Efficacy and Safety of Osimertinib Versus Placebo in EGFR Mutation-Positive Stage IB-IIIA Non-Small Cell Lung Carcinoma Post-Tumor Resection

The primary objective of this Phase III, double-blind, randomized, placebo-controlled study is to assess the **efficacy** of **Osimertinib** compared to placebo, as measured by **disease-free survival (DFS)** in patients with stage IB-IIIA non-small cell lung carcinoma harboring common sensitizing **EGFR mutations**. This is clinically relevant as it aims to determine the potential of Osimertinib to prevent cancer recurrence following complete tumor resection, with or without adjuvant chemotherapy.

Secondary objectives include:

• Further assessing the efficacy of Osimertinib compared with placebo by evaluating DFS rates at 2, 3, 4, and 5 years, as well as overall survival (OS) and OS rates at these intervals.
• Evaluating the effect of Osimertinib on health-related quality of life (HRQoL) using the SF-36 questionnaire (version 2).
• Characterizing the pharmacokinetics (PK) of Osimertinib and its metabolites (AZ5104 and AZ7550) through assessment of PK exposure parameters.
• Assessing the safety and tolerability profile of Osimertinib compared with placebo by evaluating the number and severity of adverse events, clinical chemistry, hematology, urinalysis, vital signs, physical examination, body weight, digital electrocardiogram (ECG), left ventricular ejection fraction (LVEF), World Health Organization (WHO) Performance Status, and ophthalmologic assessment.

The clinical trial involves a total of **429 participants** diagnosed with **Stage IB-IIIA non-small cell lung carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who have undergone complete tumor resection with or without adjuvant chemotherapy. Participants were selected based on a histologically confirmed diagnosis of primary non-small cell lung cancer, predominantly non-squamous, and must have a centrally confirmed common sensitizing **EGFR mutation**. The trial includes individuals who have fully recovered from surgery and any standard post-operative therapy, with a World Health Organization Performance Status of 0 to 1. Lifestyle considerations such as adequate contraceptive measures for female participants are noted, and all participants must have undergone an MRI or CT scan of the brain prior to surgery. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the efficacy of Osimertinib compared to placebo in terms of disease-free survival.

The clinical trial is a **Phase III**, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of **osimertinib** compared to placebo in patients with **Stage IB-IIIA non-small cell lung carcinoma** harboring common sensitizing **EGFR mutations**. The trial aims to assess disease-free survival (DFS) as the primary endpoint, with secondary endpoints including overall survival (OS), health-related quality of life, and safety assessments. The study is expected to commence recruitment on May 7, 2024, and conclude by January 31, 2029.

Participants will be randomly assigned to receive either **osimertinib** or placebo, administered orally in the form of film-coated tablets. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be at least 18 years old, have a confirmed diagnosis of non-small cell lung cancer, and have undergone complete tumor resection. Exclusion criteria are not specified in the provided data.

The expected duration of participant involvement will vary depending on individual response and the occurrence of any adverse events. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study will employ rigorous monitoring to ensure participant safety and data integrity throughout the trial duration.

The clinical trial involves the administration of **TAGRISSO** (osimertinib) in two different dosages as the experimental medication. **TAGRISSO** is available in the form of **film-coated tablets** and is manufactured by AstraZeneca AB. The trial utilizes two strengths of the medication: 80 mg and 40 mg tablets. The active substance, **osimertinib**, is a chemical compound also known by the synonym AZD9291. The tablets are intended for **oral use**. The maximum daily dose for both the 80 mg and 40 mg formulations is 80 mg, with the total dose not exceeding this amount. The clinical tablets differ from commercial ones in that they are plain on both sides and packaged in HDPE bottles, whereas commercial tablets are debossed and packed in aluminum blisters. The trial aims to assess the efficacy of osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this double-blind, randomized, placebo-controlled study. The placebo is not specified in terms of pharmaceutical form or active substance, as it is intended to serve as a control to evaluate the efficacy of the experimental drug. The placebo is administered in a manner consistent with the experimental medication to maintain the study's blinding and integrity. The trial's primary objective is to measure disease-free survival (DFS) in patients following complete tumor resection, with or without adjuvant chemotherapy.

The efficacy of the clinical trial will be assessed primarily through **Disease Free Survival (DFS)**, as determined by investigator assessments. This endpoint will evaluate the time during which patients remain free from any signs or symptoms of the disease following treatment. Secondary endpoints include the assessment of DFS rates at 2, 3, 4, and 5 years, as well as the analysis of **Overall Survival (OS)** and OS rates at the same intervals. Additionally, patient health-related quality of life and symptoms will be evaluated using the SF-36 questionnaire (version 2, standard). Pharmacokinetic (PK) exposure parameters will be derived from plasma concentrations of **Osimertinib** and its metabolites, AZ5104 and AZ7550, with data analyzed using a population PK approach. Safety and tolerability will be assessed by monitoring the number and severity of adverse events, clinical chemistry, hematology, urinalysis, vital signs, physical examination, body weight, digital electrocardiogram (ECG), left ventricular ejection fraction (LVEF), World Health Organization (WHO) Performance Status, and ophthalmologic assessments.