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LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy

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ClinicalTrials.gov Identifier: NCT01523587
Recruitment Status : Completed
First Posted : February 1, 2012
Results First Posted : November 21, 2014
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Interventions Drug: afatinib
Drug: erlotinib
Enrollment 795
Recruitment Details Open-Label Phase-III trial to compare the efficacy of afatinib with erlotinib for the second-line treatment of patients with advanced non-small cell lung cancer, who completed at least 4 cycles of platinum-based doublet chemotherapy. Randomization ratio was 1:1. Stratification was based on race.
Pre-assignment Details Patients screened to ensure that they met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met. Tumor assessments at screening were completed within 21 days and other screening assessments were completed within 28 days, of randomization.
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events. Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Period Title: Overall Study
Started 398 397
Treated 392 395
Completed 0 0
Not Completed 398 397
Reason Not Completed
Other than listed             5             5
Worsening of underlying cancer disease             19             34
Adverse Event             68             52
Protocol Violation             5             3
Lost to Follow-up             2             2
Withdrawal by Subject             28             20
Withdrew due to Progressive disease             265             279
Randomised but bot treated             6             2
Arm/Group Title Afatinib Erlotinib Total
Hide Arm/Group Description Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events. Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events. Total of all reporting groups
Overall Number of Baseline Participants 398 397 795
Hide Baseline Analysis Population Description
Randomized Set (RS): All patients who were randomized, regardless of whether they received investigational treatment.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 398 participants 397 participants 795 participants
64.9  (8.39) 63.4  (8.98) 64.1  (8.72)
[1]
Measure Analysis Population Description: Randomised set
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 398 participants 397 participants 795 participants
Female
63
  15.8%
66
  16.6%
129
  16.2%
Male
335
  84.2%
331
  83.4%
666
  83.8%
[1]
Measure Analysis Population Description: Randomised set
Race (NIH/OMB)   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 398 participants 397 participants 795 participants
American Indian or Alaska Native
2
   0.5%
2
   0.5%
4
   0.5%
Asian
97
  24.4%
94
  23.7%
191
  24.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
7
   1.8%
8
   2.0%
15
   1.9%
White
288
  72.4%
291
  73.3%
579
  72.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
4
   1.0%
2
   0.5%
6
   0.8%
[1]
Measure Description: Ethnicity was not captured in this trial.
[2]
Measure Analysis Population Description: Randomised set
1.Primary Outcome
Title Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1
Hide Description Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized Set (RS): All patients who were randomized, regardless of whether they received investigational treatment.
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Median (95% Confidence Interval)
Unit of Measure: Months
2.63
(2.00 to 2.86)
1.94
(1.87 to 2.10)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments A Cox proportional hazards model without the randomization stratification variable was used for each subgroup category, along with the corresponding log-rank test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0103
Comments P-value from log-rank stratified by Race (two-sided). Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazards model stratified by Race.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.814
Confidence Interval (2-Sided) 95%
0.693 to 0.956
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival
Hide Description Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.
Time Frame From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Median (95% Confidence Interval)
Unit of Measure: Months
7.82
(7.19 to 8.71)
6.77
(5.85 to 7.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments A Cox proportional-hazards model, stratified by race, was used to estimate the hazard ratio and 95% confidence interval (CI) between the two treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0193
Comments P-value from log-rank stratified by Race (two-sided). Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazards model stratified by Race.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.841
Confidence Interval (2-Sided) 95%
0.727 to 0.973
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants With Objective Response According to RECIST 1.1
Hide Description A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Measure Type: Number
Unit of Measure: Participants
22 11
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0551
Comments Odds ratio (Afatinib vs Erlotinib), 95% CI and p-value (two-sided) from logistic regression stratified by race.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.06
Confidence Interval (2-Sided) 95%
0.98 to 4.32
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With Disease Control According to RECIST 1.1
Hide Description Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Measure Type: Number
Unit of Measure: Participants
201 157
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments [Not Specified]
Method Regression, Logistic
Comments Odds ratio (Afatinib vs Erlotinib), 95% CI and p-value (two-sided) from logistic regression stratified by race.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.56
Confidence Interval (2-Sided) 95%
1.18 to 2.06
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Tumour Shrinkage
Hide Description

Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation.

A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size.

Post-baseline mean is adjusted for baseline sum of diameters and race.
