Presented at Winter Clinical Derm 2023, January 13–18, 2023 (encore of previous presentation at the European Association of Dermato Oncology [EADO] Congress 2022, April 21–23, Stratigos AJ et al.). Reused with permission. Phase 2 study of cemiplimab in patients with locally advanced basal cell carcinoma after hedgehog inhibitor therapy: Long-term follow-up Alexander J Stratigos,1 Aleksandar Sekulic,2 Ketty Peris,3 Oliver Bechter,4 Sorilla Prey,5 Martin Kaatz,6 Karl D Lewis,7 Nicole Basset-Seguin,8 Anne Lynn S Chang,9 Stéphane Dalle,10 Almudena Fernandez Orland,11 Lisa Licitra,12 Caroline Robert,13 Claas Ulrich,14 Axel Hauschild,15 Michael R Migden,16 Reinhard Dummer,17 Suk-Young Yoo,18 Ebony Coates,18 Emmanuel Okoye,18 Ioannis Bassukas,19 Carmen Loquai,20 Vincenzo De Giorgi,21 Zeynep Eroglu,22 Ralf Gutzmer,23 Jens Ulrich,24 Susana Puig,25 Frank Seebach,18 Israel Lowy,18 Matthew G Fury18 1Department of Dermatology-Venereology, Andreas Sygros Hospital-National and Kapodistrian University of Athens, Athens, Greece; 2Department of Dermatology, Arizona Mayo Clinic, Scottsdale, AZ, USA; 3Institute of Dermatology, Catholic University of the Sacred Heart and Fondazione Policlinico Universitario A Gemelli-IRCCS, Rome, Italy; 4Department of General Medical Oncology, University Hospitals, Leuven, Belgium; 5Department of Dermatology, Bordeaux University Hospital, Bordeaux, France; 6Department of Dermatology, SRH Wald-Klinikum Gera GmbH, Gera, Germany; 7School of Medicine, University of Colorado, Aurora, CO, USA; 8Department of Dermatology, Hôpital Saint-Louis, Paris, France; 9Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA; 10Department of Dermatology, Centre Hospitalier Lyon-Sud, Lyon, France; 11Department of Dermatology, Hospital Universitario Virgen Macarena, Seville, Spain; 12Medical Oncology Head and Neck Cancer Department, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; 13Dermatology Unit, Gustave Roussy Cancer Center and Paris-Saclay University, Villejuif, France; 14Skin Cancer Centre, Charite-Universitiitsmedizin Berlin, Berlin, Germany; 15Department of Dermatology, University of Kiel, Kiel, Germany; 16Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 17Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; 18Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 19Department of Skin and Venereal Diseases, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece; 20Department of Dermatology, University Medical Center Mainz, Mainz, Germany; 21Departments of Dermatology and Human Pathology and Oncology, University of Florence, Florence, Italy; 22Department of Cutaneous Oncology at Moffitt Cancer Center, Tampa, FL, USA; 23Johannes Westling Medical Center, Ruhr University Bochum, Minden, Germany; 24Academic Teaching Hospital of the University Otto von Guericke Magdeburg, Magdeburg, Germany; 25Dermatology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Results Patients • Eighty-four patients with laBCC were enrolled in this study, 66.7% were male, and median age was 70 years (range, 42−89). Patient characteristics are provided in Table 2. • The primary site of tumor location was head and neck (89.3%). • Most common reasons for discontinuation of HHI therapy were progression of disease on HHIs (71.4%), intolerance to prior HHIs (38.1%), and no better than stable disease after 9 months on HHIs (8.3%) (Table 2). • Median duration of follow-up was 15.9 months (range, 0.5−39.7). Table 2. Patient demographics and baseline characteristics Characteristic laBCC (N=84) Age, median (range), years 70 (42–89) ≥65 to <75, n (%) 19 (22.6) ≥75, n (%) 34 (40.5) Male, n (%) 56 (66.7) ECOG performance status, n (%) 0 51 (60.7) 1 33 (39.3) Patients with prior cancer-related radiotherapy, n (%) 42 (50.0) Patients with prior HHI therapy, n (%) Vismodegib 79 (94.0) Sonidegib 14 (16.7) Vismodegib + sonidegib 9 (10.7) Reason for discontinuation of prior HHI, n (%)† Progression of disease on HHI 60 (71.4) No better than stable disease after 