Testing the Addition of an Immunotherapy Drug, Cemiplimab (REGN2810), Plus Surgery to the Usual Surgery Alone for Treating Advanced Skin Cancer

May 12, 2026 updated by: National Cancer Institute (NCI)

Randomized Phase III Trial of Neoadjuvant Immunotherapy With Response-Adapted Treatment Versus Standard-of-Care Treatment for Resectable Stage III/IV Cutaneous Squamous Cell Carcinoma (C-PRE)

This phase III trial compares the effect of adding cemiplimab to standard therapy (surgery with or without radiation) versus standard therapy alone in treating patients with stage III/IV squamous cell skin cancer that is able to be removed by surgery (resectable) and that may have come back after a period of improvement (recurrent). The usual treatment for patients with resectable squamous cell skin cancer is the removal of the cancerous tissue (surgery) with or without radiation, which uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cemiplimab has been approved for the treatment of skin cancer that has spread or that cannot be removed by surgery, but it has not been approved for the treatment of skin cancer than can be removed by surgery. Adding cemiplimab to the usual treatment of surgery with or without radiation may be more effective in treating patients with stage III/IV resectable squamous cell skin cancer than the usual treatment alone.

Study Overview

Status

Suspended

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if neoadjuvant immunotherapy combined with response-adapted oncologic surgery improves site-reported event-free survival (EFS) compared to standard-of-care surgery in resectable stage III/IV cutaneous squamous cell carcinoma (CSCC).

SECONDARY OBJECTIVES:

I. To compare utilization of adjuvant radiation between arms. II. To compare disease-free survival (DFS) between arms. III. To compare overall survival (OS) between arms. IV. To compare adverse events (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0) between arms.

V. To assess pathologic complete response in arm 2.

PATIENT-REPORTED OUTCOMES:

I. Compare changes in patient reported quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at 1, 6, and 12 months after surgery between treatment arms. (Primary objective) II. To compare patient reported symptoms functioning, and quality of life, as measured by the Cutaneous Squamous Cell Carcinoma NeoAdjuvant, Adjuvant and Perioperative 32 question scale (CSCC NAAP-32), Patient Reported Outcomes Measurement Information System (PROMIS)-Short Form (SF)-Anxiety, PROMIS-SF-Fatigue, and EuroQol-5D (EQ-5D), between arms at 1, 6, and 12 months after surgery.

III. Develop a scoring algorithm and validate the CSCC-NAAP-32 for use in this patient population.

EXPLORATORY OBJECTIVES:

I. To compare disease-specific survival (DSS) between arms. II. To correlate pathologic response with DFS in arm 2. III. To assess overall response rate (ORR) in arm 2. IV. To compare patterns of failure between arms. V. To compare pathologic measurements of lymph node yield between arms. VI. To compare primary tumor specimen dimensions and volume between arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo surgery per standard of care within 6 weeks of randomization. Starting within 6-12 weeks of surgery, patients may undergo image-guided radiation therapy (IGRT) with intensity modulated radiation therapy (IMRT) for 5 fractions per week for 6 weeks as clinically indicated. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)/CT prior to treatment, and CT and/or MRI during follow up. Patients may also undergo optional collection of tissue, whole blood, and plasma on study.

ARM 2: Patients receive cemiplimab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo response-adaptive surgery 21 days after last dose of cemiplimab. Starting within 12 weeks of surgery, patients may undergo IGRT with IMRT for 5 fractions per week for 6 weeks as clinically indicated. Starting within 6 weeks of completion of surgery or radiation therapy (if indicated), patients without pathologic complete response (pCR) receive cemiplimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and/or PET/CT prior to treatment, and CT and/or MRI on study and during follow up. Patients may also undergo optional collection of tissue, whole blood, and plasma on study.

After completion of study treatment, patients are followed up at 1, 6, and 12 months post-surgery then every 3 months for 2 years, every 6 months in year 3, and then annually thereafter.

Study Type

Interventional

Enrollment (Estimated)

