Eur J Cancer. 2020;128:60–82. 3. Que SKT et al. J Am Acad Dermatol. 2018;78:237–247. 4. Burova E et al. Mol Cancer Ther. 2017;16:861–870. 5. Regeneron Pharmaceuticals, Inc and Sanofi-Aventis US LLC. LIBTAYO® [cemiplimab-rwlc] injection full US prescribing information; 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761097s007lbl.pdf. Accessed August 31, 2022. 6. European Medicines Agency. LIBTAYO® EPAR; 2022. Available at: https://www.ema.europa.eu/en/documents/product-information/libtayo-epar- product-information_en.pdf. Accessed August 31, 2022. 7. 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 August 31, 2022. 8. Ministry of Health Israel. The Israeli Drug Registry - LIBTAYO®; 2021. Available at: https://mohpublic.z6.web.core.windows.net/IsraelDrugs/ Rishum01_1_1299478321.pdf. Accessed August 31, 2022. 9. Stratigos AJ et al. Eur J Cancer. 2020;128:83–102. 10. National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Squamous Cell Skin Cancer (Version 2.2022); 2022. Available at: https://www.nccn.org/professionals/ physician_gls/pdf/squamous.pdf. Accessed August 31, 2022. 11. Rischin D et al. J Immunother Cancer. 2021;9:e002757. 12. Migden MR et al. N Engl J Med. 2018;379:341–351. 13. Migden MR et al. Lancet Oncol. 2020;21:294–305. 14. Rischin D et al. J Immunother Cancer. 2020;8:e000775. Presented at Winter Clinical Derm 2023, January 13–18, 2023 (encore of previous presentation at the European Society of Medical Oncology [ESMO] 2022, September 8–13, Migden MR et al.). Reused with permission. Conclusions • This final update to the EMPOWER-CSCC-1 study confirms the efficacy, durability, and safety profile of cemiplimab in patients with advanced CSCC. • No new safety concerns were identified on longer follow-up. • Cemiplimab remains a standard-of-care option for metastatic or locally advanced CSCC patients who are not candidates for curative surgery or radiation. Table 3. TEAEs† TEAEs, n (%) Advanced CSCC, n=193 Any grade Grade ≥3 Any 192 (99.5) 95 (49.2) Serious 75 (38.9) 60 (31.1) Leading to discontinuation 20 (10.4) 13 (6.7) Leading to death 5 (2.6) 5 (2.6) Occurring in ≥10% of patients (any grade) Fatigue 67 (34.7) 5 (2.6) Diarrhea 53 (27.5) 2 (1.0) Nausea 46 (23.8) 0 Pruritus 41 (21.2) 0 Constipation 28 (14.5) 1 (0.5) Vomiting 25 (13.0) 1 (0.5) Arthralgia 34 (17.6) 1 (0.5) Cough 32 (16.6) 0 Rash 32 (16.6) 1 (0.5) Anemia 22 (11.4) 8 (4.1) Hypothyroidism 22 (11.4) 0 Actinic keratosis 23 (11.9) 0 Rash, maculo-papular 23 (11.9) 1 (0.5) Upper respiratory tract infection 21 (10.9) 0 Headache 21 (10.9) 0 †TEAEs occurring in ≥10% of patients are reported here. Adverse events were coded according to the Preferred Terms of the Medical Dictionary for Regulatory Activities, version 22.1. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. RTI, respiratory tract infection; TEAE, treatment-emergent adverse event. Introduction • CSCC is the second most common malignancy in the USA, with approximately 186,000–420,000 cases diagnosed each year.1 • While most cases of CSCC are cured by complete surgical excision, a small but substantial number of patients develop advanced disease, including locally advanced (laCSCC) or metastatic (mCSCC) disease.2,3 • Cemiplimab is a high-affinity, fully human, hinge-stabilized, immunoglobulin G4 anti–programmed cell death-1 (PD-1) antibody that blocks the interaction of the PD-1 receptor with its ligands, PD-L1 and PD-L2.4 • Cemiplimab is approved in the US and Europe, and by multiple other health authorities, for the treatment of patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or