Testing the Addition of an Immunotherapy Drug, Cemiplimab (REGN2810), Plus Surgery to the Usual Surgery Alone for Treating Advanced Skin Cancer
NCT Number: NCT06568172
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Recurrent Cutaneous Squamous Cell Carcinoma of the Head and Neck|Recurrent Skin Squamous Cell Carcinoma|Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck|Resectable Skin Squamous Cell Carcinoma|Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8|Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8
Interventions: PROCEDURE: Biospecimen Collection|BIOLOGICAL: Cemiplimab|PROCEDURE: Computed Tomography|RADIATION: Image Guided Radiation Therapy|RADIATION: Intensity-Modulated Radiation Therapy|PROCEDURE: Magnetic Resonance Imaging|PROCEDURE: Positron Emission Tomography|OTHER: Questionnaire Administration|PROCEDURE: Surgical Procedure|PROCEDURE: Surgical Procedure
Sponsor: National Cancer Institute (NCI)
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 420
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: SINGLE (OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2025-01-09
Completion Date: 2031-08-14

Summary:
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.

Primary Outcome Measures: Event-free survival (EFS), 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: Disease-free survival (DFS), DFS will use the same analytic methods as EFS., From randomization to recurrent or death, assessed up to 6 years|Overall survival (OS), OS will use the same analytic methods as EFS., From randomization to death, assessed up to 6 years|Incidence of adverse events, Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events version 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|Pathologic complete response, 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
Other Outcome Measures: Quality of life, 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), 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, 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), 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, 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, Failure patterns (local, regional, and distant metastasis) for EFS will be summarized for each treatment arm., Up to 6 years|Lymph node yield, 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, 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|Utilization of adjuvant radiation, Rates of utilization of adjuvant radiation for each arm will be computed using a binomial distribution assumption. A 95% CI for the rate difference between arms will be calculated using the stratified Newcombe (Wilson) method., Up to 6 years|Treatment effect HR estimates, 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, 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, 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, Estimates of the primary outcome treatment effect and the corresponding 95% CIs by ethnicity will be provided., Up to 6 years