420

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • New South Wales
      • Camperdown, New South Wales, Australia, 2050
        • Chris O'Brien Lifehouse
      • Wollongong, New South Wales, Australia, 2500
        • Wollongong Hospital
    • Queensland
      • Townsville, Queensland, Australia, 4814
        • Townsville General Hospital
      • Woolloongabba, Queensland, Australia, 4102
        • Princess Alexandra Hospital
    • Victoria
      • Fitzroy, Victoria, Australia, 3065
        • Saint Vincent's Hospital
      • Melbourne, Victoria, Australia, 3000
        • Peter MacCallum Cancer Centre
    • Western Australia
      • Murdoch, Western Australia, Australia, 6150
        • Fiona Stanley Hospital
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • BCCA-Vancouver Cancer Centre
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • University Health Network-Princess Margaret Hospital
      • Toronto, Ontario, Canada, M4N 3M5
        • Odette Cancer Centre- Sunnybrook Health Sciences Centre
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham Cancer Center
    • Arizona
      • Gilbert, Arizona, United States, 85234
        • Banner MD Anderson Cancer Center
      • Phoenix, Arizona, United States, 85054
        • Mayo Clinic Hospital in Arizona
    • California
      • Beverly Hills, California, United States, 90211
        • Tower Cancer Research Foundation
      • Duarte, California, United States, 91010
        • City of Hope Comprehensive Cancer Center
      • Encinitas, California, United States, 92024
        • UC San Diego Health System - Encinitas
      • Irvine, California, United States, 92618
        • City of Hope at Irvine Lennar
      • La Jolla, California, United States, 92093
        • UC San Diego Moores Cancer Center
      • Lancaster, California, United States, 93534
        • City of Hope Antelope Valley
      • Los Angeles, California, United States, 90033
        • USC / Norris Comprehensive Cancer Center
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Medical Center
      • Los Angeles, California, United States, 90025
        • The Angeles Clinic and Research Institute - West Los Angeles Office
      • Oakland, California, United States, 94611
        • Kaiser Permanente-Oakland
      • Palo Alto, California, United States, 94304
        • Stanford Cancer Institute Palo Alto
      • Sacramento, California, United States, 95817
        • University of California Davis Comprehensive Cancer Center
      • Sacramento, California, United States, 95823
        • Kaiser Permanente-South Sacramento
      • San Diego, California, United States, 92103
        • UC San Diego Medical Center - Hillcrest
      • San Francisco, California, United States, 94115
        • Kaiser Permanente-San Francisco
      • South Pasadena, California, United States, 91030
        • City of Hope South Pasadena
      • Torrance, California, United States, 90505
        • Torrance Memorial Physician Network - Cancer Care
      • Upland, California, United States, 91786
        • City of Hope Upland
      • Walnut Creek, California, United States, 94596
        • Kaiser Permanente-Walnut Creek
    • Colorado
      • Aurora, Colorado, United States, 80045
        • UCHealth University of Colorado Hospital
      • Colorado Springs, Colorado, United States, 80909
        • UCHealth Memorial Hospital Central
      • Colorado Springs, Colorado, United States, 80920
        • Memorial Hospital North
    • Connecticut
      • Greenwich, Connecticut, United States, 06830
        • Smilow Cancer Hospital Care Center at Greenwich
      • Guilford, Connecticut, United States, 06437
        • Smilow Cancer Hospital Care Center - Guilford
      • New Haven, Connecticut, United States, 06520
        • Yale University
      • Trumbull, Connecticut, United States, 06611
        • Smilow Cancer Hospital Care Center-Trumbull
      • Waterbury, Connecticut, United States, 06708
        • Smilow Cancer Hospital-Waterbury Care Center
      • Waterford, Connecticut, United States, 06385
        • Smilow Cancer Hospital Care Center - Waterford
    • Delaware
      • Newark, Delaware, United States, 19713
        • Helen F Graham Cancer Center
      • Newark, Delaware, United States, 19713
        • Medical Oncology Hematology Consultants PA
    • Florida
      • Aventura, Florida, United States, 33180
        • UM Sylvester Comprehensive Cancer Center at Aventura
      • Coral Gables, Florida, United States, 33146
        • UM Sylvester Comprehensive Cancer Center at Coral Gables
      • Deerfield Beach, Florida, United States, 33442
        • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
      • Doral, Florida, United States, 33166
        • UM Sylvester Comprehensive Cancer Center at Doral
      • Jacksonville, Florida, United States, 32224-9980
        • Mayo Clinic in Florida
      • Miami, Florida, United States, 33136
        • University of Miami Miller School of Medicine-Sylvester Cancer Center
      • Miami, Florida, United States, 33176
        • Miami Cancer Institute
      • Miami, Florida, United States, 33176
        • UM Sylvester Comprehensive Cancer Center at Kendall
      • N. Venice, Florida, United States, 34275
        • Sarasota Memorial Hospital-Venice
      • Plantation, Florida, United States, 33324
        • UM Sylvester Comprehensive Cancer Center at Plantation
      • Sarasota, Florida, United States, 34239
        • Sarasota Memorial Hospital
      • Sarasota, Florida, United States, 34232
        • Florida Cancer Specialists - Sarasota
      • Sarasota, Florida, United States, 34236
        • Florida Cancer Specialists - Sarasota Downtown
      • Sarasota, Florida, United States, 34243
        • Sarasota Memorial Health Care Center at University Parkway
      • Sarasota, Florida, United States, 34239
        • First Physicians Group - Silverstein Institute at Floyd Street
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
      • Tampa, Florida, United States, 33607
        • Moffitt Cancer Center-International Plaza
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center - McKinley Campus
      • Venice, Florida, United States, 34285
        • Florida Cancer Specialists - Venice Island
      • Venice, Florida, United States, 34275
        • Florida Cancer Specialists - Venice Pinebrook
    • Georgia
      • Atlanta, Georgia, United States, 30308
        • Emory University Hospital Midtown
      • Atlanta, Georgia, United States, 30322
        • Emory University Hospital/Winship Cancer Institute
    • Illinois
      • Alton, Illinois, United States, 62002
        • Alton Memorial Hospital
      • Chicago, Illinois, United States, 60611
