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

• ClinicalTrials.gov Identifier: NCT01121393
• Recruitment Status: Completed
• First Posted: May 12, 2010
• Results First Posted: January 26, 2015
• Last Update Posted: December 14, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung; Adenocarcinoma	Drug: Gemcitabine+Cisplatin; Drug: BIBW 2992	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 364 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 19, 2010
• Actual Primary Completion Date: November 23, 2017
• Actual Study Completion Date: November 26, 2017

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival [ Time Frame: 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 ]

   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.

Secondary Outcome Measures :

1. Objective Response (OR) [ Time Frame: 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 ]

   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.)

2. Disease Control (DC) [ Time Frame: 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 ]
   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.
3. Overall Survival (OS) [ Time Frame: From randomisation up to 374 weeks ]

   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.

4. Time to Objective Response (OR) [ Time Frame: 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 ]

   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.

5. Duration of Objective Response [ Time Frame: 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 ]

   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.

6. Duration of Disease Control [ Time Frame: 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 ]
   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.
7. Tumour Shrinkage [ Time Frame: 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 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.

8. Change From Baseline in Body Weight [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]
   The change from baseline to the lowest and the last body weight recorded or during the the study.
9. Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

   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;

   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 selfcare, unable to carry out any work activities;
   3. Capable of only limited self care, confined to bed or chair more then 50 percent of waking hours;
   4. Completely disabled, cannot carry on any selfcare, totally confined to bed or chair;
   5. Dead
10. Health Related Quality of Life (HRQOL): Time of Deterioration in Coughing [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    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.

11. Health Related Quality of Life (HRQOL): Time of Deterioration in Dyspnoea [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    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.

12. Health Related Quality of Life (HRQOL): Time of Deterioration in Pain [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    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.

13. Pharmacokinetics of Afatinib at Day 22 [ Time Frame: Day 22 (course 2, visit 1) ]
    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).
14. Pharmacokinetics of Afatinib at Day 29 [ Time Frame: Day 29 (course 2, visit 2) ]
    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).
15. Pharmacokinetics of Afatinib at Day 43 [ Time Frame: Day 43 (course 3, visit 1) ]
    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).
16. Safety of Afatinib as Indicated by Intensity and Incidence of Adverse Events [ Time Frame: From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks. ]
    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.
17. Changes in Safety Laboratory Parameters [ Time Frame: From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks. ]

    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

China

Beijing Chao-Yang Hospital

Beijing, China, 100020

307 Hospital of PLA

Beijing, China, 100071

Peking Union Medical College Hospital

Beijing, China, 100730

Beijing Chest Hospital

Beijing, China, 101149

First Hospital of Jilin University

Changchun, China, 130021

Xiangya Hospital, Central South University

Changsha, China, 410008

Hunan Province Tumor Hospital

Changsha, China

West China Hospital

Chengdu, China, 610041

Fujian Provincial Tumor Hospital

Fuzhou, China, 350014

Guangdong General Hospital

Guangzhou, China, 510080

Guangzhou Institute of Respiratory Disease

Guangzhou, China, 510120

NanFang Hosptial

Guangzhou, China, 510515

The Third Affiliated Hospital of Harbin Medical University

Haerbin, China, 150081

Zhejiang Cancer Hospital

Hangzhou, China, 310022

Hubei Cancer Hospital

HongShan, China

Yunnan Provincial Tumor Hospital

Kunming, China, 650118

Lin Yi Tumor Hospital

Linyi, China, 276001

The Affiliated Cancer Hospital, Guangxi Medical University

Nan Ning, China

the 81th Hospital of PLA

Nanjing, China, 210002

Jiangsu Cancer Hospital

Nanjing, China, 210009

The affiliated hospital of medicalcollege qingdao university

Qingdao, China, 266101

Shanghai Changzheng Hospital

Shanghai, China, 200003

Shanghai Chest Hospital

Shanghai, China, 200030

Zhongshan Hospital Fudan University

Shanghai, China, 200032

Shanghai Pulmonary Hospital

Shanghai, China, 200433

Changhai Hospital

Shanghai, China, 200443

The First Hospital of Chinese Medical University

Shenyang, China, 110001

Hebei Provincial Tumor Hospital

Shijiazhuang, China

Tangdu Hospital

Xi'An, China, 710038

Northern Jiangsu People's Hospital

Yangzhou, China, 225001

Korea, Republic of

Kosin University Gospel Hospital

Busan, Korea, Republic of, 602-702

Chungbuk National University Hospital

Cheongju, Korea, Republic of, 361711

Yeungnam University Medical Center

Daegu, Korea, Republic of, 705-717

Konkuk University Medical Center

Seoul, Korea, Republic of, 143-729

Korea University Guro Hospital

Seoul, Korea, Republic of, 152-703

Thailand

Songklanagarind Hospital

Songkla, Thailand, 90110

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:

Study Protocol  [PDF] October 16, 2013

Statistical Analysis Plan  [PDF] December 5, 2012

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01121393
• Other Study ID Numbers: 1200.34
• First Posted: May 12, 2010
• Results First Posted: January 26, 2015
• Last Update Posted: December 14, 2018
• Last Verified: December 2018

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Gemcitabine; Afatinib; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors