LUX-Lung 7: A Phase IIb Trial of Afatinib(BIBW2992) Versus Gefitinib for the Treatment of 1st Line EGFR Mutation Positive Adenocarcinoma of the Lung

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01466660
• Collaborator: (none)
• Enrollment: 319
• Locations: 63
• Arms: 2
• Actual Duration (Months): 88
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.

Condition or Disease	Intervention/Treatment	Phase
Lung Neoplasms	Drug: Afatinib; Drug: gefitinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 319 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: LUX-Lung 7: A Randomised, Open-label Phase IIb Trial of Afatinib Versus Gefitinib as First-line Treatment of Patients With EGFR Mutation Positive Advanced Adenocarcinoma of the Lung
• Actual Study Start Date: Dec 13, 2011
• Actual Primary Completion Date: Apr 8, 2016
• Actual Study Completion Date: Apr 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: afatinib afatinib once daily.	Drug: Afatinib; afatinib once daily; Other Names: Giotrif® / Gilotrif®
Active Comparator: gefitinib gefitinib once daily	Drug: gefitinib; Gefitinib once daily

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.]

   Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.

2. Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016) [From first drug administration until last drug administration, up to 1482 days]

   Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.

3. Overall Survival [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.]

   Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.

Secondary Outcome Measures

1. Objective Response Rate [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.]

   Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

2. Time to Objective Response [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.]

   Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

3. Duration of Objective Response [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.]

   Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

4. Disease Control [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.]

   Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.

5. Duration of Disease Control [From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.]

   Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment.

6. Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016) [From first drug administration until last drug administration, up to 1482 days]

   Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.

7. Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) [Every 8 weeks, up to 56 weeks]

   Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Pathologically confirmed diagnosis of Stage IIIB / IV adenocarcinoma of the lung.

2. Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues.

3. At least one measurable lesion according to response evaluation criteria in solid tumours version 1.1

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

5. Age >= 18 years.

6. Adequate organ function as defined by the following criteria:

Serum aspartate transaminase(AST) and serum alanine transaminase(ALT) =< 3 x upper limit of normal (ULN), or AST and ALT =<5 x ULN if liver function abnormalities are due to underlying malignancy Total serum bilirubin =<1.5 x ULN Absolute neutrophil count (ANC)

=1.5 x 109/L Creatinine clearance > 45ml / min Platelets >= 75 x 109/L

Exclusion criteria:

1. Prior systemic chemotherapy for stage IIIB or IV non-small cell lung cancer. Neo-/adjuvant chemotherapy, chemoradiation or radiotherapy is permitted if at least 12 months has elapsed prior to disease progression.

2. Prior treatment with epidermal growth factor receptor targeting small molecules or antibodies.

3. Major surgery within 4 weeks of study randomisation.

4. Active brain metastases

5. Meningeal carcinomatosis.

6. Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured in the opinion of investigator.

7. Known pre-existing interstitial lung disease.

8. Clinically relevant cardiovascular abnormalities as judged by the investigator.

9. Cardiac left ventricular function with resting ejection fraction of less than institutional lower limit of normal.

10. Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended.

