# Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: Results from a Pivotal Open-label Study with a median follow-up of ≥2 years

Emily Ruiz, Eva Muñoz-Couselo, Henri Montaudié, Miguel Angel Berciano-Guerrero, Maria del Carmen Álamo de la Gala, Julie Charles, Gaëlle Quéreux, Charlée Nardin, Ricardo Yaya Tur, Stéphane Dalle, et al.

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Emily Ruiz, Eva Muñoz-Couselo, Henri Montaudié, Miguel Angel Berciano-Guerrero, Maria del Carmen Álamo de la Gala, et al.. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: Results from a Pivotal Open-label Study with a median follow-up of ≥2 years. Journal of The American Academy of Dermatology, 2025, Online ahead of print. 10.1016/j.jaad.2025.09.009. inserm-05305585

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ORIGINAL ARTICLE

# Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: Results from a Pivotal Open-label Study with a median follow-up of ≥2 years

Emily S. Ruiz, MD,ª Eva Muñoz-Couselo, MD, PhD,ᵇ Henri Montaudié, MD, PhD,ᶜ

Miguel Angel Berciano-Guerrero, MD, PhD,ᵈ Maria del Carmen Álamo de la Gala, MD, PhD,ᶜ

Julie Charles, MD, PhD,f Gaëlle Quéreux, MD, PhD,g Charlée Nardin, MD, PhD,h Ricardo Yaya Tur, MD, PhD,i

Stéphane Dalle, MD, PhD,j Marie Beylot-Barry, MD, PhD,k Rahul Ladwa, MBChB, MPhil,l,m

Margaret McGrath, MBBS,m Daniel Brungs, MBBS, PhD,n Dean Harris, MBChB, FRACP,o

Hong Shue, MBBS, FRACP,p Andrea Tazbirkova, MD, FRACP,q Samuel Fourie, MBChB, MMed,r

Daniel R. Malan, MSc Pharm Med, MPhil,s James Oliviero, CFA,t Lauren Neighbours Wilcoxen, PhD, RAC,t

W. Garrett Gray,t and Philip Clingan, DSc (HC), MBBS, FRACPu

**Background:** Cosibelimab-ipdl, a high-affinity, programmed death-ligand 1-blocking antibody, is approved by the US Food and Drug Administration for treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or radiation.

**Objective:** To report long-term efficacy and safety outcomes from a pivotal study of cosibelimab in mCSCC or laCSCC.

From the Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusettsª; Medical Oncology, Vall d'Hebron Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spainb; Dermatology, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, Francec; Medical Oncology Department, Regional University Hospital, IBIMA Plataforma BIONAND, Malaga, Spaind; Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spaine; Dermatology, Grenoble Alpes University Hospital/Grenoble Alpes University UGA, Grenoble, Francef; Department of Dermatology, CHU Nantes, Nantes University, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, Nantes, Franceg; Dermatology, Centre Hospitalier Universitaire de Besançon, Université de Marie et Louis Pasteur, INSERM, Besançon, Franceh; Medical Oncology, Fundacion Instituto Valenciano de Oncologia, Valencia, Spaini; Department of Dermatology, Lyon Cancer Research Center, INSERM, Hôpital Lyon Sud, HCL, Pierre Bénite, Francej; Dermatology, CHU Bordeaux - Hôpital St. André, Bordeaux, Francek; Division of Cancer Services, Princess Alexandra Hospital, Woolloongabba, QLD, Australial; Medical Oncology, Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD, Australiam; Medical Oncology, Cancer Care Wollongong and Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australiap; Medical Oncology, Christchurch Hospital, Te Whatu Ora, Waitaha/Canterbury, Christchurch, New Zealandq; University of the Sunshine Coast Clinical Trials Unit, Sunshine Coast Hematology and Oncology Clinic, Buderim, QLD, Australiab;

Medical Oncology, Pindara Private Hospital, Benowa, QLD, Australiaq; Wilgers Oncology Center, Pretoria, South Africaf; Research Unit, Phoenix Pharma (Pty) Ltd, Port Elizabeth, South Africas; Executive, Checkpoint Therapeutics, Waltham, Massachusettsf; and Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australiau

Funding sources: Supported by Checkpoint Therapeutics, Inc.

Presented, in part, at the European Society for Medical Oncology Congress, Barcelona, Spain, September 13-17, 2024.

IRB approval status: Reviewed and approved by an independent ethics committee or institutional review board. The list of independent ethics or institutional review boards, approval numbers, and dates of approval can be found in Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1.

Accepted for publication September 8, 2025.

Correspondence to: Lauren Neighbours Wilcoxen, PhD, RAC, Senior Vice President, Product Development and Regulatory Affairs, Checkpoint Therapeutics, Inc., 95 Sawyer Road, Suite 110, Waltham, MA. E-mail: lneighbours@checkpointtx.com.

