Efficacy of Pembrolizumab and Lenvatinib Maintenance Therapy Post-Chemoradiation in Locally Advanced PD-L1 Positive Head and Neck Squamous Cell Carcinoma

The primary objective of this study is to evaluate the **efficacy** of combined **pembrolizumab** and **lenvatinib** maintenance therapy compared to pembrolizumab alone in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who have undergone definitive chemoradiation. The focus is on prolonging the event-free survival (EFS) rate at 2 years. This is clinically relevant as it aims to improve long-term outcomes and survival rates in patients with this aggressive form of cancer, particularly in those who are **PD-L1 positive** (CPS≥1), which is a significant factor in the disease's progression and response to treatment.

The clinical trial focuses on individuals diagnosed with **locally advanced head and neck squamous cell carcinoma** (HNSCC), specifically those classified as stage III-IVB according to TNM version 8. The study population includes both male and female participants, with an age range that encompasses adults and older adults. Participants are required to have completed definitive radiochemotherapy, with a radiation dose of at least 68Gy and a minimum of 200mg/m² BSA Cisplatin, without any progression during the treatment. The trial does not include vulnerable populations. Participants must have a histological confirmation of the disease and a baseline PD-L1 CPS of 1 or higher before radiochemotherapy. Additionally, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 is required. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** and **lenvatinib** maintenance therapy compared to pembrolizumab alone following definitive radiochemotherapy in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). This is a randomized, double-blind, controlled Phase II trial. The primary objective is to assess the event-free survival (EFS) rate at two years, with disease progression evaluated radiologically according to RECIST 1.1 criteria. The trial is expected to commence recruitment on September 16, 2024, and conclude by October 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological confirmation of locally advanced HNSCC stage III-IVB, a baseline PD-L1 CPS≥1, and completion of definitive radiochemotherapy without progression. Follow-up visits will be scheduled to monitor the participants' health status and treatment efficacy, with the end-of-study visit marking the conclusion of their involvement. The expected duration of participant involvement is approximately 48 weeks, with conditions for early termination including disease progression, adverse events, or withdrawal of consent.

The trial involves the administration of **KEYTRUDA** (pembrolizumab) as a concentrate for solution for infusion and **LENVIMA** (lenvatinib) in hard capsule form. Pembrolizumab will be administered intravenously, while lenvatinib will be taken orally. The maximum daily dose for pembrolizumab is 200 mg, with a total dose not exceeding 3400 mg over the treatment period. For lenvatinib, the maximum daily dose is 20 mg, with a total dose not exceeding 6720 mg. Participants will be closely monitored for any adverse effects, and the trial will adhere to rigorous safety protocols to ensure participant well-being throughout the study duration.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name **KEYTRUDA**, which is provided as a 25 mg/mL **concentrate for solution for infusion**. This pharmaceutical form is intended for **intravenous use**. The maximum daily dose of pembrolizumab is 200 mg, with a total maximum dose of 3400 mg over a treatment period of up to 47 weeks. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to pembrolizumab, the trial includes the administration of **lenvatinib**, marketed as **LENVIMA**, which is available in the form of 10 mg **hard capsules**. Lenvatinib is administered **orally**, with a maximum daily dose of 20 mg and a total maximum dose of 6720 mg over a treatment period of up to 48 weeks. Lenvatinib is a chemically synthesized compound, classified under the ATC code L01EX08. The dosing schedule is designed to optimize therapeutic outcomes, and participant compliance is closely monitored throughout the trial.

Both pembrolizumab and lenvatinib are utilized in this study to evaluate their combined efficacy as a maintenance therapy following definitive chemoradiation in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are positive for PD-L1. The trial aims to assess the prolongation of event-free survival (EFS) at two years, comparing the combination therapy to pembrolizumab monotherapy. No placebo or additional comparator treatments are employed in this study.

The efficacy of the clinical trial will be assessed by evaluating the **event-free survival (EFS) rate** at 2 years. This primary endpoint will be measured by determining disease progression through radiological evaluation, adhering to the RECIST 1.1 criteria, and will be assessed by investigators. An event is defined as disease progression, death due to any cause, or the necessity for salvage surgery at any time point if cancer is confirmed in the pathological assessment. Additionally, a neck dissection performed more than 20 weeks after the end of radiochemotherapy will be considered an event if cancer is present in the pathological assessment.