        • Northwestern University
      • Chicago, Illinois, United States, 60612
        • University of Illinois
      • Chicago, Illinois, United States, 60612
        • Rush MD Anderson Cancer Center
      • DeKalb, Illinois, United States, 60115
        • Northwestern Medicine Cancer Center Kishwaukee
      • Decatur, Illinois, United States, 62526
        • Decatur Memorial Hospital
      • Geneva, Illinois, United States, 60134
        • Northwestern Medicine Cancer Center Delnor
      • Orland Park, Illinois, United States, 60462
        • Northwestern Medicine Orland Park
      • Shiloh, Illinois, United States, 62269
        • Memorial Hospital East
      • Warrenville, Illinois, United States, 60555
        • Northwestern Medicine Cancer Center Warrenville
    • Indiana
      • Carmel, Indiana, United States, 46032
        • IU Health North Hospital
      • Goshen, Indiana, United States, 46526
        • Goshen Center for Cancer Care
      • Indianapolis, Indiana, United States, 46237
        • Franciscan Health Indianapolis
      • Indianapolis, Indiana, United States, 46202
        • Indiana University/Melvin and Bren Simon Cancer Center
    • Iowa
      • Council Bluffs, Iowa, United States, 51503
        • Heartland Oncology and Hematology LLP
      • Council Bluffs, Iowa, United States, 51503
        • Methodist Jennie Edmundson Hospital
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • University of Kansas Cancer Center
      • Overland Park, Kansas, United States, 66210
        • University of Kansas Cancer Center-Overland Park
      • Overland Park, Kansas, United States, 66211
        • University of Kansas Hospital-Indian Creek Campus
      • Westwood, Kansas, United States, 66205
        • University of Kansas Hospital-Westwood Cancer Center
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky/Markey Cancer Center
      • Louisville, Kentucky, United States, 40202
        • The James Graham Brown Cancer Center at University of Louisville
      • Louisville, Kentucky, United States, 40245
        • UofL Health Medical Center Northeast
    • Louisiana
      • Baton Rouge, Louisiana, United States, 70805
        • LSU Health Baton Rouge-North Clinic
      • Baton Rouge, Louisiana, United States, 70808
        • Our Lady of the Lake Physician Group
      • New Orleans, Louisiana, United States, 70112
        • University Medical Center New Orleans
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Rogel Cancer Center
      • Brighton, Michigan, United States, 48116
        • University of Michigan - Brighton Center for Specialty Care
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hospital
      • Grand Rapids, Michigan, United States, 49503
        • Corewell Health Grand Rapids Hospitals - Butterworth Hospital
      • West Bloomfield, Michigan, United States, 48322
        • Henry Ford West Bloomfield Hospital
      • Wyoming, Michigan, United States, 49519
        • University of Michigan Health - West
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota/Masonic Cancer Center
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester
    • Missouri
      • City of Saint Peters, Missouri, United States, 63376
        • Siteman Cancer Center at Saint Peters Hospital
      • Columbia, Missouri, United States, 65212
        • MU Health - University Hospital/Ellis Fischel Cancer Center
      • Creve Coeur, Missouri, United States, 63141
        • Siteman Cancer Center at West County Hospital
      • Kansas City, Missouri, United States, 64154
        • University of Kansas Cancer Center - North
      • Lee's Summit, Missouri, United States, 64064
        • University of Kansas Cancer Center - Lee's Summit
      • St Louis, Missouri, United States, 63110
        • Washington University School of Medicine
      • St Louis, Missouri, United States, 63129
        • Siteman Cancer Center-South County
      • St Louis, Missouri, United States, 63136
        • Siteman Cancer Center at Christian Hospital
    • Nebraska
      • Bellevue, Nebraska, United States, 68123
        • Nebraska Medicine-Bellevue
      • Omaha, Nebraska, United States, 68114
        • Nebraska Methodist Hospital
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska Medical Center
      • Omaha, Nebraska, United States, 68118
        • Nebraska Medicine-Village Pointe
      • Omaha, Nebraska, United States, 68114
        • Nebraska Cancer Specialists/Oncology Hematology West PC - MECC
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756
        • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
    • New Jersey
      • Basking Ridge, New Jersey, United States, 07920
        • Memorial Sloan Kettering Basking Ridge
      • Middletown, New Jersey, United States, 07748
        • Memorial Sloan Kettering Monmouth
      • Montvale, New Jersey, United States, 07645
        • Memorial Sloan Kettering Bergen
    • New Mexico
      • Albuquerque, New Mexico, United States, 87106
        • University of New Mexico Cancer Center
    • New York
      • Commack, New York, United States, 11725
        • Memorial Sloan Kettering Commack
      • Harrison, New York, United States, 10604
        • Memorial Sloan Kettering Westchester
      • Lake Success, New York, United States, 11042
        • Northwell Health/Center for Advanced Medicine
      • Mineola, New York, United States, 11501
        • NYU Langone Hospital - Long Island
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
      • New York, New York, United States, 10016
        • Laura and Isaac Perlmutter Cancer Center at NYU Langone
      • New York, New York, United States, 10075
        • Lenox Hill Hospital
      • New York, New York, United States, 10065
        • Manhattan Eye Ear and Throat Hospital
      • Rochester, New York, United States, 14642
        • University of Rochester
      • Stony Brook, New York, United States, 11794
        • Stony Brook University Medical Center
      • Syracuse, New York, United States, 13210
        • State University of New York Upstate Medical University
      • Syracuse, New York, United States, 13215
        • SUNY Upstate Medical Center-Community Campus
      • The Bronx, New York, United States, 10461
        • Montefiore Medical Center-Einstein Campus
      • The Bronx, New York, United States, 10467
        • Montefiore Medical Center - Moses Campus
      • The Bronx, New York, United States, 10461
        • Montefiore Medical Center-Weiler Hospital
      • Uniondale, New York, United States, 11553
        • Memorial Sloan Kettering Nassau
      • Webster, New York, United States, 14580
        • Wilmot Cancer Institute at Webster
    • North Carolina