Published online October 6, 2025.

0190-9622

© 2025 The Author(s). Published by Elsevier Inc. on behalf of the American Academy of Dermatology, Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

https://doi.org/10.1016/j.jaad.2025.09.009
**Methods:** Patients received intravenous cosibelimab 800 mg every 2 weeks (mCSCC and laCSCC cohorts) or 1200 mg every 3 weeks (mCSCC cohort). The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR) and safety.

**Results:** With a median follow-up duration of 29.3 months for the mCSCC cohort (n = 78), ORR was 50.0% (complete response [CR], 12.8%), median DOR was not reached, and estimated 24-month DOR was 72.1%. With a median follow-up duration of 24.1 months for the laCSCC cohort (n = 31), ORR was 54.8% (CR, 25.8%), median DOR was not reached, and the estimated 24-month DOR was 80.2%. Immune-related adverse event rate was 27.6%; 3.6% grade 3, no grade ≥4 events.

**Limitations:** Nonrandomized; limited biomarker analysis.

**Conclusion:** Cosibelimab demonstrated robust and durable ORRs with increasing CR rates in advanced CSCC and low rates of severe immune-related adverse events. (J Am Acad Dermatol https://doi.org/10.1016/j.jaad.2025.09.009.)

**Key words:** advanced cutaneous squamous cell carcinoma; cosibelimab; immune checkpoint inhibitors; immunotherapy; programmed death-ligand 1; skin cancer; skin neoplasms.

INTRODUCTION

Cutaneous squamous cell carcinoma (CSCC) is the second most common form of skin cancer; however, robust global estimates are limited, as CSCC is excluded from many national cancer registries, including those in the United States.¹,² Historically, the prevalence ratio of basal cell carcinoma to CSCC cases was estimated at 4:1.³,⁴ However, recent data from US insurance claims databases suggest this ratio is nearing 1:1, reflecting a relative increase in the incidence of CSCC.⁴,⁵ In the United States, the estimated annual incidence of CSCC is 1.8 million cases, including ~40,000 advanced cases, with an estimated 15,000 deaths annually.⁶,⁷

Before the introduction of immunotherapy, patients who presented with locally advanced CSCC (laCSCC) or metastatic CSCC (mCSCC) had poor prognosis and more limited treatment options, given the advanced stage of disease.⁸ Locally advanced or metastatic disease is associated with substantial morbidity and mortality, with 10-year survival rates of <20% for patients with regional lymph node involvement and <10% for patients with distant metastases.¹,⁹ CSCC is characterized by high tumor mutational burden with a large amount of ultraviolet radiation-related mutations, thereby making CSCC tumors highly sensitive to immunotherapy.³,¹⁰,¹¹ Programmed death-ligand 1 (PD-L1) is often upregulated in CSCC

CAPSULE SUMMARY

* Programmed death receptor-1 inhibitors have been shown to be efficacious for cutaneous squamous cell carcinoma (CSCC), but there are limited data on other immunotherapies in CSCC, including programmed death-ligand 1 (PD-L1) inhibitors.

* Cosibelimab, a PD-L1 inhibitor, shows long-term, durable responses with increasing complete response rates and a low incidence of severe immune-related adverse events, prompting priority consideration in clinical treatment strategies.

tumors. Binding of PD-L1 to its receptor, programmed death receptor-1 (PD-1), in tumor cells leads to inhibition of peripheral T-cell activation, evasion of detection by immune cells, facilitation of tumor growth, and increased risk of metastasis.³,¹²,¹³ As such, inhibiting the PD-L1/ PD-1 pathway has been targeted by multiple pharmaceutical therapies to treat solid tumors, including CSCC. Cemiplimab and pembrolizumab, both PD-1-targeting monoclonal antibodies, are approved by the US Food and Drug Administration

(FDA) for patients with mCSCC or laCSCC who are ineligible for curative surgery or radiotherapy. For eligible patients, immunotherapy is now the standard of care for this patient population.³,¹⁴,¹⁵ This represents an important advancement in the management of CSCC; however, PD-1-blocking antibodies are associated with higher risk of severe adverse events (AEs) compared with PD-L1-blocking antibodies.¹⁶ Higher incidences of grade ≥3 treatment-related AEs, including immune-related AEs (irAEs), have been reported for PD-1 inhibitors compared with PD-L1 inhibitors in other cancers, indicating the potential for PD-L1 therapies to have a more tolerable safety profile for patients with CSCC.¹⁷,¹⁸

Cosibelimab (UNLOXCYT; Checkpoint Therapeutics, Inc.) is a high-affinity, fully human monoclonal antibody that binds to PD-L1 and inhibits
Abbreviations used:

<table><tr><td>AE:</td><td>adverse event</td></tr><tr><td>CI:</td><td>confidence interval</td></tr><tr><td>CR:</td><td>complete response</td></tr><tr><td>CSCC:</td><td>cutaneous squamous cell carcinoma</td></tr><tr><td>DOR:</td><td>duration of response</td></tr><tr><td>ECOG PS:</td><td>Eastern Cooperative Oncology Group performance status</td></tr><tr><td>FDA:</td><td>US Food and Drug Administration</td></tr><tr><td>irAE:</td><td>immune-related adverse event</td></tr><tr><td>ICH:</td><td>International Conference on Harmonisation</td></tr><tr><td>ICR:</td><td>independent central review</td></tr><tr><td>laCSCC:</td><td>locally advanced cutaneous squamous cell carcinoma</td></tr><tr><td>mCSCC:</td><td>metastatic cutaneous squamous cell carcinoma</td></tr><tr><td>NSCLC:</td><td>non-small cell lung cancer</td></tr><tr><td>ORR:</td><td>objective response rate</td></tr><tr><td>PD-1:</td><td>programmed death receptor-1</td></tr><tr><td>PD-L1:</td><td>programmed death-ligand 1</td></tr><tr><td>Q2W:</td><td>every 2 weeks</td></tr><tr><td>Q3W:</td><td>every 3 weeks</td></tr><tr><td>SD:</td><td>standard deviation</td></tr><tr><td>TEAE:</td><td>treatment-emergent adverse event</td></tr></table>

its interaction with the PD-1 and B7.1 receptors.⁸,¹⁹,²⁰
Additionally, cosibelimab has a functional fragment crystallizable domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against tumor cells.⁸,²⁰
Modeling data demonstrate that cosibelimab sustains >99% tumor target occupancy to block the PD-L1 interaction with PD-1 and reactivate T cells to help restore an antitumor immune response.²⁰,²¹

Pivotal results based on an initial predefined data cutoff from the open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab in patients with mCSCC or laCSCC (ClinicalTrials.gov identifier: NCT03212404) formed the basis of the FDA approval of cosibelimab-ipdl for the treatment of adults with mCSCC or laCSCC who are not candidates for curative surgery or radiation in December 2024.¹⁹ These results demonstrated objective response rates (ORRs) of 47.4% (95% confidence interval [CI]: 36.0% to 59.1%) and 48.4% (95% CI: 30.2% to 66.9%) at a median follow-up of 15.4 months (range, 0.4-40.5 months) and 10.7 months (range, 2.7-22.3 months) in mCSCC and laCSCC, respectively, as of the data cutoff for the FDA marketing application (November 18, 2021).¹⁹,²² The most frequent serious adverse reactions (≥2% of participants) were sepsis (2.8%), pneumonia (2.8%), and pyrexia (2.1%), with no reported treatment-related deaths.¹⁹,²²

We present long-term follow-up data from the pivotal phase 1 trial of cosibelimab in patients with advanced CSCC who are not candidates for curative

surgery or radiation, including data for the laCSCC cohort that have not previously been published.

## METHODS

### Patient population

This ongoing, open-label, multicenter, multicohort trial was conducted in 2 parts. Briefly, part 1 was a dose-escalation study to evaluate fixed doses of cosibelimab monotherapy administered every 2 weeks (Q2W) or every 3 weeks (Q3W) in participants with advanced cancers. Part 2 assessed the antitumor activity and safety of cosibelimab in various expansion cohorts of patients with advanced cancers, including pivotal cohorts of patients with mCSCC and laCSCC. Key inclusion and exclusion criteria are detailed in the Supplementary Methods available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1.

### Study design

Patients received intravenous cosibelimab 800 mg Q2W (group 1, mCSCC; group 2, laCSCC) on days 1 and 15 of each 28-day treatment cycle or 1200 mg Q3W (group 3, mCSCC) on day 1 (Supplementary Figure 1, available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1). Cosibelimab dosing regimens of 800 mg Q2W and 1200 mg Q3W are comparable based on the pharmacokinetics-related criteria outlined in the FDA guidance for alternative dosing regimens for PD-L1-blocking antibodies.²² Treatment was continued until confirmed complete response (CR), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (for radiological scans) and clinical response criteria using bidimensional measurements in accordance with World Health Organization (WHO) criteria (for digital photography), worsening progressive disease, toxicity, or clinical deterioration, followed by a posttreatment follow-up period. Treatment following CR could be extended if specifically requested by the Investigator and deemed in the best interest of the patient. Both the investigator and an independent central review (ICR) conducted end-of-cycle tumor assessments between days 24 and 28 in cycles 2, 4, 6, and 8 and every 3 cycles thereafter for groups 1 and 2, and between days 17 and 21 in cycles 3, 6, 9, and 12 and every 4 cycles thereafter for group 3 (Supplementary Figure 1, available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1). There was no randomization, and neither patients nor study investigators were blinded. Patients were contacted by telephone quarterly about survival and tumor treatment status after treatment was stopped and the required follow-up visits were completed. The study design details were previously published (Supplementary Methods, available via
Mendeley at https://data.mendeley.com/datasets/ztgwsjgdkvt/1).⁸

The study was conducted according to the principles of the Declaration of Helsinki, the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines outlined in the ICH E6 Tripartite Guideline, and the Code of Federal Regulations Title 21 (part 312) at the various participating sites, with approval of an independent ethics committee or institutional review board. Written informed consent was obtained from each patient before study enrollment.

