Phase 3 Randomized Study of Petosemtamab and Pembrolizumab in First-Line Treatment of Recurrent/Metastatic PD-L1+ Head and Neck Squamous Cell Carcinoma

The primary objective of this phase 3 study is to compare **overall survival** (OS) in the first-line setting for patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (HNSCC) who are eligible for pembrolizumab monotherapy. These patients have tumors expressing PD-L1 with a combined positive score (CPS) of 1 or greater and have not received prior anti-PD-(L)1 or EGFR therapies. The study evaluates the efficacy of combining petosemtamab with pembrolizumab. This objective is clinically relevant as it aims to improve survival outcomes in a patient population with limited treatment options.

Secondary objectives include evaluating the antitumor activity of the treatment combination in terms of:

• Progression-free survival (PFS) per RECIST v1.1
• Duration of response (DOR) per RECIST v1.1
• Clinical benefit rate (CBR) per RECIST v1.1
• Percentage of patients with PFS per RECIST v1.1

The clinical trial involves a total of **316 participants** diagnosed with **recurrent or metastatic PD-L1+ head and neck squamous cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are eligible for pembrolizumab monotherapy. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of head and neck squamous cell carcinoma (HNSCC) with evidence of metastatic or locally recurrent disease. The trial population is characterized by individuals who have not received previous systemic therapy in the incurable recurrent or metastatic setting, although prior systemic therapy as part of multimodal treatment for locally advanced disease is permissible if progressive disease occurred at least six months after the last platinum-containing therapy dose. Participants must have measurable disease as defined by RECIST v1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria include adequate organ function and a life expectancy of at least 12 weeks, as assessed by the investigator.

The clinical trial is a **phase 3** randomized, open-label study designed to evaluate the efficacy and safety of **petosemtamab** in combination with **pembrolizumab** for the first-line treatment of recurrent or metastatic PD-L1+ head and neck squamous cell carcinoma (HNSCC). The trial aims to compare overall survival (OS) and objective response rate (ORR) in patients eligible for pembrolizumab monotherapy, with tumors expressing PD-L1 (CPS ≥1), who have not received previous anti PD-(L)1 and EGFR therapies. The study is expected to commence recruitment on August 15, 2024, and conclude by February 15, 2028.

Participants will be randomly assigned to receive either the investigational combination therapy or the control treatment. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, histological confirmation of HNSCC, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted per RECIST v1.1 guidelines. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 24 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints of the trial are ORR and OS, while secondary endpoints include progression-free survival (PFS), duration of response (DoR), and clinical benefit rate (CBR), all evaluated per RECIST v1.1 criteria.

The clinical trial involves the administration of **petosemtamab**, an experimental medication, which is provided in the form of a **solution for infusion**. The pharmaceutical form is specifically designed for intravenous administration. The maximum daily dose of petosemtamab is 1500 mg, with a total maximum dose of 72000 mg over a treatment period of 24 weeks. The active substance, petosemtamab, is a protein of other origin, and the product is identified by the sponsor product code MCLA-158. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to petosemtamab, the study includes the administration of **pembrolizumab**, which serves as a comparator treatment. Pembrolizumab is provided as a **concentrate for solution for injection** and is also administered intravenously. The maximum daily dose for pembrolizumab is 400 mg, with a total maximum dose of 7200 mg over the same 24-week treatment period. Pembrolizumab is a humanized monoclonal anti-programmed cell death-1 (PD-1) antibody, and its role in the trial is to evaluate its efficacy and safety in combination with petosemtamab for the treatment of recurrent or metastatic PD-L1+ head and neck squamous cell carcinoma. Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial will be assessed using primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** and **Overall Survival (OS)**. These endpoints will be evaluated in patients with recurrent or metastatic PD-L1+ head and neck squamous cell carcinoma (HNSCC) treated with a combination of petosemtamab and pembrolizumab. The secondary endpoints include Progression-Free Survival (PFS) per RECIST v1.1, Duration of Response (DoR) per RECIST v1.1, Clinical Benefit Rate (CBR) per RECIST v1.1, and the percentage of patients with PFS per RECIST v1.1, all assessed by investigator review.

The trial will utilize the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines version 1.1 to measure and analyze these efficacy parameters. The schedule for measuring these endpoints will be determined by the trial protocol, with specific timepoints for assessment not explicitly detailed in the provided data. The trial aims to compare the efficacy of the combination therapy in the first-line setting for patients eligible for pembrolizumab monotherapy, with tumors expressing PD-L1 (CPS ≥1) and without previous anti PD-(L)1 and EGFR therapies.