      • Albemarle, North Carolina, United States, 28002
        • Atrium Health Stanly/LCI-Albemarle
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Lineberger Comprehensive Cancer Center
      • Charlotte, North Carolina, United States, 28203
        • Carolinas Medical Center/Levine Cancer Institute
      • Charlotte, North Carolina, United States, 28210
        • Atrium Health Pineville/LCI-Pineville
      • Charlotte, North Carolina, United States, 28262
        • Atrium Health University City/LCI-University
      • Concord, North Carolina, United States, 28025
        • Atrium Health Cabarrus/LCI-Concord
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
      • Gastonia, North Carolina, United States, 28054
        • Levine Cancer Institute-Gaston
      • Monroe, North Carolina, United States, 28112
        • Atrium Health Union/LCI-Union
      • Raleigh, North Carolina, United States, 27609
        • Duke Cancer Center Raleigh
      • Shelby, North Carolina, United States, 28150
        • Atrium Health Cleveland/LCI-Cleveland
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Health Sciences
    • Ohio
      • Avon, Ohio, United States, 44011
        • UH Seidman Cancer Center at UH Avon Health Center
      • Beachwood, Ohio, United States, 44122
        • UHHS-Chagrin Highlands Medical Center
      • Centerville, Ohio, United States, 45459
        • Miami Valley Hospital South
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati Cancer Center-UC Medical Center
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
      • Cleveland, Ohio, United States, 44109
        • MetroHealth Medical Center
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center
      • Dayton, Ohio, United States, 45415
        • Miami Valley Hospital North
      • Franklin, Ohio, United States, 45005-1066
        • Atrium Medical Center-Middletown Regional Hospital
      • Greenville, Ohio, United States, 45331
        • Miami Valley Cancer Care and Infusion
      • Mentor, Ohio, United States, 44060
        • UH Seidman Cancer Center at Lake Health Mentor Campus
      • Troy, Ohio, United States, 45373
        • Upper Valley Medical Center
      • West Chester, Ohio, United States, 45069
        • University of Cincinnati Cancer Center-West Chester
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • University of Oklahoma Health Sciences Center
    • Oregon
      • Portland, Oregon, United States, 97213
        • Providence Portland Medical Center
    • Pennsylvania
      • Chadds Ford, Pennsylvania, United States, 19317
        • Christiana Care Health System-Concord Health Center
      • Erie, Pennsylvania, United States, 16505
        • UPMC Hillman Cancer Center Erie
      • Erie, Pennsylvania, United States, 16544
        • Saint Vincent Hospital
      • Hershey, Pennsylvania, United States, 17033-0850
        • Penn State Milton S Hershey Medical Center
      • Johnstown, Pennsylvania, United States, 15901
        • UPMC-Johnstown/John P. Murtha Regional Cancer Center
      • Monroeville, Pennsylvania, United States, 15146
        • Forbes Hospital
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University Hospital
      • Pittsburgh, Pennsylvania, United States, 15212
        • Allegheny General Hospital
      • Pittsburgh, Pennsylvania, United States, 15224
        • West Penn Hospital
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh Cancer Institute (UPCI)
      • Wexford, Pennsylvania, United States, 15090
        • Wexford Health and Wellness Pavilion
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
      • Rock Hill, South Carolina, United States, 29732
        • Levine Cancer Institute-Rock Hill
      • Rock Hill, South Carolina, United States, 29730
        • Rock Hill Radiation Therapy Center
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University/Ingram Cancer Center
    • Texas
      • Conroe, Texas, United States, 77384
        • MD Anderson in The Woodlands
      • Dallas, Texas, United States, 75390
        • UT Southwestern/Simmons Cancer Center-Dallas
      • Dallas, Texas, United States, 75237
        • UT Southwestern Simmons Cancer Center - RedBird
      • Fort Worth, Texas, United States, 76104
        • UT Southwestern/Simmons Cancer Center-Fort Worth
      • Houston, Texas, United States, 77030
        • M D Anderson Cancer Center
      • Houston, Texas, United States, 77079
        • MD Anderson West Houston
      • League City, Texas, United States, 77573
        • MD Anderson League City
      • Richardson, Texas, United States, 75080
        • UT Southwestern Clinical Center at Richardson/Plano
      • San Antonio, Texas, United States, 78229
        • University of Texas Health Science Center at San Antonio
      • Sugar Land, Texas, United States, 77478
        • MD Anderson in Sugar Land
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Huntsman Cancer Institute/University of Utah
    • Vermont
      • Berlin Corners, Vermont, United States, 05602
        • Central Vermont Medical Center/National Life Cancer Treatment
      • Burlington, Vermont, United States, 05401
        • University of Vermont Medical Center
      • Burlington, Vermont, United States, 05405
        • University of Vermont and State Agricultural College
      • Saint Johnsbury, Vermont, United States, 05819
        • Dartmouth Cancer Center - North
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia Cancer Center
      • Fairfax, Virginia, United States, 22031
        • Inova Schar Cancer Institute
      • Richmond, Virginia, United States, 23298
        • VCU Massey Comprehensive Cancer Center
    • Washington
      • Seattle, Washington, United States, 98101
        • Virginia Mason Medical Center
    • Wisconsin
      • La Crosse, Wisconsin, United States, 54601
        • Gundersen Lutheran Medical Center
      • Madison, Wisconsin, United States, 53705
        • William S Middleton VA Medical Center
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Carbone Cancer Center - University Hospital
      • Madison, Wisconsin, United States, 53718
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
      • Marshfield, Wisconsin, United States, 54449
        • Marshfield Medical Center-Marshfield
      • Menomonee Falls, Wisconsin, United States, 53051
        • Froedtert Menomonee Falls Hospital
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin
      • Oak Creek, Wisconsin, United States, 53154
        • Drexel Town Square Health Center
      • West Bend, Wisconsin, United States, 53095
        • Froedtert West Bend Hospital/Kraemer Cancer Center
      • Weston, Wisconsin, United States, 54476
        • Marshfield Medical Center - Weston

