Evaluation of Afatinib Followed by Osimertinib Versus Osimertinib Monotherapy in EGFR-Mutated/T790M-Negative Non-Squamous NSCLC: A Phase IV Randomized Study
- Trial ID
- 2024-511625-55-00
- Protocol
- AFAMOSI
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether the time to **EGFR-TKI** failure at 24 months is superior for the treatment sequence of afatinib followed by osimertinib in patients with T790M positive non-squamous non-small cell lung cancer (NSCLC) compared to osimertinib alone. This is clinically relevant as it may inform treatment strategies for patients with this specific genetic mutation, potentially improving outcomes by optimizing the sequence of targeted therapies.
Secondary objectives include:
- Time to EGFR-TKI failure comparing afatinib versus osimertinib.
- Progression-free survival (PFS) for the sequence of afatinib followed by osimertinib or ICT versus osimertinib followed by ICT.
- Overall survival (OS).
- Response rate (RR).
- Disease control rate (DCR).
- Safety and tolerability.
- Symptom control assessed by patient-reported quality of life (QoL).
Participants
The clinical trial involves participants diagnosed with **non-squamous non-small cell lung cancer (NSCLC)** harboring an EGFR mutation positive but T790M mutation negative status. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2, indicating a relatively stable general health status. Participants are required to have adequate organ function and must have recovered from any previous therapy-related toxicity to Grade 1 or lower before randomization. The trial does not specify the total number of participants, as the sponsor has not provided this information. The selection criteria include individuals who are TKI naïve for metastatic NSCLC, with unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease, and at least one evaluable lesion according to RECIST v1.1. The trial population is selected based on these criteria, ensuring that participants have a histologically confirmed diagnosis and meet the necessary health and functional requirements. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **randomized**, double-blind, controlled study designed to evaluate the efficacy and safety of a treatment sequence involving **afatinib** followed by **osimertinib** compared to **osimertinib** alone in patients with EGFR-mutated/T790M Mutation negative non-squamous non-small cell lung cancer (NSCLC). The trial is a Phase IV study, with an estimated duration from September 2020 to November 2026. Participants will be involved for a maximum treatment period of 48 months, with the primary endpoint being the time to EGFR-TKI failure within 24 months.
The study includes several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility criteria will be assessed, including histologically confirmed non-squamous NSCLC with EGFR mutation positive but T790M mutation negative status, unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease, and adequate organ function. Participants must be TKI naïve for metastatic NSCLC, although neoadjuvant or adjuvant chemotherapy is allowed. Follow-up visits will occur at regular intervals to monitor progression-free survival, overall survival, response rate, disease control rate, and safety and tolerability. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or any situation where continued participation is deemed not in the participant's best interest by the investigator. The trial aims to provide comprehensive data on the comparative effectiveness of the treatment sequences, contributing valuable insights into the management of EGFR-mutated/T790M Mutation negative non-squamous NSCLC.
Treatment
The clinical trial involves the administration of **GIOTRIF** film-coated tablets, which contain the active substance **afatinib**. Afatinib is a chemical compound classified as an EGFR-Tyrosinkinase inhibitor, used in the treatment of non-squamous non-small cell lung cancer (NSCLC) with EGFR mutations. The pharmaceutical form of GIOTRIF is a film-coated tablet, available in dosages of 20 mg, 30 mg, and 40 mg. The tablets are administered orally, with a maximum daily dose of 20 mg, 30 mg, or 40 mg, depending on the specific tablet strength. The maximum treatment period is 48 weeks. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
Another experimental medication used in the trial is **TAGRISSO** film-coated tablets, containing the active substance **osimertinib**. Osimertinib is a chemical compound that acts as a kinase inhibitor, specifically targeting EGFR mutations in lung cancer. TAGRISSO is available in film-coated tablet form, with dosages of 40 mg and 80 mg. The tablets are administered orally, with a maximum daily dose of 40 mg or 80 mg, depending on the tablet strength. The treatment duration is capped at 48 weeks. Participant compliance with the dosing schedule is closely monitored to ensure accurate administration of the medication.
In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is on evaluating the efficacy and safety of the treatment sequence involving afatinib followed by osimertinib, compared to osimertinib alone, in patients with EGFR-mutated/T790M Mutation negative non-squamous NSCLC in the first-line setting. The trial aims to determine whether the time to EGFR-TKI failure at 24 months is improved with the sequential treatment approach.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the time to **EGFR-TKI** failure within 24 months for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib alone. Secondary endpoints include time to EGFR-TKI failure (afatinib versus osimertinib), progression-free survival (PFS) for afatinib followed by osimertinib or ICT versus osimertinib followed by ICT, overall survival (OS), response rate (RR) at 12 months and 24 months, disease control rate (DCR) at 12 months and 24 months, safety and tolerability, and symptom control assessed by patient-reported quality of life (QoL) using EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC29.
The efficacy parameters will be measured and collected at specified timepoints throughout the trial, including at 12 months and 24 months. The analysis will involve comparing the outcomes between the treatment groups to determine the efficacy of the treatment sequence. The tools and instruments used for efficacy assessments include validated scales for patient-reported outcomes, such as the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC29, which are designed to evaluate the quality of life and symptom control in patients. The trial is designed to provide comprehensive data on the efficacy of the treatment regimens in patients with non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing
- Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease
- TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed
- At least one evaluable lesion according to RECIST v1.1
- Age ≥ 18 years
- ECOG performance status 0 - 2
- Adequate organ function, defined as all of the following: a. Absolute neutrophil count (ANC) ≥ 1500/mm3. (ANC > 1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the coordinating investigator) b. Platelet count ≥ 75,000/mm3 c. Estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73 m2 according to the Cockcroft-Gault formula (Refer to Appendix 1) d. If history of cardiac comorbidity: Left ventricular function with resting ejection fraction ≥ 50% or above the institutional lower limit of normal (LLN) e. Total Bilirubin ≤ 1.5 times upper limit of normal (ULN), (if related to liver metastases ≤ 3 times ULN). (Patients with Gilbert’s syndrome total bilirubin must be ≤ 4 times institutional upper limit of normal) f. Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 3 times the upper limit of normal (ULN) (if related to liver metastases ≤ 5 times ULN)
- Recovered from any previous therapy related toxicity to ≤ Grade 1 at before randomization (except for stable sensory neuropathy ≤ Grade 2 and alopecia)
- Written informed consent
Exclusion Criteria
- Any investigational drug within 30 days or hormonal anticancer treatment within 2 weeks prior to randomization (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted)
- T790M mutation positive tumors (by local testing)
- Radiotherapy within 2 weeks prior to randomization, except as follows: a. Palliative radiation to target organs other than chest may be allowed up to 1 week prior to randomization b. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with coordinating investigator prior to enrolling
- Major surgery within 2 weeks before starting study treatment or scheduled for surgery during the projected course of the study
- Known hypersensitivity to afatinib or osimertinib or the excipients of any of the trial drugs
- History or presence of clinically relevant cardiovascular abnormalities such as a. uncontrolled hypertension b. congestive heart failure NYHA classification of ≥ 3 c. unstable angina or poorly controlled arrhythmia as determined by the investigator d. Myocardial infarction within 6 months prior to randomization e. Clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 ms) or QTc interval prolongation with signs/symptoms of serious arrhythmia f. Congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or intake of medicinal products that are known to prolong the QTc interval
- Patients with a past or present medical history of a. Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD b. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug c. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) d. Known active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier e. Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured
- Pregnancy and contraception: a. Women who are pregnant, nursing, or who plan to become pregnant while in the trial b. Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of study participation and for at least 2 months for females and 4 months for males after last dose
- Requiring treatment with any of the prohibited concomitant medications (P-Glycoprotein Inhibitors/Inductors CYP3A4/5 Inhibitors/Inductors as listed in Section 4.1.9.2 and Appendix 3) that cannot be stopped for the duration of trial participation or concomitant St. John’s Wort
- Uncontrolled brain metastases (Patients with brain or subdural metastases are not eligible, unless they have completed local therapy (≤ 2 weeks apart from last radiotherapy or radiosurgery) and have discontinued the use of corticosteroids, anticonvulsants or have been on stable dose of corticosteroids (i.e. Dexamethasone ≤ 8 mg) for at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment) or Leptomeningeal carcinomatosis
- Other contraindications to study treatment (Investigators opinion) or legal incapacity or limited legal capacity
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Sept 2020 | 126 |
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 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 40 | 48 | PRD3702399 |
GIOTRIF 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 40 | 48 | PRD1777306 |
GIOTRIF 30 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 30 | 48 | PRD1776818 |
GIOTRIF 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 20 | 48 | PRD1776953 |
GIOTRIF 30 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 30 | 48 | PRD1776819 |
GIOTRIF 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 20 | 48 | PRD1776955 |
GIOTRIF 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 40 | 48 | PRD1777304 |
GIOTRIF 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 40 | 48 | PRD1777305 |
GIOTRIF 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 20 | 48 | PRD1776954 |
GIOTRIF 30 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 30 | 48 | PRD1776825 |