Phase 3 Randomized Study of Nivolumab + Relatlimab FDC with Chemotherapy vs. Pembrolizumab with Chemotherapy in Stage IV/Recurrent NSCLC with PD-L1 ≥1%

The primary objective of this study is to evaluate whether the combination of **nivolumab** and **relatlimab** in a fixed-dose combination with chemotherapy improves **overall survival** (OS) compared to **pembrolizumab** with chemotherapy in patients with non-squamous, Stage IV or recurrent non-small cell lung cancer (NSCLC) with tumor cell PD-L1 expression ≥1%. This is clinically relevant as it aims to determine a potentially more effective first-line treatment option for this patient population, which could lead to improved survival outcomes.

Secondary objectives include:

• Assessing **progression-free survival** (PFS) to determine how long patients live without their cancer worsening.
• Evaluating the **overall response rate** (ORR) by examining the number of patients whose tumors shrink with each treatment.
• Determining the **time to deterioration** (TTD) of cancer symptoms.
• Monitoring the safety of the drugs in participants from both treatment arms.
• Checking the safety of the treatments and identifying potential side effects.

The clinical trial involves a total of **712 participants** diagnosed with **non-squamous, Stage IV or recurrent non-small cell lung cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including the presence of a certain protein level, PD-L1, in cancer cells, and the requirement that the cancer is visible on a CT or MRI scan conducted within 32 days prior to the study treatment. The participants are generally healthy, with a performance status score of 1 or less, indicating they can perform daily activities with minimal assistance. They are expected to have a life expectancy of at least three months from the start of the study. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is a **Phase III** study designed to evaluate the efficacy of a **nivolumab** and **relatlimab** fixed-dose combination with chemotherapy compared to **pembrolizumab** with chemotherapy in patients with non-squamous, stage IV or recurrent non-small cell lung cancer (NSCLC) with tumor cell PD-L1 expression ≥1%. The trial employs a randomized, open-label design, ensuring that participants are randomly assigned to one of the treatment arms, and both the participants and investigators are aware of the treatment being administered. The primary objective is to compare overall survival (OS) between the two treatment arms, while secondary endpoints include progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), and safety of the study drugs.

The trial is expected to commence recruitment on June 30, 2025, and conclude by May 24, 2027. Participants will be involved in the study for the duration of the treatment period, which is determined by the progression of the disease and the participant's response to the treatment. The study includes 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 final outcomes. The inclusion criteria specify that participants must be adults aged 18 years or older with confirmed stage IV or recurrent NSCLC, measurable disease on CT or MRI, and a performance status score of 1 or less. Exclusion criteria are not specified in the provided data.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study drugs, including **pemetrexed disodium**, **cisplatin**, **carboplatin**, and **pembrolizumab**, are administered via **intravenous infusion**. The trial aims to provide valuable insights into the comparative effectiveness of these treatment regimens, potentially informing future therapeutic strategies for NSCLC. The trial's design and methodology adhere to rigorous scientific standards to ensure the reliability and validity of the results.

The clinical trial involves the administration of several experimental and comparator medications. **Pemetrexed disodium** is utilized in two pharmaceutical forms: as a concentrate for solution for infusion and as a powder for concentrate for solution for infusion. It is administered via **intravenous infusion**. The dosage is measured in milligrams per square meter (mg/m²), with a maximum daily and total dose amount set at 9999 mg/m². The treatment period is capped at 9999 days. This medication is not a pediatric formulation and is classified as a chemical substance.

**Cisplatin** is another comparator treatment used in the study. It is provided as a concentrate for solution for infusion and administered through intravenous infusion. The dosage is also calculated in mg/m², with the same maximum daily and total dose limits as pemetrexed disodium. The treatment duration is similarly limited to 9999 days. Cisplatin is a chemical substance and is not formulated for pediatric use.

**Pembrolizumab** is included in the trial as a solution for infusion, administered intravenously. The dosage is expressed in milligrams per milliliter (mg/ml), with a maximum daily and total dose of 9999 mg/ml. The treatment period is restricted to 9999 days. Pembrolizumab is a protein-based substance and is not intended for pediatric patients.

**Carboplatin** is administered as a concentrate for solution for infusion via intravenous infusion. The dosage is measured in mg/m², with a maximum daily and total dose of 9999 mg/m². The treatment period is limited to 9999 days. Carboplatin is a chemical substance and is not a pediatric formulation.

The experimental treatment in this trial is the **Relatlimab + Nivolumab Fixed Dose Combination (FDC)**, provided as a solution for infusion. It is administered intravenously, with the dosage expressed in mg/ml. The maximum daily and total dose is 9999 mg/ml, and the treatment period is capped at 9999 days. This combination is a protein-based formulation and is not designed for pediatric use. The sponsor product code for this combination is BMS-986213.

The efficacy of the clinical trial will be assessed primarily through the comparison of **Overall Survival (OS)** between two treatment arms: Arm A, which includes participants receiving nivolumab + relatlimab fixed-dose combination with chemotherapy, and Arm B, which includes participants receiving pembrolizumab with chemotherapy. This primary endpoint will provide insights into the survival benefits of the treatment regimens for participants with non-squamous, Stage IV or recurrent non-small cell lung cancer (NSCLC) with tumor cell PD-L1 expression ≥1%.

Secondary endpoints will include the comparison of **Progression-Free Survival (PFS)**, **Duration of Response (DoR)**, and **Objective Response Rate (ORR)** between the two arms. These parameters will help evaluate the efficacy of the treatments in terms of delaying disease progression and achieving tumor response. Additionally, the safety of the study drugs will be assessed, along with the **Time to Deterioration (TTD)** of participants' health status.