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)

Non-Small Cell Lung Cancer Clinical Trial

— FLAURA2  

Official title:

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).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04035486
• Other study ID #: D5169C00001
• Secondary ID: 2019-000650-61
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 2, 2019
• Est. completion date: June 3, 2026

Study information

• Verified date: February 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 587
• Est. completion date: June 3, 2026
• Est. primary completion date: April 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 110 Years

Eligibility

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).

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Osimertinib
Drug: Osimertinib (Oral) Other Names: AZD9291
• 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.
• 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.

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Caba
Argentina	Research Site	Ciudad de Buenos Aires
Argentina	Research Site	Cordoba
Argentina	Research Site	Santa Fe
Australia	Research Site	Camperdown
Australia	Research Site	Chermside
Australia	Research Site	Elizabeth Vale
Australia	Research Site	Heidelberg
Australia	Research Site	Kogarah
Australia	Research Site	Melbourne
Brazil	Research Site	Barretos
Brazil	Research Site	Florianópolis
Brazil	Research Site	Londrina
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	São José do Rio Preto
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	Vitoria
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Toronto	Ontario
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Temuco
Chile	Research Site	Viña del Mar
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Changchun
China	Research Site	Changsha
China	Research Site	Chengdu
China	Research Site	Chongqing
China	Research Site	Guangzhou
China	Research Site	Haikou
China	Research Site	Hangzhou
China	Research Site	Hangzhou
China	Research Site	Harbin
China	Research Site	Hefei
China	Research Site	Jinan
China	Research Site	Nanjing
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shenyang
China	Research Site	Urumqi
China	Research Site	Wuhan
China	Research Site	Xi'an
China	Research Site	Zhengzhou
Czechia	Research Site	Olomouc
Czechia	Research Site	Ostrava - Vitkovice
Czechia	Research Site	Praha
Czechia	Research Site	Praha 5
France	Research Site	Bordeaux Cedex
France	Research Site	Lyon
France	Research Site	Montpellier
France	Research Site	Villejuif Cedex
India	Research Site	Belagavi
India	Research Site	Bengaluru
India	Research Site	Gurgaon
India	Research Site	Kolkata
India	Research Site	New Delhi
India	Research Site	Pune
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Fukuoka
Japan	Research Site	Hidaka-shi
Japan	Research Site	Himeji-shi
Japan	Research Site	Iwakuni-shi
Japan	Research Site	Kanazawa
Japan	Research Site	Kashiwa
Japan	Research Site	Koto-ku
Japan	Research Site	Osaka-shi
Japan	Research Site	Sakai-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sendai-shi
Japan	Research Site	Sunto-gun
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Cheongju-si
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Peru	Research Site	Arequipa
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	San Isidro
Philippines	Research Site	Cebu City
Philippines	Research Site	Davao City
Philippines	Research Site	Iloilo City
Philippines	Research Site	Las Pinas
Philippines	Research Site	Legazpi City
Philippines	Research Site	Quezon City
Philippines	Research Site	Quezon City
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Murmansk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Syktyvkar
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Kosice
Slovakia	Research Site	Poprad
South Africa	Research Site	Johannesburg
South Africa	Research Site	Port Elizabeth
South Africa	Research Site	Rondebosch
Taiwan	Research Site	Changhua
Taiwan	Research Site	Hualien City
Taiwan	Research Site	Kaohsiung City
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Hat Yai
Thailand	Research Site	Khon Kaen
Thailand	Research Site	Muang
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	Maidstone
United Kingdom	Research Site	Manchester
United States	Research Site	Albany	New York
United States	Research Site	Bellflower	California
United States	Research Site	Blacksburg	Virginia
United States	Research Site	Boston	Massachusetts
United States	Research Site	Canton	Ohio
United States	Research Site	Fairfax	Virginia
United States	Research Site	Fullerton	California
United States	Research Site	Henderson	Nevada
United States	Research Site	Houston	Texas
United States	Research Site	Kansas City	Kansas
United States	Research Site	La Jolla	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Orlando	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	San Antonio	Texas
United States	Research Site	Santa Monica	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Tampa	Florida
United States	Research Site	Vancouver	Washington
United States	Research Site	West Hollywood	California
United States	Research Site	Whittier	California
Vietnam	Research Site	Hanoi
Vietnam	Research Site	Ho Chi Minh

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Vietnam,  Argentina,  Australia,  Brazil,  Canada,  Chile,  China,  Czechia,  France,  India,  Japan,  Korea, Republic of,  Peru,  Philippines,  Russian Federation,  Slovakia,  South Africa,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.