11. Pregnancy or breast-feeding.

12. Active hepatitis and/or known HIV carrier

13. Any prohibited concomitant medications for therapy with afatinib or gefitinib

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chris Obrien Lifehouse	Camperdown	New South Wales	Australia	2050
2	St George Hospital	Kogarah	New South Wales	Australia	2217
3	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
4	Haematology & Oncology Clinics of Australasia (HOCA)	South Brisbane	Queensland	Australia	4101
5	Box Hill Hospital	Box Hill	Victoria	Australia	3128
6	Austin Health	Heidelberg	Victoria	Australia	3084
7	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009
8	Cross Cancer Institute (University of Alberta)	Edmonton	Alberta	Canada	T6G 1Z2
9	British Columbia Cancer Agency (BCCA) - Fraser Valley Cancer	Surrey	British Columbia	Canada	V1V 1Z2
10	BC Cancer Agency - Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
11	Lakeridge Health Oshawa	Oshawa	Ontario	Canada	L1G 2B9
12	The Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
13	Montreal General Hospital - McGill University Health Centre	Montreal	Quebec	Canada	H3G 1A4
14	Cancer Hospital of Chinese Academy of Medical Science	Beijing		China	100021
15	Beijing Cancer Hospital	Beijing		China	100036
16	Sun Yat-Sen University Cancer Center	Guangzhou		China	510060
17	The Affiliated Cancer Hospital, Guangxi Medical University	Nan Ning		China	530021
18	Shanghai Chest Hospital	Shanghai		China	200030
19	Zhongshan Hospital Fudan University	Shanghai		China	200032
20	The First Hospital of Chinese Medical University	Shenyang		China	110001
21	CTR Oncologie du Pays Basque, Onco, Bayonne	Bayonne		France	64100
22	CTR François Baclesse	Caen		France	14076
23	HOP Intercommunal	Créteil		France	94010
24	HOP Michallon	La Tronche		France	38700
25	HOP Dupuytren 1	Limoges Cedex		France	87042
26	CTR Leon Berard	Lyon		France	69373
27	CTR René Gauducheau	Saint Herblain		France	44805
28	HOP Sud-Réunion, Pneumo, Saint Pierre	St-Pierre - La Réunion		France	97448
29	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen		Germany	45122
30	Klinikum Esslingen GmbH	Esslingen		Germany	73730
31	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
32	Queen Mary Hospital	Hongkong		Hong Kong
33	Prince of Wales Hospital	Shatin		Hong Kong
34	Beaumont Hospital	Dublin 9		Ireland	D09 Y5R3
35	St James's Hospital	Dublin		Ireland	8
36	Chungbuk National University Hospital	Cheongju		Korea, Republic of	361-771
37	Gachon University Gil Medical Center	Incheon		Korea, Republic of	405-760
38	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
39	Severance Hospital	Seoul		Korea, Republic of	120-752
40	Samsung Medical Center	Seoul		Korea, Republic of	135-710
41	Asan Medical Center	Seoul		Korea, Republic of	138-736
42	Oslo Universitetssykehus HF, Radiumhospitalet	Oslo		Norway	N-0379
43	National Cancer Centre	Singapore		Singapore	169610
44	Johns Hopkins Singapore International Medical Center	Singapore		Singapore	308433
45	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
46	Hospital Regional Universitario de Málaga	Malaga		Spain	29010
47	Hospital Central de Asturias	Oviedo		Spain	33006
48	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008
49	Hospital Virgen del Rocío	Sevilla		Spain	41013
50	Sahlgrenska US, Göteborg	Göteborg		Sweden	413 45
51	Universitetssjukhuset, Linköping	Linköping		Sweden	581 85
52	Skånes universitetssjukhus, Lund	Lund		Sweden	221 85
53	Karolinska Univ. sjukhuset	Stockholm		Sweden	171 76
54	Taichung Veterans General Hospital	Taichung		Taiwan	407
55	NCKUH	Tainan		Taiwan	704
56	National Taiwan University Hospital	Taipei		Taiwan	100
57	Taipe Veterans General Hospital	Taipei		Taiwan	112
58	Chang Gung Memorial Hospital(Linkou)	Tao-Yuan		Taiwan	333
59	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
60	Birmingham City Hospital	Birmingham		United Kingdom	B18 7QH
61	Velindre Cancer Centre	Cardiff		United Kingdom	CF14 2TL
62	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
63	Royal Surrey County Hospital	Guildford		United Kingdom	GU2 7XX

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01466660
• Other Study ID Numbers: 1200.123; 2011-001814-33
• First Posted: Nov 8, 2011
• Last Update Posted: Apr 7, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Adenocarcinoma; Lung Neoplasms; Adenocarcinoma of Lung; Gefitinib; Afatinib

Study Results

Participant Flow

Recruitment Details	Two-arm, randomised (1:1 ratio), open-label, parallel group trial. In the study disease response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
Pre-assignment Detail	All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Period Title: Overall Study
STARTED	160	159
COMPLETED	0	0
NOT COMPLETED	160	159

Baseline Characteristics

Arm/Group Title	Afatinib	Gefitinib	Total
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Total of all reporting groups
Overall Participants	160	159	319
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.7 (11.5)	63.0 (10.4)	62.4 (11.0)
Sex: Female, Male (Count of Participants)
Female	91 56.9%	106 66.7%	197 61.8%
Male	69 43.1%	53 33.3%	122 38.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	94 58.8%	88 55.3%	182 57.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.6%	0 0%	1 0.3%
White	48 30%	54 34%	102 32%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	17 10.6%	17 10.7%	34 10.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

Randomised set which included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	159
Median (95% Confidence Interval) [Months]	12.78	11.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0891
	Comments	p-value was not adjusted for multiple comparisons
	Method	Log Rank
	Comments	Stratified by Epidermal Growth Factor Receptor (EGFR) mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.822
	Confidence Interval	(2-Sided) 95%; 0.655 to 1.032
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Cox proportional hazards model, stratified by EGFR mutation group and presence of baseline brain metastases was used to estimate the hazard ratio calculated as Afatinib divided by Gefitinib.

2. Primary Outcome

Title	Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016)
Description	Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.
Time Frame	From first drug administration until last drug administration, up to 1482 days

Outcome Measure Data

Analysis Population Description

Randomised set which included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	159
Median (95% Confidence Interval) [Months]	13.67	11.53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0136
	Comments	p-value was not adjusted for multiple comparisons
	Method	Log Rank
	Comments	Stratified by EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.750
	Confidence Interval	(2-Sided) 95%; 0.595 to 0.944
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio calculated as Afatinib divided by Gefitinib

3. Primary Outcome

Title	Overall Survival
Description	Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

Randomised set which included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	159
Median (95% Confidence Interval) [Months]	27.86	24.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2343
	Comments	p-value was not adjusted for multiple comparisons
	Method	Log Rank
	Comments	Stratified by EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.862
	Confidence Interval	(2-Sided) 95%; 0.674 to 1.101
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Cox proportional hazards model, stratified by EGFR mutation group and presence of baseline brain metastases was used to estimate the hazard ratio calculated as Afatinib divided by Gefitinib.