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pathologically (histologically or cytologically) proven diagnosis of invasive cutaneous squamous cell carcinoma (CSCC) or regional lymph node or in-transit metastasis of CSCC

    • The following CSCC subtypes are eligible according to World Health Organization (WHO) classification if the predominant histology is confirmed CSCC.

      • Spindle cell squamous cell carcinoma (SCC)
      • Squamous cell carcinoma with sarcomatoid differentiation
      • Acantholytic SCC
      • Clear cell SCC

      • Lymphoepithelial carcinoma

        • Note: Keratoacanthoma SCC and Verrucous SCC subtypes are not eligible.

    • For patients with regional metastasis without a primary tumor at screening: a clinical history of CSCC that drains to the involved regional lymph nodes or in-transit metastases in question is required

      • For example, a parotid mass shown to be SCC by cytologic analysis of a fine needle aspirate in a patient with a clinical history of CSCC on the ipsilateral scalp would be eligible
    • For patients with regional metastases without a primary tumor and an ambiguous clinical history: tumor genomic sequencing suggesting a primary tumor of cutaneous origin would be acceptable evidence to establish eligibility
    • NOTE: Tumor genomic sequencing is not required to determine eligibility, but may be part of the routine evaluation of patients with cancers of unknown primary at some institutions. For example, a parotid mass shown to be SCC by cytologic analysis of fine needle aspirate without a primary tumor and an ambiguous clinical history, but with a tumor genomic sequencing assay demonstrating a high tumor mutation burden (≥ 10 mutations/Mb) and/or a high fraction of ultraviolet (UV) related mutations (> 50% of mutations [cytosine (C)/thymine (T)]C > T or CC > TT) and/or the presence of "signature 7" mutations would be eligible (Chang 2021)
  • Previously untreated or recurrent CSCC
  • Clinical American Joint Committee on Cancer (AJCC) 8th Edition (eyelid, head and neck sites) or Union for International Cancer Control (UICC) (non-head and neck sites) stage III or IV
  • Primary tumor site must be in the head and neck cutaneous region, other non-head and neck cutaneous regions, or eyelid cutaneous region
  • No mucosal squamous cell carcinoma (vermillion lip, nasal, oral, sinonasal, conjunctival, anogenital)
  • Tumor must be resectable with curative intent. Note: Tumor with bony skull base invasion and/or skull base foramen involvement (T4b) is not eligible. (Patients with T4b eyelid tumors using UICC Staging, and not involving the brain, are eligible.)
  • At least 1 lesion that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • No definitive clinical or radiologic evidence of distant metastatic disease (M1), visceral and/or distant nodal disease
  • Age ≥ 18
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