## Endpoints

The primary objective was to evaluate ORR (CR + partial response) by ICR according to RECIST version 1.1 (for radiological scans) and clinical response criteria using bidimensional measurements in accordance with WHO criteria (for digital photography), assessed by the CSCC group. Key secondary objectives included evaluation of duration of response (DOR) by ICR as well as incidence and severity of treatment-emergent AEs (TEAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

## RESULTS

### Patient population

As of the March 31, 2023, data cutoff, 192 patients who were enrolled and treated in the 3 CSCC groups (group 1, mCSCC, n = 78; group 2, laCSCC, n = 58; group 3, mCSCC, n = 56) comprised the safety population (Supplementary Table II and Figure 2, available via Mendeley at https://data.mendeley.com/datasets/ztgwsjgdkvt/1). Patients who were eligible (n = 109) for long-term efficacy assessment in group 1 mCSCC (n = 78) and group 2 laCSCC (n = 31) were included in the efficacy population (Table I), representing all patients included in the prespecified primary/interim analyses, as outlined in the statistical analysis plan (data cutoff: November 18, 2021). Patients with mCSCC had a mean (SD) age of 71.2 (12.9) years, 75.6% were male, and 88.5% were white; patients with laCSCC had a mean (SD) age of 76.5 (8.2) years, 61.3% were male, and 77.4% were white. Most patients had an Eastern Cooperative Oncology Group performance status of 1 (mCSCC, 70.5%; laCSCC, 54.8%) and had undergone prior cancer surgery (mCSCC, 60.3%; laCSCC, 80.6%) and radiation therapy (mCSCC, 65.4%; laCSCC, 77.4%), but the majority had not undergone prior systemic therapy (mCSCC, 91.0%; laCSCC, 96.8%).

### Efficacy

With a median follow-up duration of 29.3 months (range, 0.4-52.0 months) for group 1 mCSCC and 24.1 months (range, 2.8-37.3 months) for group 2

<figure><img src="image_2.png" /><figcaption>**Fig 1.** ORRs and CR rates per ICR at the primary/interim analyses and at 16 months of additional follow-up for the mCSCC and laCSCC cohorts. CR, Complete response; ICR, independent central review; *laCSCC*, locally advanced cutaneous squamous cell carcinoma; *mCSCC*, metastatic cutaneous squamous cell carcinoma; ORR, objective response rate.</figcaption></figure>

laCSCC, the ORR per ICR was 50.0% (95% CI, 38.5%-61.5%) and 54.8% (95% CI, 36.0%-72.7%), respectively (Table II; Fig 1). Robust and durable reductions in the sum of target lesion diameters were observed for participants in both groups (Supplementary Figure 3, available via Mendeley at https://data.mendeley.com/datasets/ztgwsjgdkvt/1). The CR rate was 12.8% and 25.8% for groups 1 and 2, respectively. Median DOR was not reached in both populations (group 1: range, 1.4-45.3+ months; group 2: range, 8.3-31.3+ months), with a median duration of follow-up for responding participants of 21.3 and 18.9 months for groups 1 and 2, respectively. The Kaplan-Meier-estimated probabilities of maintaining a response at 6, 12, and 24 months were 89.5%, 75.4%, and 72.1% in group 1 and 100%, 88.2%, and 80.2% in group 2, respectively (Table II; Fig 2).
<figure><img src="image_3.png" /><figcaption>**Fig 2.** Kaplan-Meier curves of DOR per ICR in patients with mCSCC and laCSCC. CR, Complete response; DOR, duration of response; ICR, independent central review; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma; PR, partial response. DOR is measured from the time measurement criteria are first met for response (CR or PR, whichever is first recorded) until the first date of recurrent or progressive disease (radiographic), or death due to any cause.</figcaption></figure>

Exploratory subgroup analyses by demographics are presented in Supplementary Figure 4 (available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1). Samples for baseline tumor PD-L1 status assessment were available for 70.5% and 87.1% of the group 1 and 2 cohorts, respectively. The ORR by ICR was 51.0% (19 of 37) among participants with PD-L1-positive (≥1%) tumors and 44.0% (8 of 18) among participants with PD-L1-negative tumors in the mCSCC cohort. For participants in the laCSCC cohort, the ORR by ICR was 53.0% (10 of 19) among participants with PD-L1-positive (≥1%) tumors and 38.0% (3 of 8) among participants with PD-L1-negative tumors. There was no statistical correlation between response and PD-L1 status for participants in both cohorts.

