Evaluation of Petosemtamab Versus Investigator's Choice Monotherapy in Previously Treated Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma

The primary objective of this phase 3 study is to compare the **antitumor activity** in overall response rate (ORR) and overall survival (OS) in patients with incurable, metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) treated with **petosemtamab** monotherapy versus investigator’s choice monotherapy. This is clinically relevant as it aims to determine the efficacy of petosemtamab in improving response rates and survival outcomes in a challenging patient population with limited treatment options.

Secondary objectives include: - Evaluating antitumor activity in ORR, duration of response (DOR), time to response (TTR), progression-free survival (PFS), and clinical benefit rate (CBR) as assessed by both blinded independent central review (BICR) and investigator review. - Assessing the safety and tolerability of petosemtamab monotherapy. These objectives are crucial for understanding the broader impact of petosemtamab on tumor control and patient safety, providing comprehensive insights into its therapeutic potential.

The clinical trial involves a total of **280 participants** diagnosed with incurable, metastatic, or recurrent **head and neck squamous cell carcinoma** (HNSCC). The study population includes both male and female subjects, aged 18 years and older, who have a life expectancy of at least 12 weeks and adequate organ function. Participants have histologically confirmed HNSCC with evidence of metastatic or locally advanced disease that is not amenable to standard therapy with curative intent. Eligible primary tumor locations include the oropharynx, oral cavity, hypopharynx, and larynx. All participants have progressed on or after anti-PD-1 therapy and platinum-containing therapy. The trial population was selected based on specific inclusion criteria, including documentation of p16 status for patients with primary oropharyngeal cancer and measurable disease as defined by RECIST v1.1. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring that all participants are willing and able to provide signed informed consent prior to the initiation of any study procedures.

The clinical trial is a **randomized**, controlled study designed to evaluate the efficacy and safety of **petosemtamab** compared to investigator's choice monotherapy in patients with incurable, metastatic/recurrent head and neck squamous cell carcinoma. The trial is open-label and is expected to run from August 2024 to March 2028. Participants will be randomly assigned to receive either petosemtamab or a monotherapy selected by the investigator. The primary endpoints include objective response rate (ORR) and overall survival (OS), while secondary endpoints assess additional efficacy measures and safety profiles.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and disease status. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments such as imaging studies to evaluate tumor response according to RECIST v1.1 criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to six months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol. The trial aims to provide valuable insights into the comparative effectiveness of petosemtamab in this patient population.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Petosemtamab** is the experimental medication in this study. It is provided as a **solution for infusion** and is administered intravenously. The maximum daily dose is 1500 mg, with a total maximum dose of 18000 mg over a treatment period of up to 6 months. Petosemtamab is a protein-based substance, specifically categorized as "Protein - Other," and is developed by MERUS B.V. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.

**Methotrexate** is one of the comparator treatments used in this trial. It is available as a **solution for injection** and is administered intravenously. The maximum daily dose is 60 mg/m², with a total maximum dose of 1440 mg/m² over a 6-month period. Methotrexate is a chemical substance provided by ACCORD HEALTHCARE LIMITED. The dosing schedule is designed to align with standard clinical practices, and compliance is monitored throughout the study.

Another comparator treatment is **Docetaxel**, provided as a concentrate for the preparation of a **solution for infusion**. It is administered via intravenous infusion, with a maximum daily dose of 40 mg/m² and a total maximum dose of 960 mg/m² over the course of 6 months. Docetaxel is a chemical substance manufactured by EVER VALINJECT GMBH. The administration is conducted under controlled conditions to ensure participant safety and adherence to the study protocol.

**Cetuximab** is also used as a comparator treatment in this trial. It is available as a **solution for infusion** and is administered through intravenous infusion. The maximum daily dose is 400 mg/m², with a total maximum dose of 6150 mg/m² over a 6-month period. Cetuximab is a protein-based substance, categorized as "Protein - Other," and is provided by MERCK EUROPE B.V. The dosing regimen is consistent with established therapeutic guidelines, and participant compliance is rigorously monitored.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** as assessed by Blinded Independent Central Review (BICR) and **Overall Survival (OS)**. Secondary endpoints encompass ORR per RECIST v1.1 as assessed by investigator review, Duration of Response (DOR) per RECIST v1.1 as assessed by both BICR and investigator review, Time to Response (TTR) per RECIST v1.1, Progression-Free Survival (PFS) per RECIST v1.1, and Clinical Benefit Rate (CBR) per RECIST v1.1, all assessed by BICR and investigator review. Additionally, the trial will evaluate the number of patients experiencing treatment-emergent adverse events (TEAEs), serious TEAEs, discontinuation of study treatment due to TEAEs, and dose modifications due to TEAEs.