A Study of Osimertinib With or Without Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (FLAURA2) (FLAURA2)

A Phase III, Open-label, Randomized Study of Osimertinib With or Without Platinum Plus Pemetrexed Chemo, as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2).

The reason for the study is to find out if an experimental combination of an oral medication called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective than giving osimertinib alone for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for their patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR).

Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the benefit observed for patients treated with osimertinib, the vast majority of cancers are expected to develop resistance to the drug over time. The exact reasons why resistance develops are not fully understood but based upon clinical research it is hoped that combining osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the onset of resistance and the worsening of a patient's cancer.

In total the study aims to enroll approximately 586 patients, consisting of approximately 30 patients who will participate in a safety run-in component of the trial, and approximately 556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the main trial. In the main part of the trial there is a one in two chance of receiving osimertinib alone, and the treatment is decided at random by a computer.

The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst receiving study medication, it is expected patients will attend, on average, approximately 15 visits over the first 12 months and then approximately 4 visits per year afterwards. Each visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the study centre.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Osimertinib; Drug: Pemetrexed/Carboplatin; Drug: Pemetrexed/Cisplatin

• Study Type: Interventional
• Enrollment (Actual): 587
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1056ABJ
    • Research Site
  • Buenos Aires, Argentina, C1125ABD
    • Research Site
  • CABA, Argentina, C1012AAR
    • Research Site
  • CABA, Argentina, C1019ABS
    • Research Site
  • Ciudad de Buenos Aires, Argentina, 1280
    • Research Site
  • Córdoba, Argentina, 5001
    • Research Site
  • Santa Fe, Argentina, 2000
    • Research Site
• Australia
  • Camperdown, Australia, 2050
    • Research Site
  • Chermside, Australia, 4032
    • Research Site
  • Elizabeth Vale, Australia, 5112
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  • Heidelberg, Australia, 3084
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  • Kogarah, Australia, 2217
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  • Melbourne, Australia, 3000
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• Brazil
  • Barretos, Brazil, 14784-400
    • Research Site
  • Florianópolis, Brazil, 88034-000
    • Research Site
  • Londrina, Brazil, 86015-520
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  • Porto Alegre, Brazil, 91350-200
    • Research Site
  • Ribeirão Preto, Brazil, 14021-636
    • Research Site
  • São José do Rio Preto, Brazil, 15090-000
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  • São Paulo, Brazil, 01246-000
    • Research Site
  • São Paulo, Brazil, 04029-000
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  • Vitória, Brazil, 29043-260
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• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 5G2
      • Research Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
• Chile
  • Santiago, Chile, 7500713
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  • Santiago, Chile, 8420383
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  • Temuco, Chile, 4810469
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  • Viña del Mar, Chile, 2540488
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• China
  • Beijing, China, 100142
    • Research Site
  • Beijing, China, 100853
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  • Beijing, China, 100191
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  • Changchun, China, 130000
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  • Changsha, China, 410013
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  • Chengdu, China, 610041
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  • Chongqing, China, 400030
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  • Guangzhou, China, 510515
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  • Haikou, China, 570312
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  • Hangzhou, China, 310022
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  • Hangzhou, China, 310003
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  • Harbin, China, 150081
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  • Hefei, China, 230001
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  • Jinan, China, 250001
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  • Nanjing, China, 210009
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  • Shanghai, China, 200032
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  • Shanghai, China, 200030
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  • Shenyang, China, 110001
    • Research Site
  • Wuhan, China, 430030
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  • Xi'an, China, 710061
    • Research Site
  • Zhengzhou, China, 450008
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  • Ürümqi, China, 830000
    • Research Site
• Czechia
  • Olomouc, Czechia, 775 21
    • Research Site
  • Ostrava - Vitkovice, Czechia, 703 84
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  • Prague, Czechia, 150 06
    • Research Site
  • Prague, Czechia, 140 59
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• France
  • Bordeaux, France, 33075
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  • Lyon, France, 69373
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  • Montpellier, France, 34298