Time Frame First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from the randomised set with tumour assessments are considered for the analysis of this endpoint.
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 307 311
Least Squares Mean (Standard Error)
Unit of Measure: Millimeter (mm)
78.8  (1.26) 80.0  (1.24)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The analysis will compare the treatments using analysis of covariance (ANCOVA) for minimum sum of diameters, using baseline sum of diameters as a covariate. The randomization strata will be included as classification factors.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.500
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-4.67 to 2.28
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.77
Estimation Comments Mean was adjusted for baseline sum of diameters and race.
6.Secondary Outcome
Title Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire
Hide Description Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.
Time Frame From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Measure Type: Number
Unit of Measure: Participants
Improved Cough Number Analyzed 339 participants 341 participants
147 120
Improved Dyspnoea Number Analyzed 339 participants 340 participants
174 150
Improved Pain Related Number Analyzed 343 participants 342 participants
138 134
Improved Global Health Status Number Analyzed 339 participants 339 participants
121 96
7.Secondary Outcome
Title Summary of Time to Deterioration in Coughing, Dyspnoea and Pain.
Hide Description Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration.
Time Frame From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Median (95% Confidence Interval)
Unit of Measure: Months
Time to Deterioration - Coughing Number Analyzed 180 participants 182 participants
4.53
(2.86 to 4.93)
3.65
(2.79 to 4.66)
Time to Deterioration - Dyspnoea Number Analyzed 238 participants 244 participants
2.63
(1.97 to 2.86)
1.91
(1.87 to 2.33)
Time to Deterioration - Pain Number Analyzed 243 participants 232 participants
2.50
(2.00 to 2.79)
2.37
(1.91 to 2.76)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Time to Deterioration in Coughing.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2562
Comments p-value calculated using log rank test stratified by race.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.72 to 1.09
Estimation Comments Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Time to Deterioration in Dyspnoea
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0078
Comments p-value calculated using log rank test stratified by race.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.66 to 0.94
Estimation Comments Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Time to Deterioration in Pain
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8690
Comments p-value calculated using log rank test stratified by race
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.82 to 1.18
Estimation Comments Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.
8.Secondary Outcome
Title Change in Score Over Time in Coughing,Dyspnoea and Pain
Hide Description

Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race.

Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant.

The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.
Time Frame From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description:
Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.
Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Number of Participants Analyzed 398 397
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
Coughing Number Analyzed 340 participants 333 participants
15.8  (2.40) 19.3  (2.37)
Dyspnoea Number Analyzed 340 participants 332 participants
11.4  (1.83) 14.9  (1.85)
Pain Number Analyzed 343 participants 334 participants
10.3  (2.13) 13.1  (2.17)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Change in scores over time for: Coughing.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0091
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-6.15 to -0.88
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.34
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Change in scores over time for: Dyspnoea.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0024
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-5.75 to -1.25
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.15
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Afatinib, Erlotinib
Comments The results shown relate to Change in scores over time for: Pain.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0384
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.7
Confidence Interval (2-Sided) 95%
-5.33 to -0.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.32
Estimation Comments [Not Specified]
Time Frame From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Adverse Event Reporting Description All adverse events (AEs) reported for this trial are on treatment AEs.
