TriangleNCT04035486 · CITED IN SOURCE DOCUMENTS
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)
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- ACTIVE NOT RECRUITING
- Registry last update
- 2026-09-03
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.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only)
Progression-free Survival (PFS) (Randomized Component)
Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component)
Overall Survival (OS) (Safety Run-In Treatment Arms Only)
Duration of Response (DoR) (Safety Run-In Treatment Arms Only)
Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only)
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only)
Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only)
Overall Survival (OS) (Randomized Component)
Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component)
Objective Response Rate (ORR) (Randomized Component)
Duration of Response (DoR) (Randomized Component)
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component)
Disease Control Rate (DCR) by Investigator (Randomized Component)
Progression Free Survival 2 (PFS2) (Randomized Component)
Time to First Subsequent Therapy (TFST) or Death (Randomized Component)
Time to Second Subsequent Therapy (TSST) or Death (Randomized Component)
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)
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)
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)
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)
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)
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)
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component)
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component)
Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component)
Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component)
Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component)
Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component)
Mean AUCss of Osimertinib (Randomized Component)
Mean AUCss of AZ5104 (Randomized Component)
Mean CLss/F of Osimertinib (Randomized Component)
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- 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).
- healthy Volunteers
- false
- maximum Age
- 110 Years
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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.
- intervention Names
- Drug: Osimertinib
- label
- Osimertinib 80mg QD
- type
- ACTIVE_COMPARATOR
- description
- 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.
- intervention Names
- Drug: Pemetrexed/Carboplatin
- Drug: Pemetrexed/Cisplatin
- label
- Osimertinib 80 mg QD and platinum-based chemotherapy
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Osimertinib 80mg QD
- description
- Drug: Osimertinib (Oral) Other Names: AZD9291
- name
- Osimertinib
- other Names
- AZD9291
- type
- DRUG
- arm Group Labels
- Osimertinib 80 mg QD and platinum-based chemotherapy
- description
- 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.
- name
- Pemetrexed/Carboplatin
- type
- DRUG
- arm Group Labels
- Osimertinib 80 mg QD and platinum-based chemotherapy
- description
- 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.
- name
- Pemetrexed/Cisplatin
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- intervention Model Description
- Parallel Assignment
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 587
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- measure
- Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only)
- time Frame
- From first dose date to 28 days following last dose, up to 45 months
- description
- 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.
- measure
- Progression-free Survival (PFS) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.3 months)
- description
- 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.
- measure
- Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.2 months).
- secondary Outcomes
- description
- 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.
- measure
- Overall Survival (OS) (Safety Run-In Treatment Arms Only)
- time Frame
- Up to 45 months (maximum follow up 44.6 months)
- description
- 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.
- measure
- Duration of Response (DoR) (Safety Run-In Treatment Arms Only)
- time Frame
- Up to 45 months
- description
- 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.
- measure
- Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only)
- time Frame
- Up to 45 months
- description
- 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.
- measure
- Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only)
- time Frame
- Up to 45 months
- description
- 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.
- measure
- Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only)
- time Frame
- Up to 45 months
- description
- 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.
- measure
- Overall Survival (OS) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
- description
- 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.
- measure
- Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
- description
- 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).
- measure
- Objective Response Rate (ORR) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized.
- description
- 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.
- measure
- Duration of Response (DoR) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized.
- description
- 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.
- measure
- Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized.
- description
- 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).
- measure
- Disease Control Rate (DCR) by Investigator (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized.
- description
- 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.
- measure
- Progression Free Survival 2 (PFS2) (Randomized Component)
- time Frame
- Up to approximately 33 months after the first patient is randomized.
Full study description
- brief Summary
- 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.
Source references
- references
- citation
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- pmid
- 33199228
- type
- DERIVED
- see Also Links
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Source notices and limitations
Discovery and provenance
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- e efficacy of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was demonstrated in a randomized, multicenter, open-label trial (FLAURA2 [NCT04035486]) in patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive locally advanced or metastatic NSCLC, who had not received previous systemic treatm
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Preserved source evidence · Not medical advice