AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC

AFAMOSI: Prospective, Randomized, Multicenter Phase IV Study to Evaluate the Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Non-squamous NSCLC in the First-line Setting

This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. Neoadjuvant or adjuvant systemic treatments had to be finished at least (≥) 6 months before study inclusion. In conclusion, this study is investigating the important clinical question whether tumor growth and long term overall survival for a patient is better controlled in a specific treatment sequence of different EGFR-inhibitors. Patients will be treated with registered compounds according to their label in both treatment arms. Thus, all patients will get an effective treatment regimen and patients who progressed on afatinib, and who developed a T790M mutation will be treated subsequently with osimertinib. Those who progressed under osimertinib or under afatinib without T790M mutation will be treated according to the current treatment guidelines with Investigator´s choice of active therapy (ICT) including but not limited to platin doublet chemotherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-squamous NSCLC
• Intervention / Treatment: Drug: Afatinib; Drug: Osimertinib

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anne Ehrlich, Dr med; Phone Number: 9945 +49 6131 17; Email: ehrich@izks-mainz.de
• Study Contact Backup: Name: Thomas Wehler, Prof Dr. med.; Phone Number: 58544 +49 641985; Email: thomas.wehler@innere.med.uni-giessen.de

Study Locations

• Germany
  • Berlin, Germany, 13125
    • Evangelische Lungenklinik Berlin
  • Bremen, Germany, 28325
    • Klinikum Bremen-Ost
  • Hamburg, Germany, 20251
    • Studiengesellschaft Hämato-Onkologie Hamburg
  • Hamm, Germany, 59063
    • Evangelisches Krankenhaus Hamm
  • Immenstadt, Germany, 87509
    • Klinikverbund Allgäug gGmbH, Klinik für Pneumologie, c/o Klinik
  • Konstanz, Germany, 78464
    • Gemeinnützige Krankenhausbetriebsgesellschaft Konstanz Mbh
  • Löwenstein, Germany, 74245
    • Klinik Löwenstein gGmbH
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Bayern
    • München, Bayern, Germany, 80336
      • Klinikum der Ludwig-Maximilians-Universität München
  • Hessen
    • Gießen, Hessen, Germany, 35392
      • Universitätsklinikum Gießen Marburg
    • Offenbach, Hessen, Germany, 63069
      • Sana-Klinikum Offenbach

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. 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)
  2. Platelet count ≥ 75,000/mm3
  3. Estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73 m2 according to the Cockcroft-Gault formula 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 consen

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:

  1. Palliative radiation to target organs other than chest may be allowed up to 1 week prior to randomization
  2. 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

  1. uncontrolled hypertension
  2. congestive heart failure NYHA classification of ≥ 3
  3. unstable angina or poorly controlled arrhythmia as determined by the investigator
  4. Myocardial infarction within 6 months prior to randomization
  5. 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
  6. 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

  1. Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD
  2. 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
  3. 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)
  4. 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
  5. 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:

  1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
  2. 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 protein Inhibitors/Inductors CYP3A4/5 Inhibitors/Inductors 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 11. Other contraindications to study treatment (Investigators opinion) or legal incapacity or limited legal capacity

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Afatinib; Afatinib followed by osimertinib or ICT depending on T790M status	Drug: Afatinib; Afatinib followed by osimertinib or ICT; Other Names: Osimertinib; Drug: Osimertinib; Osimertinib followed by ICT
Active Comparator: Osimertinib; Osimertinib followed by ICT	Drug: Osimertinib; Osimertinib followed by ICT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib	The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to EGFR-TKI failure (afatinib versus osimertinib)	Time from randomization until ICT is indicated	24 months
Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)	Time from randomization until disease progression according to RECIST or death	24 months
Overall Survival (OS)	Survival Status	24 months
Response Rate (RR)	CR+PR according to RECIST	12 months
Response Rate (RR)	CR+PR according to RECIST	24 months
Disease Control Rate (DCR)	CR+PR+SD according to RECIST	12 months
Disease Control Rate (DCR)	CR+PR+SD according to RECIST	24 months
Adverse Events	Adverse Events as assessed by intensity of the of the adverse events and the causal relation to trial medication Intensity/Severity: investigator will use the following definitions of severity in accordance with National Cancer Institute common terminology criteria for adverse events, CTCAE, version 5.0; assessment of the relationship of an adverse event to the administration of study drug is a clinical decision by the investigator Institute common terminology criteria for adverse events, CTCAE, version 5.0	24 months
Symptom control assessed by patient-reported quality of life (QoL): EQ-5D	patient-reported quality of life assessed by European Quality of Life 5 Dimensions Questionnaire (EQ-5D)	24 months
Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-C30	patient-reported quality of life assessed by Questionnaire of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	24 months
Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-LC29	EORTC QLQ-LC29	24 months

Collaborators and Investigators

• Sponsor: Michael Hopp
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Thomas Wehler, Prof Dr med, Universitätsklinikum Gießen Marburg

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2020
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: June 1, 2020
• First Posted (Actual): June 2, 2020

Study Record Updates

• Last Update Posted (Actual): June 2, 2023
• Last Update Submitted That Met QC Criteria: June 1, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Osimertinib; Afatinib
• Other Study ID Numbers: AFAMOSI; 2019-002197-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No