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  • Villejuif, France, 94805
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• India
  • Belagavi, India, 590010
    • Research Site
  • Bengaluru, India, 560027
    • Research Site
  • Gūrgaon, India, 122001
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  • Kolkata, India, 700160
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  • New Delhi, India, 110 085
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  • Pune, India, 411004
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• Japan
  • Bunkyō City, Japan, 113-8431
    • Research Site
  • Bunkyō City, Japan, 113-8603
    • Research Site
  • Fukuoka, Japan, 812-8582
    • Research Site
  • Hidaka-shi, Japan, 350-1298
    • Research Site
  • Himeji-shi, Japan, 670-8520
    • Research Site
  • Iwakuni-shi, Japan, 740-8510
    • Research Site
  • Kanazawa, Japan, 920-8641
    • Research Site
  • Kashiwa, Japan, 227-8577
    • Research Site
  • Kōtoku, Japan, 135-8550
    • Research Site
  • Osaka, Japan, 541-8567
    • Research Site
  • Sakaishi, Japan, 591-8555
    • Research Site
  • Sapporo, Japan, 003-0804
    • Research Site
  • Sendai, Japan, 981-0914
    • Research Site
  • Sunto-gun, Japan, 411-8777
    • Research Site
  • Yokohama, Japan, 241-8515
    • Research Site
• Peru
  • Arequipa, Peru, AREQUIPA01
    • Research Site
  • Lima, Peru, LIMA 34
    • Research Site
  • Lima, Peru, Lima 32
    • Research Site
  • Lima, Peru, 15036
    • Research Site
  • San Isidro, Peru, 27
    • Research Site
• Philippines
  • Cebu City, Philippines, 6000
    • Research Site
  • Davao City, Philippines, 8000
    • Research Site
  • Iloilo City, Philippines, 5000
    • Research Site
  • Las Piñas, Philippines, 1740
    • Research Site
  • Legaspi, Philippines, 4500
    • Research Site
  • Quezon City, Philippines, 1112
    • Research Site
  • Quezon City, Philippines, 1100
    • Research Site
• Russia
  • Moscow, Russia, 115478
    • Research Site
  • Moscow, Russia, 143423
    • Research Site
  • Murmansk, Russia, 183047
    • Research Site
  • Saint Petersburg, Russia, 197758
    • Research Site
  • Saint Petersburg, Russia, 198255
    • Research Site
  • Saint Petersburg, Russia, 194356
    • Research Site
  • Syktyvkar, Russia, 167904
    • Research Site
• Slovakia
  • Bratislava, Slovakia, 82606
    • Research Site
  • Košice, Slovakia, 041 91
    • Research Site
  • Poprad, Slovakia, 05801
    • Research Site
• South Africa
  • Johannesburg, South Africa, 2196
    • Research Site
  • Port Elizabeth, South Africa, 6045
    • Research Site
  • Rondebosch, South Africa, 7700
    • Research Site
• South Korea
  • Cheongju-si, South Korea, 28644
    • Research Site
  • Goyang-si, South Korea, 10408
    • Research Site
  • Seoul, South Korea, 03080
    • Research Site
  • Seoul, South Korea, 05505
    • Research Site
  • Seoul, South Korea, 06351
    • Research Site
• Taiwan
  • Changhua, Taiwan, 500
    • Research Site
  • Hualien City, Taiwan, 97002
    • Research Site
  • Kaohsiung City, Taiwan, 00807
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 40447
    • Research Site
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei, Taiwan, 23561
    • Research Site
• Thailand
  • Bangkok, Thailand, 10210
    • Research Site
  • Bangkok, Thailand, 10330
    • Research Site
  • Bangkok, Thailand, 10400
    • Research Site
  • Hat Yai, Thailand, 90110
    • Research Site
  • Khon Kaen, Thailand, 40002
    • Research Site
  • Muang, Thailand, 50200
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Research Site
  • Leicester, United Kingdom, LE1 5WW
    • Research Site
  • Liverpool, United Kingdom, L7 8YA
    • Research Site
  • Maidstone, United Kingdom, ME16 9QQ
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
• United States
  • California
    • Bellflower, California, United States, 90706
      • Research Site
    • Fullerton, California, United States, 92835
      • Research Site
    • La Jolla, California, United States, 92093
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
    • Santa Rosa, California, United States, 95403
      • Research Site
    • West Hollywood, California, United States, 90048
      • Research Site
    • Whittier, California, United States, 90602
      • Research Site
  • Florida
    • Orlando, Florida, United States, 32804
      • Research Site
    • Tampa, Florida, United States, 33612
      • Research Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Nevada
    • Henderson, Nevada, United States, 89074
      • Research Site
  • New York
    • Albany, New York, United States, 12208
      • Research Site
  • Ohio
    • Canton, Ohio, United States, 44710
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15212
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • Texas
    • Houston, Texas, United States, 77090
      • Research Site
    • San Antonio, Texas, United States, 78240
      • Research Site
  • Virginia
    • Blacksburg, Virginia, United States, 24060
      • Research Site
    • Fairfax, Virginia, United States, 22031
      • Research Site
  • Washington
    • Vancouver, Washington, United States, 98684
      • Research Site
• Vietnam
  • Hanoi, Vietnam, 100000
    • Research Site
  • Ho Chi Minh City, Vietnam, 70000
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, at least 18 years of age; patients from Japan at least 20 years of age.
2. Pathologically confirmed non-squamous Non-Small Cell Lung Cancer (NSCLC). NSCLC of mixed histology is allowed.
3. Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic Non-Small Cell Lung Cancer (NSCLC) (clinical stage IVA or IVB) or recurrent Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy.
4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M.
5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy.
6. WHO PS of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks.
7. Life expectancy >12 weeks at Day 1.
8. Willing to use contraception as appropriate during the study and for a period of time after discontinuing study treatment.

Exclusion Criteria:

1. Spinal cord compression; and unstable brain metastases, with stable brain metastases who have completed definitive therapy, are not on steroids, and have a stable neurological status for at least 2 weeks after completion of the definitive therapy and steroids can be enrolled. Patients with asymptomatic brain metastases can be eligible for inclusion if in the opinion of the Investigator immediate definitive treatment is not indicated
2. Past medical history of Interstitial Lung Disease (ILD), drug-induced Interstitial Lung Disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active Interstitial Lung Disease.
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including Hep. B, Hep. C and HIV. Screening for chronic conditions is not required. Active infection will include any patients receiving treatment for infection.
4. QT prolongation or any clinically important abnormalities in rhythm.

5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   • Absolute neutrophil count below the lower limit of normal (<LLN)
   • Platelet count below the LLN
   • Hemoglobin <90 g/L. The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
   • ALT >2.5 x the upper limit of normal (ULN) if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases
   • AST >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases
   • Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases
   • Creatinine clearance <60 mL/min calculated by Cockcroft and Gault equation or 24 hour urine collection (refer to Appendix I for appropriate calculation)
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 osimertinib.
7. Prior treatment with any systemic anti-cancer therapy for advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiation including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapies, investigational agents are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease.
8. Prior treatment with an Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI).
9. Major surgery within 4 weeks of the first dose of investigational product (IP). Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery are permitted.
10. Radiotherapy treatment to more than 30% of the bone marrow or( with a wide field of radiation within 4 weeks of the first dose of investigational product (IP).
11. History of hypersensitivity to active or inactive excipients of investigational product (IP) or drugs with a similar chemical structure or class to investigational product (IP).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Osimertinib 80mg QD; Osimertinib (AZD9291) 80mg QD. All patients randomized into this will only receive Osimertinib 80mg. Dose may be reduced to allow for the management of IP related toxicity.	Drug: Osimertinib; Drug: Osimertinib (Oral) Other Names: AZD9291; Other Names: AZD9291
Experimental: Osimertinib 80 mg QD and platinum-based chemotherapy; Osimertinib 80 mg in combination with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of 21day cycles (every 3 weeks) for 4 cycles, followed by Osimertinib daily with pemetrexed maintenance (500 mg/m2) every 3 weeks. Dose may be reduced to allow for the management of IP related toxicity.	Drug: Pemetrexed/Carboplatin; Drug: Pemetrexed (500 mg/m2) plus carboplatin (AUC5) on Day 1 of 21day cycles (every 3 weeks) for 4 cycles, followed by Osimertinib daily with pemetrexed maintenance (500 mg/m2) every 3 weeks.; Drug: Pemetrexed/Cisplatin; Drug: Pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on Day 1 of 21day cycles (every 3 weeks) for 4 cycles, followed by Osimertinib daily with pemetrexed maintenance (500 mg/m2) every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only)	Adverse events were summarized by maximum reported Common Terminology Criteria for Adverse Event (CTCAE) grade, version 5.0. Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 (Severe or medically significant but not immediately life-threatening): hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 (Life-threatening consequences): urgent intervention indicated. Grade 5: Death related to AE. Includes adverse events with onset date on or after the date of first dose and up to and including 28 days following discontinuation of treatment but prior to the start of a new anti-cancer therapy.	From first dose date to 28 days following last dose, up to 45 months
Progression-free Survival (PFS) (Randomized Component)	Progression-free survival (PFS) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients.	Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.3 months)
Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component)	Sensitivity analysis for progression-free survival (PFS) by blinded independent central review (BICR) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients.	Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.2 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) (Safety Run-In Treatment Arms Only)	Overall survival is defined as the time from the date of first dose until death due to any causes. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall survival calculated using the Kaplan-Meier method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.	Up to 45 months (maximum follow up 44.6 months)
Duration of Response (DoR) (Safety Run-In Treatment Arms Only)	Duration of response (DoR) is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression (i.e. date of progression free survival event or censoring - date of first response + 1). The end of response should coincide with the date of progression or death from any cause used for the progression free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first visit that was Complete response or Partial response that was subsequently confirmed. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.	Up to 45 months
Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only)	Confirmed objective response rate (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of subjects with at least 1 visit response of Completed Response (CR) or Partial Response (PR), where each CR or PR must be subsequently confirmed at least 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. Confidence Interval is calculated using the exact Clopper-Pearson method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.	Up to 45 months
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only)	Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.	Up to 45 months
Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only)	Disease control rate is defined as the percentage of subjects who have a best overall response of Complete response (CR) or Partial response (PR) or Stable disease (SD) by RECIST 1.1 as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the first dose. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.	Up to 45 months
Overall Survival (OS) (Randomized Component)	Overall survival is defined as the time from the date of randomization until death due to any cause. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall Survival calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component)	Landmark Overall Survival at 1, 2, and 3 years looks at the percent of patients alive at 1, 2 and 3 year time points. Overall survival at 36 months not included to data cut off prior to 36-month timepoint. Overall survival percentage calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
Objective Response Rate (ORR) (Randomized Component)	Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of Complete Response or Partial Response. Data obtained up until progression, or the last evaluable assessment in the absence of progression, was included in the assessment of Objective Response Rate. The investigator-assessed ORR was summarized with a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).	Up to approximately 33 months after the first patient is randomized.