 
Arm/Group Title Afatinib Erlotinib
Hide Arm/Group Description Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events. Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
All-Cause Mortality
Afatinib Erlotinib
Affected / at Risk (%) Affected / at Risk (%)
Total   77/392 (19.64%)   71/395 (17.97%) 
Hide Serious Adverse Events
Afatinib Erlotinib
Affected / at Risk (%) Affected / at Risk (%)
Total   174/392 (44.39%)   175/395 (44.30%) 
Blood and lymphatic system disorders     
Anaemia † 1  5/392 (1.28%)  2/395 (0.51%) 
Febrile neutropenia † 1  1/392 (0.26%)  1/395 (0.25%) 
Leukopenia † 1  1/392 (0.26%)  0/395 (0.00%) 
Neutropenia † 1  1/392 (0.26%)  0/395 (0.00%) 
Thrombocytopenia † 1  2/392 (0.51%)  0/395 (0.00%) 
Cardiac disorders     
Atrial fibrillation † 1  4/392 (1.02%)  2/395 (0.51%) 
Cardiac arrest † 1  1/392 (0.26%)  1/395 (0.25%) 
Cardiac failure † 1  1/392 (0.26%)  3/395 (0.76%) 
Cardiac failure congestive † 1  1/392 (0.26%)  0/395 (0.00%) 
Cardiac tamponade † 1  0/392 (0.00%)  1/395 (0.25%) 
Cardio-respiratory arrest † 1  0/392 (0.00%)  1/395 (0.25%) 
Cardiopulmonary failure † 1  1/392 (0.26%)  1/395 (0.25%) 
Myocardial infarction † 1  0/392 (0.00%)  4/395 (1.01%) 
Myocardial ischaemia † 1  1/392 (0.26%)  0/395 (0.00%) 
Palpitations † 1  2/392 (0.51%)  0/395 (0.00%) 
Pericardial effusion † 1  0/392 (0.00%)  2/395 (0.51%) 
Pericarditis † 1  0/392 (0.00%)  1/395 (0.25%) 
Sinus tachycardia † 1  1/392 (0.26%)  0/395 (0.00%) 
Supraventricular tachycardia † 1  3/392 (0.77%)  0/395 (0.00%) 
Tachycardia † 1  1/392 (0.26%)  0/395 (0.00%) 
Congenital, familial and genetic disorders     
Tracheo-oesophageal fistula † 1  1/392 (0.26%)  0/395 (0.00%) 
Endocrine disorders     
Inappropriate antidiuretic hormone secretion † 1  0/392 (0.00%)  1/395 (0.25%) 
Gastrointestinal disorders     
Abdominal pain † 1  5/392 (1.28%)  5/395 (1.27%) 
Abdominal pain upper † 1  0/392 (0.00%)  2/395 (0.51%) 
Anal fissure † 1  1/392 (0.26%)  0/395 (0.00%) 
Aphagia † 1  1/392 (0.26%)  0/395 (0.00%) 
Constipation † 1  0/392 (0.00%)  1/395 (0.25%) 
Diarrhoea † 1  18/392 (4.59%)  7/395 (1.77%) 
Dysphagia † 1  0/392 (0.00%)  3/395 (0.76%) 
Gastric perforation † 1  0/392 (0.00%)  1/395 (0.25%) 
Gastric ulcer † 1  1/392 (0.26%)  2/395 (0.51%) 
Gastritis † 1  1/392 (0.26%)  0/395 (0.00%) 
Gastrointestinal haemorrhage † 1  1/392 (0.26%)  1/395 (0.25%) 
Gastrointestinal perforation † 1  1/392 (0.26%)  0/395 (0.00%) 
Gastrointestinal telangiectasia † 1  0/392 (0.00%)  1/395 (0.25%) 
Intestinal obstruction † 1  1/392 (0.26%)  1/395 (0.25%) 
Intestinal perforation † 1  0/392 (0.00%)  1/395 (0.25%) 
Melaena † 1  0/392 (0.00%)  1/395 (0.25%) 
Nausea † 1  2/392 (0.51%)  3/395 (0.76%) 
Oesophageal stenosis † 1  1/392 (0.26%)  1/395 (0.25%) 
Pancreatic duct dilatation † 1  0/392 (0.00%)  1/395 (0.25%) 
Pancreatitis † 1  0/392 (0.00%)  1/395 (0.25%) 
Proctalgia † 1  1/392 (0.26%)  0/395 (0.00%) 
Small intestinal haemorrhage † 1  0/392 (0.00%)  1/395 (0.25%) 