curative radiation.5–8 Additionally, cemiplimab is recommended for the treatment of patients with metastatic or locally advanced CSCC not amenable to curative surgery or curative radiation by the European Association of Dermato-Oncology, European Organization for Research and Treatment of Cancer, and the National Comprehensive Cancer Network.9,10 • In the primary and follow-up analysis from the EMPOWER-CSCC-1 Phase 2 study, cemiplimab demonstrated substantial clinical benefit and an acceptable safety profile in patients with advanced CSCC (NCT02760498).11–14 – Cemiplimab achieved an objective response rate (ORR) of 46.1% in patients with advanced CSCC, with complete response rates of 20.3%, 12.8%, and 16.1% for Groups 1, 2, and 3, respectively.11 • Here, we provide the final update from study Groups 1, 2 and 3. Objectives • Primary objective: To assess the clinical benefits of cemiplimab as measured by ORR (complete + partial response) per independent central review (ICR). • Key secondary objectives: Duration of response (DOR), progression-free survival (PFS), overall survival (OS), complete response rate, and safety and tolerability. Methods • EMPOWER-CSCC-1 is an open-label, non-randomized, multicenter, international Phase 2 study of patients with advanced CSCC (NCT02760498). • Patients with histologically confirmed mCSCC or unresectable laCSCC received cemiplimab 3 mg/kg intravenous (IV) every 2 weeks for up to 96 weeks (Group 1, mCSCC; Group 2, laCSCC) or cemiplimab 350 mg IV every 3 weeks for up to 54 weeks (Group 3, mCSCC) (Figure 1). • The data cutoff was March 1, 2022. Results Patients • A total of 193 patients were enrolled (Group 1, n=59; Group 2, n=78; Group 3, n=56) with a median age of 72.0 years (range, 38–96). Most patients had a primary cancer site of the head and neck (n=131, 67.9%) (Table 1). • Median duration of follow up was 15.7 months (range, 0.6–43.4) and median duration of exposure was 51.1 weeks (range, 2.0–109.3). Response • Tumor response per ICR, median PFS and OS remained generally consistent with the previous update (data cutoff: October 11, 2020) (Table 2). • Median PFS was 22.1 months (95% confidence interval [CI], 10.4–32.3) and the overall median DOR was 41.3 months (95% CI, 38.8−46.3) (Figures 2 and 3A). • Median OS was not reached. The Kaplan–Meier estimated probability of OS at 48 months was 61.8% (95% CI, 54.0−68.7) (Figure 3B). Safety • All but one patient (n=192, 99.5%) experienced at least one treatment-emergent adverse event (TEAE) of any grade (Table 3). • The most common TEAE of any grade was fatigue (n=67, 34.7%), followed by diarrhea (n=53, 27.5%), nausea (n=46, 23.8%), and pruritus (n=41, 21.2%). Phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC): Final analysis from EMPOWER-CSCC-1 Groups 1, 2, and 3 Michael R Migden,1 Chrysalyne D Schmults,2 Nikhil I Khushalani,3 Alexander Guminski,4 Anne Lynn S Chang,5 Karl D Lewis,6 George Ansstas,7 Samantha Bowyer,8 Brett G Hughes,9 Dirk Schadendorf,10 Badri Modi,11 Lara A Dunn,12 Lukas Flatz,13 Axel Hauschild,14 Suk-Young Yoo,15 Jocelyn Booth,15 Frank Seebach,15 Israel Lowy,15 Matthew G Fury,15 Danny Rischin16 1Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA; 4Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; 5Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA; 6University of Colorado Denver Cancer Center, Aurora, CO, USA; 7Surgical Oncology, Washington University School of Medicine, St Louis, MO, USA; 8School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia; 9Royal Brisbane & Women’s Hospital and University of