Duration of Response (DoR) (Randomized Component)	The duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. The end of response should coincide with the date of progression or death from any cause used for the progression-free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first response of Partial response or Complete response. Median values of the duration of response, along with two-sided 95% CI in each treatment group were computed using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component)	Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast.	Up to approximately 33 months after the first patient is randomized.
Disease Control Rate (DCR) by Investigator (Randomized Component)	Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the randomization. The adjusted disease control rate was calculated using a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).	Up to approximately 33 months after the first patient is randomized.
Progression Free Survival 2 (PFS2) (Randomized Component)	Progression Free Survival 2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary Progression Free Survival (PFS), or death in absence of a first or second progression. The second progression event must have occurred after subsequent treatment administered after the initial progression free survival event. Any participant that was lost to follow-up, withdrew consent or discontinued for other reasons at the time of the analysis were censored at the last evaluable progression assessment. Median second progression free survival (months) calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Time to First Subsequent Therapy (TFST) or Death (Randomized Component)	Time to first subsequent therapy (TFST) or death is defined as the time from the date of randomization to the earlier of the date of anti- cancer therapy start date following IP discontinuation or death. Any patient not known to have had a subsequent therapy or not known to have died at the time of the analysis were censored at the last known time to have not received subsequent therapy; i.e., the last follow-up visit where this was confirmed. Median time to first subsequent therapy or death calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Time to Second Subsequent Therapy (TSST) or Death (Randomized Component)	Time to second subsequent therapy (TSST) or death is defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following IP discontinuation or death. Any patient not known to have died at the time of the analysis and not known to have had a second subsequent therapy will be censored at the last known time to have not received second subsequent therapy, i.e., the last follow-up visit where this was confirmed. If a patient terminated the study for reason other than death before second subsequent therapy, these patients will be censored at the earliest of their last known to be alive and termination dates. Median time to second subsequent therapy or death calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)	QLQ-C30 has 30 questions and scores range from 0-100 after a linear transformation. Questions are combined to produce symptom scales, individual symptom items, functional scales, and global health status (GHS)/quality of life (QoL). Positive change from baseline scores on the GHS/QoL and functioning scales indicate improvement on health status/function, and negative change scores on symptom scales/items represent less symptom severity/improvement on symptom status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (random effect), treatment, visit (fixed effect & repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction.	Up to approximately 33 months after the first patient is randomized.
Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)	The EORTC QLQ-C30 consists of 30 questions that are combined to produce 3 symptom scales (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, insomnia, appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, cognitive, emotional, and social), and a global measure of health status/QoL. Scores range from 0-100 after a linear transformation. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)	EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. While the QLQ-LC13 includes more scales, only the Coughing, Pain in chest, and Dyspnea subscale scores were analyzed for this endpoint. Negative change from baseline scores indicates less symptom severity, and thus improvement on health status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (as a random effect), treatment, visit (as fixed effect and repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction.	Up to approximately 33 months after the first patient is randomized.
Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)	EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method.	Up to approximately 33 months after the first patient is randomized.
Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component)	Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with EXON 19 Deletion, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis.	Screening/Baseline
Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component)	Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with L858R, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis.	Screening/Baseline
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component)	PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.	Up to approximately 33 months after the first patient is randomized.
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component)	PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.	Up to approximately 33 months after the first patient is randomized.
Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component)	An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose.	Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component)	An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose.	Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component)	Cmin,ss is the minimum plasma concentration of Osimertinib at steady state. Cmax,ss is the maximum plasma concentration of Osimertinib at steady state.	Up to approximately 33 months after the first patient is randomized.
Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component)	Cmin,ss is the minimum plasma concentration of AZ5104 at steady state. Cmax,ss is the maximum plasma concentration of AZ5104 at steady state.	Up to approximately 33 months after the first patient is randomized.
Mean AUCss of Osimertinib (Randomized Component)	AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state.	Up to approximately 33 months after the first patient is randomized.
Mean AUCss of AZ5104 (Randomized Component)	AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state.	Up to approximately 33 months after the first patient is randomized.
Mean CLss/F of Osimertinib (Randomized Component)	CLss/F is the apparent plasma clearance at steady state.	Up to approximately 33 months after the first patient is randomized.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Pasi A. Jänne, MD, Dana Farber Cancer Institute, 450 Brookline Avenue, LC4114, Boston, MA 02215, USA; Principal Investigator: Kunihiko Kobayashi, MD, Department of Respiratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan; Principal Investigator: David Planchard, MD, Department of Medical Oncology - Institut Gustave Roussy (IGR) - Villejuif - France

Publications and helpful links

General Publications

• Planchard D, Feng PH, Karaseva N, Kim SW, Kim TM, Lee CK, Poltoratskiy A, Yanagitani N, Marshall R, Huang X, Howarth P, Janne PA, Kobayashi K. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open. 2021 Oct;6(5):100271. doi: 10.1016/j.esmoop.2021.100271. Epub 2021 Sep 17.
• White MN, Piotrowska Z, Stirling K, Liu SV, Banwait MK, Cunanan K, Sequist LV, Wakelee HA, Hausrath D, Neal JW. Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression. Clin Lung Cancer. 2021 May;22(3):201-209. doi: 10.1016/j.cllc.2021.01.010. Epub 2021 Jan 27.
• Asahina H, Tanaka K, Morita S, Maemondo M, Seike M, Okamoto I, Oizumi S, Kagamu H, Takahashi K, Kikuchi T, Isobe T, Sugio K, Kobayashi K. A Phase II Study of Osimertinib Combined With Platinum Plus Pemetrexed in Patients With EGFR-Mutated Advanced Non-Small-cell Lung Cancer: The OPAL Study (NEJ032C/LOGIK1801). Clin Lung Cancer. 2021 Mar;22(2):147-151. doi: 10.1016/j.cllc.2020.09.023. Epub 2020 Oct 16.
• Murat-Onana ML, Ramalingam SS, Janne PA, Gray JE, Ahn MJ, John T, Yatabe Y, Huang X, Rukazenkov Y, Javey M, Brown H, Li-Sucholeiki X. EGFR mutation testing across the osimertinib clinical program. Lung Cancer. 2025 Jun;204:108549. doi: 10.1016/j.lungcan.2025.108549. Epub 2025 Apr 18.
• Janne PA, Planchard D, Kobayashi K, Cheng Y, Lee CK, Valdiviezo N, Laktionov K, Yang TY, Yu Y, Kato T, Jiang L, Chewaskulyong B, Lucien Geater S, Maurel JM, Rojas C, Takahashi T, Havel L, Shepherd FA, Tanaka K, Ghiorghiu D, Amin NP, Armenteros-Monterroso E, Huang X, Chaudhry AA, Yang JC. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2024 Mar 1;42(7):808-820. doi: 10.1200/JCO.23.02219. Epub 2023 Dec 2.
• Planchard D, Janne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. doi: 10.1056/NEJMoa2306434. Epub 2023 Nov 8.

Helpful Links

• CSP_Redacted
• SAP_Redacted
• CSR_Synopsis_Redacted

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2019
• Primary Completion (Actual): April 3, 2023
• Study Completion (Estimated): December 22, 2026

Study Registration Dates

• First Submitted: June 27, 2019
• First Submitted That Met QC Criteria: July 25, 2019
• First Posted (Actual): July 29, 2019

Study Record Updates

• Last Update Posted (Estimated): October 10, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Non-Small Cell Lung Cancer; Carcinoma; Locally; Advanced; Metastatic; Osimertinib; Tagrisso
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Carcinoma; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Platinum Compounds; Pemetrexed; Carboplatin; Cisplatin; osimertinib
• Other Study ID Numbers: D5169C00001; 2019-000650-61 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

IPD Sharing 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.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No