Efficacy and Safety of Osimertinib in EGFR-Mutant Stage IA2-IA3 Non-Small Cell Lung Cancer Post-Resection: A Phase III Randomized Controlled Trial
- Trial ID
- 2023-509943-28-00
- Protocol
- D516FC00001(ADAURA2)
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of osimertinib compared to placebo, as measured by disease-free survival (DFS) in participants within the high-risk stratum. This is clinically relevant as it aims to determine the potential benefit of osimertinib in prolonging DFS in patients with Stage IA2-IA3 non-small cell lung carcinoma, characterized by EGFR mutation, following complete tumor resection. Understanding the efficacy in this specific high-risk group could inform treatment decisions and improve patient outcomes.
Secondary objectives include:
- Demonstrating the effectiveness of osimertinib versus placebo by assessing DFS in the overall population.
- Evaluating overall survival (OS) in both the high-risk stratum and the overall population.
- Assessing the impact on physical functioning in both the high-risk stratum and overall population.
- Evaluating central nervous system disease-free survival (DFS) in both the high-risk stratum and the overall population.
- Characterizing the pharmacokinetics of osimertinib and its metabolites in the overall population.
- Assessing the safety and tolerability profile of osimertinib versus placebo in the overall population.
Participants
The clinical trial involves a total of **361 participants** diagnosed with **Stage IA2-IA3 non-small cell lung carcinoma** with specific **EGFR mutations** (Ex19del, L858R) following complete tumor resection. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their diagnosis of non-squamous histology NSCLC and must have undergone complete surgical resection of the primary tumor. The trial includes individuals with a World Health Organization performance status of 0 or 1, indicating they are in good general health. Participants must have a minimum life expectancy of more than 6 months and have recovered completely from surgery at the time of randomization. The trial requires the provision of a tumor sample for central pathology assessment to confirm the presence of the specified EGFR mutations. Both genders are included, and the study considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **Phase III**, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of **osimertinib** in comparison to placebo in participants with **Stage IA2-IA3 non-small cell lung carcinoma** harboring EGFR mutations (Ex19del, L858R) following complete tumor resection. The primary objective is to assess disease-free survival in the high-risk stratum, with secondary endpoints including overall survival, impact on physical functioning, and safety profile. The trial is expected to commence recruitment on August 9, 2024, and conclude by November 1, 2032.
Participants will be randomly assigned to receive either TAGRISSO 40 mg or 80 mg film-coated tablets, or a placebo, administered orally. The maximum treatment period is 36 months. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health status and treatment efficacy, and an end-of-study visit to assess final outcomes. Participants are required to have a minimum life expectancy of over six months and must have completed surgical resection of the primary tumor. The study intervention cannot begin within four weeks post-surgery, and randomization must occur within 12 weeks post-surgery.
Participant involvement is expected to last up to 36 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any situation where continued participation is deemed not in the participant's best interest by the investigator. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout its duration.
Treatment
The clinical trial involves the administration of **osimertinib**, marketed under the name TAGRISSO, in two different dosages: 40 mg and 80 mg film-coated tablets. The active substance, osimertinib, is a chemical compound also known by the synonym AZD9291. The pharmaceutical form of the medication is a film-coated tablet, and it is administered orally. The maximum daily dose for both the 40 mg and 80 mg formulations is 80 mg, with a maximum treatment period of 36 months. The clinical tablets are plain on both sides and packaged in HDPE bottles, differing from the commercial tablets, which are debossed and packed in aluminum blisters. The acceptance criteria for the assay of the drug product, as well as the sites for packing, QP release, and shelf-life, vary between the clinical and commercial products.
The trial also includes a **placebo** group to serve as a comparator treatment. The placebo is not specified in terms of pharmaceutical form, active substance, or route of administration. It is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. This helps in objectively assessing the efficacy and safety of osimertinib in comparison to the placebo.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating **disease-free survival (DFS)** in participants with EGFR mutation-positive Stage IA2-IA3 Non-small Cell Lung Cancer (NSCLC) following complete tumor resection. The primary endpoint is the DFS in the high-risk stratum, as determined by investigators' assessment. Secondary endpoints include DFS in the overall population, overall survival (OS) in both the high-risk stratum and overall population, and the impact of osimertinib versus placebo on physical functioning. Additionally, the effectiveness of osimertinib versus placebo will be assessed by evaluating central nervous system DFS in both the high-risk stratum and the overall population. The pharmacokinetics of osimertinib and its metabolites will also be characterized, alongside the safety and tolerability profile of osimertinib versus placebo in the overall population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, at least ≥ 18 years.
- NSCLC, of non-squamous histology.
- Stage IA2 or IA3 disease, based on TNM8 classification.
- Complete surgical resection (R0) of the primary NSCLC by lobectomy, bilobectomy, segmentectomy or sleeve resection.
- Complete recovery from surgery at the time of randomisation. Study intervention cannot commence within 4 weeks following surgery. No more than 12 weeks may have elapsed between surgery and randomisation for participants.
- World Health Organization performance status of 0 or 1.
- Provision of tumour sample for central pathology assessment of pathologic risk factors and to assess EGFR mutation status prior to randomisation.
- A tumour which harbours one of the 2 EGFR mutations (Ex19del, L858R).
- Minimum life expectancy of > 6 months.
- Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential. Male subjects must be willing to use barrier contraception.
Exclusion Criteria
- Mixed small cell and non-small cell cancer history.
- Participants with incomplete (R1/R2) resection, or who have undergone pneumonectomy or only wedge resection.
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including HCV and HIV or active uncontrolled HBV infection.
- History of another primary malignancy, including any known or suspected synchronous primary lung cancer, except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence.
- Any of the following cardiac criteria: Mean resting QTcF interval > 470 ms, obtained from triplicate ECGs performed at screening / Any abnormalities in rhythm, conduction, or morphology of resting ECG / Any factors that increase the risk of QTcF prolongation or risk of arrhythmic events.
- History of interstitial lung disease.
- Inadequate bone marrow reserve or organ function.
- Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study intervention.
- Prior treatment with any anticancer therapy for NSCLC (including chemotherapy, radiotherapy, immunotherapy, and EGFR-TKIs).
- Major surgery or significant traumatic injury within 4 weeks of the first dose of study intervention.
- Participants currently receiving medications or herbal supplements known to be strong inducers of CYP3A4.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 09 Aug 2024 | 1 |
 Italy | Not Recruiting | 09 Aug 2024 | 14 |
 Poland | Not Recruiting | 09 Aug 2024 | 3 |
 Romania | Not Recruiting | 09 Aug 2024 | 1 |
 Spain | Not Recruiting | 09 Aug 2024 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TAGRISSO 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 80 | 36 | PRD4954971 |
TAGRISSO 80 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 80 | 36 | PRD4954976 |
Placebo | Placebo | N/A | — | — | — | N/A |