## Safety

TEAEs were reported in 181 patients (94.3%; Table III); 63 patients (32.8%) experienced ≥1 serious TEAE.

The most common TEAEs of any grade were fatigue (22.9%), anemia (20.3%), constipation (16.1%), and diarrhea (15.1%). Fifty-three patients (27.6%) experienced irAEs, of which only 7 patients (3.6%) were classified as grade 3 irAEs, which included increased transaminases (n = 2), acute generalized exanthematous pustulosis, increased aspartate aminotransferase, cholestatic jaundice, pemphigoid, and pruritic rash (n = 1 each). There were no reported grade ≥4 irAEs. Permanent treatment discontinuation due to TEAEs, regardless of attribution, occurred in 12 patients (6.3%); the most common reason was COVID-19 or COVID-19 pneumonia (1.6%). The most common treatment-related TEAEs of any grade were pruritus and fatigue (each, 12.0%) and rash (8.9%; Supplementary Table III available via Mendeley at https://data.mendeley.com/datasets/zgwsjgdkvt/1). The most common grade ≥3 TEAE was anemia (5.2%). There were no events of grade ≥3 pneumonitis, colitis, hepatitis, nephritis, or endocrinopathies. TEAEs led to death in 6 patients
<table><caption>**Table I.** Patient demographics and baseline characteristics (efficacy population, N = 109)</caption><thead><tr><th>Demographic/character-<br>istic, n (%)</th><th>Group 1 mCSCC<br>800 mg Q2W<br>(n = 78)</th><th>Group 2 laCSCC<br>800 mg Q2W<br>(n = 31)</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td></tr><tr><td>Female</td><td>19 (24.4)</td><td>12 (38.7)</td></tr><tr><td>Male</td><td>59 (75.6)</td><td>19 (61.3)</td></tr><tr><td>Age</td><td></td><td></td></tr><tr><td>&lt;65 y</td><td>22 (28.2)</td><td>2 (6.5)</td></tr><tr><td>≥65 y</td><td>56 (71.8)</td><td>29 (93.5)</td></tr><tr><td>Race</td><td></td><td></td></tr><tr><td>Asian</td><td>6 (7.7)</td><td>0</td></tr><tr><td>Black or African American</td><td>1 (1.3)</td><td>0</td></tr><tr><td>White</td><td>69 (88.5)</td><td>24 (77.4)</td></tr><tr><td>Other race</td><td>0</td><td>1 (3.2)</td></tr><tr><td>Missing*</td><td>2 (2.6)</td><td>6 (19.4)</td></tr><tr><td>Ethnicity</td><td></td><td></td></tr><tr><td>Hispanic or Latino</td><td>3 (3.8)</td><td>5 (16.1)</td></tr><tr><td>Not Hispanic or Latino</td><td>73 (93.6)</td><td>19 (61.3)</td></tr><tr><td>Unknown</td><td>0</td><td>1 (3.2)</td></tr><tr><td>Missing*</td><td>2 (2.6)</td><td>6 (19.4)</td></tr><tr><td>Country/region</td><td></td><td></td></tr><tr><td>Asia</td><td>6 (7.7)</td><td>0</td></tr><tr><td>Australia/New Zealand</td><td>45 (57.7)</td><td>13 (41.9)</td></tr><tr><td>Europe</td><td>19 (24.4)</td><td>17 (54.8)</td></tr><tr><td>South Africa</td><td>8 (10.3)</td><td>1 (3.2)</td></tr><tr><td>ECOG PS</td><td></td><td></td></tr><tr><td>0</td><td>23 (29.5)</td><td>14 (45.2)</td></tr><tr><td>1</td><td>55 (70.5)</td><td>17 (54.8)</td></tr><tr><td>Primary CSCC site</td><td></td><td></td></tr><tr><td>Head/neck</td><td>46 (59.0)</td><td>28 (90.3)</td></tr><tr><td>Extremity</td><td>18 (23.1)</td><td>2 (6.5)</td></tr><tr><td>Trunk</td><td>9 (11.5)</td><td>1 (3.2)</td></tr><tr><td>Other</td><td>5 (6.4)</td><td>0</td></tr><tr><td>Type of metastatic<br>disease</td><td></td><td></td></tr><tr><td>Distant</td><td>52 (66.7)</td><td>NA</td></tr><tr><td>Nodal</td><td>26 (33.3)</td><td>NA</td></tr><tr><td>Prior cancer-related<br>surgery</td><td></td><td></td></tr><tr><td>Yes</td><td>47 (60.3)</td><td>25 (80.6)</td></tr><tr><td>No</td><td>31 (39.7)</td><td>6 (19.4)</td></tr><tr><td>Prior radiation therapy</td><td></td><td></td></tr><tr><td>Yes</td><td>51 (65.4)</td><td>24 (77.4)</td></tr><tr><td>No</td><td>27 (34.6)</td><td>7 (22.6)</td></tr><tr><td>Prior systemic therapy</td><td></td><td></td></tr><tr><td>Yes</td><td>7 (9.0)</td><td>1 (3.2)</td></tr><tr><td>No</td><td>71 (91.0)</td><td>30 (96.8)</td></tr></tbody></table>

CSCC, Cutaneous squamous cell carcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; laCSCC, locally advanced CSCC; mCSCC, metastatic CSCC; NA, not applicable; Q2W, every 2 weeks.