  • Not pregnant and not nursing

    • Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
  • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3
  • Platelets ≥ 75,000 cells/mm^3
  • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)
  • Creatinine clearance (CrCL) > 30mL/min by the Cockcroft-Gault formula
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (NOTE: For patients with Gilbert's syndrome, total bilirubin ≤ 3 x ULN. Gilbert's syndrome must be documented appropriately as past medical history.)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN
  • No prior systemic therapy for the study cancer (including patients currently receiving immunotherapy for a separate malignancy)
  • No prior radiotherapy to the region of the study cancer that would result in cumulative doses of radiation to organs at risk for radiation injury that exceed protocol limitations
  • No history of myocardial infarction/unstable angina within the last 6 months
  • New York Heart Association functional classification IIb or better (New York Heart Association [NYHA] functional classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification)
  • No active infection requiring systemic antibiotics, antiviral, or antifungal treatments
  • No history of allogeneic stem cell transplantation, or autologous stem cell transplantation
  • No history of a solid organ transplant (other than corneal transplant)

  • No active, known, or suspected autoimmune disease

    • Active or known disease is defined as:

      • Requiring higher than physiologic steroid levels (> 10mg prednisone/day or equivalent) or
      • Requiring disease-modifying agents or
      • Ongoing or recent (within 5 years prior to registration) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events (irAEs)

    • NOTES:

      • Patients meeting the following criteria are not considered immunosuppressed and are eligible to enroll:

        • Patients who require a brief course of steroids (eg, prophylaxis for imaging assessments due to hypersensitivity to contrast agents) are not excluded
        • Patients with type I diabetes mellitus, and endocrinopathies (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
        • Physiologic replacement doses ≤ 10 mg prednisone/day or equivalent allowed, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted

      • Patients with the following immunosuppressed conditions are eligible to enroll:

        • Patients with HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible
        • Patients with chronic lymphocytic leukemia (CLL) with no history of anti-CLL therapy within 6 months prior to registration are eligible
  • No history of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing pneumonia)
  • No active, noninfectious pneumonitis requiring immune-suppressive therapy
  • No active tuberculosis
  • No live vaccines within 28 days prior to registration
  • No history of allergic reaction to the study agent, compounds of similar chemical or biologic composition to the study agent (or any of its excipients)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm 1 (surgery, radiation)
Patients undergo surgery per standard of care within 6 weeks of randomization. Starting within 6-12 weeks of surgery, patients may undergo IGRT with IMRT for 5 fractions per week for 6 weeks as clinically indicated. Patients also undergo CT, MRI, and/or PET/CT prior to treatment, and CT and/or MRI during follow up. Patients may also undergo optional collection of tissue, whole blood, and plasma on study.
Other: Questionnaire Administration
Ancillary studies
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
  • Radiation, Intensity-Modulated Radiotherapy
  • Intensity modulated radiation therapy (procedure)
Radiation: Image Guided Radiation Therapy
Undergo IGRT
Other Names:
  • IGRT
  • image-guided radiation therapy
  • Image-Guided Radiotherapy
  • Image Guided Radiotherapy
Procedure: Positron Emission Tomography
Undergo PET/CT
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • PT
  • Positron emission tomography (procedure)
Procedure: Computed Tomography
Undergo CT and/or PET/CT
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
  • Diagnostic CAT Scan
  • Diagnostic CAT Scan Service Type
Procedure: Biospecimen Collection
Undergo collection of blood and/or plasma
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Sample Collection
Procedure: Surgical Procedure
Undergo surgery per SOC
Other Names:
  • Operation
  • Surgery
  • Surgery Type
  • Surgical
  • Surgical Intervention
  • Surgical Interventions
  • Surgical Procedures
  • Type of Surgery
  • Surgery, NOS
Procedure: Surgical Procedure
Undergo response-adaptive surgery
Other Names:
  • Operation
  • Surgery
  • Surgery Type
  • Surgical
  • Surgical Intervention
  • Surgical Interventions
  • Surgical Procedures
  • Type of Surgery
  • Surgery, NOS
Experimental: Arm 2 (cemiplimab, surgery, radiation)
Patients receive cemiplimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo response-adaptive surgery 21 days after last dose of cemiplimab. Starting within 12 weeks of surgery, patients may undergo IGRT with IMRT for 5 fractions per week for 6 weeks as clinically indicated. Starting within 6 weeks of completion of surgery or radiation therapy (if indicated), patients without pCR receive cemiplimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and/or PET/CT prior to treatment, and CT and/or MRI on study and during follow up. Patients may also undergo optional collection of tissue, whole blood, and plasma on study.
Other: Questionnaire Administration
Ancillary studies
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
  • Radiation, Intensity-Modulated Radiotherapy
  • Intensity modulated radiation therapy (procedure)
Biological: Cemiplimab
Given IV
Other Names:
  • REGN2810
  • Cemiplimab RWLC
  • Cemiplimab-rwlc
  • Libtayo
  • REGN 2810
  • REGN-2810
Radiation: Image Guided Radiation Therapy
Undergo IGRT
Other Names:
  • IGRT
  • image-guided radiation therapy
  • Image-Guided Radiotherapy
  • Image Guided Radiotherapy
Procedure: Positron Emission Tomography
Undergo PET/CT
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • PT
  • Positron emission tomography (procedure)
Procedure: Computed Tomography
Undergo CT and/or PET/CT
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
  • Diagnostic CAT Scan
  • Diagnostic CAT Scan Service Type
Procedure: Biospecimen Collection
Undergo collection of blood and/or plasma
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Sample Collection
Procedure: Surgical Procedure
Undergo surgery per SOC
Other Names:
  • Operation
  • Surgery
  • Surgery Type
  • Surgical
  • Surgical Intervention
  • Surgical Interventions
  • Surgical Procedures
  • Type of Surgery
  • Surgery, NOS
Procedure: Surgical Procedure
Undergo response-adaptive surgery
Other Names:
  • Operation
  • Surgery
  • Surgery Type
  • Surgical
  • Surgical Intervention
  • Surgical Interventions
  • Surgical Procedures
  • Type of Surgery
  • Surgery, NOS

