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)

Study Overview
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Brief Summary
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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.

Official Title
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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).

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Pemetrexed/Carboplatin
* Drug: Pemetrexed/Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, at least 18 years of age; patients from Japan at least 20 years of age. Pathologically confirmed non-squamous Non-Small Cell Lung Cancer (NSCLC). NSCLC of mixed histology is allowed. 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. 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. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. WHO PS of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks. Life expectancy >12 weeks at Day 1. Willing to use contraception as appropriate during the study and for a period of time after discontinuing study treatment. Exclusion Criteria: 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 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. 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. QT prolongation or any clinically important abnormalities in rhythm. 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) 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. 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. Prior treatment with an Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). 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. 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). 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Osimertinib 80mg QD<br>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<br>* Drug: Osimertinib (Oral) Other Names: AZD9291<br>* Other names: AZD9291;|
| Experimental: Osimertinib 80 mg QD and platinum-based chemotherapy<br>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<br>* 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.<br>Drug: Pemetrexed/Cisplatin<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Primary endpoint revised to: Progression-free survival (PFS) using Investigator assessment as defined by RECIST 1.1. 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 . An additional sensitivity analysis will be performed for PFS by BICR assessment. | The primary analysis of Progression-free survival (PFS) based on investigator assessment will occur when PFS maturity is observed at approximately 33 months after the first patient is randomized. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from the date of randomization until death due to any cause. | Overall Survival will be analyzed at 2 time points: when PFS maturity is observed at approximately 33 months after the first patient is randomized, and when OS maturity is observed at approximately 70 months after the first patient is randomized | 
| Landmark Overall Survival (LOS) | Landmark Overall Survival at 1, 2, and 3 years will look at the number of patients alive at 1, 2 and 3 year time points. | The analysis of Landmark Overall Survival will be conducted at 2 time points: when PFS maturity is observed at approximately 33 months, and when Overall Survival maturity is observed at approximately 70 months after the first patient is randomized. | 
| Objective Response Rate (ORR) | 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, will be included in the assessment of Objective Response Rate | Objective Response Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Duration of Response (DoR) | Duration of Response is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. | Duration of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Depth of Response | Depth of response (ie. tumor shrinkage / change in tumor size) by Investigator is defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) target lesions at the nadir in the absence of New Lesions (NLs) or progression of Non-Target Lesions when compared to baseline. | Depth of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Disease Control Rate (DCR) by Investigator | 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. | Disease Control Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Progression Free Survival 2 (PFS2) | 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. | Progression Free Survival 2 analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Change from baseline and time to deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30) | Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib. | European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Change from baseline and time to deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items (EORTC QLQ-LC13) | Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib. | European Organization for Research & Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized | 
| Concordance of epidermal growth factor receptor mutation status between the local epidermal growth factor receptor mutation test and the central cobas® epidermal growth factor receptor Mutation Test v2 results from tumor samples with evaluable results | Compare the local epidermal growth factor receptor mutation test result used for patient selection with the retrospective central cobas® epidermal growth factor receptor Mutation Test v2 results from baseline tumor samples. | Analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Progression-free survival (PFS) by Investigator by plasma epidermal growth factor receptor mutation status. | Determine efficacy of osimertinib monotherapy vs. osimertinib combined with chemotherapy based on the cobas® epidermal growth factor receptor mutation Test v2 plasma screening test result for Exon 19 deletions or Exon 21 (L858R) epidermal growth factor receptor mutations. | Analysis will occur when Progression-free survival (PFS)maturity is observed at approximately 33 months from the first patient being randomized. | 
| Plasma concentration of osimertinib when given with or without chemotherapy | An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose. | Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 
| Plasma concentration of metabolite AZ5104 when osimertinib is given with or without chemotherapy | An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose. | Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally, Advanced, Metastatic, Carcinoma, Non-Small Cell Lung Cancer, Osimertinib, Tagrisso