Patient case: 54-year-old female with non-small cell lung cancer; genetic feature: EGFR (D770N)

Clinical trial: Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

Summary: To assess if targeting activating EGFR and HER2 mutations in Non-Small Cell Lung Cancer (NSCLC) is more effective when these mutations are truncal dominant mutations (≥50%), as opposed to non-dominant (≥5 to <50%) or low frequency mutations (<5%).
  This trial will only be available to patients registered to the TRACERx study (NCT01888601).


Eligibility: Inclusion Criteria:
  This therapeutic trial is only relevant for patients involved in the TRACERx observational study.
  -  Subjects must be willing to have a biopsy of relapsed disease. Consent will be obtained through the TRACERx study. Procurement of the biopsy sample is not necessary at the time of trial registration. However, patients must undergo a biopsy prior to commencement of afatinib.
  -  Patients must have tumours harbouring a sensitising EGFR mutation or HER2 mutation in at least one biopsy at recurrence, or region of the primary sample.
  -  Written Informed consent for DARWIN1.
  -  ECOG performance status 0-3
  -  No previous exposure to an EGFR TKI (other than afatinib) or HER2 targeted therapy
  -  Measurable disease by RECIST v1.1.
  -  At least 18 years of age.
  -  Anticipated life expectancy of at least three months.
  -  Adequate organ function as defined by the following baseline values:
  -  Absolute neutrophil count (ANC) ≥1.5x109/L
  -  Platelets ≥100x109/L
  -  Serum bilirubin ≤1.5 x upper limit of normal (ULN). In patients with known Gilbert's syndrome, total bilirubin ≤3xULN with direct bilirubin ≤1.5xULN
  -  Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤3xULN or ≤5x ULN if liver metastases are present
  -  Creatinine clearance must be ≥30mL/min
  -  Women with child-bearing potential, or men who are able to father a child, must be willing to practice acceptable methods of birth control during the trial and for 1 month after the end of treatment.
  -  Women of childbearing potential must have a negative pregnancy test within 14 days before the first dose of trial medication.
  Exclusion Criteria:
  -  • Suitable for radical radiotherapy.
  -  Palliative radiotherapy within 2 weeks prior to registration.
  -  Palliative radiotherapy to a solitary target lesion.
  -  Requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption or any medical comorbidity affecting gastrointestinal absorption.
  -  Patients with current or pre-existing interstitial lung disease.
  -  Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption, or CTCAE v4.03 Grade ≥3 diarrhoea of any etiology at baseline.
  -  Known hypersensitivity to afatinib or to any of the excipients.
  -  Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
  -  Anti-cancer therapy including chemotherapy, radiation therapy, immunotherapy, biologic therapy, or major surgery within 14 days prior to start of trial therapy.
  -  Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection. Subjects with evidence of hepatitis B virus clearance may be enrolled.
  -  History of other malignancy; Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumor lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible.
  -  The following cardiac abnormalities:
  -  Corrected QT (QTc) interval ≥480 msecs
  -  History of acute coronary syndromes (including unstable angina) within the past 24 weeks
  -  Coronary angioplasty, or stenting within the past 24 weeks
  -  Class III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  -  History of known arrhythmias (except sinus arrhythmia) within the past 24 weeks
  -  Myocardial infarction within the last 6 months
  -  Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to comply with the requirements of the trial, trial protocol or to provide informed consent.
  -  Pregnant, lactating or actively breastfeeding females.

Relevance to patient case: possibly relevant