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-free survival (EFS)
Time Frame: Up to 6 years
Defined as the time from randomization to any of the following events: progression of disease that precludes surgery, toxic effects related to treatment that preclude surgery, inability to resect all gross disease), disease recurrence (local, regional, or distant) after surgery (or after radiographic complete response), disease progression after radiographic partial response or stable disease without surgery (or biopsy, as applicable), or death due to any cause, whichever occurs first. EFS rates will be estimated using the Kaplan-Meier method, and the stratified log-rank test will be used to assess whether perioperative immunotherapy (neoadjuvant/adjuvant) with response-adapted oncologic surgery improves EFS as recorded by the site compared to standard-of-care surgery in resectable stage III/IV cutaneous squamous cell carcinoma (CSCC).
Up to 6 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-free survival (DFS)
Time Frame: From randomization to recurrent or death, assessed up to 6 years
DFS will use the same analytic methods as EFS.
From randomization to recurrent or death, assessed up to 6 years
Overall survival (OS)
Time Frame: From randomization to death, assessed up to 6 years
OS will use the same analytic methods as EFS.
From randomization to death, assessed up to 6 years
Pathologic complete response
Time Frame: At 1 and 2 years
Site-reported pathologic response will be assessed using the following categories: pathological complete, major, and partial response, no pathological response (i.e., no complete, major, or partial response), and no pathological evaluation. Pathological responses at 1 and 2 years will be summarized using frequencies and percentages and tested using a chi-square test at a two-sided 5% significance level.
At 1 and 2 years
Utilization of adjuvant radiation
Time Frame: Up to 6 years
Rates of utilization of adjuvant radiation for each arm will be computed using a binomial distribution assumption. A 95% confidence interval (CI) for the rate difference between arms will be calculated using the stratified Newcombe (Wilson) method (Yan 2010).
Up to 6 years
Incidence of adverse events
Time Frame: At 30 days and then up to 6 years
Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events version (v) 5.0. Counts and frequencies of all AEs by grade will be provided by each treatment arm. For the experimental arm, AEs will be summarized for each treatment phase (neoadjuvant, adjuvant, and post-treatment [after adjuvant]). Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The proportion of patients with at least one grade 3 or higher AE, serious AEs, AEs leading to discontinuation or death will be reported for each treatment arm. These analyses will be descriptive.
At 30 days and then up to 6 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life
Time Frame: From baseline up to 12 months after surgery
The primary patient-reported outcome (PRO) is the global health status score as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. For all PRO scheduled assessment visits, patient disposition will be summarized. PRO completion rate and available data rate will be computed and reported at each timepoint. Mixed effects model with repeated measures (MMRM) will be performed for the global health status score incorporating all PRO assessment timepoints. The adjusted means for each treatment and the estimated treatment differences for the treatment comparisons will be presented together with 95% CIs.
From baseline up to 12 months after surgery
Validation and scoring of Cutaneous Squamous Cell Carcinoma NeoAdjuvant, Adjuvant and Perioperative 32 question scale (CSCC NAAP-32)
Time Frame: From baseline up to 12 months after surgery
Item response distributions, inter-item correlations, factor analysis and internal consistency will be assessed. Confirmatory factor analyses will be used to confirm the underlying structure hypothesized by the conceptual framework. Items capturing perceptions and effect of treatments will be evaluated with single-item scores. Completion rate and available data rate will be computed and reported at each timepoint. CSCC-NAAP-32 item responses will be described at baseline to evaluate floor/ceiling effects, missingness, outliers, and multi-modal distributions. Internal consistency reliability for multi-item scales will be evaluated at baseline using both Cronbach's alpha and McDonald Omega coefficients. Test-retest reliability will be assessed using intraclass correlation coefficients between two time points. Construct validity and ability to detect change over time will be assessed.
From baseline up to 12 months after surgery
Change in patient-reported symptoms, functioning, and quality of life
Time Frame: From baseline up to 12 months after surgery
PRO instruments will be scored based on their respective scoring algorithms. Descriptive statistics, MMRMs, and assessment of missing data will be performed.
From baseline up to 12 months after surgery
Disease-specific survival (DSS)
Time Frame: From randomization to death due to study cancer, date of precluding event, or last follow up, assessed up to 6 years
The cause-specific log-rank test and cause-specific Cox models will also be used to compare cause-specific HRs between treatment arms and estimate cause-specific treatment-effect HRs, respectively. The cumulative incidence method will be used to estimate the incidence of cancer-specific mortality with between-arm differences tested using the stratified Gray's test. Stratified sub-distribution HR and 95% CI for treatment effect from Fine-Gray models will be computed to supplement the DSS analysis.
From randomization to death due to study cancer, date of precluding event, or last follow up, assessed up to 6 years
Pathologic response
Time Frame: Up to 6 years
Will evaluate the association of pathologic response with DFS in the experimental arm. Will compare EFS between patients with complete response versus others (major/partial/no response/not evaluable) using a log-rank test. DFS rates for each pathological response subgroup will be estimated using the Kaplan-Meier method. Furthermore, DFS rates for each pathological response subgroup will be calculated using the Kaplan-Meier method as an exploratory analysis.
Up to 6 years
Failure patterns
Time Frame: Up to 6 years
Failure patterns (local, regional, and distant metastasis) for EFS will be summarized for each treatment arm.
Up to 6 years
Lymph node yield
Time Frame: At time of surgery
The pathologic measurements of lymph node yield (i.e., number of lymph nodes) will be compared between arms using the Mann-Whitney test.
At time of surgery
Primary tumor specimen dimensions
Time Frame: At time of surgery
The pathologic measurements of the primary tumor specimens' length, width, and volume will be compared between arms using the t-test for independent samples. A Mann-Whitney test will be used if the distribution of a variable does not pass the normality test.
At time of surgery
Treatment effect HR estimates
Time Frame: Up to 6 years

