Evaluation of Pembrolizumab, Patritumab Deruxtecan, and Drug Combinations in Stage IV Non-Small Cell Lung Cancer: A Phase 2 Umbrella Study

The primary objective of this study is to evaluate the **Objective Response Rate (ORR)** per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR) in treatment-naïve participants with Stage IV Non-small Cell Lung Cancer (NSCLC). This is clinically relevant as ORR is a critical measure of the efficacy of cancer treatments, indicating the proportion of patients with a significant reduction in tumor size. Additionally, the study aims to assess the safety and tolerability of investigational treatment combinations based on the proportion of adverse events (AEs), which is essential for determining the risk-benefit profile of the treatments.

Secondary objectives include: - Evaluating the **Duration of Response (DOR)** per RECIST 1.1 as assessed by BICR, which provides insights into the sustainability of the treatment effect. - Assessing **Progression-Free Survival (PFS)** per RECIST 1.1 as assessed by BICR, a key endpoint that reflects the time during which a patient's disease does not worsen. - Evaluating **Overall Survival (OS)**, which is the ultimate measure of treatment benefit, indicating the length of time patients remain alive following treatment.

The clinical trial involves a total of **83 participants** diagnosed with **Stage IV Non-small cell lung cancer**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of Stage IV squamous or non-squamous non-small cell lung cancer, and an **ECOG performance status** of 0 or 1. The trial does not include a vulnerable population. Participants with well-controlled HIV on ART and those with hepatitis B who have received antiviral therapy and have an undetectable viral load are eligible. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures a focus on individuals with a confirmed diagnosis and stable health conditions, allowing for a comprehensive evaluation of the investigational treatment's efficacy and safety.

The clinical trial is designed to evaluate the **safety** and efficacy of investigational treatment combinations in participants with Stage IV non-small cell lung cancer (NSCLC). This is a Phase II, randomized, double-blind, controlled trial with a primary objective to assess the Objective Response Rate (ORR) per RECIST 1.1 as evaluated by Blinded Independent Central Review (BICR). The trial will also monitor the safety and tolerability of the treatment combinations based on the proportion of adverse events (AEs). The trial is expected to commence recruitment on January 27, 2025, and is estimated to conclude by July 17, 2032.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of Stage IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Following randomization, participants will receive treatment with investigational agents, including **pembrolizumab**, with or without platinum-based chemotherapy. The trial includes multiple follow-up visits to assess treatment response and monitor for AEs. The end-of-study visit will evaluate the overall treatment outcomes and collect final safety data.

The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of up to 105 weeks for some investigational agents. Conditions that may lead to early termination from the study include the occurrence of severe AEs, disease progression, or withdrawal of consent by the participant. The trial will also measure secondary endpoints such as Duration of Response (DOR), Progression-Free Survival (PFS), and Overall Survival (OS) to provide a comprehensive assessment of the treatment's impact on the disease.

The clinical trial involves the administration of several investigational and comparator treatments. **Patritumab deruxtecan**, identified by the sponsor product code MK-1022, is an experimental medication used in this study. It is a **powder for solution for infusion** and is classified as a biological product. The active substance is a protein of other origin, specifically an anti-HER3 IgG1 human monoclonal antibody conjugated to deruxtecan. The administration route is specified as "other use," with a dosing unit of milligrams per kilogram, although specific dosing details are not provided.

**Paclitaxel** is used as a comparator treatment in the trial. It is a chemical substance administered as an **intravenous infusion**. The pharmaceutical form is denoted as PHF00230MIG. The maximum daily dose is 500 mg, with a total maximum dose of 2000 mg over a treatment period of up to 12 weeks.

**Pembrolizumab**, marketed as KEYTRUDA, is another investigational agent in the study. It is a **concentrate for solution for infusion** and is classified as a biological product. The active substance is a protein of other origin. Pembrolizumab is administered via **intravenous infusion** with a maximum daily dose of 200 mg and a total maximum dose of 7000 mg over a treatment period of up to 105 weeks.

**Pemetrexed disodium** is included as a comparator treatment. It is a chemical substance administered as an **intravenous infusion**. The pharmaceutical form is PHF00200MIG. The maximum daily dose is 1250 mg, with a total maximum dose of 500 mg/m² over a treatment period of up to 60 weeks.

**Paclitaxel albumin-bound** is another comparator treatment in the trial. It is a **powder for dispersion for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 250 mg, with a total maximum dose of 3000 mg over a treatment period of up to 12 weeks.

**Carboplatin** is also used as a comparator treatment. It is a chemical substance administered as an **intravenous infusion**. The pharmaceutical form is PHF00230MIG. The maximum daily dose is 900 mg, with a total maximum dose of 3600 mg over a treatment period of up to 12 weeks.

Efficacy in this clinical trial will be assessed using several key endpoints. The primary efficacy endpoint is the **Objective Response Rate (ORR)**, which will be evaluated according to RECIST 1.1 criteria as assessed by a Blinded Independent Central Review (BICR). Secondary efficacy endpoints include **Duration of Response (DOR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**. These parameters will provide a comprehensive evaluation of the investigational treatment combinations' effectiveness in participants with Stage IV Non-small Cell Lung Cancer (NSCLC).

The trial will involve the administration of investigational agents in combination with **Pembrolizumab**, with or without platinum-based chemotherapy. The efficacy assessments will be conducted at specified intervals throughout the study duration, although the exact schedule for these assessments is not detailed in the provided data. The trial aims to determine the efficacy of these treatment combinations in treatment-naïve participants, with a focus on both response rates and survival outcomes.