Queensland, Brisbane, Queensland, Australia; 10University Hospital Essen, Essen and German Cancer Consortium, Essen, Germany; 11Department of Surgery, Division of Dermatology, City of Hope, Duarte, CA, USA; 12Department of Medicine, Head and Neck Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 13University Hospital Tübingen, Tübingen, Germany; 14Schleswig-Holstein University Hospital, Kiel, Germany; 15Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 16Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Table 1. Patient demographics and baseline characteristics Advanced CSCC (n=193) Age, years, median (range) 72.0 (38–96) Male, n (%) 161 (83.4) ECOG performance status, n (%) 0 86 (44.6) 1 107 (55.4) Primary CSCC site: head and neck, n (%) 131 (67.9) mCSCC, n (%) 115 (59.6) laCSCC, n (%) 78 (40.4) Patients with cemiplimab as first-line therapy, n (%) 128 (66.3) Patients with prior systemic therapy, n (%)† 65 (33.7) Duration of exposure to cemiplimab, weeks, median (range) 51.1 (2.0–109.3) Number of cemiplimab doses administered, median (range) 18.0 (1–48) †Settings for prior lines of therapy included metastatic disease, adjuvant, chemotherapy with concurrent radiation, or other, and the most common types of prior systemic therapy were platinum compounds (n=46/65, 70.8%) and monoclonal antibodies (n=18/65, 27.7%). CSCC, cutaneous squamous cell carcinoma; ECOG, Eastern Cooperative Oncology Group; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma. Table 2. Tumor response per ICR PD-L1 (22C3) Group 1 (mCSCC) 3 mg/kg Q2W (n=59) Group 2 (laCSCC) 3 mg/kg Q2W (n=78) Group 3 (mCSCC) 350 mg Q3W (n=56) Total (n=193) Duration of follow-up, months, median (range) 18.5 (1.1–41.0) 15.5 (0.8–43.2) 17.3 (0.6–43.4) 15.7 (0.6–43.4) ORR, % (95% CI) 50.8 (37.5–64.1) 44.9 (33.6–56.6) 46.4 (33.0–60.3) 47.2 (39.9–54.4) Complete response, n (%) 12 (20.3) 10 (12.8) 11 (19.6) 33 (17.1) Partial response, n (%) 18 (30.5) 25 (32.1) 15 (26.8) 58 (30.1) DOR, months, median (95% CI) NR (20.7–NE) 41.9 (20.5–54.6) 41.3 (40.8–46.3) 41.3 (38.8–46.3) PFS, months, median (95% CI) 18.4 (7.3–53.2) 18.5 (11.1–43.8) 21.7 (3.8–43.3) 22.1 (10.4–32.3) OS, months, median (95% CI) 57.7 (29.3–NE) NR (58.3–NE) 48.4 (29.5–NE) NR (56.0–NE) CI, confidence interval; DOR, duration of response; ICR, independent central review; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma; NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks. Group 1 – Adults with metastatic (nodal and/or distant) CSCC Group 3 – Adults with metastatic (nodal and/or distant) CSCC Group 2 – Adults with locally advanced CSCC Cemiplimab 3 mg/kg Q2W for up to 96 weeks† Tumor imaging every 8 weeks for the assessment of clinical activity‡ Tumor imaging every 9 weeks for the assessment of clinical activity Tumor response assessment by an independent central review (ICR) committee Cemiplimab 350 mg Q3W for up to 54 weeks Key inclusion criteria Key exclusion criteria • ECOG performance status of 0 or 1 • Adequate organ function • Groups 1 and 3: – At least one lesion measurable by RECIST version 1.1 • Group 2: – At least one lesion measurable by digital medical photography – CSCC lesion that is not amenable to surgery or radiation therapy per investigators’ assessment • Ongoing or recent (within 5 years) autoimmune disease requiring systemic immunosuppression • Prior treatments with anti-PD-1 or anti-PD-L1 therapy • History of solid organ transplant, hematologic malignancies, or concurrent malignancies (unless indolent or not considered life threatening; e.g., basal cell carcinoma) Figure 1. Study