Phase III Study of Datopotamab Deruxtecan ± Osimertinib vs. Platinum-Based Chemotherapy in EGFR-Mutated Advanced NSCLC Post-Osimertinib Progression

The primary objective of this study is to demonstrate the superiority of **Dato-DXd** monotherapy compared to chemotherapy in terms of progression-free survival (**PFS**) in patients with non-squamous non-small cell lung cancer (**NSCLC**) that has progressed following prior osimertinib treatment. Additionally, the study aims to demonstrate the superiority of Dato-DXd combined with **osimertinib** compared to chemotherapy in terms of PFS. These objectives are clinically relevant as they aim to establish more effective treatment options for patients with advanced NSCLC, potentially improving patient outcomes by delaying disease progression.

Secondary objectives include: - Assessing the superiority of Dato-DXd with or without osimertinib compared to chemotherapy in terms of overall survival (**OS**). - Evaluating the superiority of Dato-DXd with or without osimertinib compared to chemotherapy in terms of blinded independent central review (**BICR**)-assessed central nervous system (**CNS**) progression-free survival.

The clinical trial involves a total of **661 participants** diagnosed with **non-squamous non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of non-squamous NSCLC and documented pre-existing EGFR mutations associated with sensitivity to EGFR tyrosine kinase inhibitors. The trial includes individuals who have experienced extra-cranial radiologic progression on prior osimertinib monotherapy. Participants are required to have a World Health Organization/Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are in relatively good health. The trial also considers vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse groups. Lifestyle factors such as diet and physical activity are not specified, focusing instead on the medical and clinical criteria for inclusion.

The clinical trial is designed as a **randomized**, open-label, sponsor-blind, controlled study to evaluate the efficacy and safety of Dato-DXd with or without **osimertinib** compared to platinum-based doublet chemotherapy in participants with **EGFR-mutated** locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on prior osimertinib treatment. The trial aims to demonstrate the superiority of Dato-DXd monotherapy and Dato-DXd combined with osimertinib in terms of progression-free survival (PFS) compared to chemotherapy. The study is expected to commence recruitment on December 19, 2024, and is estimated to conclude by February 8, 2028.

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 confirmed non-squamous NSCLC, documented progression on prior osimertinib monotherapy, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies to evaluate disease progression according to RECIST v1.1 criteria. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may result from disease progression, unacceptable toxicity, or withdrawal of consent.

The expected length of participant involvement in the trial is contingent upon individual response to treatment and disease progression, with the maximum treatment period set at 999,999 days. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or the investigator's discretion based on clinical judgment. The trial will assess primary endpoints such as PFS and secondary endpoints including overall survival, objective response rate, and duration of response, among others. The study will utilize both oral and intravenous administration routes for the investigational products, with Dato-DXd being administered as a solution for infusion.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **TAGRISSO** (osimertinib) is provided in two dosages: 40 mg and 80 mg film-coated tablets. These tablets are administered orally. The clinical tablets are plain on both sides and packed in HDPE bottles, differing from the commercial tablets, which are debossed and packed in aluminum blisters. Osimertinib functions as an **EGFR tyrosine kinase inhibitor** and is used in the study to evaluate its efficacy in combination with other treatments.

**Datopotamab deruxtecan** is another experimental medication used in this trial. It is an **antibody-drug conjugate** provided as a solution for infusion. The administration route is intravenous infusion, and the dosing is based on milligrams per kilogram of body weight. This investigational drug is being evaluated for its potential to improve progression-free survival in participants with non-small cell lung cancer.

The trial also includes several comparator treatments, which are standard-of-care chemotherapeutic agents. **Cisplatin** is administered as a concentrate for solution for infusion, delivered via intravenous infusion. It is classified as an **alkylating agent** and is dosed in milligrams per square meter of body surface area. **Pemetrexed**, another comparator, is also provided as a concentrate for solution for infusion and administered intravenously. It is an **antifolate** agent, dosed similarly to cisplatin. Lastly, **Carboplatin** is included as a comparator, provided in the same pharmaceutical form and route of administration as cisplatin and pemetrexed. It is classified as an **antineoplastic agent** and dosed in milligrams.

All treatments are monitored for participant compliance, and the dosing schedules are designed to ensure the safety and efficacy of the medications. The trial aims to compare the efficacy of the experimental treatments against the standard chemotherapy regimens in terms of progression-free survival in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to progression as assessed by Blinded Independent Central Review (BICR) using RECIST v1.1 criteria or death from any cause. Secondary endpoints include Overall Survival (OS), Central Nervous System Progression-Free Survival (CNS PFS), Objective Response Rate (ORR), Duration of Response (DoR), and Progression-Free Survival-2 (PFS-2). Additionally, time to deterioration in pulmonary symptoms, physical functioning, and Global Health Status/Quality of Life (GHS/QoL) will be evaluated.

Measurements will be conducted at specified intervals throughout the trial, with assessments including imaging studies for tumor progression, patient-reported outcomes for symptom and quality of life evaluations, and laboratory tests for pharmacokinetic and immunogenicity analyses. The ORR and DoR will be determined by the proportion of participants achieving a confirmed complete or partial response, as assessed by BICR per RECIST v1.1. Time to deterioration will be measured using validated scales such as the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form 8c and the EORTC IL172 GHS/QoL scale. The presence of antidrug antibodies (ADAs) for Dato-DXd will also be assessed to evaluate immunogenicity.