Phase 3 Study of Trastuzumab Deruxtecan vs. Platinum-Based Chemotherapy in HER2-Mutant Unresectable or Metastatic NSCLC

The primary objective of this study is to evaluate the **efficacy** of Trastuzumab Deruxtecan (T-DXd) compared to a regimen of platinum with pemetrexed plus pembrolizumab. This evaluation is based on the assessment of **Progression-Free Survival (PFS)** by Blinded Independent Central Review (BICR) in participants with unresectable, locally advanced, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring HER2 exon 19 or 20 mutations. The clinical relevance of this objective lies in determining the potential of T-DXd as a first-line treatment option, which could significantly impact treatment strategies for this patient population.

Secondary objectives include: - Assessing the efficacy of T-DXd relative to the comparator regimen by evaluating **Overall Survival (OS)**. - Evaluating efficacy in terms of PFS by investigator assessment, **Objective Response Rate (ORR)**, **Duration of Response (DoR)**, time to second progression or death (PFS2), and landmark analysis of PFS12 and OS24. - Assessing efficacy by evaluating **CNS-PFS** (per RECIST 1.1). - Evaluating the **safety and tolerability** of T-DXd compared to the comparator regimen. - Assessing the **pharmacokinetics (PK)** of T-DXd, total anti-HER2 antibody, and DXd in serum. - Investigating the **immunogenicity** of T-DXd. - Assessing the benefit of T-DXd relative to the comparator regimen with patient-reported pulmonary symptoms associated with NSCLC. - Describing patient-reported tolerability of T-DXd as compared to the comparator regimen.

The clinical trial involves a total of **290 participants** diagnosed with **unresectable, locally advanced, or metastatic Non-Small Cell Lung Cancer** (NSCLC) characterized by HER2 exon 19 or 20 mutations. The study population includes both male and female participants who are at least 18 years of age. Participants were selected based on specific criteria, including having a histologically documented non-squamous NSCLC with HER2 mutations, being treatment-naïve for palliative intent systemic therapy, and possessing a left ventricular ejection fraction of at least 50%. The trial population is required to have measurable disease as assessed by the investigator and must demonstrate protocol-defined adequate organ function, including cardiac, renal, and hepatic function. The Eastern Cooperative Oncology Group (ECOG) performance status of participants is between 0 and 1. Additionally, participants must have tumor tissue available for central testing. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an open-label, randomized, multicenter, Phase 3 study to evaluate the efficacy and safety of **trastuzumab deruxtecan** as a first-line treatment for patients with unresectable, locally advanced, or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations. The trial will compare the investigational product against a combination of platinum-based chemotherapy with **pemetrexed** and **pembrolizumab**. The primary objective is to assess progression-free survival (PFS) as determined by a blinded independent central review (BICR). Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety assessments.

Participants will be randomly assigned to receive either the investigational product or the comparator regimen. The trial will be conducted over an estimated period ending in March 2027, with recruitment anticipated to start in June 2024. The study will involve multiple visits, beginning with a screening visit to confirm eligibility based on criteria such as age, disease stage, and specific genetic mutations. Participants must have a left ventricular ejection fraction (LVEF) of at least 50% and meet protocol-defined organ function requirements.

Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of vital signs. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or withdrawal of consent.

The expected duration of participant involvement will vary depending on individual response to treatment and disease progression. The trial is designed to ensure rigorous monitoring and data collection to support the evaluation of the investigational product's efficacy and safety profile. The study will adhere to ethical standards and regulatory requirements to ensure the integrity and reliability of the trial outcomes.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Trastuzumab deruxtecan**, also known as DS-8201a, is the primary investigational drug in this study. It is an antibody-drug conjugate formulated as a solution for infusion. The administration route is **intravenous**, with dosing based on **mg/kg** (milligrams per kilogram). The maximum treatment period is set at an extensive duration, allowing for prolonged administration as required by the study protocol.

**Pemetrexed** is utilized as a comparator treatment in this trial. It is provided in two pharmaceutical forms: a powder for concentrate and a concentrate for solution, both intended for infusion. The active substance is of chemical origin, and the administration is conducted intravenously. The dosing is calculated in **mg/m²** (milligrams per square meter), with no specified maximum daily or total dose, indicating flexibility in dosing as per clinical requirements.

**Cisplatin** is another comparator treatment, presented as a concentrate for solution for infusion. Like pemetrexed, it is of chemical origin and administered intravenously. The dosing follows the **mg/m²** metric, with the same dosing flexibility as pemetrexed, allowing for adjustments based on patient-specific factors.

**Pembrolizumab** is included as a comparator treatment, formulated as a solution for infusion. It is a protein-based therapeutic, administered intravenously. The dosing is measured in **mg** (milligrams), with no fixed maximum daily or total dose, providing adaptability in treatment regimens.

**Carboplatin** is also used as a comparator, available as a solution for infusion. It is chemically derived and administered intravenously. The dosing is expressed in **mg/ml** (milligrams per milliliter), with no predetermined maximum daily or total dose, allowing for tailored dosing strategies.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the protocol. The study does not specify the use of a placebo, focusing instead on the comparison between the investigational drug and established chemotherapy agents. The trial aims to evaluate the efficacy and safety of trastuzumab deruxtecan in comparison to the platinum-based chemotherapy regimen combined with pembrolizumab in patients with unresectable, locally advanced, or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations.

The efficacy of the investigational treatment in this clinical trial will be primarily assessed through **Progression-Free Survival (PFS)**, which is defined as the time from randomization until disease progression as per RECIST 1.1 criteria or death from any cause. This primary endpoint will be evaluated by Blinded Independent Central Review (BICR). Secondary efficacy endpoints include **Overall Survival (OS)**, which measures the time from randomization until death from any cause, and additional PFS assessments by investigator evaluation. Other secondary endpoints involve the **Objective Response Rate (ORR)**, **Duration of Response (DoR)**, and specific time landmarks such as PFS at 12 months (PFS12) and OS at 24 months (OS24). These will be assessed using both BICR and investigator evaluations.

Additional secondary endpoints include **CNS-PFS**, which is the time from randomization until CNS progression or death in the absence of CNS progression, and various safety and tolerability measures such as adverse events (AEs), serious adverse events (SAEs), and changes in laboratory parameters. Pharmacokinetics (PK) of the investigational drug, presence of anti-drug antibodies (ADAs), and patient-reported outcomes using validated questionnaires like the NSCLC-Symptom Assessment Questionnaire (SAQ) and EORTC-QLQ-30 will also be evaluated. The schedule for these assessments will be aligned with the trial protocol, ensuring comprehensive data collection and analysis throughout the study duration.