9 months on HHI therapy 7 (8.3) Intolerant to prior HHI therapy 32 (38.1) Intolerant to vismodegib 32 (38.1) Intolerant to sonidegib 4 (4.8) Primary site of tumor, n (%) Head and neck 75 (89.3) Trunk 7 (8.3) Extremity 2 (2.4) Duration of exposure, median (range), weeks 47.2 (2.1–97.9) Median number of doses of cemiplimab administered (range) 15.0 (1–31) †Sum is >84 because some patients had more than one reason for discontinuation. ECOG, Eastern Cooperative Oncology Group; HHI, hedgehog inhibitor; laBCC, locally advanced basal cell carcinoma. Table 1. Inclusion and exclusion criteria Inclusion criteria Exclusion criteria • Histologically confirmed diagnosis of invasive BCC • Prior progression or intolerance to HHI therapy or no better than stable disease after 9 months on HHI therapy • At least one measurable baseline lesion • ECOG performance status of 0 or 1 • Ongoing or recent (within 5 years) autoimmune disease requiring systemic immunosuppression • Prior anti–PD-1 or anti–PD-L1 therapy • Concurrent malignancy other than BCC and/or history of malignancy other than BCC within 3 years of date of first planned dose of cemiplimab, except for tumors with negligible risk of metastasis or death BCC, basal cell carcinoma; ECOG, Eastern Cooperative Oncology Group; HHI, hedgehog inhibitor; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1. Conclusions • This long-term follow-up analysis further confirms the safety and efficacy of cemiplimab in patients with laBCC after progression on or intolerance to HHI therapy. • There were no new safety signals compared with previous analyses of cemiplimab in laBCC.12 • Combined with the primary analysis12 in the laBCC cohort and interim analysis13 from the mBCC cohort, these results confirm cemiplimab has substantial activity in advanced BCC tumors. References 1. Puig S et al. Clin Transl Oncol. 2015;17:497–503. 2. Monroe M et al. Otolaryngol Clin North Am. 2021;54:271–280. 3. Sekulic A et al. N Engl J Med. 2012;366:2171–2179. 4. Migden MR et al. Lancet Oncol. 2015;16:716–728. 5. Basset-Seguin N et al. Lancet Oncol. 2015;16:729–736. 6. Burova E et al. Mol Cancer Ther. 2017;16:861–870. 7. Regeneron Pharmaceuticals, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2021/761097s007lbl.pdf. [Accessed January 22, 2022]. 8. Regeneron Pharmaceuticals, Inc. 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 22, 2022]. 9. Health Canada. 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 22, 2022]. 10. Ministry of Health Israel. Available at: https://israeldrugs.health.gov.il/#!/medDetails/164%2099%2036023%2000. [Accessed January 22, 2022]. 11. Brazilian Health Authority - ANVISA. Available at: https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/novos- medicamentos-e-indicacoes/libtayo-cemiplimabe-nova-indicacao. [Accessed January 22, 2022]. 12. Stratigos AJ et al. Lancet Oncol. 2021;22:848–857. 13. Lewis K et al. J Immunother Cancer. 2020;8:Abstract 428. Acknowledgments The authors thank the patients 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. Disclosures Alexander J Stratigos reports advisory board or steering committee roles with Janssen, Regeneron Pharmaceuticals, Roche and Sanofi; and research support from AbbVie, Bristol-Myers Squibb, Genesis Pharma and Novartis. Table 4. TEAEs† laBCC (N=84) TEAEs, n (%) Any grade Grade ≥3 Any 83 (98.8) 44 (52.4) Serious 31 (36.9) 24 (28.6) Led to discontinuation 15 (17.9) 9 (10.7) Associated with an outcome of death‡ 4 (4.8) 4 (4.8) Occurring in ≥10% of patients or Grade ≥3 in ≥5% of patients§ Fatigue 26 (31.0) 4 (4.8) Diarrhea 20 (23.8) 0 Pruritus 18 (21.4) 0 Asthenia 17 (20.2) 1 (1.2) Arthralgia 16 (19.0) 0 Decreased appetite 13 (15.5) 1 (1.2) Anemia 13 (15.5) 1 (1.2) Nausea 12 (14.3) 1 (1.2) Headache 12 (14.3) 1 (1.2) Urinary tract infection 12 (14.3) 3 (3.6) Dyspnea 10 (11.9) 0 Cough 9 (10.7) 0 Tumor hemorrhage 9 (10.7) 0 †AEs were coded according to the Preferred Terms of the Medical Dictionary for Regulatory Activities, version 