<table><caption>**Table II.** Tumor response to cosibelimab by ICR (efficacy population, N = 109)</caption><thead><tr><th></th><th>Group 1 mCSCC<br>800 mg Q2W<br>(n = 78)</th><th>Group 2 laCSCC<br>800 mg Q2W<br>(n = 31)</th></tr></thead><tbody><tr><td>Median follow-up<br>duration (95% CI),<br>months</td><td>29.3 (25.3-34.8)</td><td>24.1 (22.6-26.9)</td></tr><tr><td>ORR (95% CI), %</td><td>50.0 (38.5-61.5)</td><td>54.8 (36.0-72.7)</td></tr><tr><td>Best overall response,<br>n (%)</td><td></td><td></td></tr><tr><td>Complete response</td><td>10 (12.8)</td><td>8 (25.8)</td></tr><tr><td>Partial response</td><td>29 (37.2)</td><td>9 (29.0)</td></tr><tr><td>Stable disease</td><td>11 (14.1)</td><td>10 (32.3)</td></tr><tr><td>Progressive disease</td><td>20 (25.6)</td><td>3 (9.7)</td></tr><tr><td>Not evaluable</td><td>8 (10.3)</td><td>1 (3.2)</td></tr><tr><td>Median observed time<br>to response<br>(min-max), months</td><td>1.9 (1.6-16.9)</td><td>3.6 (1.7-10.1)</td></tr><tr><td>Median DOR<br>(min-max), months</td><td>NR (1.4-45.3+)</td><td>NR (8.3-31.3+)</td></tr><tr><td>Median follow-up<br>duration for<br>durability of<br>response, months</td><td>21.3</td><td>18.9</td></tr><tr><td>KM-estimated 6-month<br>DOR probability<br>(95% CI), %</td><td>89.5 (74.3-95.9)</td><td>100 (NE)</td></tr><tr><td>KM-estimated<br>12-month DOR<br>probability<br>(95% CI), %</td><td>75.4 (57.9-86.4)</td><td>88.2 (60.6-96.9)</td></tr><tr><td>KM-estimated<br>24-month DOR<br>probability<br>(95% CI), %</td><td>72.1 (54.1-84.0)</td><td>80.2 (49.6-93.3)</td></tr></tbody></table>

CI, Confidence interval; DOR, duration of response; ICR, independent central review; KM, Kaplan-Meier; laCSCC, locally advanced cutaneous squamous cell carcinoma; mCSCC, metastatic cutaneous squamous cell carcinoma; NE, not evaluable; NR, not reached; ORR, objective response rate; Q2W, every 2 weeks.

(3.1%); all events were considered unrelated to cosibelimab treatment. Of these 6 participants, 2 died of COVID-19, 1 died of COVID-19 pneumonia, 1 with a history of cardiovascular disease died of cardiac arrest, 1 died of Fournier's gangrene, and 1 died of sepsis. The safety profile of cosibelimab was generally comparable across groups and dosing regimens.

## DISCUSSION

Cosibelimab is the first PD-L1-targeting monoclonal antibody approved by the FDA for the treatment of adults with mCSCC or laCSCC who are not

