BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)

LUX-Lung 6: A Randomized, 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

To investigate the efficacy and safety of BIBW 2992 compared to standard first-line chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma; Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: BIBW 2992; Drug: Gemcitabine+Cisplatin

• Study Type: Interventional
• Enrollment (Actual): 364
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100071
    • 307 Hospital of PLA
  • Beijing, China, 100730
    • Peking Union Medical College Hospital
  • Beijing, China, 100020
    • Beijing Chao-Yang Hospital
  • Beijing, China, 101149
    • Beijing Chest Hospital
  • Changchun, China, 130021
    • First Hospital of Jilin University
  • Changsha, China, 410008
    • Xiangya Hospital, Central South University
  • Changsha, China
    • Hunan Province Tumor Hospital
  • Chengdu, China, 610041
    • West China Hospital
  • Fuzhou, China, 350014
    • Fujian Provincial Tumor Hospital
  • Guangzhou, China, 510080
    • Guangdong General Hospital
  • Guangzhou, China, 510120
    • Guangzhou Institute of Respiratory Disease
  • Guangzhou, China, 510515
    • NanFang Hosptial
  • Haerbin, China, 150081
    • The Third Affiliated Hospital of Harbin Medical University
  • Hangzhou, China, 310022
    • Zhejiang Cancer Hospital
  • HongShan, China
    • Hubei Cancer Hospital
  • Kunming, China, 650118
    • Yunnan Provincial Tumor Hospital
  • Linyi, China, 276001
    • Lin Yi Tumor Hospital
  • Nan Ning, China
    • The Affiliated Cancer Hospital, Guangxi Medical University
  • Nanjing, China, 210009
    • Jiangsu Cancer Hospital
  • Nanjing, China, 210002
    • the 81th Hospital of PLA
  • Qingdao, China, 266101
    • The affiliated hospital of medicalcollege qingdao university
  • Shanghai, China, 200030
    • Shanghai Chest Hospital
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital
  • Shanghai, China, 200032
    • Zhongshan Hospital Fudan University
  • Shanghai, China, 200003
    • Shanghai Changzheng Hospital
  • Shanghai, China, 200443
    • Changhai Hospital
  • Shenyang, China, 110001
    • The First Hospital of Chinese Medical University
  • Shijiazhuang, China
    • Hebei Provincial Tumor Hospital
  • Xi'An, China, 710038
    • Tangdu Hospital
  • Yangzhou, China, 225001
    • Northern Jiangsu People's Hospital
• Korea, Republic of
  • Busan, Korea, Republic of, 602-702
    • Kosin University Gospel Hospital
  • Cheongju, Korea, Republic of, 361711
    • Chungbuk National University Hospital
  • Daegu, Korea, Republic of, 705-717
    • Yeungnam University Medical Center
  • Seoul, Korea, Republic of, 143-729
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 152-703
    • Korea University Guro Hospital
• Thailand
  • Songkla, Thailand, 90110
    • Songklanagarind Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. pathologically confirmed diagnosis of stage IIIB or stage IV adenocarcinoma of the Lung
2. EGFR(Epidermal Growth Factor Receptor) mutation detected by central laboratory analysis of tumor biopsy material
3. Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST)1.1
4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
5. Age>=18 years
6. life expectancy of at least three months
7. Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines.

Exclusion criteria:

1. Prior chemotherapy for relapsed and/or metastatic NSCLC.
2. Prior treatment with EGFR targeting small molecules or antibodies.
3. Radiotherapy or surgery(other than biopsy) within 4 weeks prior to randomization
4. Active brain metastases
5. Any other current malignancy or malignancy diagnosed within the past 5 years
6. Known pre-existing interstitial lung disease
7. Significant or recent acute gastrointestinal disorders with diarrhoea as a a major symptoms.
8. History or presence of clinically relevant cardiovascular abnormalities
9. Cardiac left ventricular function with resting ejection fraction of less than 50%.
10. 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.
11. Absolute neutrophil count(ANC)<1500/mm3
12. Platelet count<100,000/mm3
13. Creatinine clearance<60ml/min or serum creatinine>1.5 times Upper Limit of Normal (ULN).
14. Bilirubin>1.5 times ULN
15. Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) > 3 times ULN
16. Women of childbearing potential, or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial
17. Pregnancy of breast-feeding
18. Patients unable to comply with the protocol
19. Active hepatitis B infection, active hepatitis C infection or known HIV(Human Immunodeficiency Virus) carrier.
20. Known or suspected active drug or alcohol abuse.
21. requirement for treatment with any of the prohibited concomitant medications listed in section 4.2.2
22. Any contraindications for therapy with gemcitabine/cisplatin
23. Known hypersensitivity to BIBW2992 or the excipient of any of the trial drugs
24. Use of any investigational drug within 4 weeks of randomization.

