Phase III Randomized Study of Rilvegostomig vs. Pembrolizumab with Platinum-based Chemotherapy in PD-L1 Expressing Metastatic Squamous NSCLC

The primary objective of this study is to demonstrate the efficacy of **rilvegostomig** plus chemotherapy relative to **pembrolizumab** plus chemotherapy by assessing overall survival (OS) and progression-free survival (PFS) in patients with metastatic squamous non-small cell lung cancer (NSCLC) whose tumors express PD-L1. This is clinically relevant as it aims to establish a potentially more effective first-line treatment option for this patient population, which could lead to improved survival outcomes.

Secondary objectives include:

• Characterizing the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessing OS, PFS, and duration of response (DoR).
• Comparing the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessing second progression-free survival (PFS2).
• Characterizing and comparing the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessing the objective response rate (ORR).
• Assessing the pharmacokinetics (PK) of rilvegostomig, patient-reported physical functioning, global health status/quality of life (GHS/QoL), patient-reported lung cancer symptoms of NSCLC, and the safety and tolerability of rilvegostomig plus chemotherapy compared to pembrolizumab plus chemotherapy.
• Investigating the immunogenicity of rilvegostomig.
• Assessing the safety and tolerability of rilvegostomig plus chemotherapy compared to pembrolizumab plus chemotherapy.

The clinical trial involves a total of **648 participants** diagnosed with **Metastatic Squamous Non-small Cell Lung Cancer** whose tumors express PD-L1. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The trial population was selected based on specific inclusion criteria, such as histologically or cytologically documented squamous NSCLC, Stage IV mNSCLC not amenable to curative treatment, and the absence of actionable driver oncogenes for which there are locally approved targeted first-line therapies. Participants are required to provide a tumor sample to confirm PD-L1 expression and must have at least one measurable lesion. Adequate organ and bone marrow function is also necessary. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, multicenter, global study designed to evaluate the efficacy of **rilvegostomig** in combination with platinum-based chemotherapy compared to **pembrolizumab** plus chemotherapy for the first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) whose tumors express PD-L1. The trial aims to assess overall survival (OS) and progression-free survival (PFS) as primary endpoints, with secondary endpoints including overall response rate (ORR), duration of response (DoR), and adverse events (AEs) graded by CTCAE version 5.0.

The trial is expected to commence recruitment on December 2, 2024, and is estimated to conclude by October 8, 2029. Participants will be involved in the study for a maximum treatment period of 59 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as histologically documented squamous NSCLC and adequate organ function, followed by regular follow-up visits to monitor treatment response and safety. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will utilize intravenous infusion as the route of administration for the investigational products, with **rilvegostomig** and **pembrolizumab** being the primary agents under investigation. The study is not classified as low intervention and is conducted under rigorous scientific and ethical standards to ensure the validity and reliability of the results.

**Rilvegostomig** is an experimental medication used in this clinical trial. It is a **solution for infusion** administered via **intravenous infusion**. The active substance, **rilvegostomig**, is a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. The pharmaceutical form is a solution for infusion, and the treatment period is up to 59 days. The dosing schedule and participant compliance are monitored according to the study protocol.

**Infliximab** is used as a non-experimental treatment in this study. It is provided as a **powder for concentrate for solution for infusion** and administered through **intravenous infusion**. The maximum daily dose is 5 mg/kg, with no specified maximum total dose. The treatment period is extensive, allowing for long-term administration as required by the study design.

**Abraxane**, containing **paclitaxel albumin-bound**, is another non-experimental treatment. It is available as a **powder for dispersion for infusion** and administered via **intravenous infusion**. The maximum daily dose is 100 mg/m², with a total dose limit of 1200 mg/m² over a 12-week treatment period. This chemotherapy drug is used in combination with other treatments as per the trial protocol.

**Paclitaxel** is provided as a **concentrate for solution for infusion** and administered through **intravenous infusion**. The maximum daily dose is 200 mg/m², with a total dose limit of 800 mg/m² over a 12-week period. This chemotherapy drug is part of the standard treatment regimen in the trial.

**Carboplatin** is administered as a **concentrate for solution for infusion** via **intravenous infusion**. The maximum daily dose is 6 mg, with a total dose limit of 24 mg over a 12-week period. This chemotherapy drug is used in conjunction with other treatments in the study.

**Pembrolizumab**, marketed as **Keytruda**, is used as a comparator treatment. It is a **solution for infusion** administered through **intravenous infusion**. The maximum daily dose is 200 mg, with a total dose limit of 17000 mg over a 59-day treatment period. This protein-based drug is part of the immunotherapy regimen in the trial.

**Mycophenolate mofetil** is included as a non-experimental treatment. It is provided in **capsule** form and administered **orally**. The maximum daily dose is 3 g, with no specified total dose limit. This chemical drug is used to support the treatment regimen as outlined in the study protocol.

The efficacy of the clinical trial will be assessed through the primary endpoints of **Overall Survival (OS)** and **Progression-Free Survival (PFS)**. These endpoints will provide a measure of the effectiveness of the treatment regimens being compared, specifically rilvegostomig plus chemotherapy versus pembrolizumab plus chemotherapy, in patients with metastatic squamous non-small cell lung cancer (NSCLC) whose tumors express PD-L1.

Secondary endpoints will include landmark OS and PFS rates, time to second progression or death (PFS2), overall response rate (ORR), and duration of response (DoR). Additionally, the concentration of rilvegostomig in serum and the presence of antidrug antibodies (ADAs), including titer and neutralizing antibodies, will be evaluated. The trial will also assess the proportion of participants with maintained or improved physical functioning, time to deterioration of global health status/quality of life (GHS/QoL) and pulmonary symptoms, as well as adverse events (AEs) graded by CTCAE version 5.0, clinical laboratory assessments, vital signs, physical examinations, and Eastern Cooperative Oncology Group (ECOG) performance status.