Title A randomized, open-label Phase III trial of afatinib versus erlotinib in patients with advanced squamous cell carcinoma of the lung as second-line therapy following first-line platinum-based chemotherapy

IRB BIP 1512

CC 12-671

Hospital Main Campus

Stage N/A

Phase Phase 3

Disease Lung

Drug Afatinib, Erlotinib



  1. Primary Objective
    • The primary objective of the trial is to compare the efficacy of afatinib with erlotinib as second-line treatment for this group of patients, as measured by PFS.
  2. Secondary Objectives
    • The key secondary trial objective is to compare the OS in both treatment groups.
    • Other secondary objectives are to compare the ORR, DCR and tumour shrinkage of afatinib with erlotinib, and the assessment of HRQoL and safety in both treatment groups.
Inclusion Criteria

Inclusion Criteria

  1. Diagnosis of advanced stage NSCLC considered to be squamous histology, including mixed histology, in the opinion of the investigator.
  2. Completion of at least 4 cycles of platinum-based doublet chemotherapy, with or without additional [non-EGFR] targeted agents, as 1st line treatment of Stage IIIB/IV NSCLC. Note the below scenarios are also considered to meet this requirement: Patients relapsing within 6 months of completing adjuvant/neo-adjuvant/curative -intent chemotherapy/chemoradiotherapy. (Note: these patients are still required to have had the equivalent of 4 cycles of platinum based doublet chemotherapy EXCEPT in setting noted next). Patients intending to receive four cycles of platinum based doublet chemotherapy but due to toxicity, and not PD, discontinue just the platinum agent after at least two cycles of platinum doublet has been administered.
  3. Eligible to receive 2nd line therapy in the opinion of the investigator. Patients who received non-EGFR based therapy for maintenance are eligible.
  4. Measurable disease according to RECIST 1.1 (R09-0262). Refer to Appendix 10.1.
  5. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (R01-0787). Refer toAppendix 10.2.
  6. Availability of tumour tissue material for correlative studies (refer to Section 5.6). Archived tumour tissue is acceptable.
  7. Adequate organ function, defined as all of the following:
    • LVEF >50% or within institution normal values.
    • 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 sponsor).
    • Platelet count >75,000 / mm³.
    • Estimated creatinine clearance > 45ml / min. Refer to Appendix 10.3.
    • Total bilirubin < 1.5 times institutional ULN (Patients with Gilbert’s Syndrome total bilirubin must be < 4 times institutional ULN).
    • Aspartate amino transferase (AST) or alanine amino transferase (ALT) < three times the institutional upper limit of normal (ULN) (if related to liver metastases < five times institutional ULN).
  8. Recovered from any previous therapy related toxicity to ≤CTCAE Grade 1 at study entry (except for stable sensory neuropathy ≤CTCAE Grade 2 and alopecia).
  9. Ability to take oral medication in the opinion of the investigator.
  10. Age ≥ 18 years.
  11. Written informed consent that is consistent with ICH-GCP guidelines.
Exclusion Criteria

Exclusion Criteria

  1. Prior treatment with EGFR directed small molecules or antibodies.
  2. Curative intent chemoradiotherapy as the only treatment for stage IIIB NSCLC unless relapse occurs within 6 months of completion of treatment, and in the opinion of the investigator the patient has received an equivalent of 4 cycles of platinum-based doublet therapy.
  3. Radiotherapy within 4 weeks prior to randomization, except as follows:
    • Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to randomization, and
    • Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.
  4. Active brain metastases (stable for <4 weeks, symptomatic, or leptomeningeal disease). Dexamethasone therapy will be allowed if administered as a stable dose for at least 4 weeks before randomization.
  5. Any other current malignancy or malignancy diagnosed within the past three (3) years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer).
  6. Known pre-existing interstitial lung disease.
  7. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn’s disease, malabsorption or CTC grade ≥2 diarrhoea of any aetiology, based on investigator assessment.
  8. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3 (Refer to Appendix 10.4), unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to randomisation.
  9. Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
  10. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended. Adequate methods of contraception and Women of Child-Bearing Potential are discussed in Section
  11. Female patients of childbearing potential (see Section who are nursing or arepregnant.
  12. Patients unable to comply with the protocol in the opinion of the investigator.
  13. Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
  14. Known or suspected active drug or alcohol abuse in the opinion of the investigator.
  15. Requirement for treatment with any of the prohibited concomitant medications listed in Section 4.2.3.
  16. Any contraindications for therapy with afatinib or erlotinib.
  17. Known hypersensitivity to erlotinib, afatinib or the exipients of any of the trial drugs.
  18. Major surgery within 4 weeks of starting study treatment.
  19. Prior participation in an afatinib clinical study, even if not assigned to afatinib.
  20. Use of any investigational drug within 4 weeks of randomisation (unless a longer time period is required by local regulations or by the guidelines for the investigational product).
  21. Patients without Progressive disease.