Phase 3 Evaluation of Zimberelimab and Domvanalimab Versus Pembrolizumab in PD-L1-High Advanced Non-Small Cell Lung Cancer

The primary objective of this Phase 3 study is to evaluate the **efficacy** of the combination therapy of zimberelimab and domvanalimab compared to pembrolizumab in terms of overall survival (OS) in patients with front-line, PD-L1-high, locally advanced or metastatic non-small cell lung cancer (NSCLC). This is clinically relevant as improving OS is a critical endpoint in the treatment of advanced NSCLC, providing insights into the potential benefits of the combination therapy over the current standard treatment.

Secondary objectives include:

• Evaluating the efficacy of zimberelimab and domvanalimab combination therapy compared to pembrolizumab in progression-free survival (PFS) and overall response rate (ORR).
• Assessing the safety profile of the combination therapy relative to pembrolizumab.
• Comparing the effect of the combination therapy on health-related quality of life (QOL) using the NSCLC-SAQ.

The clinical trial involves a total of **686 participants** diagnosed with **Non-Small Cell Lung Cancer** (NSCLC), including both squamous and non-squamous subtypes. The study population comprises both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The trial includes individuals with a histologically confirmed, treatment-naïve, locally advanced or metastatic NSCLC, with documented high PD-L1 expression. Participants were selected based on specific inclusion criteria, such as an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and adequate organ and marrow function. The trial also considers lifestyle factors, as participants must have stable central nervous system (CNS) disease if they have brain or meningeal metastases. The study population includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse patient groups.

The clinical trial is designed to evaluate the efficacy of **zimberelimab** and **domvanalimab** combination therapy compared to **pembrolizumab** in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. This is a Phase 3, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on August 31, 2023, and conclude by February 29, 2028. Participants will be randomly assigned to receive either the combination therapy or pembrolizumab alone, with all treatments administered via intravenous infusion.

The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes. The inclusion criteria require participants to have histologically confirmed, treatment-naïve, locally advanced or metastatic NSCLC with high PD-L1 expression, an ECOG performance status of 0 or 1, and at least one measurable lesion. Participants with stable brain metastases may be included under specific conditions. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, objective response rate, and the presence of treatment-emergent adverse events.

Participant involvement is expected to last up to 735 days, 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 trial aims to provide comprehensive data on the efficacy and safety of the investigational combination therapy compared to the standard treatment with pembrolizumab.

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 7000 mg over a treatment period of up to 735 days. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is manufactured by Merck Sharp & Dohme BV. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**Domvanalimab** is another investigational product used in this trial, provided as a concentrate for solution for infusion. It is also administered via the **intravenous route**. The maximum daily dose for domvanalimab is 1200 mg, with a total maximum dose of 42000 mg over a treatment period of up to 735 days. Domvanalimab is a humanized IgG1 monoclonal antibody targeting TIGIT, developed by Arcus Biosciences Europe Limited. The dosing schedule is carefully monitored to maintain participant compliance and ensure the integrity of the trial data.

The trial also includes the administration of **zimberelimab**, known by the sponsor product code AB122, which is provided in a vial for intravenous use. The maximum daily dose of zimberelimab is 360 mg, with a total maximum dose of 12600 mg over a treatment period of up to 735 days. Zimberelimab is a monoclonal antibody developed by Arcus Biosciences Europe Limited. As with the other investigational products, the administration of zimberelimab is closely monitored to ensure compliance with the dosing schedule and to collect accurate trial data.

No non-experimental treatments, such as standard-of-care therapy or placebo, are specified in the trial protocol. The trial aims to evaluate the efficacy of the combination therapy of zimberelimab and domvanalimab compared to pembrolizumab in patients with locally advanced or metastatic non-small cell lung cancer. The trial's design and administration protocols are structured to ensure rigorous assessment of the investigational treatments' efficacy and safety.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **Overall Survival (OS)**. This will involve comparing the combination therapy of zimberelimab and domvanalimab against pembrolizumab in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. Secondary endpoints include Progression-Free Survival (PFS) according to RECIST v1.1, confirmed Objective Response Rate (ORR) as assessed by blinded independent central review (BICR), the presence of treatment-emergent adverse events, changes in vital signs and clinical laboratory parameters, and the time to first symptom deterioration in the NSCLC-SAQ total score.

Measurements for these endpoints will be conducted at specified intervals throughout the trial, with assessments performed by central laboratories and independent reviewers to ensure objectivity and accuracy. The trial will utilize validated scales and laboratory tests to collect and analyze data, ensuring adherence to established clinical guidelines. The trial is designed to provide comprehensive data on the efficacy of the investigational therapies in improving survival outcomes and managing disease progression in the target patient population.