<footnote>*Some sites in Europe did not report race and ethnicity owing to privacy laws.</footnote>
<table><caption>**Table III.** Summary of TEAEs regardless of attribution (safety population, N = 192)</caption><thead><tr><th rowspan="2">TEAE, n (%)</th><th colspan="2">Advanced CSCC</th></tr><tr><th>Any grade</th><th>Grade ≥3</th></tr></thead><tbody><tr><td>Any TEAE</td><td>181 (94.3)</td><td>87 (45.3)</td></tr><tr><td>Any serious TEAE</td><td>63 (32.8)</td><td></td></tr><tr><td>Immune-related TEAE</td><td>53 (27.6)</td><td>7 (3.6)</td></tr><tr><td>Most common immune-related TEAEs (≥1%)</td><td></td><td></td></tr><tr><td>Hypothyroidism</td><td>17 (8.9)</td><td>—</td></tr><tr><td>Hyperthyroidism</td><td>9 (4.7)</td><td>—</td></tr><tr><td>Rash</td><td>8 (4.2)</td><td>—</td></tr><tr><td>Pruritus</td><td>6 (3.1)</td><td>—</td></tr><tr><td>Adrenal insufficiency</td><td>3 (1.6)</td><td>—</td></tr><tr><td>Arthralgia</td><td>3 (1.6)</td><td>—</td></tr><tr><td>Rash maculopapular</td><td>3 (1.6)</td><td>—</td></tr><tr><td>Transaminases increased</td><td>2 (1.0)</td><td>2 (1.0)</td></tr><tr><td>Pneumonitis</td><td>2 (1.0)</td><td>—</td></tr><tr><td>Most common TEAEs (≥10%)</td><td></td><td></td></tr><tr><td>Fatigue</td><td>44 (22.9)</td><td>4 (2.1)</td></tr><tr><td>Anemia</td><td>39 (20.3)</td><td>10 (5.2)</td></tr><tr><td>Constipation</td><td>31 (16.1)</td><td>1 (0.5)</td></tr><tr><td>Diarrhea</td><td>29 (15.1)</td><td>—</td></tr><tr><td>Pruritus</td><td>26 (13.5)</td><td>—</td></tr><tr><td>Nausea</td><td>25 (13.0)</td><td>—</td></tr><tr><td>Rash</td><td>24 (12.5)</td><td>1 (0.5)</td></tr><tr><td>Asthenia</td><td>22 (11.5)</td><td>1 (0.5)</td></tr><tr><td>Arthralgia</td><td>21 (10.9)</td><td>—</td></tr><tr><td>Skin lesion</td><td>20 (10.4)</td><td>—</td></tr><tr><td>Headache</td><td>20 (10.4)</td><td>—</td></tr><tr><td>TEAEs leading to discontinuation</td><td>12 (6.3)</td><td>—</td></tr><tr><td>TEAEs leading to death</td><td>6 (3.1)</td><td>—</td></tr></tbody></table>

CSCC, Cutaneous squamous cell carcinoma; TEAE, treatment-emergent adverse event.

candidates for curative surgery or radiation.¹⁹ Here, we present the long-term data of cosibelimab from the pivotal phase 1 trial in advanced CSCC, including data for the laCSCC cohort that have not previously been published, to continue characterization of the safety and efficacy profile of cosibelimab. Overall, cosibelimab was associated with long-term efficacy in participants with mCSCC and laCSCC, as evidenced by clinically meaningful ORRs, high CR rates, and durable DORs. Consistent with the primary/interim analyses, cosibelimab was associated with a low rate of grade 3 irAEs and no grade ≥4 irAEs.

Cosibelimab demonstrated robust and durable ORRs and CR rates in patients with mCSCC and laCSCC. After 16 months of additional follow-up, these results showed deepening of responses over time, resulting in higher ORR and CR rates than reported at the primary/interim analyses.⁸ The response rates are

comparable to those reported in long-term studies of pembrolizumab and cemiplimab in patients with advanced CSCC albeit with longer median follow-up durations (pembrolizumab: 63.1 months; cemiplimab: 42.5 months).²³,²⁴ Median DOR was not reached for both the mCSCC and laCSCC cosibelimab cohorts. Kaplan-Meier-estimated probability of survival at 24 months was 72.1% and 80.2% for the mCSCC and laCSCC cohorts, respectively, suggesting ongoing durable responses to cosibelimab treatment. These durable responses are especially significant for patients with CSCC presenting as tumors in the head and neck region, forming the majority of primary CSCC sites, which can be challenging to manage surgically due to the heightened risk of disfigurement and morbidity.²⁵

PD-L1 expression has demonstrated predictive value for clinical response in certain cancers, including non-small cell lung cancer (NSCLC) and bladder cancer.¹² Our preliminary analysis showed that cosibelimab was associated with durable responses irrespective of baseline tumor PD-L1 status in both cohorts. This suggests that PD-L1 expression alone cannot predict clinical response to cosibelimab in patients with advanced CSCC. Similar observations have been reported with cemiplimab, although results have been inconsistent with pembrolizumab.²⁴,²⁶⁻²⁹ Future studies are warranted to explore whether other candidate biomarkers or clinical factors may be important for clinical decision-making.

