Phase III Randomized Study of Datopotamab Deruxtecan and Rilvegostomig Versus Pembrolizumab in Advanced Non-Squamous NSCLC with High PD-L1 Expression

The primary objective of this study is to evaluate the **superiority** of Datopotamab Deruxtecan (Dato-DXd) in combination with Rilvegostomig compared to Pembrolizumab by assessing progression-free survival (PFS) and overall survival (OS) in participants with TROP2 biomarker-positive, locally-advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations. This is clinically relevant as it aims to improve treatment outcomes in a specific subset of NSCLC patients who have limited therapeutic options.

Secondary objectives include: - Demonstrating the superiority of Dato-DXd in combination with Rilvegostomig relative to Pembrolizumab by assessment of PFS by blinded independent central review (BICR) in the full analysis set (FAS) population. - Demonstrating the superiority of Dato-DXd in combination with Rilvegostomig relative to Pembrolizumab by assessment of OS in the FAS population.

The clinical trial involves a total of **476 participants** diagnosed with **locally-advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)**, characterized by high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations. 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 selection process for the trial population was based on specific inclusion criteria, such as histologically or cytologically documented non-squamous NSCLC, absence of sensitizing EGFR mutations, and ALK and ROS1 rearrangements. Participants must provide a tumor sample to determine PD-L1 and TROP2 status, and have an ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial also considers vulnerable populations, ensuring adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention. 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, global study to evaluate the efficacy and safety of **datopotamab deruxtecan** in combination with **rilvegostomig** or rilvegostomig monotherapy compared to **pembrolizumab** monotherapy. The trial targets participants with locally-advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) characterized by high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations. The primary objectives are to demonstrate the superiority of the combination therapy in terms of progression-free survival (PFS) and overall survival (OS) in TROP2 biomarker-positive participants. Secondary endpoints include assessments of PFS and OS in the full analysis set (FAS) population, objective response rate (ORR), duration of response (DoR), and participant-reported outcomes related to lung cancer symptoms and quality of life.

The trial is expected to commence recruitment on January 10, 2025, with an estimated completion date of May 24, 2030. Participants will be involved in the study for the duration of the treatment period, which is determined by the absence of disease progression or unacceptable toxicity. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as documented non-squamous NSCLC, absence of specific genomic alterations, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted at regular intervals. The end-of-study visit will occur after the final treatment cycle or upon early termination due to disease progression or adverse events.

Participants are expected to remain in the study until disease progression, unacceptable toxicity, or withdrawal of consent. Conditions that may lead to early termination include the development of new medical conditions that contraindicate continued participation or non-compliance with study procedures. The trial will adhere to rigorous scientific and ethical standards, ensuring the collection of high-quality data to evaluate the investigational treatments' efficacy and safety.

The clinical trial involves several treatments, including both experimental and comparator medications. **Datopotamab deruxtecan** is an experimental medication used in this study. It is administered as a **solution for infusion** and is delivered intravenously. The dosing is based on the patient's weight, measured in milligrams per kilogram (mg/kg). The maximum treatment period for this medication is extensive, allowing for long-term administration as required by the study protocol.

**Rilvegostomig**, also known by its sponsor product code AZD2936, is another experimental treatment in the trial. It is a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. Rilvegostomig is provided as a **solution for infusion** and is administered intravenously. The dosing is in milligrams (mg), and the treatment period is set to a maximum of 99999 time units, ensuring flexibility in treatment duration.

**Pembrolizumab**, marketed as KEYTRUDA, serves as the comparator treatment in this study. It is a **solution for infusion** administered intravenously. The dosing is in milligrams (mg), and the treatment period is also set to a maximum of 99999 time units. Pembrolizumab is a well-established therapy used in the treatment of various cancers, including non-squamous non-small cell lung cancer (NSCLC).

**Infliximab** and **Mycophenolate mofetil** are auxiliary treatments included in the study. Infliximab is provided as a **concentrate for solution for infusion** and is administered via infusion. Mycophenolate mofetil is available in a **hard capsule** form and is administered orally. Both medications are included to support the primary treatments and are not the focus of the study's primary objectives.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the protocol. The study is designed to assess the efficacy and safety of the experimental treatments compared to the standard-of-care therapy, pembrolizumab, in participants with locally-advanced or metastatic non-squamous NSCLC with high PD-L1 expression and without actionable genomic alterations.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the assessment of **Progression-Free Survival (PFS)** by Blinded Independent Central Review (BICR) and **Overall Survival (OS)** in participants who are TROP2 biomarker positive. Secondary endpoints will evaluate PFS by BICR in the Full Analysis Set (FAS) population, OS in the FAS population, Objective Response Rate (ORR), Duration of Response (DoR), and participant-reported outcomes such as lung cancer symptoms and Global Health Status/Quality of Life (GHS/QOL) in participants treated with Datopotamab Deruxtecan (Dato-DXd) in combination with Rilvegostomig compared to Pembrolizumab.

Additional secondary endpoints include pharmacokinetics (PK), immunogenicity, Second Progression-Free Survival (PFS2), and safety and tolerability evaluated in terms of adverse events (AEs). The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with the use of validated scales and laboratory tests where applicable. The trial is designed to demonstrate the superiority of the Dato-DXd in combination with Rilvegostomig relative to Pembrolizumab, focusing on the improvement of PFS and OS in the specified participant population.