Treatment effect HR estimates and 95% CIs for the primary and secondary endpoints (EFS, DFS, DSS, OS) will be calculated using a (cause-specific) Cox model with treatment by factor interaction for the following subgroups:

  • Immunosuppressed (Yes versus [vs.] no)
  • Advanced nodal disease (N3 or in-transit metastases vs. other).
  • Clinical Union for International Cancer Control or American Joint Committee on Cancer 8th Edition stage III vs. IV
  • Female vs. male
  • Age < 70 vs. ≥ 70 years
  • Eastern Cooperative Oncology Group performance status (0 vs. 1-2)
  • Females vs. males
  • White vs. other race
  • Head and neck vs. trunk/extremities
  • T stage (Tx-2 vs. > T2)
  • N stage (N0-1 vs. > N1)
  • Country A forest plot with these treatment effect HR estimates will be provided.
Up to 6 years
Treatment effect estimates by sex
Time Frame: Up to 6 years
Estimates of the primary outcome treatment effect and the corresponding 95% CIs by sex will be provided.
Up to 6 years
Treatment effect estimates by race
Time Frame: Up to 6 years
Estimates of the primary outcome treatment effect and the corresponding 95% CIs by race will be provided.
Up to 6 years
Treatment effect estimates by ethnicity
Time Frame: Up to 6 years
Estimates of the primary outcome treatment effect and the corresponding 95% CIs by ethnicity will be provided.
Up to 6 years
Overall response rate
Time Frame: Up to 6 years
Will be assessed using Response Evaluation Criteria in Solid Tumors v. 1.1 and summarized by time-point using frequencies and relative frequencies. The best objective response (complete response + partial response) rate will be estimated using a 95% confidence interval obtained using the normal approximation for a binomial proportion.
Up to 6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Neil D Gross, NRG Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 18, 2025

Primary Completion (Estimated)

August 14, 2031

Study Completion (Estimated)

August 14, 2031

Study Registration Dates

First Submitted

August 22, 2024

First Submitted That Met QC Criteria

August 22, 2024

First Posted (Actual)

August 23, 2024

Study Record Updates

Last Update Posted (Actual)

May 13, 2026

Last Update Submitted That Met QC Criteria

May 12, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2024-03425 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U10CA180868 (U.S. NIH Grant/Contract)
  • NRG-HN014 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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