Efficacy of Volrustomig (MEDI5752) Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy in Metastatic Non-Small Cell Lung Cancer with PD-L1 < 1%

The primary objective of this study is to evaluate whether **volrustomig** combined with chemotherapy enhances progression-free survival (PFS) and overall survival (OS) compared to pembrolizumab plus chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC) with PD-L1 expression less than 1%. This is clinically relevant as it aims to improve treatment outcomes in a specific subset of mNSCLC patients, potentially offering a more effective first-line treatment option.

The secondary objective is to assess whether volrustomig plus chemotherapy improves PFS and OS in patients with mNSCLC where PD-L1 is less than 50% when compared with pembrolizumab plus chemotherapy. This objective seeks to determine the broader applicability and efficacy of volrustomig in a larger patient population with varying levels of PD-L1 expression.

The clinical trial involves a total of **623 participants** diagnosed with **Metastatic Non-Small Cell Lung Cancer (mNSCLC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having histologically or cytologically documented squamous or non-squamous NSCLC at Stage IV, and a PD-L1 expression of less than 50%. The trial also excludes individuals with certain genetic mutations or rearrangements, such as EGFR, ALK, and ROS1, which are associated with other targeted therapies. The population includes vulnerable groups, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label, multi-center, Phase III study to evaluate the efficacy of **volrustomig** in combination with chemotherapy compared to **pembrolizumab** plus chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC). The primary objective is to assess whether volrustomig plus chemotherapy improves progression-free survival (PFS) and overall survival (OS) in participants with mNSCLC where PD-L1 is less than 1%. The trial is expected to commence recruitment on November 1, 2023, and conclude by May 16, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically documented squamous or non-squamous NSCLC, stage IV NSCLC, and absence of specific genetic mutations. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be conducted to monitor treatment response and safety, with assessments including radiological evaluations to determine PFS and OS. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.

The expected duration of participant involvement in the study is contingent upon individual response to treatment and disease progression, with a maximum treatment period of 12 months for certain chemotherapy agents. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or investigator decision based on clinical judgment. The study will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout the trial duration.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Volrustomig**, also known as MEDI5752, is the primary investigational drug in this study. It is a **solution for infusion** containing a human IgG1 monoclonal antibody with an engineered Fc domain targeting PD-1 and CTLA-4. Volrustomig is administered via **intravenous use**. The dosing schedule and maximum daily dose are not specified, and the treatment period is extensive, potentially lasting indefinitely.

**Pemetrexed Accord** is a **concentrate for solution for infusion** with an active substance of **pemetrexed**. It is administered through **intravenous infusion** at a maximum daily dose of 500 mg/m². The treatment period is limited to 12 cycles. This medication is used as part of the chemotherapy regimen in the study.

**Remsima** is a **powder for concentrate for solution for infusion** containing **infliximab**. It is administered via **intravenous use** with a maximum daily dose of 5 mg/kg. The treatment duration is not limited, allowing for long-term administration. Remsima serves as an auxiliary treatment in the trial.

**Carboplatin Hikma** is a **solution for infusion** with the active substance **carboplatin**. It is delivered through **intravenous infusion** with a maximum daily dose of 6 mg. The treatment is administered over a period of 12 cycles. This drug is part of the chemotherapy regimen.

**Paclitaxel Bendalis** is a **solution for infusion** containing **paclitaxel**. It is administered via **intravenous infusion** with a maximum daily dose of 200 mg/m². The treatment period is also limited to 12 cycles. Paclitaxel is included in the chemotherapy regimen.

**KEYTRUDA** is a **concentrate for solution for infusion** with the active substance **pembrolizumab**. It is administered through **intravenous use** with a maximum daily dose of 200 mg. The treatment duration is not specified, allowing for long-term administration. KEYTRUDA is used as a comparator treatment in the study.

**Mycofit** is a **hard capsule** containing **mycophenolate mofetil**. It is administered orally with a maximum daily dose of 3 g. The treatment duration is not limited, allowing for long-term administration. Mycofit serves as an auxiliary treatment in the trial.

The efficacy of the clinical trial will be assessed using two primary endpoints: **Progression-Free Survival (PFS)** and **Overall Survival (OS)** in participants with metastatic non-small cell lung cancer (mNSCLC) where PD-L1 < 1%. PFS is defined as the time from randomization until radiological progression per RECIST 1.1, as assessed by blinded independent central review (BICR), or death due to any cause in the absence of progression. OS is defined as the time from randomization until the date of death due to any cause. Both endpoints will include all randomized participants with PD-L1 < 1%.

Secondary endpoints include overall survival and progression-free survival in all randomized patients, regardless of PD-L1 status. The trial will employ a randomized, open-label, multi-center design to compare the efficacy of volrustomig in combination with chemotherapy versus pembrolizumab plus chemotherapy. The study is designed to determine whether volrustomig plus chemotherapy improves PFS and OS compared to the control group. The trial is expected to conclude by May 2029, with recruitment starting in November 2023.