AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy. (ADAURA)

• ClinicalTrials.gov Identifier: NCT02511106
• Recruitment Status: Active, not recruiting
• First Posted: July 29, 2015
• Results First Posted: July 27, 2021
• Last Update Posted: July 27, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: July 28, 2015
• First Posted Date: July 29, 2015
• Results First Submitted Date: January 15, 2021
• Results First Posted Date: July 27, 2021
• Last Update Posted Date: July 27, 2023
• Actual Study Start Date: October 21, 2015
• Actual Primary Completion Date: January 17, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2021)

Assess the Efficacy of AZD9291 Compared to Placebo as Measured by Disease Free Survival (DFS). [ Time Frame: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence), up to approximately 4 years. ]

Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Original Primary Outcome Measures (submitted: July 28, 2015)

Disease free survival (DFS) [ Time Frame: From date of randomization until date of disease recurrence (estimated median 46 months) ]

Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Current Secondary Outcome Measures (submitted: July 6, 2021)

• Disease Free Survival (DFS) Rate at 2, 3 and 5 Years [ Time Frame: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence), up to approximately 4 years. Assessed at 2 years and 3 years. ]
  Defined as the percentage of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis
• Overall Survival (OS) [ Time Frame: From date of randomization until date of death due to any cause, up to approximately 4 years. ]
  Defined as the time from the date of randomization until date of death due to any cause.
• Overall Survival (OS) [ Time Frame: From date of randomization until date of death due to any cause, up to approximately 4 years. ]
  Defined as the time from the date of randomization until date of death due to any cause
• Overall Survival Rate at 2, 3 and 5 Years [ Time Frame: From date of randomization until date of death due to any cause, up to approximately 4 years. Assessed at 2 years and 3 years. ]
  Defined as the percentage of patients alive at 2, 3 and 5 years, respectively, estimated from a Kaplan Meier plot of OS at the time of the primary analysis
• Patient Health-related Quality of Life and Symptoms (HRQoL) by SF-36v2 Health Survey. [ Time Frame: Measured by SF-36 Questionnaire at baseline, 12 week, 24 week and then every 24 weeks until study complete, disease recurrence or other discontinuation criteria met, up to approximately 3 years. ]
  Change from baseline will be calculated for each domain and summary scale at each scheduled post-baseline assessment. The SF-36 includes eight domains: Physical Functioning (PF); Role Limitations-Physical (RP), Vitality (VT), General Health Perceptions (GH), Bodily Pain (BP), Social Function (SF), Role Limitations-Emotional (RE), and Mental Health (MH) and two summary scores: The Physical Component Summary (PCS) and Mental Component Summary (MCS). Final scores for each scale range from 0-100 with higher scores indicating better health.
• Plasma Concentrations of AZD9291 [ Time Frame: Collected at pre-dose, 0.5-1.5hours and 2-4hours post-dose up to 96 weeks (approximately 24 months) ]
  The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291
• Plasma Concentrations of AZ5104 Metabolites [ Time Frame: From date of dosing to week 96 (approximately 24 months) ]
  The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 metabolites
• Plasma Concentrations of AZ7550 Metabolites [ Time Frame: From date of dosing to week 96 (approximately 24 months) ]
  The pharmacokinetics exposure parameters derived from plasma concentrations of AZ7550 metabolites

Original Secondary Outcome Measures (submitted: July 28, 2015)

• Disease free survival (DFS) rate at 2, 3 and 5 years [ Time Frame: From date of randomization until date of disease recurrence (estimated median 46 months) ]
  Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis
• Overall Survival (OS) [ Time Frame: From date of randomization until date of death (estimated median 96 months) ]
  Defined as the time from the date of randomization until date of death due to any cause
• Overall Survival rate at 5 years [ Time Frame: From date of randomization until date of death (estimated median 96 months) ]
  Defined as the proportion of patients alive at 5 years, estimated from a Kaplan Meier plot of OS at the time of the primary analysis
• Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey [ Time Frame: From date of randomization until treatment completion at 36 months (approximately 36 months) ]
  Measured by SF-36 Questionnaire consisting in 36 items that is an instrument for assessing a person's general health status over the past 28 days
• Plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550; and ratio of metabolite to AZD9291 [ Time Frame: From date of dosing to month 24 (approximately 24 months) ]
  The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: July 28, 2015)

Incidence of Adverse Events (AEs) [ Time Frame: From date of randomization until 28 days after treatment completion (approximately 37 months) ]

