Phase III Randomized Study of Durvalumab with SBRT and Osimertinib in Unresected Stage I/II Lymph-Node Negative NSCLC with EGFR Mutation

The primary objective of this study is to evaluate the **efficacy** of **durvalumab** in combination with standard of care **Stereotactic Body Radiation Therapy (SBRT)** compared to placebo with SBRT in terms of progression-free survival (PFS) in patients with T1 to T3N0M0 non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine whether the addition of durvalumab can improve outcomes in patients with early-stage, lymph-node negative NSCLC, potentially offering a more effective treatment option.

Secondary objectives include:

• Assessing the efficacy of durvalumab with SBRT compared to placebo with SBRT in terms of overall survival (OS).
• Evaluating the efficacy of durvalumab with SBRT compared to placebo with SBRT in terms of PFS at 24 months (PFS24), time to progression (TTP), time to distant metastasis (TTDM), and PFS2.
• Assessing the pharmacokinetics (PK) of durvalumab.
• Investigating the immunogenicity of durvalumab.
• Evaluating symptoms and health-related quality of life in patients treated with durvalumab with SBRT compared to placebo with SBRT using the EORTC QLQ-C30.
• Assessing the safety and tolerability profile of durvalumab with standard of care SBRT compared to placebo with standard of care SBRT.
• For the osimertinib cohort, assessing PFS by independent central review (ICR) according to RECIST 1.1, OS, TTP, time to central nervous system (CNS) progression, and PFS2.
• Evaluating the safety, tolerability, and compliance of a maximum of 3 years of osimertinib following standard of care SBRT.

The clinical trial involves a total of **542 participants** diagnosed with unresected Stage I/II, lymph-node negative **Non-small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, with a World Health Organization/Eastern Cooperative Oncology Group Performance Status (WHO/ECOG PS) of 0, 1, or 2. Participants were selected based on their histologically or cytologically documented Stage I to II NSCLC, with clinical T1 to T3N0M0 Stage I/II disease, and are planned to receive definitive treatment with Stereotactic Body Radiation Therapy (SBRT). The trial does not include a vulnerable population. Participants may be medically inoperable or are medically operable but refuse surgery or choose SBRT as definitive therapy. The study does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include adequate organ and marrow function, a life expectancy of at least 12 weeks for the main cohort, and confirmation of a sensitizing EGFR mutation for the osimertinib cohort. The trial aims to assess the efficacy of durvalumab with standard of care SBRT compared to placebo, and the efficacy of osimertinib following SBRT in terms of progression-free survival (PFS).

The clinical trial is a **Phase III**, randomized, placebo-controlled, double-blind, multi-center international study designed to evaluate the efficacy of **durvalumab** in combination with stereotactic body radiation therapy (SBRT) for patients with unresected Stage I/II, lymph-node negative non-small cell lung cancer (NSCLC). The trial also includes an open-label, single-arm cohort for patients with unresected Stage I/II NSCLC harboring a sensitizing EGFR mutation, treated with **osimertinib** following SBRT. The primary objective is to assess progression-free survival (PFS) in both cohorts, with secondary endpoints including overall survival, safety, and quality of life assessments.

The trial is expected to commence recruitment on April 25, 2024, and conclude by January 30, 2028. Participants will be involved for a maximum treatment period of 36 months for the osimertinib cohort and 24 months for the durvalumab cohort. The study visits will follow a structured sequence, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, disease stage, and planned SBRT treatment. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the final outcomes and collect any remaining data.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent prior to any study-specific procedures. The study will utilize a double-blind design for the main cohort to minimize bias, while the osimertinib cohort will be open-label due to its single-arm nature. The trial's methodology is designed to provide robust data on the efficacy and safety of the investigational treatments in the specified patient populations.

The clinical trial involves the administration of **osimertinib**, marketed as TAGRISSO, in two different dosages: 40 mg and 80 mg film-coated tablets. These tablets are administered orally. The maximum daily dose for both formulations is 80 mg, with a treatment period extending up to 36 months. Osimertinib is a synthetic molecule, chemically derived, and is used in the treatment of patients with unresected stage I/II, lymph-node negative non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation. The pharmaceutical form is a film-coated tablet, ensuring ease of oral administration and patient compliance.

**Durvalumab**, marketed as IMFINZI, is provided as a 50 mg/mL concentrate for solution for infusion. This medication is administered intravenously, with a treatment period of up to 24 months. Durvalumab is a protein-based therapeutic agent, specifically classified as a protein - other, and is utilized in combination with standard-of-care stereotactic body radiation therapy (SBRT) for the treatment of patients with unresected stage I/II, lymph-node negative NSCLC. The administration schedule and dosage are determined based on the specific protocol requirements of the trial.

**Infliximab** is provided as a powder for concentrate for solution for infusion and is administered intravenously. It is a protein-based therapeutic agent used as an auxiliary treatment in the trial. The specific dosing schedule and treatment duration are determined by the trial protocol, with a focus on ensuring participant safety and treatment efficacy.

**Glucose** is administered as a solution for infusion, delivered intravenously. It serves as an auxiliary treatment in the trial, with a maximum treatment period of 24 months. Glucose is a chemically derived monosaccharide, used to support the metabolic needs of participants during the trial.

**Mycophenolate mofetil** is provided in the form of hard capsules and is administered orally. It is an immunosuppressive agent used as an auxiliary treatment in the trial. The dosing schedule and treatment duration are determined by the trial protocol, with a focus on maintaining participant safety and ensuring compliance with the study requirements.

The efficacy of the clinical trial will be assessed through the primary endpoint of **Progression-Free Survival (PFS)**. For the main cohort involving **durvalumab**, PFS will be evaluated in patients with a subset of T1 to T3N0M0 Non-small Cell Lung Cancer (NSCLC) using Blinded Independent Central Review (BICR). In the **osimertinib** cohort, the primary endpoint is the 4-year PFS assessed by Independent Central Review (ICR) using RECIST 1.1 criteria.

Secondary endpoints for the main cohort include overall survival, PFS24, time to progression (TTP), and time to distant metastasis (TTDM) using BICR assessments according to RECIST 1.1. Additionally, PFS2 will be evaluated using local assessment. Pharmacokinetics (PK) of durvalumab in serum, presence of anti-drug antibodies (ADA) for durvalumab, and changes in symptoms, functioning, and global health status/quality of life using the EORTC QLQ-C30 will also be assessed. Safety and tolerability will be monitored through adverse events (AEs), physical examinations, vital signs, electrocardiograms, and laboratory findings.

For the osimertinib cohort, secondary endpoints include AEs graded by CTCAE version 5, laboratory studies (chemistry, hematology, and urinalysis), clinical evaluations, ECG parameters, left ventricular ejection fraction (LVEF), WHO performance status, PFS using RECIST 1.1, overall survival (OS), site(s) of disease progression, time to central nervous system (CNS) progression, TTP, and PFS2.