A Phase III, Randomized, Controlled, Multi-center, 3-Arm Study of Neoadjuvant Osimertinib as Monotherapy or in Combination with Chemotherapy versus Standard of Care Chemotherapy Alone for the Treatment of Patients with Epidermal Growth Factor Receptor Mutation Positive, Resectable Non-small Cell Lung Cancer (NeoADAURA)

The primary objective of this study is to determine the **efficacy** of osimertinib, administered as monotherapy or in combination with chemotherapy, compared to chemotherapy alone as a neoadjuvant treatment for patients with epidermal growth factor receptor mutation-positive, resectable non-small cell lung cancer (NSCLC). This objective is clinically relevant as it aims to establish a potentially more effective treatment regimen that could improve surgical outcomes and overall survival in this patient population.

Secondary objectives include:

• Assessing the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone as neoadjuvant treatment, by evaluating pathological complete response (pCR), event-free survival (EFS), disease-free survival (DFS), downstaging, and overall survival (OS).
• Evaluating the impact of treatment on patients' disease-related symptoms and health-related quality of life.
• Assessing the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone as neoadjuvant treatment in patients with or without EGFR mutation detectable at screening in plasma-derived circulating tumor DNA (ctDNA).
• Comparing the baseline tumor EGFR mutation status in screened patients with evaluable results from baseline plasma samples.
• Comparing the local cobas® EGFR Mutation Test v2 and FoundationOne® CDx results used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results from baseline tumor samples.
• Characterizing the pharmacokinetics (PK) of osimertinib and its metabolites.

The clinical trial involves a total of **295 participants** diagnosed with **non-squamous non-small cell lung cancer (NSCLC)**, specifically those with completely resectable Stage II to IIIB N2 disease. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have a tumor harboring one of the two common EGFR mutations associated with EGFR-TKI sensitivity. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on the ability to achieve complete surgical resection of the primary NSCLC, as assessed by a multidisciplinary team. The study does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided. The trial aims to evaluate the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone as a neoadjuvant treatment.

The clinical trial is a **Phase III**, randomized, controlled, multi-center study designed to evaluate the efficacy of **osimertinib** as monotherapy or in combination with chemotherapy compared to chemotherapy alone in patients with **epidermal growth factor receptor (EGFR) mutation-positive**, resectable non-small cell lung cancer (NSCLC). The trial employs a three-arm design, ensuring a robust comparison between the treatment modalities. The study is double-blind, meaning neither the participants nor the investigators will know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to run until December 31, 2029, with recruitment starting on March 27, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and **EGFR mutation** status. Following successful screening, participants will be randomized into one of the three treatment arms. Regular follow-up visits will be scheduled to monitor the participants' health, assess treatment efficacy, and collect data on primary and secondary endpoints, including major pathological response and complete pathological response. The end-of-study visit will occur after the final treatment cycle, where comprehensive assessments will be conducted to evaluate the overall outcomes of the trial.

The expected length of participant involvement in the study is determined by the treatment arm and the individual response to therapy, with a maximum treatment period of 36 months for those receiving **osimertinib**. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the potential benefits of **osimertinib** in the neoadjuvant setting for NSCLC, contributing to the optimization of treatment strategies for this patient population.

The clinical trial involves the administration of several treatments, including **Armisarte** 25 mg/ml concentrate for solution for infusion, which contains the active substance **pemetrexed**. This pharmaceutical form is a concentrate for solution for infusion, administered via **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily dose of 500 mg/m². The treatment period is extensive, with a maximum duration of 999,999 days, ensuring flexibility in treatment administration. Participant compliance is monitored through regular assessments of infusion administration and dosage adherence.

Another treatment in the trial is **TAGRISSO** film-coated tablets, available in 40 mg and 80 mg dosages, containing the active substance **osimertinib**. These tablets are administered orally, with a maximum daily dose of 40 mg. The treatment period is limited to 36 days. The clinical tablets differ from commercial ones in packaging and debossing, with clinical tablets being plain and packed in HDPE bottles. Compliance is monitored through pill counts and patient diaries to ensure adherence to the dosing schedule.

The trial also includes the administration of **carboplatin** and **cisplatin**, both administered as intravenous infusions. **Carboplatin** has a maximum total dose of 2250 mg/m², while **cisplatin** has a maximum total dose of 75 mg/m². Both treatments are administered over a maximum period of 999,999 days. Compliance is monitored through infusion records and regular assessments of patient response to treatment.

A **placebo** is also used in the trial, formulated as a film-coated tablet for oral administration. The placebo is administered with a maximum daily dose of 40 mg over a treatment period of 36 days. Compliance is monitored similarly to active treatments, ensuring blinding and adherence to the study protocol.

The efficacy of the investigational treatments in this Phase III clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **Major Pathological Response (MPR)**, defined as having ≤10% residual cancer cells in the main tumor, as evaluated by a central pathology laboratory following surgery. Secondary endpoints include Complete Pathological Response (pCR), Event-Free Survival (EFS), Disease-Free Survival (DFS), downstaging, and Overall Survival (OS). Additionally, changes from baseline in patient-reported outcomes (ePRO) will be measured, along with the concordance of EGFR mutation status between tumor tissue DNA and patient-matched plasma-derived ctDNA, and between local and central cobas EGFR mutation test results from baseline tumor samples. Pharmacokinetic (PK) plasma concentrations of osimertinib will also be monitored.