Small intestinal obstruction † 1  0/392 (0.00%)  1/395 (0.25%) 
Stomatitis † 1  1/392 (0.26%)  0/395 (0.00%) 
Vomiting † 1  4/392 (1.02%)  5/395 (1.27%) 
General disorders     
Asthenia † 1  6/392 (1.53%)  3/395 (0.76%) 
Chest discomfort † 1  0/392 (0.00%)  2/395 (0.51%) 
Chest pain † 1  0/392 (0.00%)  6/395 (1.52%) 
Condition aggravated † 1  1/392 (0.26%)  1/395 (0.25%) 
Death † 1  4/392 (1.02%)  2/395 (0.51%) 
Device occlusion † 1  0/392 (0.00%)  1/395 (0.25%) 
Discomfort † 1  0/392 (0.00%)  1/395 (0.25%) 
Fatigue † 1  1/392 (0.26%)  2/395 (0.51%) 
General physical health deterioration † 1  11/392 (2.81%)  6/395 (1.52%) 
Mucosal inflammation † 1  2/392 (0.51%)  1/395 (0.25%) 
Multi-organ failure † 1  1/392 (0.26%)  1/395 (0.25%) 
Necrosis † 1  1/392 (0.26%)  0/395 (0.00%) 
Non-cardiac chest pain † 1  1/392 (0.26%)  0/395 (0.00%) 
Oedema peripheral † 1  0/392 (0.00%)  2/395 (0.51%) 
Pain † 1  2/392 (0.51%)  3/395 (0.76%) 
Performance status decreased † 1  0/392 (0.00%)  1/395 (0.25%) 
Pyrexia † 1  3/392 (0.77%)  4/395 (1.01%) 
Sudden death † 1  1/392 (0.26%)  1/395 (0.25%) 
Hepatobiliary disorders     
Hepatic function abnormal † 1  0/392 (0.00%)  1/395 (0.25%) 
Hepatitis toxic † 1  0/392 (0.00%)  1/395 (0.25%) 
Hepatomegaly † 1  0/392 (0.00%)  1/395 (0.25%) 
Hyperbilirubinaemia † 1  0/392 (0.00%)  1/395 (0.25%) 
Jaundice † 1  0/392 (0.00%)  1/395 (0.25%) 
Infections and infestations     
Anal abscess † 1  1/392 (0.26%)  0/395 (0.00%) 
Bronchitis † 1  2/392 (0.51%)  6/395 (1.52%) 
Bronchopneumonia † 1  0/392 (0.00%)  1/395 (0.25%) 
Endocarditis † 1  0/392 (0.00%)  1/395 (0.25%) 
Folliculitis † 1  1/392 (0.26%)  0/395 (0.00%) 
Gastroenteritis † 1  0/392 (0.00%)  1/395 (0.25%) 
Hepatitis C † 1  0/392 (0.00%)  1/395 (0.25%) 
Herpes virus infection † 1  0/392 (0.00%)  1/395 (0.25%) 
Infection † 1  1/392 (0.26%)  1/395 (0.25%) 
Lower respiratory tract infection † 1  1/392 (0.26%)  3/395 (0.76%) 
Lung infection † 1  2/392 (0.51%)  5/395 (1.27%) 
Oral fungal infection † 1  0/392 (0.00%)  1/395 (0.25%) 
Peritonitis † 1  1/392 (0.26%)  1/395 (0.25%) 
Pneumonia † 1  26/392 (6.63%)  16/395 (4.05%) 
Pneumonia bacterial † 1  0/392 (0.00%)  1/395 (0.25%) 
Pulmonary tuberculosis † 1  0/392 (0.00%)  1/395 (0.25%) 
Respiratory tract infection † 1  2/392 (0.51%)  0/395 (0.00%) 
Sepsis † 1  9/392 (2.30%)  2/395 (0.51%) 
Septic shock † 1  0/392 (0.00%)  1/395 (0.25%) 
Skin infection † 1  1/392 (0.26%)  0/395 (0.00%) 
Upper respiratory tract infection † 1  1/392 (0.26%)  0/395 (0.00%) 
Urinary tract infection † 1  2/392 (0.51%)  1/395 (0.25%) 
Injury, poisoning and procedural complications     
Cervical vertebral fracture † 1  0/392 (0.00%)  1/395 (0.25%) 
Femoral neck fracture † 1  2/392 (0.51%)  1/395 (0.25%) 
Femur fracture † 1  0/392 (0.00%)  1/395 (0.25%) 
Fracture † 1  0/392 (0.00%)  1/395 (0.25%) 
Injury † 1  0/392 (0.00%)  1/395 (0.25%) 
Investigations     
Blood calcium increased † 1  1/392 (0.26%)  0/395 (0.00%) 
