BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

• ClinicalTrials.gov Identifier: NCT00949650
• Recruitment Status: Completed
• First Posted: July 30, 2009
• Results First Posted: November 19, 2013
• Last Update Posted: April 6, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: July 29, 2009
• First Posted Date: July 30, 2009
• Results First Submitted Date: August 8, 2013
• Results First Posted Date: November 19, 2013
• Last Update Posted Date: April 6, 2018
• Actual Study Start Date: August 14, 2009
• Actual Primary Completion Date: February 9, 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2018)

Progression-Free Survival (PFS) Time [ Time Frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression ]

PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.

• Original Primary Outcome Measures (submitted: July 29, 2009): The primary endpoint will be progression free survival, as determined by RECIST 1.1. [ Time Frame: 2 years ]

Current Secondary Outcome Measures (submitted: March 9, 2018)

• Percentage of Patients With Objective Response (OR) [ Time Frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression ]
  OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.
• Percentage of Participants With Disease Control (DC) [ Time Frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression ]
  DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.
• Overall Survival (OS) Time [ Time Frame: From randomisation to cut-off date (17MAR2017). ]
  OS was defined as time from randomisation to death.
• Tumour Shrinkage [ Time Frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression ]
  Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.
• Change From Baseline in Body Weight [ Time Frame: Baseline and throughout the trial until progression (every 3 weeks), up to 28 months. ]
  Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [ Time Frame: Throughout the trial until progression (every 3 weeks), up to 28 months. ]
  ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction.

  1. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work.
  2. Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities.
  3. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours.
  4. Completely disabled, cannot carry on any self-care, totally confined to bed or chair.
  5. Dead.
• Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing [ Time Frame: Throughout the trial until progression (every 3 weeks). ]
  HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
• HRQOL: Time to Deterioration in Dyspnoea [ Time Frame: Throughout the trial until progression (every 3 weeks). ]
  HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
• HRQOL: Time to Deterioration in Pain [ Time Frame: Throughout the trial until progression (every 3 weeks). ]
  HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
• Trough Plasma Concentrations of Afatinib at Day 22 [ Time Frame: Day 22. ]
  Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
• Trough Plasma Concentrations of Afatinib at Day 29 [ Time Frame: Day 29. ]
  Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
• Trough Plasma Concentrations of Afatinib at Day 43 [ Time Frame: Day 43. ]
  Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

• Original Secondary Outcome Measures (submitted: July 29, 2009): Objective response (CR, PR) and Disease control (CR, PR, SD) according to RECIST 1.1, Overall survival, Deterioration of body weight and ECOG performance status, Health related quality of life (HRQOL), Pharmacokinetics of BIBW 2992, Safety of BIBW 2992 [ Time Frame: 2 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation
• Official Title: A Randomised, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients With Stage IIIB or IV Adenocarcinoma of the Lung Harbouring an EGFR Activating Mutation
• Brief Summary: This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Carcinoma, Non-Small-Cell Lung
• Adenocarcinoma

Intervention

• Drug: Pemetrexed
  Pemetrexed IV given once every 3 weeks for up to 6 cycles
• Drug: BIBW 2992
  BIBW 2992 once daily until progression
• Drug: Cisplatin
  Cisplatin IV given once every 3 weeks for up to 6 cycles

Study Arms

• Experimental: BIBW 2992
  BIBW 2992 tablet once daily until progression
  Intervention: Drug: BIBW 2992
• Active Comparator: Cisplatin/Pemetrexed
  Cisplatin and Pemetrexed IV once every 3 weeks for up to 6 cycles
  Interventions:

  • Drug: Pemetrexed
  • Drug: Cisplatin

Publications *

• Wu YL, Sequist LV, Tan EH, Geater SL, Orlov S, Zhang L, Lee KH, Tsai CM, Kato T, Barrios CH, Schuler M, Hirsh V, Yamamoto N, O'Byrne K, Boyer M, Mok T, Peil B, Marten A, Chih-Hsin Yang J, Paz-Ares L, Park K. Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials. Clin Lung Cancer. 2018 Jul;19(4):e465-e479. doi: 10.1016/j.cllc.2018.03.009. Epub 2018 Mar 17.
• Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, Hu CP, Yamamoto N, Feng J, O'Byrne K, Lu S, Hirsh V, Huang Y, Sebastian M, Okamoto I, Dickgreber N, Shah R, Marten A, Massey D, Wind S, Wu YL. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.
• Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. doi: 10.1016/j.jtho.2015.11.014. Epub 2016 Jan 25.
• Kato T, Yoshioka H, Okamoto I, Yokoyama A, Hida T, Seto T, Kiura K, Massey D, Seki Y, Yamamoto N. Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX-Lung 3. Cancer Sci. 2015 Sep;106(9):1202-11. doi: 10.1111/cas.12723. Epub 2015 Jul 25.
• Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. doi: 10.1016/S1470-2045(15)00026-1. Epub 2015 Jun 4.
• Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. doi: 10.1016/S1470-2045(14)71173-8. Epub 2015 Jan 12.
• Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. doi: 10.1200/JCO.2012.46.1764. Epub 2013 Jul 1.
• Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. doi: 10.1200/JCO.2012.44.2806. Epub 2013 Jul 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 25, 2013): 345
• Original Estimated Enrollment (submitted: July 29, 2009): 330
• Actual Study Completion Date: March 16, 2017
• Actual Primary Completion Date: February 9, 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
• Epidermal Growth Factor Receptor mutation detected by central laboratory analysis of tumour biopsy material.
• Measurable disease according to RECIST 1.1.
• Eastern Cooperative Oncology Group score of 0 or 1.
• Age >/= 18 years.
• Life expectancy of at least three months.
• Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice guidelines.

Exclusion criteria:

• Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and randomisation.
• Prior treatment with Epidermal Growth Factor Receptor targeting small molecules or antibodies.
• Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomisation.
• Active brain metastases
• Any other current malignancy or malignancy diagnosed within the past five years
• Known pre-existing interstitial lung disease.
• Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom.
• History or presence of clinically relevant cardiovascular abnormalities.
• Any other concomitant serious illness or organ system dysfunction.
• Adequate absolute neutrophil count and platelet count
• Adequate liver and kidney function
• Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, France, Germany, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Republic of, Malaysia, Peru, Philippines, Romania, Russian Federation, Taiwan, Thailand, Ukraine, United Kingdom, United States
• Removed Location Countries: Mexico

Administrative Information

• NCT Number: NCT00949650
• Other Study ID Numbers: 1200.32; 2008-005615-18 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: March 2018