AEs graded by CTCAE version 4.0

Descriptive Information

• Brief Title: AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy.
• Official Title: A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).
• Brief Summary: To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy
• Detailed Description: This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) with centrally confirmed, most common sensitising EGFR mutations (Ex19Del and L858R) either alone or in combination with other EGFR mutations as confirmed by a central test, who have had complete tumour resection, with or without postoperative adjuvant chemotherapy. Adjuvant chemotherapy should have consisted of a platinum based doublet given for a maximum of 4 cycles.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Stage IB-IIIA Non-small Cell Lung Carcinoma

Intervention

• Drug: AZD9291 80 mg/40 mg
  The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily.
• Drug: Placebo AZD9291 80 mg/40 mg
  The initial dose of Placebo AZD9291 80 mg once daily can be reduced to 40 mg once daily.
• Drug: Open-label AZD9291 80 mg/40 mg
  Eligible patients will be offered open-label osimertinib upon recurrence and in the absence of intervening systemic anti-cancer therapy.

Study Arms

• Experimental: AZD9291
  AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule.
  Interventions:

  • Drug: AZD9291 80 mg/40 mg
  • Drug: Open-label AZD9291 80 mg/40 mg
• Placebo Comparator: Placebo AZD9291
  Matching placebo for AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule.
  Intervention: Drug: Placebo AZD9291 80 mg/40 mg

Publications *

• Herbst RS, Wu YL, Tsuboi M. Osimertinib in EGFR-Mutated Lung Cancer. Reply. N Engl J Med. 2021 Feb 18;384(7):675-676. doi: 10.1056/NEJMc2033951. No abstract available.
• Majem M, Goldman JW, John T, Grohe C, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Li S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Atagi S, Zeng L, Kulkarni D, Medic N, Tsuboi M, Herbst RS, Wu YL. Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial. Clin Cancer Res. 2022 Jun 1;28(11):2286-2296. doi: 10.1158/1078-0432.CCR-21-3530.
• Wu YL, John T, Grohe C, Majem M, Goldman JW, Kim SW, Kato T, Laktionov K, Vu HV, Wang Z, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Atasoy A, Herbst RS, Tsuboi M. Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC. J Thorac Oncol. 2022 Mar;17(3):423-433. doi: 10.1016/j.jtho.2021.10.014. Epub 2021 Nov 2.
• Wu YL, Tsuboi M, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS. A plain language summary of results from the ADAURA study: osimertinib after surgery for patients who have early-stage EGFR-mutated non-small cell lung cancer. Future Oncol. 2021 Dec 1;17(35):4827-4835. doi: 10.2217/fon-2021-0752. Epub 2021 Nov 1.
• Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS; ADAURA Investigators. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Oct 29;383(18):1711-1723. doi: 10.1056/NEJMoa2027071. Epub 2020 Sep 19.
• Wu YL, Herbst RS, Mann H, Rukazenkov Y, Marotti M, Tsuboi M. ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection. Clin Lung Cancer. 2018 Jul;19(4):e533-e536. doi: 10.1016/j.cllc.2018.04.004. Epub 2018 May 1.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 12, 2021): 682
• Original Estimated Enrollment (submitted: July 28, 2015): 700
• Estimated Study Completion Date: December 31, 2030
• Actual Primary Completion Date: January 17, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female, aged at least 18 years.
2. Histologically confirmed diagnosis of primary non small lung cancer (NSCLC) on predominantly non-squamous histology
3. MRI or CT scan of the brain must be done prior to surgery as it is considered standard of care.
4. Patients must be classified post-operatively as Stage IB, II or IIIA on the basis of pathologic criteria.
5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M.
6. Complete surgical resection of the primary NSCLC is mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour.
7. Complete recovery from surgery and standard post-operative therapy (if applicable) at the time of randomization.
8. World Health Organization Performance Status of 0 to 1.
9. Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-child-bearing potential.

Exclusion Criteria:

1. Treatment with any of the following:

   • Pre-operative or post-operative or planned radiation therapy for the current lung cancer
   • Pre-operative (neo-adjuvant) platinum based or other chemotherapy
   • Any prior anticancer therapy
   • Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time
   • Major surgery (including primary tumour surgery, excluding placement of vascular access) within 4 weeks of the first dose of study drug
   • Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4
   • Treatment with an investigational drug within five half-lives of the compound or any of its related material.
2. Patients who have had only segmentectomies or wedge resections
3. History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumours curatively treated with no evidence of disease for > 5 years following the end of treatment.
4. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
5. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
6. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291.

7. Any of the following cardiac criteria:

   • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
8. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
9. Inadequate bone marrow reserve or organ function.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, China, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Romania, Russian Federation, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United States, Vietnam
• Removed Location Countries: Norway

Administrative Information

• NCT Number: NCT02511106
• Other Study ID Numbers: D5164C00001; 2015-000662-65 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Supporting Materials: 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 deidentified 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

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: July 2023