Blood creatinine increased † 1  2/392 (0.51%)  1/395 (0.25%) 
Blood urea increased † 1  1/392 (0.26%)  0/395 (0.00%) 
C-reactive protein increased † 1  1/392 (0.26%)  0/395 (0.00%) 
Eastern Cooperative Oncology Group performance status worsened † 1  0/392 (0.00%)  1/395 (0.25%) 
General physical condition abnormal † 1  0/392 (0.00%)  1/395 (0.25%) 
Hepatic enzyme increased † 1  0/392 (0.00%)  1/395 (0.25%) 
Platelet count decreased † 1  1/392 (0.26%)  0/395 (0.00%) 
Weight decreased † 1  0/392 (0.00%)  1/395 (0.25%) 
White blood cell count decreased † 1  0/392 (0.00%)  1/395 (0.25%) 
Metabolism and nutrition disorders     
Cachexia † 1  2/392 (0.51%)  0/395 (0.00%) 
Decreased appetite † 1  3/392 (0.77%)  3/395 (0.76%) 
Dehydration † 1  12/392 (3.06%)  4/395 (1.01%) 
Hypercalcaemia † 1  1/392 (0.26%)  6/395 (1.52%) 
Hyperglycaemia † 1  1/392 (0.26%)  2/395 (0.51%) 
Hyperkalaemia † 1  1/392 (0.26%)  0/395 (0.00%) 
Hyperuricaemia † 1  0/392 (0.00%)  1/395 (0.25%) 
Hypokalaemia † 1  2/392 (0.51%)  0/395 (0.00%) 
Hypophagia † 1  0/392 (0.00%)  1/395 (0.25%) 
Malnutrition † 1  0/392 (0.00%)  1/395 (0.25%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  0/392 (0.00%)  1/395 (0.25%) 
Back pain † 1  3/392 (0.77%)  1/395 (0.25%) 
Bone pain † 1  1/392 (0.26%)  1/395 (0.25%) 
Muscle spasms † 1  1/392 (0.26%)  0/395 (0.00%) 
Muscular weakness † 1  2/392 (0.51%)  2/395 (0.51%) 
Musculoskeletal chest pain † 1  2/392 (0.51%)  0/395 (0.00%) 
Musculoskeletal pain † 1  1/392 (0.26%)  1/395 (0.25%) 
Myalgia † 1  1/392 (0.26%)  0/395 (0.00%) 
Neck pain † 1  2/392 (0.51%)  1/395 (0.25%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma of colon † 1  1/392 (0.26%)  0/395 (0.00%) 
Cancer pain † 1  0/392 (0.00%)  1/395 (0.25%) 
Malignant neoplasm progression † 1  23/392 (5.87%)  16/395 (4.05%) 
Metastases to bone † 1  0/392 (0.00%)  1/395 (0.25%) 
Metastases to central nervous system † 1  2/392 (0.51%)  6/395 (1.52%) 
Metastases to liver † 1  0/392 (0.00%)  1/395 (0.25%) 
Metastases to meninges † 1  1/392 (0.26%)  0/395 (0.00%) 
Neoplasm malignant † 1  2/392 (0.51%)  0/395 (0.00%) 
Neoplasm progression † 1  2/392 (0.51%)  1/395 (0.25%) 
Non-small cell lung cancer † 1  0/392 (0.00%)  1/395 (0.25%) 
Transitional cell carcinoma † 1  1/392 (0.26%)  0/395 (0.00%) 
Tumour pain † 1  2/392 (0.51%)  0/395 (0.00%) 
Ureteric cancer † 1  0/392 (0.00%)  1/395 (0.25%) 
Nervous system disorders     
Altered state of consciousness † 1  0/392 (0.00%)  1/395 (0.25%) 
Amnesia † 1  0/392 (0.00%)  1/395 (0.25%) 
Aphasia † 1  1/392 (0.26%)  0/395 (0.00%) 
Brain oedema † 1  3/392 (0.77%)  0/395 (0.00%) 
Cerebrovascular accident † 1  1/392 (0.26%)  1/395 (0.25%) 
Convulsion † 1  4/392 (1.02%)  1/395 (0.25%) 
Dizziness † 1  2/392 (0.51%)  4/395 (1.01%) 
Dysarthria † 1  0/392 (0.00%)  1/395 (0.25%) 
Haemorrhage intracranial † 1  0/392 (0.00%)  1/395 (0.25%) 
Hemiparesis † 1  1/392 (0.26%)  0/395 (0.00%) 
Hypoaesthesia † 1  0/392 (0.00%)  2/395 (0.51%) 
Motor dysfunction † 1  0/392 (0.00%)  1/395 (0.25%) 
Myoclonus † 1  1/392 (0.26%)  0/395 (0.00%) 
Paraparesis † 1  0/392 (0.00%)  1/395 (0.25%) 
Polyneuropathy † 1  1/392 (0.26%)  0/395 (0.00%) 
Somnolence † 1  1/392 (0.26%)  0/395 (0.00%) 
Spinal cord compression † 1  0/392 (0.00%)  2/395 (0.51%) 
Syncope † 1  1/392 (0.26%)  1/395 (0.25%) 
Psychiatric disorders     
Confusional state † 1  2/392 (0.51%)  1/395 (0.25%) 
Delirium † 1  0/392 (0.00%)  1/395 (0.25%) 
Disorientation † 1  0/392 (0.00%)  2/395 (0.51%) 
Renal and urinary disorders     
Acute prerenal failure † 1  1/392 (0.26%)  0/395 (0.00%) 
Azotaemia † 1  0/392 (0.00%)  1/395 (0.25%) 
Bladder mass † 1  0/392 (0.00%)  1/395 (0.25%) 
Calculus bladder † 1  1/392 (0.26%)  0/395 (0.00%) 
Calculus ureteric † 1  1/392 (0.26%)  0/395 (0.00%) 
Haematuria † 1  0/392 (0.00%)  2/395 (0.51%) 
Hydronephrosis † 1  1/392 (0.26%)  0/395 (0.00%) 
Renal failure † 1  2/392 (0.51%)  2/395 (0.51%) 
Renal failure acute † 1  9/392 (2.30%)  1/395 (0.25%) 
Renal impairment † 1  1/392 (0.26%)  0/395 (0.00%) 
Urinary bladder polyp † 1  0/392 (0.00%)  1/395 (0.25%) 
Urinary retention † 1  0/392 (0.00%)  1/395 (0.25%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema † 1  0/392 (0.00%)  1/395 (0.25%) 
Acute respiratory distress syndrome † 1  3/392 (0.77%)  1/395 (0.25%) 
Acute respiratory failure † 1  2/392 (0.51%)  0/395 (0.00%) 
Atelectasis † 1  1/392 (0.26%)  3/395 (0.76%) 
Bronchial fistula † 1  1/392 (0.26%)  0/395 (0.00%) 
Chronic obstructive pulmonary disease † 1  5/392 (1.28%)  4/395 (1.01%) 
Cough † 1  2/392 (0.51%)  3/395 (0.76%) 
Dyspnoea † 1  12/392 (3.06%)  30/395 (7.59%) 
Dyspnoea exertional † 1  2/392 (0.51%)  0/395 (0.00%) 
Haemoptysis † 1  5/392 (1.28%)  10/395 (2.53%) 
Hypoxia † 1  1/392 (0.26%)  1/395 (0.25%) 
Interstitial lung disease † 1  4/392 (1.02%)  1/395 (0.25%) 
Lung disorder † 1  1/392 (0.26%)  0/395 (0.00%) 
Pleural effusion † 1  3/392 (0.77%)  6/395 (1.52%) 
Pleurisy † 1  1/392 (0.26%)  0/395 (0.00%) 
Pleuritic pain † 1  1/392 (0.26%)  0/395 (0.00%) 
Pneumonia aspiration † 1  1/392 (0.26%)  0/395 (0.00%) 
Pneumonitis † 1  1/392 (0.26%)  3/395 (0.76%) 
Pneumothorax † 1  2/392 (0.51%)  4/395 (1.01%) 
Pulmonary artery thrombosis † 1  1/392 (0.26%)  0/395 (0.00%) 
Pulmonary embolism † 1  10/392 (2.55%)  5/395 (1.27%) 
Pulmonary haemorrhage † 1  2/392 (0.51%)  0/395 (0.00%) 
Pulmonary hypertension † 1  0/392 (0.00%)  1/395 (0.25%) 
Pulmonary mass † 1  1/392 (0.26%)  0/395 (0.00%) 
Pulmonary oedema † 1  1/392 (0.26%)  1/395 (0.25%) 
Respiratory disorder † 1  1/392 (0.26%)  0/395 (0.00%) 
Respiratory distress † 1  2/392 (0.51%)  2/395 (0.51%) 
Respiratory failure † 1  2/392 (0.51%)  12/395 (3.04%) 
Sputum increased † 1  1/392 (0.26%)  0/395 (0.00%) 
Skin and subcutaneous tissue disorders     
Acne † 1  0/392 (0.00%)  1/395 (0.25%) 
Dermatitis acneiform † 1  1/392 (0.26%)  0/395 (0.00%) 
Dermatomyositis † 1  0/392 (0.00%)  1/395 (0.25%) 
Palmar-plantar erythrodysaesthesia syndrome † 1  1/392 (0.26%)  0/395 (0.00%) 
Skin lesion † 1  0/392 (0.00%)  1/395 (0.25%) 
Vascular disorders     
Arterial thrombosis † 1  0/392 (0.00%)  1/395 (0.25%) 
Deep vein thrombosis † 1  2/392 (0.51%)  1/395 (0.25%) 
Haemorrhage † 1  0/392 (0.00%)  2/395 (0.51%) 
Hypotension † 1  1/392 (0.26%)  1/395 (0.25%) 
Inferior vena cava syndrome † 1  1/392 (0.26%)  0/395 (0.00%) 
Ischaemia † 1  0/392 (0.00%)  1/395 (0.25%) 
Orthostatic hypotension † 1  1/392 (0.26%)  0/395 (0.00%) 
Superior vena cava syndrome † 1  1/392 (0.26%)  1/395 (0.25%) 
Thrombosis † 1  0/392 (0.00%)  1/395 (0.25%) 
1
Term from vocabulary, MedDRA 20.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Afatinib Erlotinib
Affected / at Risk (%) Affected / at Risk (%)
Total   383/392 (97.70%)   371/395 (93.92%) 
Blood and lymphatic system disorders     
Anaemia † 1  31/392 (7.91%)  41/395 (10.38%) 
Gastrointestinal disorders     
Constipation † 1  43/392 (10.97%)  42/395 (10.63%) 
Diarrhoea † 1  284/392 (72.45%)  158/395 (40.00%) 
Nausea † 1  81/392 (20.66%)  62/395 (15.70%) 
Stomatitis † 1  54/392 (13.78%)  21/395 (5.32%) 
Vomiting † 1  48/392 (12.24%)  38/395 (9.62%) 
General disorders     
Asthenia † 1  61/392 (15.56%)  48/395 (12.15%) 
Chest pain † 1  14/392 (3.57%)  20/395 (5.06%) 
Fatigue † 1  65/392 (16.58%)  67/395 (16.96%) 
Mucosal inflammation † 1  50/392 (12.76%)  14/395 (3.54%) 
Pyrexia † 1  32/392 (8.16%)  33/395 (8.35%) 
Infections and infestations     
Paronychia † 1  41/392 (10.46%)  18/395 (4.56%) 
Investigations     
Weight decreased † 1  38/392 (9.69%)  51/395 (12.91%) 
Metabolism and nutrition disorders     
Decreased appetite † 1  94/392 (23.98%)  100/395 (25.32%) 
Musculoskeletal and connective tissue disorders     
Back pain † 1  22/392 (5.61%)  25/395 (6.33%) 
Musculoskeletal pain † 1  20/392 (5.10%)  20/395 (5.06%) 
Pain in extremity † 1  14/392 (3.57%)  23/395 (5.82%) 
Nervous system disorders     
Dizziness † 1  12/392 (3.06%)  21/395 (5.32%) 
Psychiatric disorders     
Insomnia † 1  20/392 (5.10%)  17/395 (4.30%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  65/392 (16.58%)  67/395 (16.96%) 
Dyspnoea † 1  68/392 (17.35%)  69/395 (17.47%) 
Epistaxis † 1  27/392 (6.89%)  10/395 (2.53%) 
Haemoptysis † 1  44/392 (11.22%)  39/395 (9.87%) 
Productive cough † 1  14/392 (3.57%)  21/395 (5.32%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform † 1  38/392 (9.69%)  56/395 (14.18%) 
Dry skin † 1  36/392 (9.18%)  47/395 (11.90%) 
Pruritus † 1  38/392 (9.69%)  52/395 (13.16%) 
Rash † 1  196/392 (50.00%)  187/395 (47.34%) 
1
Term from vocabulary, MedDRA 20.1
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Centre
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01523587    
Other Study ID Numbers: 1200.125
2011-002380-24 ( EudraCT Number )
First Submitted: January 30, 2012
First Posted: February 1, 2012
Results First Submitted: October 6, 2014
Results First Posted: November 21, 2014
Last Update Posted: February 15, 2019