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: Arm A BIBW 2992; Patients receive a tablet of BIBW 2992 daily until progression or unacceptable toxicity	Drug: BIBW 2992; starting dose is 40 mg, in the event of no or minimal drug-related adverse events after one course, the dose will be increased to 50mg. in the event of certain drug related Adverse Event (AE), dose reduction will be increments of 10 mg, with the lowest dose being 20mg.
Active Comparator: Arm B Chemotherapy; Patients receive Gemcitabine and Cisplatin, maximum is 6 courses	Drug: Gemcitabine+Cisplatin; Gemcitabine d1,8, Cisplatin d1, 21 days as a course, up to 6 courses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	The primary endpoint was progression-free survival (PFS) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival was defined as the time from randomisation to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not have a PFS. Only data collected up until the analysis cut-off date (27 December 2013) were considered. Median time results from unstratified Kaplan-Meier estimates.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 168

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response (OR)	OR is defined as a best overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with OR. CR is defined as the disappearance of all target lesions and non-target lesions and no new lesions. PR is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD, non-Progressive Disease or non evaluation of all non-target lesions and no new lesions. (Exact 95% Confidence interval by Clopper and Pearson.)	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Disease Control (DC)	DC is defined as a patient with objective response (OR) or stable disease (SD) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with DC.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Overall Survival (OS)	OS is defined as the time from randomisation to death. For patients who had not died until 7 December 2017, the date they were last known to be alive was derived from patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date. Median time results from unstratified Kaplan-Meier estimates.	From randomisation up to 374 weeks
Time to Objective Response (OR)	OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1. For patients with an objective response, time to objective response was defined as the time from randomisation to the first objective response. Outcome data are the percentage of patients with OR by each scheduled tumour assessment.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Duration of Objective Response	OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1. For patients with an objective response, duration of objective response was defined as the time from the first objective response to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Duration of Disease Control	For patients with disease control, duration of disease control was defined as the time from randomisation to progression or death whichever occurs first. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Tumour Shrinkage	Tumour shrinkage is calculated as the minimum post-baseline sum of longest diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) (SLD), as assessed by central independent review. The mean of these minimum values are presented after adjusting for baseline sum of longest diameters and EGFR mutation category. Only data collected up until the analysis cut-off date (27 Dec 2013) were considered. A negative value means the smallest post-baseline SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline. The means are adjusted for baseline sum of lesions and EGFR mutation category.	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374
Change From Baseline in Body Weight	The change from baseline to the lowest and the last body weight recorded or during the the study.	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.
Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	The last ECOG performance score category recorded during the study. Outcome data are the percentage of patients with an shift of ECOG performance status from baseline to the last ECOG performance status. 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; Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work;; Ambulatory (>50 percent of waking hours), capable of all selfcare, unable to carry out any work activities;; Capable of only limited self care, confined to bed or chair more then 50 percent of waking hours;; Completely disabled, cannot carry on any selfcare, totally confined to bed or chair;; Dead	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.
Health Related Quality of Life (HRQOL): Time of Deterioration in Coughing	HRQOL as measured by standardised questionnaires (EuropeanOrganisation for Research and Treatment of Cancer (EORTC)) quality of life questionaires (OLQ-C30) and its lung cancer module (QLQ-LC13). Analysis for cough: QLQ-LC13, question 1. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.
Health Related Quality of Life (HRQOL): Time of Deterioration in Dyspnoea	HRQOL as measured by OLQ-C30 and its lung cancer module (QLQ-LC13). Analysis for dyspnoea: composite of QLQ-LC13, questions 3 to 5; individual item from QLQ-C30, question 8. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.
Health Related Quality of Life (HRQOL): Time of Deterioration in Pain	HRQOL as measured by OLQ-C30 and its lung cancer module QLQ-LC13. Analysis for pain: composite of QLQ-C30, questions 9 and 19; individual items from QLQ-LC13, questions 10, 11 and 12. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.
Pharmacokinetics of Afatinib at Day 22	Outcome data are the trough plasma concentrations of afatinib at day 22 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the Pharmacokinetics (PK) assessment period).	Day 22 (course 2, visit 1)
Pharmacokinetics of Afatinib at Day 29	Outcome data are the trough plasma concentrations of afatinib at day 29 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).	Day 29 (course 2, visit 2)
Pharmacokinetics of Afatinib at Day 43	Outcome data are the trough plasma concentrations of afatinib at day 43 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).	Day 43 (course 3, visit 1)
Safety of Afatinib as Indicated by Intensity and Incidence of Adverse Events	Safety of Afatinib as indicated by intensity and incidence of adverse events graded according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Presented as the percentage of patients with an Adverse Events during the on-treatment period by highest CTCAE grade.	From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks.
Changes in Safety Laboratory Parameters	Outcome data presented are the percentage of patients by worst CTCAE grade (only Grades 2 to 4 presented) on treatment for the following laboratory parameters: Potassium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Creatine and Creatine Kinase. For Potassium; only CTCAE grades resulting from hypokalemia (low values) are presented.	From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Wu YL, Xu CR, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Marten A, Fan J, Peil B, Zhou C. Afatinib versus gemcitabine/cisplatin for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: subgroup analysis of the LUX-Lung 6 trial. Onco Targets Ther. 2018 Nov 30;11:8575-8587. doi: 10.2147/OTT.S160358. eCollection 2018.
• 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.
• 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.
• Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. doi: 10.1016/S1470-2045(13)70604-1. Epub 2014 Jan 15.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2010
• Primary Completion (Actual): November 23, 2017
• Study Completion (Actual): November 26, 2017

Study Registration Dates

• First Submitted: April 21, 2010
• First Submitted That Met QC Criteria: May 11, 2010
• First Posted (Estimate): May 12, 2010

Study Record Updates

• Last Update Posted (Actual): December 14, 2018
• Last Update Submitted That Met QC Criteria: December 13, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Afatinib
• Other Study ID Numbers: 1200.34