Phase 3 Study of Acasunlimab and Pembrolizumab Versus Docetaxel in PD-L1 Positive Metastatic NSCLC Post PD-1/PD-L1 Inhibitor and Platinum Chemotherapy

The primary objective of this study is to determine the clinical efficacy of **acasunlimab** in combination with **pembrolizumab** versus **docetaxel** as second- or third-line therapy in patients with metastatic non-small cell lung cancer (NSCLC) who have previously been treated with a PD-1/PD-L1 inhibitor and platinum-containing standard of care. This objective is clinically relevant as it aims to establish a potentially more effective treatment regimen for patients with advanced NSCLC, a condition with limited therapeutic options after initial treatments fail.

Secondary objectives include:

• Assessing the efficacy and antitumor activity of acasunlimab in combination with pembrolizumab versus docetaxel as second/third-line therapy in metastatic NSCLC after PD-1/PD-L1-inhibitor- and platinum-containing standard of care.
• Evaluating the safety and tolerability of acasunlimab in combination with pembrolizumab.
• Characterizing the pharmacokinetics (PK) and immunogenicity of acasunlimab in combination with pembrolizumab.
• Assessing the subject’s perspective on treatment-related symptom burden and the impact of acasunlimab in combination with pembrolizumab versus docetaxel.

The clinical trial involves a total of **299 participants** diagnosed with **Non-Small Cell Lung Cancer** (NSCLC). The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of metastatic NSCLC (stage IV) and progression after prior therapy involving PD-1/PD-L1 inhibitors and platinum-based chemotherapy. The trial population is characterized by a positive tumor PD-L1 expression and measurable disease according to RECIST v1.1. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, a life expectancy of at least three months, and adequate organ and bone marrow function. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **acasunlimab** in combination with **pembrolizumab** compared to **docetaxel** in patients with **non-small cell lung cancer** (NSCLC) who have previously been treated with a PD-1/PD-L1 inhibitor and platinum-based chemotherapy. The trial aims to assess the overall survival as the primary endpoint, with secondary endpoints including progression-free survival, confirmed objective response rate, duration of response, and the incidence of adverse events. The trial is expected to commence recruitment on January 11, 2025, and conclude by October 31, 2029.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed metastatic NSCLC, positive tumor PD-L1 expression, and adequate organ function. Following successful screening, participants will be randomized to receive either the investigational combination therapy or the comparator treatment. The treatment period will last up to 60 days, with regular follow-up visits to monitor safety, efficacy, and pharmacokinetics. The end-of-study visit will occur after the treatment period to assess final outcomes and collect data on any long-term effects.

Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Docetaxel** is utilized as a comparator treatment in this study. It is provided in the form of a concentrate for solution for infusion. The maximum daily dose is 75 mg/m², with a total maximum dose of 6525 mg/m² over a treatment period of 60 days. The administration route is intravenous infusion, and the pharmaceutical form is identified as PHF00230MIG. Packaging and labeling modifications are applied to the product.

**Anakinra** is used as an auxiliary treatment. It is administered via subcutaneous injection with a maximum daily dose of 200 mg. The pharmaceutical form is PHF00231MIG. If sourced locally, no modifications are made to the medicinal product. However, if centrally sourced by the sponsor, modifications include labeling and packaging.

**Pembrolizumab**, marketed as Keytruda, is a test treatment in the trial. It is provided as a 25 mg/mL concentrate for solution for infusion, administered intravenously. The maximum daily dose is 400 mg, with a total maximum dose of 7200 mg over 60 days. The product undergoes packaging and labeling modifications.

**Betamethasone sodium phosphate**, referred to as Dexamethasone in the trial, is an auxiliary treatment. It is administered intravenously with a maximum daily dose of 10 mg/kg and a total maximum dose of 4176 mg. The pharmaceutical form is PHF00169MIG.

**Tocilizumab**, marketed as RoActemra, is another auxiliary treatment. It is provided as a 20 mg/mL concentrate for solution for infusion, administered intravenously. The maximum daily dose is 2400 mg, with a total maximum dose of 3200 mg over a treatment period of 2 days. Modifications to the product include labeling and packaging if centrally sourced by the sponsor.

**Mycophenolate mofetil**, marketed as CellCept, is used as an auxiliary treatment. It is administered orally in the form of 500 mg film-coated tablets. The maximum daily dose is 1000 mg. Modifications to the product include labeling and packaging if centrally sourced by the sponsor.

**Methylprednisolone acetate** and **lidocaine hydrochloride monohydrate** are combined in an auxiliary treatment. The administration route is intravenous use, with a maximum daily dose of 1000 mg. The pharmaceutical form is PHF00243MIG.

**Prednisolone**, referred to as Prednisone in the trial, is an auxiliary treatment administered both orally and intravenously. The maximum daily dose is 100 mg, with a total maximum dose of 5400 mg over 60 days. The pharmaceutical form is PHF00245MIG.

**Acasunlimab** is a test treatment in the trial, provided as a solution for infusion. It is administered intravenously with a maximum daily dose of 100 mg and a total maximum dose of 4400 mg over 60 days. The product is subject to packaging and labeling modifications.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to determine the clinical efficacy of acasunlimab in combination with pembrolizumab versus docetaxel in subjects with PD-L1 positive metastatic non-small cell lung cancer (NSCLC) after treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy. Secondary endpoints include Progression-Free Survival (PFS), Confirmed Objective Response Rate (ORR), Duration of Response (DoR), and the number of participants with adverse events (AEs). Additionally, the trial will evaluate the time to treatment discontinuation due to AEs, plasma concentration of acasunlimab, and the number of participants with anti-drug antibodies (ADAs) to acasunlimab.

Patient-reported outcomes will also be assessed, including changes from baseline in the Functional Assessment of Cancer Therapy item GP5 (FACIT-GP5, version 4) score and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). These efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific methods and schedules for measurement determined by the trial protocol. The trial is designed to provide comprehensive data on the efficacy of the treatment regimens under investigation, contributing to the understanding of their potential benefits in the specified patient population.