Phase III Randomized Study of Osimertinib with or without Platinum-Based Chemotherapy in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer
- Trial ID
- 2023-508800-39-00
- Protocol
- D5169C00001 FLAURA2
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of osimertinib in combination with chemotherapy compared to osimertinib alone in patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) that is positive for Epidermal Growth Factor Receptor (EGFR) mutations. This evaluation is clinically relevant as it aims to determine whether the addition of chemotherapy to osimertinib can improve treatment outcomes in this patient population, potentially leading to enhanced therapeutic strategies.
Secondary objectives include:
- To further assess the efficacy of osimertinib plus chemotherapy compared with osimertinib alone, including post-progression scenarios.
- To evaluate disease-related symptoms and health-related quality of life (QoL) in patients treated with osimertinib plus chemotherapy versus osimertinib alone.
- To assess the pharmacokinetics (PK) of osimertinib when administered with or without chemotherapy.
- To compare local EGFR mutation test results used for patient selection with retrospective central cobas® EGFR Mutation Test v2 results from baseline tumor samples.
- To determine the efficacy of osimertinib monotherapy versus osimertinib combined with chemotherapy based on the cobas® EGFR Mutation Test v2 plasma screening test results for Exon 19 Deletions and L858R EGFR mutations.
Participants
The clinical trial involves a total of **517 participants** diagnosed with locally-advanced or metastatic **EGFRm** (Ex19del and/or L858R) Non-Small Cell Lung Cancer (NSCLC). The study population includes both male and female subjects, aged 18 years and older, with a specific age requirement of at least 20 years for participants from Japan. Participants were selected based on their pathologically confirmed nonsquamous NSCLC, with tumors harboring one of the two common EGFR mutations associated with EGFR-TKI sensitivity. The trial does not include a vulnerable population. Participants are required to have a World Health Organization Performance Status (WHO PS) of 0 to 1 at screening, indicating a generally good health status with no significant deterioration in the previous two weeks. Lifestyle considerations such as diet and physical activity are not specified, but female participants who are not abstinent must use highly effective contraceptive measures. The trial excludes individuals with previously treated advanced NSCLC that is amenable to curative surgery or radiotherapy, ensuring that only those with untreated advanced NSCLC are included. The sponsor has not provided additional information regarding specific lifestyle factors or habits of the participants.
Plans and Procedures
The clinical trial is a **Phase III**, open-label, randomized study designed to evaluate the efficacy of **osimertinib** with or without platinum-based chemotherapy, specifically **carboplatin**, **cisplatin**, and **pemetrexed**, as a first-line treatment for patients with locally advanced or metastatic **non-small cell lung cancer** (NSCLC) harboring specific **EGFR** mutations. The trial aims to compare progression-free survival (PFS) and overall survival (OS) between the treatment groups. The study is expected to commence recruitment on May 23, 2024, and conclude by June 3, 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a WHO performance status of 0 to 1, a life expectancy greater than 12 weeks, and the presence of measurable disease. Following successful screening, participants will be randomized to receive either osimertinib alone or in combination with chemotherapy. The trial will include regular follow-up visits to monitor treatment response, adverse events, and compliance with the study protocol. The end-of-study visit will assess the final outcomes and gather data for analysis.
The expected duration of participant involvement is until disease progression or unacceptable toxicity occurs, with a maximum treatment period of approximately two years. Conditions that may lead to early termination from the study include significant protocol deviations, withdrawal of consent, or the occurrence of serious adverse events. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable insights into the treatment of EGFR mutation-positive NSCLC.
Treatment
The clinical trial involves the administration of **osimertinib**, marketed as TAGRISSO, which is provided in the form of 80 mg film-coated tablets. The tablets are intended for **oral use** and are administered once daily. The clinical tablets differ from the commercial version in that they are plain on both sides and packaged in HDPE bottles, whereas the commercial tablets are debossed and packed in aluminum blisters. The maximum daily dose is 80 mg, and the treatment period is extensive, allowing for long-term administration. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
In addition to osimertinib, the trial includes the administration of **carboplatin** as a comparator treatment. Carboplatin is provided as an **intravenous infusion** with a maximum daily dose of 750 mg/m². The treatment is administered over a period of up to 4 cycles, with each cycle lasting 3 weeks. The dosing schedule is designed to optimize therapeutic outcomes while minimizing potential adverse effects. Compliance is monitored through infusion records and participant follow-up visits.
Another comparator treatment used in the trial is **cisplatin**, which is also administered as an **intravenous infusion**. The maximum daily dose for cisplatin is 75 mg/m², and similar to carboplatin, it is administered over a maximum of 4 cycles, each lasting 3 weeks. The administration of cisplatin is carefully monitored to ensure participant safety and adherence to the protocol.
**Pemetrexed** is included in the trial as an additional comparator treatment. It is administered via **intravenous infusion** with a maximum daily dose of 500 mg/m². The treatment period for pemetrexed is extensive, allowing for long-term administration as needed. The dosing schedule is structured to maximize efficacy while monitoring for potential side effects. Participant compliance is ensured through regular infusion records and follow-up assessments.
Efficacy
The efficacy of the treatment in this clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will be evaluated using the Investigator's assessment as defined by RECIST 1.1 criteria. Secondary endpoints include Overall Survival (OS), with landmark analyses at 1, 2, and 3 years, Objective Response Rate (ORR), Duration of Response (DoR), depth of response, and Disease Control Rate (DCR) as assessed by the Investigator. Additional secondary endpoints involve PFS2, Time to First Subsequent Therapy (TFST), and Time to Second Subsequent Therapy (TSST).
Patient-reported outcomes will be measured by changes from baseline and time to deterioration in the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Pharmacokinetic parameters such as steady-state plasma concentrations and appropriate PK parameters (CLss/F, Cmax,ss, Cmin,ss, and AUCss) of osimertinib and its metabolite, AZ5104, will be summarized. The concordance of EGFR mutation status between local EGFR mutation tests and central cobas® EGFR Mutation Test v2 results from tumor samples with evaluable results will also be assessed. PFS by Investigator by plasma EGFR mutation status is another secondary endpoint.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses.
- For patients who agree to the optional genetic testing, provision of signed and dated genetic testing section of the written Main ICF prior to collection of a sample for genetic analysis for inclusion in the optional genetic research as allowed by local regulations.
- Male or female, at least 18 years of age; patients from Japan at least 20 years of age.
- Pathologically confirmed nonsquamous NSCLC. NSCLC of mixed histology is allowed.
- Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC (per Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology), not amenable to curative surgery or radiotherapy.
- The tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M, assessed by a CLIA-certified (US sites) or an accredited (outside of the US) local laboratory or by central prospective tissue testing.
- Mandatory provision of a baseline plasma sample and an unstained, archival tumor tissue sample in a quantity sufficient to allow for central confirmation of the EGFR mutation status.
- Patients must have untreated advanced NSCLC not amenable to curative surgery or radiotherapy. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapy, investigational agents, are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease.
- 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.
- At least 1 lesion, not previously irradiated that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis of ≥15 mm) with CT or MRI, and that is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days of the baseline tumor assessment scans.
- Female patients who are not abstinent (in line with the preferred and usual lifestyle choice of the patient) and intend to be sexually active with a male partner must be using highly effective contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of IP or must have evidence of nonchild-bearing potential by fulfilling 1 of the following criteria at screening: a. Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments b. Women under 50 years old would be considered as postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution c. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
- Male patients must be willing to use barrier contraception.
Exclusion Criteria
- Spinal cord compression and unstable brain metastases. Patients 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 ILD, drug induced ILD, radiation pneumonitis that required steroid treatment/any evidence of clinically active ILD
- 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 hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. Active infection will include any patients receiving treatment for infection.
- Any of the ff: cardiac criteria a.Mean resting corrected QT interval >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value b.Any clinically important abnormalities in rhythm, conduction/morphology of resting ECG; eg, complete left bundle branch block, 3rd degree heart block, 2nd degree heart block c.Any factors that increase the risk of QTc prolongation/risk of arrhythmic events such as electrolyte abnormalities including serum/plasma potassium, magnesium & calcium below the LLN, heart failure, congenital long QT syndrome, family history of long QT syndrome/unexplained sudden death under 40 years of age in first degree relatives/any concomitant medication known to prolong the QT interval & cause Torsades de Pointes
- Inadequate bone marrow reserve/organ function as demonstrated by any of the ff: lab values a.Absolute neutrophil count below the lower limit of normal b.Platelet count below the LLN c.Hemoglobin <90 g/L d.ALT >2.5 x the upper limit of normal if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases e.AST >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases f.Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia)/liver metastases g.Creatinine clearance <60 mL/min calculated by Cockcroft & Gault equation/24hr urine collection
- Any concurrent &/other active malignancy that has required treatment within 2 years of 1st dose of IP
- Any unresolved toxicities from prior systemic therapy (eg, adjuvant chemo) greater than CTCAE Grade 1 at the time of starting study treatment except for alopecia & Grade 2 prior platinum-therapy related neuropathy
- Refractory nausea & vomiting, chronic GI 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 NSCLC not amenable to curative surgery or radiation including chemo, biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant & neo-adjuvant therapies (chemo, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with/without regimens including immunotherapy, biologic therapies, investigational agents are permitted if treatment was completed at least 12 months prior to the development of recurrent disease
- Prior treatment with an EGFR-TKI
- Major surgery within 4 wks of the 1st dose of 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/with a wide field of radiation within 4 wks of the 1st dose of IP
- Current use of (or unable to stop use prior to receiving the 1st dose of study treatment) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4 (at least 3 wks prior)
- Participation in another clinical study with an investigational product during the 4 wks prior to Day 1. Patients in the follow-up period of an interventional study are permitted
- Involvement in the planning &/or conduct of the study (applies to both AZ staff & staff at the study site)
- Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions & requirements
- Previous treatment allocation (safety run in)/randomization (randomization period) in the present study
- Currently pregnant (confirmed with positive preg. test)/breastfeeding
- History of hypersensitivity to active or inactive excipients of IP or drugs with a similar chemical structure/class to IP
- In addition, the following are considered criteria for exclusion from the exploratory genetic research: Prior allogeneic bone marrow transplant, Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection
- In addition, the following are considered criteria for exclusion from the exploratory genetic research: Prior allogeneic bone marrow transplant, Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 23 May 2024 | 21 |
 France | Not Recruiting | 23 May 2024 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TAGRISSO 80 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 80 | 999999 | PRD4954972 |
CARBOPLATIN | Test | — | INTRAVENOUS INFUSION | 750 | 4 | SUB06614MIG |
CISPLATIN | Test | — | INTRAVENOUS INFUSION | 75 | 4 | SUB07483MIG |
PEMETREXED | Test | — | INTRAVENOUS INFUSION | 500 | 999999 | SUB09655MIG |