Overall, cosibelimab had a manageable safety profile, regardless of attribution, with notable low rates of grade 3 irAEs, no grade ≥4 irAEs, and no treatment-related deaths. The rate of severe irAEs reported in this study (3.6%) is lower than those reported in studies with PD-1-targeting agents (pembrolizumab: 8.8%; cemiplimab: 10.7% to 19.2%).²⁴,³⁰,³¹ This may be due to preservation of the PD-L2/PD-1 interaction, which may maintain levels of checkpoint signaling, resulting in decreased blockade of the negative inhibitory signal and decreased autoimmunity. Additionally, the PD-L2/PD-1 interaction reduces PD-L2 binding to other molecules (eg, repulsive guidance molecule b), which could contribute to irAEs (eg, pneumonitis) with PD-1-targeting agents.¹⁶,¹⁸,³² Studies of patients aged ≥65 years with NSCLC have found the incidence of irAEs to be high.³³ This is relevant for patients with advanced CSCC as the median age for patients in the cosibelimab trial and other PD-1 inhibitor trials is >70 years.²⁴,²⁶⁻³⁰ Management of elderly patients is complicated by potential comorbidity, frailty, organ dysfunction, and polypharmacy; therefore, selecting a drug with low rates of severe irAEs is very important.³³ Furthermore, the safety profile of cosibelimab makes it an attractive agent to study further in special CSCC populations at higher risk of toxicities, such as solid
organ transplant recipients and patients with a history of hematologic malignancies or autoimmune disorders, where irAEs limit utilization.³⁻³⁶

Study limitations have been described in the primary mCSCC publication and include the single-cohort design, short duration of follow-up at data cutoff, limited biomarker analysis, and absence of pathologic confirmation of complete response in externally visible target lesions.⁸ However, the data presented herein provide longer-term follow-up with sustained efficacy. These results further support that cosibelimab at 800 mg Q2W and 1200 mg Q3W has a manageable safety profile and provides clinically meaningful activity for patients with mCSCC and laCSCC, as evidenced by ORR and DOR.

## CONCLUSION

In this pivotal study of patients with mCSCC and laCSCC, cosibelimab was associated with robust and clinically meaningful ORRs ≥50% and CR rates, durable DORs, and a manageable safety profile with low rates of grade 3 irAEs and no grade ≥4 irAEs. These results provide additional support for the use of cosibelimab in patients with mCSCC and laCSCC.

The authors would like to thank the participants, their families, and all investigational site members involved in this study. Funding for this study was provided by Checkpoint Therapeutics. Writing and editorial support were provided under the direction of the authors by Ella A. Kasanga, PhD, PMP, CMPP, and Erin Reineck, ELS, of Fingerpaint Medical, and funded by Checkpoint Therapeutics. Data reported in this manuscript were presented in part at the European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain.

## Conflicts of interest

ESR has served as a consultant for Checkpoint Therapeutics, Feldan Therapeutics, Merck & Co., Regeneron Pharmaceuticals, and Replimune. EM-C has served as a consultant and/or scientific advisor for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Regeneron; received research funding from Merck Sharp & Dohme, Sanofi, and Bristol Myers Squibb; served as a speaker for Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Regeneron; and served as a principal investigator for clinical trials for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Replimune, Iovance, and Bioinvent. HM has served as a consultant and/or scientific advisor for Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. MAB-G has served as a consultant, in an advisory role, or on a speakers' bureau for Bristol Myers Squibb, Merck Sharp & Dohme, Regeneron, Novartis, and Pierre Fabre; and received financial support for travel or accommodation expenses from Bristol Myers Squibb, Merck

Sharp & Dohme, Regeneron, Novartis, and Pierre Fabre. GQ has served as a consultant for Sanofi. CN has served as a consultant or member of an advisory board for Bristol Myers Squibb, Merck Sharp & Dohme, Regeneron, and Novartis; and received financial support for travel and accommodation expenses from Bristol Myers Squibb, Merck Sharp & Dohme, and Novartis. SD has received research funding from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, and Regeneron; financial support for travel expenses from Bristol Myers Squibb and Merck Sharp & Dohme; and served as a member of a Data Safety Monitoring Board/advisory board for Bristol Myers Squibb and Merck Sharp & Dohme. RL has served as a consultant and/or scientific advisor for AstraZeneca, Merck Sharp & Dohme, and Sanofi and been a speaker for Merck Sharp & Dohme. MM has served as a scientific advisor and speaker for Merck Sharp & Dohme. DB has served on an advisory board for and received honoraria from Merck Sharp & Dohme. DH has received reimbursements for serving as a clinical investigator for the CK-301-101 trial sponsored by Checkpoint Therapeutics. SF has received honoraria from Merck Sharp & Dohme, MundiPharma, Roche, and Sanofi and serves as a board director for ICON Oncology Holdings Pty Ltd, Drs. Alberts Bouwer Jordaan Inc., and Gamma Knife South Africa. DRM serves as director for Phoenix Pharma. JO is an employee of Checkpoint Therapeutics and holds stock and other ownership interests in the company and has served in leadership roles at Checkpoint Therapeutics. LNW is an employee of Checkpoint Therapeutics and holds stock and other ownership interests in the company. WGG is an employee of Checkpoint Therapeutics and holds stock and other ownership interests in the company and has served in leadership roles at Checkpoint Therapeutics. MCAG, JC, RYT, MB-B, HS, AT, and PC have no conflicts of interest to declare.

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