Phase III Randomized Study of Datopotamab Deruxtecan, Durvalumab, and Carboplatin vs. Pembrolizumab with Platinum Chemotherapy in Advanced NSCLC Without Genomic Alterations

The primary objective of this study is to demonstrate the **superiority** of Datopotamab Deruxtecan (Dato-DXd) in combination with durvalumab and carboplatin compared to pembrolizumab in combination with platinum-based chemotherapy. This will be assessed through the evaluation of progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS) in the first-line treatment of participants with non-squamous TROP2 biomarker-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). The clinical relevance of this objective lies in potentially improving treatment outcomes for patients with advanced NSCLC, a condition with limited therapeutic options and significant morbidity and mortality.

Secondary objectives include demonstrating the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum-based chemotherapy in various populations, including intention-to-treat (ITT), non-squamous, and TROP2 biomarker-defined groups. This will be evaluated by assessing PFS by BICR, OS, objective response rate (ORR) by BICR, duration of response (DoR) by BICR and investigator assessment, PFS by investigator assessment, and time to second progression or death. Additional assessments will include clinical outcomes, pharmacokinetics, and immunogenicity.

The clinical trial involves a total of **838 participants** diagnosed with **Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have been diagnosed with locally-advanced or metastatic NSCLC that is not amenable to surgical resection or definitive chemoradiation. Participants were selected based on specific criteria, including the absence of certain tumor genomic alterations and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals with adequate bone marrow reserve and organ function. The study population is diverse, encompassing a vulnerable population, and considers various lifestyle factors, although specific details on diet or physical activity are not provided. The selection process ensures that participants have histologically or cytologically documented NSCLC and meet the necessary health requirements to participate in the trial.

The clinical trial is designed as a **randomized**, open-label, multicenter, global study to evaluate the efficacy of **Datopotamab deruxtecan** in combination with **Durvalumab** and **Carboplatin** compared to **Pembrolizumab** with platinum-based chemotherapy for the first-line treatment of patients with locally advanced or metastatic **Non-Small Cell Lung Cancer (NSCLC)** without actionable genomic alterations. The trial aims to demonstrate the superiority of the investigational combination by assessing progression-free survival (PFS) and overall survival (OS) in participants with non-squamous TROP2 biomarker-positive NSCLC. The study is expected to conclude by February 2027, with recruitment having commenced in January 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, disease stage, and absence of specific genomic alterations. Eligible participants will be randomized to receive either the investigational or comparator treatment. Follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination. The expected duration of participant involvement will vary depending on individual response and progression, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

Key elements of the research methodology include the use of **intravenous** administration for all investigational and comparator products, with the exception of **Mycophenolate Mofetil**, which is administered orally. The trial will employ objective response rate assessments, duration of response, and pharmacokinetics as secondary endpoints. Participants will be monitored for clinical outcomes using the NSCLC-SAQ and PROMIS Physical Function short form 8c. The trial is not classified as low intervention and is categorized as a Phase III study, aligning with the protocol and application dossier. The trial's primary endpoints focus on PFS and OS, assessed by blinded independent central review (BICR) and investigator assessment, ensuring robust and unbiased evaluation of treatment efficacy.

The clinical trial involves the administration of **Datopotamab deruxtecan**, an experimental medication, which is an antibody-drug conjugate. It is provided in the form of a solution for infusion and is administered intravenously. The dosing is based on milligrams per kilogram (mg/kg) of body weight, although specific dosage amounts are not provided. The treatment period is extensive, with a maximum duration set at 999,999 days, indicating long-term administration potential.

**Durvalumab**, marketed as Imfinzi, is another experimental treatment used in this trial. It is a protein-based medication provided as a 50 mg/mL concentrate for solution for infusion. Durvalumab is administered intravenously, with the dosing unit in milligrams (mg). The maximum treatment period is also set at 9,999,999 days, suggesting prolonged use.

**Carboplatin** is used as a comparator treatment in the study. It is a chemical-origin drug provided as a concentrate for solution for infusion. The administration route is intravenous, with dosing measured in milligrams per milliliter (mg/mL). The maximum treatment period is 9,999,999 days, indicating potential for long-term administration.

**Pembrolizumab** is another comparator treatment, provided as a solution for infusion. It is a protein-based medication administered intravenously, with dosing in milligrams (mg). The maximum treatment period is 9,999,999 days, allowing for extended use.

**Cisplatin** is included as a comparator treatment, provided as a concentrate for solution for infusion. It is a chemical-origin drug administered intravenously, with dosing in milligrams per square meter (mg/m²). The maximum treatment period is 9,999,999 days, indicating potential for long-term administration.

**Paclitaxel** is also used as a comparator treatment. It is a chemical-origin drug provided as a concentrate for solution for infusion and administered intravenously. The dosing is in milligrams per square meter (mg/m²), with a maximum treatment period of 999,999 days.

**Pemetrexed** is another comparator treatment, provided as a concentrate for solution for infusion. It is a chemical-origin drug administered intravenously, with dosing in milligrams per square meter (mg/m²). The maximum treatment period is 9,999,999 days, indicating potential for long-term administration.

**Mycophenolate mofetil** is used as an auxiliary treatment in the study. It is provided in capsule form, specifically as Mycophenolate Mofetil Accord 250 mg capsules. The administration route is oral, with dosing in milligrams (mg). The maximum treatment period is 999,999 days, suggesting long-term use.

**Infliximab** is another auxiliary treatment, provided as a powder for concentrate for solution for infusion. It is a protein-based medication administered intravenously, with dosing in milligrams (mg). The maximum treatment period is 999,999 days, indicating potential for extended use.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)** in patients with non-squamous TROP2 biomarker-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). PFS is defined as the time from randomization until disease progression as per RECIST 1.1 criteria or death from any cause, while OS is defined as the time from randomization until death from any cause.

Secondary endpoints will further evaluate efficacy through additional measures such as Objective Response Rate (ORR), Duration of Response (DoR), and Time to Second Progression or Death. These will be assessed by both blinded independent central review (BICR) and investigator assessment. Clinical outcome assessments will be conducted using the NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) and the PROMIS Physical Function short form 8c. Pharmacokinetics and immunogenicity will also be evaluated as part of the secondary endpoints.

The trial will employ a randomized, open-label, multicenter design to compare the efficacy of Datopotamab Deruxtecan in combination with Durvalumab and Carboplatin versus Pembrolizumab in combination with platinum-based chemotherapy. The study will focus on first-line treatment for patients with locally advanced or metastatic NSCLC without actionable genomic alterations. Efficacy assessments will be conducted at specified intervals throughout the trial duration, with the estimated end date set for February 22, 2027.