22.1. The severity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. ‡None of the deaths were considered treatment related. §AEs are listed in descending order of frequency in any grade. AE, adverse event; laBCC, locally advanced basal cell carcinoma; TEAE, treatment-emergent adverse event. Synopsis • Basal cell carcinoma (BCC) is the most common human malignancy worldwide.1 Most patients with BCC are cured by surgical excision, but a small proportion develop advanced BCC, which includes locally advanced (laBCC) and metastatic (mBCC) disease.1,2 • Hedgehog signaling pathway inhibitors (HHIs), such as vismodegib and sonidegib, are indicated for patients with mBCC or laBCC who are not candidates for curative surgery or radiotherapy.3-5 Most patients with advanced BCC, however, progress on or are intolerant to HHI therapy. • Cemiplimab is a high-affinity, fully human, hinge-stabilized immunoglobulin G4 anti– programmed cell death-ligand 1 (PD-L1) antibody that potently blocks the interaction of programmed cell death-1 (PD-1) with its ligand.6 • Cemiplimab (cemiplimab-rwlc in the US) is the first immunotherapy indicated for treatment of patients with mBCC and laBCC after HHI treatment or for whom HHIs are not appropriate.7-11 • In the primary analysis of the Phase 2 study (NCT03132636), cemiplimab demonstrated clinically meaningful activity and an acceptable safety profile in patients with laBCC after HHI therapy or for whom HHIs were not appropriate.12 Here, we present the long-term follow-up data at approximately 40 months after the primary analysis of the first group in this study. Objectives • The primary objective is to evaluate objective response rate (ORR) by independent central review (ICR). • Key secondary endpoints include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), complete response rate, and safety and tolerability. Methods • In this open-label, multicenter, single-arm, Phase 2 trial, patients received cemiplimab 350 mg intravenously (IV) every 3 weeks (Q3W) for up to 93 weeks or until disease progression, unacceptable toxicity, withdrawal of consent, or confirmed complete response (Figure 1). The study design was previously reported in detail.12 Figure 1. Study design Group 1 – Adult patients with metastatic (nodal and distant) BCC Cemiplimab 350 mg IV Q3W for up to 93 weeks (or until disease progression, unacceptable toxicity, or withdrawal of consent) Tumor assessments 1–5 Q9W, 6–9 Q12W Tumor response assessment by ICR (RECIST 1.1 for visceral lesions or modified WHO criteria for skin lesions)† Group 2 – Adult patients with laBCC †Or by composite response criteria for patient with both visceral and skin lesions, including ICR review of digital medical photography, radiology and pathology reports from on-treatment biopsies (if any). BCC, basal cell carcinoma; ICR, independent central review; IV, intravenous; laBCC, locally advanced basal cell carcinoma; Q3W, every 3 weeks; Q9W, every 9 weeks; Q12W, every 12 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization. • Inclusion and exclusion criteria are provided in Table 1. • Tumor assessments were done at the end of each treatment cycle, every 9 weeks (Q9W) for the first five cycles, and every 12 weeks (Q12W) for the subsequent four cycles. • An updated analysis of the response was prespecified to be performed after all responding patients had been followed for a minimum of 12 months from onset of response. • The data cutoff date was May 20, 2021. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 P a ti e n ts w it h r e s p o n s e Month Complete response Partial response Stable disease Progressive disease Unable to evaluate Ongoing study Figure 2. Time to response and DOR in responding patients per ICR Each horizontal bar represents one patient. All patients completed treatment. Patients with confirmed complete response after a minimum of 48 weeks of treatment may elect to discontinue treatment and continue with all relevant study assessments. DOR, duration of response; ICR, independent central review; laBCC, locally advanced basal cell carcinoma. Table 3. Tumor response per ICR Outcome laBCC (N=84) Duration of follow-up, median (range), months 15.9 (0.5–39.7) Best overall response per ICR ORR, % (95% CI) 32.1 (22.4–43.2)† Complete response, n (%) 6 (7.1) Partial response, n (%) 21 (25.0) Stable disease, n (%) 40 (47.6) Non-complete response/non-progressive disease, n (%) 0 Progressive disease, n (%) 9 (10.7) Not evaluable, n (%)‡ 8 (9.5) Observed DOR at 6 months, n (%)# 23 (85.2) Disease control rate, % (95% CI)§ 79.8 (69.6–87.7) Durable disease control rate, % (95% CI)¶ 59.5 (48.3–70.1) Time to response, median (range), months# 4.3 (2.1–21.4) Kaplan-Meier estimation of DOR, median (95% CI), months# NR (15.5–NE) 6 months 88.5 (68.4–96.1) 12 months 83.8 (62.2–93.6) 24 months 56.6 (29.6–76.6) †ORR per investigator assessment was 36.9% (95% CI, 26.6–48.1). ‡NE response includes the missing and unknown tumor response. §Defined as the proportion of patients with complete response, partial response, stable disease, or non-partial response/non-progressive disease. ¶Defined as the proportion of patients with complete response, partial response, stable disease, or non-partial response/non-progressive disease for ≥182 days without progressive disease. #Data shown are for patients with response. CI, confidence interval; DOR, duration of response; ICR, independent central review; laBCC, locally advanced basal cell carcinoma; NE, not evaluable; NR, not reached; ORR, objective response rate. Clinical activity • ORR per ICR was 32.1% (95% confidence interval [CI], 22.4–43.2) including six complete responses and 21 partial responses (Table 3). – Six (22.2%) responding patients had evidence of disease progression at the time of this analysis (Figure 2). – The disease control rate was 79.8% (95% CI, 69.6–87.7). – The durable disease control rate was 59.5% (95% CI, 48.3–70.1). • As of data cutoff, median DOR had not been reached. Kaplan-Meier estimates of DOR were 83.8% (95% CI, 62.2–93.6) at 12 months and 56.6% (95% CI, 29.6–76.6) at 24 months (Table 3). • Median PFS was 16.5 months (95% CI, 8.6–21.4). Kaplan-Meier estimates of PFS were 56.7% (95% CI, 44.5−67.1) at 12 months and 31.7% (95% CI, 20.4–43.5) at 24 months (Figure 3A). • Median OS had not been reached at the time these data were reported. Kaplan- Meier–estimated OS at 24 months was 80.3% (95% CI, 69.0–87.9) (Figure 3B). 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 P ro b a b ili ty o f P F S Month B 84 32 27 26 23 15 12 9 9 7 4 3 2 0 0 0384148566476 17 A 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 P ro b a b ili ty o f O S Month 84 65 65 60 56 51 48 44 40 32 21 15 9 0 0 0677172778083 53No. of patients at risk No. of patients at risk Figure 3. Kaplan-Meier curves for PFS and OS laBCC, locally advanced basal cell carcinoma; PFS, progression-free survival; OS, overall survival. Safety • Eighty-three (98.8%) patients experienced treatment-emergent adverse events (TEAEs) of any grade regardless of attribution. • The most common TEAEs of any grade were fatigue (n=26, 31.0%), diarrhea (n=20, 23.8%), pruritus (n=18, 21.4%), asthenia (n=17, 20.2%) and arthralgia (n=16, 19.0%). Grade ≥3 TEAEs occurred in 44 (52.4%) patients (Table 4). • Fifteen (17.9%) patients discontinued treatment due to TEAEs of any grade. Four (4.8%) patients died of TEAEs of any grade (Table 4). • Treatment-related AEs (TRAEs) were reported in 66 (78.6%) patients, with the most common being fatigue (n=21, 25%), asthenia (n=12, 14.3%), diarrhea (n=11, 13.1%), pruritis (n=11, 13.1%), nausea (n=9, 10.7%), decreased appetite (n=8, 9.5%) and hypothyroidism (n=8, 9.5%). • No Grade ≥3 TRAEs occurred in more than one patient or led to an outcome of death. • Twenty-three (27.4%) patients experienced sponsor-identified immune-related AEs (irAEs) of any grade. Grade ≥3 irAEs occurred in nine (10.7%) patients. Scan the QR code for co-author disclosures