Phase III Randomized Trial of Avelumab, Cetuximab, and Radiotherapy Versus Standard Care in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

The primary objective of this Phase III randomized trial is to demonstrate that treatment with **avelumab** in combination with **cetuximab**-radiotherapy (RT) is superior to standard of care (SOC) **cisplatin**-RT and/or SOC cetuximab-RT alone in terms of progression-free survival (PFS) in front-line patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Each cohort will be analyzed separately. This is clinically relevant as it aims to improve treatment outcomes for patients with this aggressive cancer type.

Secondary objectives include:

• Comparing overall survival (OS), local regional control, and distant metastases of avelumab in combination with cetuximab-RT versus SOC cisplatin-RT or SOC cetuximab-RT alone.
• Evaluating the overall safety and tolerability profile of avelumab in combination with cetuximab-RT compared to SOC cisplatin-RT or cetuximab-RT alone.
• Assessing the effect of avelumab in combination with cetuximab-RT on health-related quality of life compared to SOC CT-RT or cetuximab-RT alone.
• Evaluating candidate immune-related predictive biomarkers of sensitivity or insensitivity to treatment with avelumab in pre-treatment tumor samples and in blood, and exploring potential correlations between treatment outcome and the immune landscape, TCR sequencing, and antitumor cellular responses.
• Comparing PFS2, where events are progression on subsequent therapy after a first locoregional relapse or distant metastasis, or death of any cause, between patients randomized in the experimental arm avelumab-cetuximab-RT and patients randomized in the SOC arm in each cohort (cisplatin-RT for fit cohort and cetuximab-RT for unfit cohort).

The clinical trial involves a total of **one participant** diagnosed with **squamous cell carcinoma** of the oral cavity, oropharynx, hypopharynx, or larynx, specifically at stage III, IVa (operable but not operated), or IVb (non-resectable). The study population includes both male and female subjects aged between 18 and 80 years, with a performance status of ECOG 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their histologically confirmed diagnosis of previously untreated squamous cell carcinoma and their ability to receive high-dose cisplatin treatment. The trial does not include a vulnerable population. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study does not provide additional information on the general health status or specific lifestyle considerations of the participant.

The clinical trial is a **Phase III randomized** study designed to evaluate the efficacy of avelumab in combination with cetuximab and radiotherapy compared to standard care treatments in patients with locally advanced **squamous cell carcinoma of the head and neck**. The trial employs a **double-blind, controlled** methodology to ensure unbiased results. The estimated duration of the trial is from July 2024 to December 2027, with participant involvement expected to last up to 57 weeks, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific medical conditions. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of progression-free survival (PFS) and overall survival, as well as evaluations of adverse events and quality of life. The end-of-study visit will conclude the participant's involvement, with a final assessment of treatment outcomes.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoint of the trial is PFS, defined as the time from randomization to disease progression or death. Secondary endpoints include overall survival, incidence of locoregional and distant metastatic failure, and patient-reported outcomes. The trial aims to demonstrate the superiority of the investigational treatment regimen over standard care in improving PFS in the target patient population.

The clinical trial involves the administration of several treatments, including both experimental and standard-of-care therapies. **Cisplatin Accord Healthcare** is utilized as a standard-of-care treatment. It is a **solution for infusion** with a concentration of 1 mg/mL. The active substance is **cisplatin**, a chemical compound classified under the ATC code L01XA01. The solution is administered via **intravenous infusion**. The maximum daily dose is 100 mg/m², with a total maximum dose of 300 mg/m² over a treatment period of 43 days. This medication is provided by Accord Healthcare B.V. and is used as a cytostatic antineoplastic agent.

**Bavencio**, with the active substance **avelumab**, is an experimental treatment in this trial. It is a **concentrate for solution for infusion** with a concentration of 20 mg/mL. Avelumab is a recombinant human monoclonal IgG1 antibody targeting programmed death ligand-1. The administration route is **intravenous infusion**, with a maximum daily dose of 10 mg/kg and a total maximum dose of 290 mg/kg over a 14-day treatment period. This product is supplied by Merck Europe B.V. and is used here for a therapeutic indication different from its original authorization.

**Erbitux**, containing the active substance **cetuximab**, is used both as an experimental and comparator treatment. It is a **solution for infusion** with a concentration of 5 mg/mL. Cetuximab is a protein-based therapeutic agent. The administration is conducted via **solution for infusion**, with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m² over a 57-day treatment period. This product is also provided by Merck Europe B.V.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy of avelumab in combination with cetuximab and radiotherapy compared to standard-of-care cisplatin and/or cetuximab with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to the first event of disease progression or death from any cause, evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include overall survival, cumulative incidence of locoregional failure, cumulative incidence of distant metastatic failure, and cumulative incidence of death without prior progression. Safety will be monitored through the incidence of acute adverse events and laboratory abnormalities, graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patient-reported outcomes will be assessed using the EORTC QLQ-C30 and H&N35 questionnaires to evaluate health-related quality of life. Additionally, **Progression-Free Survival 2 (PFS2)** will be measured, defined as the time from randomization to progression on subsequent treatment, locoregional relapse, distant metastasis, or death from any cause.