AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

Detailed Description
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This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. Subjects must be chemotherapy naive and must agree to provide a biopsy for central confirmation of T790 mutation status following confirmed disease progression on their first line EGFR-TKI treatment (e.g. erlotinib, gefitinib or afatinib). Suitable subjects will then be randomized to receive either Osimertinib (80mg orally, once daily) or platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 + carboplatin area under the plasma concentration-time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2) on Day 1 of every 21-day cycle in a 2:1 (Osimertinib: platinum-based doublet chemotherapy) ratio. Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. The primary objective of the study is to assess the efficacy of Osimertinib compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival (PFS), using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1), as well as asensitivity analysis of Progression Free Survival using Blinded Independent Central Review (BICR).

Official Title
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A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).

Conditions
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Anticancer Treatment

Intervention / Treatment
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* Drug: Chemotherapy
* Drug: Cross-over to Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with histologically or cytologically documented NSCLC. Locally advanced or metastatic NSCLC Radiological documentation of disease progression following 1st line EGFR TKI Treatment without any further treatment Eligible to receive treatment with the selected doublet-chemotherapy Central confirmation of T790M+ mutation status World Health Organization (WHO) performance status 0-1 At least one lesion, not previously irradiated. Exclusion Criteria: • Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior of starting 1st EGFR TKI treatment Treatment with more than one prior line of treatment for advanced NSCLC Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within 8 days or approximately 5x half-life of the first dose of study treatment Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment Previous treatment with Osimertinib, or a 3rd generation EGFR TKI For subjects who cross-over to Osimertinib: Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review. At least 14 days since last dose of platinum-based doublet chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Osimertinib<br>Osimertinib 80 mg, orally, once daily | Drug: Chemotherapy<br>* Randomization to either Osimertinib or platinum-based doublet-chemotherapy on Day 1 of every 21d cycle in a 2:1 (Osimertinib:platinum-based doublet-chemotherapy) ratio<br>* Other names: Platinum-based Doublet-Chemotherapy;Drug: Cross-over to Osimertinib<br>* Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. Subjects who stop platinum-based doublet chemotherapy for reasons other than objective disease progression according to RECIST 1.1 will not be eligible to cross-over to Osimertinib.<br>|
| Active Comparator: Platinum-based doublet chemotherapy<br>pemetrexed 500mg/m2 + carboplatin AUC5 or pemetrexed 500mg/m2 + cisplatin 75mg/m2 | Drug: Chemotherapy<br>* Randomization to either Osimertinib or platinum-based doublet-chemotherapy on Day 1 of every 21d cycle in a 2:1 (Osimertinib:platinum-based doublet-chemotherapy) ratio<br>* Other names: Platinum-based Doublet-Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Investigator Assessment | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) by Investigator Assessment | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy. | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | 
| Duration of Response (DoR) by Investigator Assessment | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | 
| Disease Control Rate (DCR) by Investigator Assessment | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at >=6 weeks, prior to any progressive disease (PD). | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | 
| Tumour Shrinkage by Investigator Assessment | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response. | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | 
| Secondary: Overall Survival (OS) |  | From date of randomization until time of final OS analysis, a median follow-up of 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Non-Small Cell Lung Cancer; T790M Mutation Positive