design †Retreatment optional for patients with disease progression during follow-up. ‡Confirmatory scans performed no sooner than 4 weeks following initial documentation of tumor response. The severity of TEAEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). CSCC, cutaneous squamous cell carcinoma; ECOG, Eastern Cooperative Oncology Group; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1; TEAE, treatment-emergent adverse event. P ro b a b ili ty o f P F S Month mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W 59 78 56 43 61 50 39 49 35 37 44 33 33 41 33 28 39 31 28 36 29 28 32 29 28 30 28 28 25 28 26 24 28 26 24 27 23 23 26 22 22 24 22 21 21 22 21 20 20 17 13 17 14 11 17 14 11 16 14 11 8 9 10 1 3 9 1 1 2 1 1 1 1 1 1 1 1 0 1 1 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.0 A 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P ro b a b ili ty o f O S Month mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W 59 78 56 56 76 52 52 73 49 49 67 46 47 65 45 47 65 44 46 64 38 41 62 38 39 59 38 39 55 37 38 53 37 38 53 35 37 51 34 35 47 32 34 47 31 33 46 30 33 45 29 31 44 28 29 43 27 29 43 27 29 43 27 29 41 27 29 36 26 29 33 21 28 30 17 28 23 5 28 22 1 27 19 0 23 13 0 16 9 0 12 5 0 3 4 0 1 2 0 0 0 0 0 0 0 0 0 0 1.0 B 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Number of subjects at risk Number of subjects at risk Figure 3. Kaplan–Meier curves of (A) PFS and (B) OS CSCC, cutaneous squamous cell carcinoma; ICR, independent central review; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks. Figure 2. Kaplan–Meier curves of DOR per ICR P ro b a b ili ty o f n o p ro g re s s io n o r d e a th Month mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W Number of subjects at risk mCSCC cemiplimab: 3 mg/kg Q2W laCSCC cemiplimab: 3 mg/kg Q2W mCSCC cemiplimab: 350 mg Q3W 30 35 26 30 33 26 29 32 26 28 31 25 24 29 23 24 27 23 23 24 23 23 23 22 23 19 22 21 19 22 20 18 21 18 16 19 18 16 17 18 15 15 18 14 14 17 11 10 13 11 9 13 11 9 12 10 7 9 6 5 0 2 5 0 1 1 0 1 1 0 1 1 0 1 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 CSCC, cutaneous squamous cell carcinoma; DOR, duration of response; ICR, independent central review; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma; Q2W, every 2 weeks; Q3W, every 3 weeks. Disclosure Michael R Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., Novartis, Genentech, and Eli Lilly. Acknowledgments The authors thank the patients, their families, all other investigators, and all investigational site members who participated in this study. Medical writing and editorial support under the direction of the authors was provided by Sameen Yousaf, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc., and Sanofi according to Good Publication Practice guidelines. Responsibility for all opinions, conclusions and data interpretation lies with the authors. • Grade ≥3 TEAEs were reported in 95 patients (49.2%). The most common Grade ≥3 TEAEs were hypertension (n=9, 4.7%), cellulitis, and anemia (each n=8, 4.1%), pneumonia (n=8, 4.1%), pneumonitis (n=6, 3.1%), sepsis (n=5, 2.6%), and fatigue (n=5, 2.6%). • In total, 19 patients (9.8%) experienced at least one sponsor-identified Grade ≥3 immune-related adverse event, the most common of which were pneumonitis (n=6, 3.1%), diarrhea, and autoimmune hepatitis (each n=2, 1.0%). • Twenty patients (10.4%) discontinued treatment due to TEAEs of any grade (Supplementary Table 1). Beyond what has previously been reported,6–8 no new TEAE-related deaths occurred. Scan the QR code for supplementary material and co-author disclosures