A Global Study to Assess the Effects of Osimertinib in Participants With EGFRm Stage IA2-IA3 NSCLC Following Complete Tumour Resection

Study Overview
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Brief Summary
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This is a global study to assess the effects of osimertinib in participants with EGFRm stage IA2-IA3 non-small cell lung cancer following complete tumour resection.

Detailed Description
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This is a Phase III, double-blind, randomised, placebo-controlled, 2-arm, international study assessing the efficacy and safety of adjuvant osimertinib versus placebo in participants with stage IA2-IA3 EGFRm Non-Small Cell Lung Cancer, who have previously undergone complete tumour resection. All participants must have had a tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). Eligible participants will be randomised in a 1:1 ratio to one of the 2 intervention arms: osimertinib 80 mg or matching placebo, once daily for 3 years unless discontinuation criteria is met.

Official Title
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A Phase III, Double-blind, Randomised, Placebo-Controlled, International Study to Assess the Efficacy and Safety of Adjuvant Osimertinib Versus Placebo in Participants With EGFR Mutation-positive Stage IA2-IA3 Non-small Cell Lung Cancer, Following Complete Tumour Resection

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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, 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) by cobas® EGFR Mutation Test v2 (Roche Diagnostics) or FoundationOne® test. 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, bilobectomy or only wedge resection. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and HIV. History of another primary malignancy 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 QTc 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 QTc 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Osimertinib<br>Osimertinib 80mg, orally, once daily (Dose may be reduced to 40 mg once daily if required at the discretion of the investigator) | Drug: Osimertinib<br>* The initial dose of Osimertinib 80mg once daily can be reduced to 40mg once daily. Treatment can continue until disease recurrence, unacceptable toxicity or other discontinuation criteria are met.<br>* Other names: AZD9291; TAGRISSO;|
| Placebo Comparator: Placebo<br>Matching placebo for osimertinib, orally, once daily | Drug: Placebo<br>* Matching placebo. Initial dose of 80mg once daily can be reduced to 40mg once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) in high-risk stratum | DFS is defined as the time from the date of randomisation until the date of disease recurrence or date of death (by any cause in the absence of recurrence), whichever occurs first. Stratification to the high risk stratum will be based on pathologic features assessed by central pathology review during screening. | From date of randomisation up to approximately 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) in overall population | DFS is defined as the time from the date of randomisation until the date of disease recurrence or date of death (by any cause in the absence of recurrence), whichever occurs first. | From date of randomisation up to approximately 10 years | 
| Overall Survival (OS) in high-risk stratum and the overall population | OS is defined as the time from the date of randomisation until death due to any cause. | From date of randomization up to approximately 10 years | 
| PK plasma concentrations of osimertinib and of metabolite AZ5104 in overall population | Ratio of metabolite-to-osimertinib to be calculated at predose, and at 0.5-2 hours postdose. | From date of randomisation up to approximately 10 years | 
| Impact of osimertinib versus placebo on physical functioning | Assess the impact of osimertinib versus placebo on physical functioning in both the high-risk stratum and the overall population as measured by SF-36 V2 health survey | From date of randomisation up to approximately 10 years | 
| Central Nervous System (CNS) Disease-Free Survival (DFS) in both the high-risk stratum and the overall population | CNS DFS is defined as the time from randomisation to the time of a CNS lesion (as assessed by investigator) or death due to any cause, regardless of whether the participant withdraws from study intervention or receives other anti-cancer therapy. | From date of randomisation up to approximately 10 years | 
| Safety and tolerability in overall population | AEs graded by CTCAE version 5.0 | From date of randomisation up to approximately 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osimertinib, Tagrisso, NSCLC, Non-small Cell Lung Cancer, Resectable, EGFRm Positive, Adjuvant, Stage IA2-IA3