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AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3)

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ClinicalTrials.gov Identifier: NCT02151981
Recruitment Status : Active, not recruiting
First Posted : June 2, 2014
Results First Posted : July 21, 2017
Last Update Posted : September 13, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
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

Condition or disease Intervention/treatment Phase
Anticancer Treatment Drug: Chemotherapy Drug: Cross-over to Osimertinib Phase 3

Detailed Description:
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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 419 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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).
Actual Study Start Date : August 4, 2014
Actual Primary Completion Date : April 15, 2016
Estimated Study Completion Date : December 29, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Osimertinib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Osimertinib
Osimertinib 80 mg, orally, once daily
 Drug: Chemotherapy
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
Other Names:
  • Osimertinib
  • Platinum-based Doublet-Chemotherapy

Drug: 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, 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.
Active Comparator: Platinum-based doublet chemotherapy
pemetrexed 500mg/m2 + carboplatin AUC5 or pemetrexed 500mg/m2 + cisplatin 75mg/m2
 Drug: Chemotherapy
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
Other Names:
  • Osimertinib
  • Platinum-based Doublet-Chemotherapy


Outcome Measures
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Primary Outcome Measures :
  1. Progression Free Survival (PFS) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    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.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    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.

  2. Duration of Response (DoR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    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.

  3. Disease Control Rate (DCR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    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).

  4. Tumour Shrinkage by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    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.

  5. Secondary: Overall Survival (OS) [ Time Frame: From date of randomization until time of final OS analysis, a median follow-up of 43 months ]

Other Outcome Measures:
  1. Time to First Subsequent Therapy (TFST) [ Time Frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months ]
    Time from randomisation to first subsequent anti-cancer therapy (FST) following randomised treatment discontinuation, or death if no FST administered. Any patient not known to have died nor received any subsequent anti-cancer therapy (ST) was censored at the last time known not to have received ST, ie, the last follow-up visit this was confirmed.

  2. Time to Second Subsequent Therapy (TSST) [ Time Frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months ]
    Time from randomisation to second subsequent anti-cancer therapy (SST) following randomised treatment discontinuation, or death if no SST administered. Any patient not known to have died nor received any SST was censored at the last time known not to have received SST, ie, the last follow-up visit this was confirmed.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02151981


Locations
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Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Yilong Wu, MD Guangdong General Hospital, Guangdong, 510030, China
Principal Investigator: Vassiliki A Papadimitrakopoulou, MD The University of Texas/M.D. Anderson Cancer Center, Houston, Tx, USA
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] January 10, 2017
Statistical Analysis Plan  [PDF] July 7, 2016

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02151981    
Other Study ID Numbers: D5160C00003
2014-000594-39 ( EudraCT Number )
First Posted: June 2, 2014    Key Record Dates
Results First Posted: July 21, 2017
Last Update Posted: September 13, 2023
Last Verified: September 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Keywords provided by AstraZeneca:
Advanced Non-Small Cell Lung Cancer; T790M Mutation Positive
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
 Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents