Evaluation of Osimertinib Combined with Chemotherapy in First-Line Treatment of Stage IV Non-Small Cell Lung Cancer with Atypical EGFR Mutations
- Trial ID
- 2024-516790-78-00
- Protocol
- FLAURARE
- Sponsor
- Heidelberg University
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of osimertinib in combination with chemotherapy in patients with stage IV non-small-cell lung cancer (NSCLC) who possess atypical EGFR mutations. This is clinically relevant as it aims to determine the potential benefits of this treatment regimen in a specific subset of NSCLC patients, potentially leading to improved therapeutic strategies and outcomes.
Secondary objectives include:
- Evaluating the efficacy of the treatment.
- Assessing the safety profile of the combination therapy.
- Determining the impact on the quality of life of patients receiving osimertinib along with chemotherapy.
Participants
The clinical trial involves participants diagnosed with **stage IV non-small-cell lung cancer (NSCLC)**, specifically those with atypical EGFR mutations in Exons 18-21, excluding L858R, Exon 19 del, Exon 20 Ins, or T790M mutation. The study population includes both male and female subjects aged 18 years and older, with no prior systemic treatment for metastatic stage. Participants are required to have a histologically or cytologically confirmed diagnosis of stage IV NSCLC (adenocarcinoma) and must exhibit adequate hepatic, renal, and bone marrow function. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 12 weeks. Participants must have at least one measurable lesion according to RECIST v1.1 criteria. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific genetic and health criteria, and both genders are included, with considerations for reproductive health and contraceptive use during and after the treatment period. The study also involves a vulnerable population, although specific details about this group are not disclosed.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **osimertinib** in combination with chemotherapy for patients diagnosed with stage IV non-small-cell lung cancer (NSCLC) exhibiting atypical EGFR mutations. This study is structured as a single-arm, open-label, phase II trial. The trial will involve a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The estimated duration of the trial is from March 2025 to April 2029, with participant involvement expected to last up to 24 months, depending on the treatment regimen.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate hepatic, renal, and bone marrow function, and the presence of specific EGFR mutations. Following the screening, participants will be enrolled and randomized to receive treatment. The treatment regimen includes **pemetrexed**, **carboplatin**, and **cisplatin** administered via intravenous infusion, and **osimertinib** administered orally. The maximum treatment period for **pemetrexed** and **osimertinib** is 24 months, while **carboplatin** and **cisplatin** are administered for up to 12 months.
Study visits will include regular follow-up assessments to monitor progression-free survival (PFS) and overall survival (OS), as well as to evaluate the objective response rate (ORR) and toxicity according to CTCAE 5.0. The primary endpoint is the progression-free survival rate at 12 months, with secondary endpoints including overall survival and progression-free survival rate at subsequent intervals. The end-of-study visit will occur upon completion of the treatment regimen or in the event of disease progression or unacceptable toxicity.
Participants are expected to remain in the study for the full duration unless they experience disease progression, unacceptable adverse effects, or choose to withdraw consent. Conditions that may lead to early termination include non-compliance with study protocols or the emergence of contraindications to continued treatment. The trial aims to provide comprehensive data on the efficacy and safety of the treatment combination in this specific patient population.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Pemetrexed** is provided as a concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 500 mg/m² and a total maximum dose of 17,000 mg/m² over a treatment period of up to 24 weeks. This medication is classified as a cytostatic agent.
**Carboplatin** is also administered as an injection through intravenous infusion. The dosing regimen includes a maximum daily dose of 75 mg/m² and a total maximum dose of 300 mg/m², with a treatment duration of up to 12 weeks. Like pemetrexed, carboplatin is categorized as a cytostatic agent.
**Osimertinib**, marketed as **TAGRISSO**, is available in two formulations: 40 mg and 80 mg film-coated tablets. Both formulations are administered orally. The maximum daily dose for the 40 mg tablets is 80 mg, with a total maximum dose of 16,640 mg over 24 weeks. For the 80 mg tablets, the maximum daily dose is also 80 mg, with a total maximum dose of 58,400 mg over the same period. Osimertinib is a tyrosine kinase inhibitor.
**Cisplatin** is provided as a concentrate for solution for infusion and is administered via intravenous infusion. The dosing schedule includes a maximum daily dose of 75 mg/m² and a total maximum dose of 300 mg/m², with a treatment period of up to 12 weeks. Cisplatin is classified as a cytostatic agent.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these medications in combination as a first-line therapy for patients with stage IV non-small cell lung cancer (NSCLC) with atypical EGFR mutations.
Efficacy
The efficacy of the clinical trial evaluating **osimertinib** in combination with chemotherapy for stage IV non-small cell lung cancer (NSCLC) patients with atypical EGFR mutations will be assessed using several endpoints. The primary endpoint is the progression-free survival rate at 12 months (PFS@12), which is defined as the proportion of patients alive with non-progressive disease 12 months after enrollment. This will be estimated using the Kaplan-Meier method according to RECIST 1.1 criteria.
Secondary endpoints include progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity. PFS is defined as the time from enrollment to the date of progression or death from any cause, while OS is the time from enrollment to death from any cause. ORR is determined by the rate of patients achieving complete or partial response as the best overall response according to RECIST 1.1. Toxicity will be evaluated according to CTCAE 5.0 standards. Additionally, progression-free survival rate (PFS2) will be measured from initial trial randomization to second disease progression or death from any cause.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has provided written informed consent
- Patient is 18 years or older at time of signing the informed consent form
- Patient has histologically or cytologically confirmed stage IV NSCLC (adenocarcinoma)
- Patient did not receive prior systemic treatment for metastatic stage
- Patient has one or more EGFR mutations in Exons 18-21 excluding L858R, Exon 19 del, Exon 20 Ins or T790M mutation (tested locally)
- Patient has negative molecular testing for ALK and ROS1 alterations (tested locally)
- Patient has ECOG performance status ≤ 1
- Patient must have a life expectancy ≥ 12 weeks
- Patient has at least one measurable lesion according to RECIST v1.1
- Patient has adequate hepatic, renal and bone marrow function: a) Hemoglobin ≥ 9.0 g/dL b) Absolute neutrophil count ≥ 1.5 x 109 /L c) Platelets ≥ 100 x 109 /L d) Calculated creatinine clearance ≥ 60 mL/min (use of CKD-EPI formulation is highly recommended) and creatinine ≤ 1.5x upper limit of normal (ULN) e) Serum bilirubin ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of documented Gilbert‘s Syndrome [unconjugated hyperbilirubinemia] or liver metastases) f) AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN (or ≤5 times ULN in the presence of liver metastases) g) International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants
- Female patients who are considered as woman of childbearing potential (WOCBP) must agree to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of <1% per year during the treatment period as well as up to 2 months after last dose of osimertinib or 6 months after last dose chemotherapy, whatever is later (see section 5.2.6).
- WOCBP must have a negative serum pregnancy test and not be breast-feeding prior to start of the trial treatment
- Male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive during the treatment period as well as up to 4 months after last dose of osimertinib, 3 months after last dose of pemetrexed or up to 6 months after last dose of carboplatin or cisplatin, whatever is later. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy (see section 5.2.6).
Exclusion Criteria
- Mixed histology (small-cell and non-small cell or non-squamous and squamous; patients exhibiting the latter expression pattern may be eligible if the adenocarcinoma part predominates in >50% of analyzed tumor tissue)
- Patients having received any prior therapy with an EGFR TKI
- Patient is candidate for complete removal of oligometastatic disease. If patients refuse to undergo surgery/ablations they are allowed into the trial
- Patient received treatment with an investigational drug within five half-lives of the compound or 3 months before start of the trial treatment, whichever is greater
- Patient is currently receiving (or unable to stop prior start of the trial treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior) (see Appendix 3). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
- Patient has symptomatic, neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to trial entry (maximal acceptable dose must be ≤ 10 mg of prednisolone)
- Patient has any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of start of trial treatment, with exception of alopecia and grade 2 prior platinum-therapy-related neuropathy
- Patient has 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 jeopardise compliance with the protocol
- Patient has known active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HCV/ HIV), or active uncontrolled HBV infection. Screening for chronic conditions is not required. Patients with chronic/ resolved HBV are eligible if they meet the following criteria: • Negative for hepatitis B surface antibody (HBsAb) and positive for hepatitis B core antibody (HBcAb). In addition, patients must be receiving anti-viral prophylaxis for 2- 4 weeks prior to study treatment OR • Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV DNA levels below <100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment
- Patient has refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow tablets or previous significant bowl resection that would preclude adequate absorption of osimertinib
- Patient has any of the following cardiac criteria: • Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN) , congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes
- Leptomeningeal disease
- Patient has past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
- Known additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 years
- Known allergy or hypersensitivity to any component of the chemotherapy regimen or to osimertinib or any constituents of the products
- Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 03 Mar 2025 | 40 |
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 |
|---|---|---|---|---|---|---|
PEMETREXED | Test | — | INTRAVENOUS INFUSION | 500 | 24 | SUB09655MIG |
CARBOPLATIN | Test | — | INTRAVENOUS INFUSION | 75 | 12 | SUB06614MIG |
CISPLATIN | Test | — | INTRAVENOUS INFUSION | 75 | 12 | SUB07483MIG |
TAGRISSO 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 80 | 24 | PRD3702449 |
TAGRISSO 80 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 80 | 24 | PRD3702398 |