4. Secondary Outcome

Title	Objective Response Rate
Description	Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

Randomised set which included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	159
Number (95% Confidence Interval) [Percentage of participants]	79.4 49.6%	74.8 47%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3235
	Comments	p-value was not adjusted for multiple comparisons
	Method	Regression, Logistic
	Comments	Stratified for EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.307
	Confidence Interval	(2-Sided) 95%; 0.768 to 2.223
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio calculated as Afatinib divided by Gefitinib

5. Secondary Outcome

Title	Time to Objective Response
Description	Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

All participants in the randomised set with objective response.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	127	119
Week 4	81 50.6%	74 46.5%
Week 8	112 70%	107 67.3%
Week 16	119 74.4%	117 73.6%
Week 24	122 76.3%	118 74.2%
Week 32	125 78.1%	118 74.2%
Week 40	126 78.8%	118 74.2%
Week 48	127 79.4%	119 74.8%

6. Secondary Outcome

Title	Duration of Objective Response
Description	Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

Participants in the randomised set with objective response.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	127	119
Median (95% Confidence Interval) [Months]	11.86	11.07

7. Secondary Outcome

Title	Disease Control
Description	Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

Randomised set which included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	159
Number (95% Confidence Interval) [Percentage of participants]	94.4 59%	93.7 58.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7856
	Comments	p-value was not adjusted for multiple comparisons
	Method	Regression, Logistic
	Comments	Stratified for EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.138
	Confidence Interval	(2-Sided) 95%; 0.447 to 2.896
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio calculated as Afatinib divided by Gefitinib

8. Secondary Outcome

Title	Duration of Disease Control
Description	Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment.
Time Frame	From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Outcome Measure Data

Analysis Population Description

All participants in the randomised set with disease control, that is, with best overall response of complete response or partial response or stable disease.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	151	149
Median (95% Confidence Interval) [Months]	12.88	11.73

9. Secondary Outcome

Title	Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016)
Description	Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.
Time Frame	From first drug administration until last drug administration, up to 1482 days

Outcome Measure Data

Analysis Population Description

Participants in the randomised set with tumour assessments.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	149	151
Least Squares Mean (95% Confidence Interval) [millimetre (mm)]	34.79	38.25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0657
	Comments	p-value was not adjusted for multiple comparisons
	Method	ANCOVA
	Comments	Adjusted for baseline sum of diameters, EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.45
	Confidence Interval	(2-Sided) 95%; -7.13 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.87
	Estimation Comments	Difference calculated as Afatinib minus Gefitinib

10. Secondary Outcome

Title	Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015)
Description	Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.
Time Frame	Every 8 weeks, up to 56 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects with health-related quality of life data.

Arm/Group Title	Afatinib	Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.	Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
Measure Participants	160	158
EQ-5D UK utility score	0.77	0.80
EQ-5D Belgium utility score	0.74	0.77
EQ-VAS utility score	74.5	76.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	EQ-5D UK utility score. Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1422
	Comments	p-value was not adjusted for multiple comparisons
	Method	Mixed Models Analysis
	Comments	Adjusted for EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Difference calculated as Afatinib minus Gefitinib

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	EQ-5D Belgium utility score. Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0540
	Comments	p-value was not adjusted for multiple comparisons
	Method	Mixed Models Analysis
	Comments	Adjusted for EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.016
	Estimation Comments	Difference calculated as Afatinib divided by Gefitinib

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Gefitinib
	Comments	EQ-VAS utility score. Exploratory trial, no formal hypotheses were tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2032
	Comments	p-value was not adjusted for multiple comparisons
	Method	Mixed Models Analysis
	Comments	Adjusted for EGFR mutation group and presence of brain metastases at baseline
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -3.9 to 0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.21
	Estimation Comments	Difference calculated as Afatinib divided by Gefitinib

Adverse Events

Time Frame	From first drug administration until 28 days after last drug administration, up to 2405 days. For All-Cause Mortality: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.
Adverse Event Reporting Description	Treated set included all patients who were dispensed with and documented to have taken at least one dose of study medication. This set of patients was used for the evaluation of safety.
Arm/Group Title	Afatinib		Gefitinib
Arm/Group Description	Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.		Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
All Cause Mortality
	Afatinib		Gefitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/160 (78.8%)		132/159 (83%)
Serious Adverse Events
	Afatinib		Gefitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/160 (46.9%)		64/159 (40.3%)
Blood and lymphatic system disorders
Anaemia	0/160 (0%)		1/159 (0.6%)
Lymphoid tissue hyperplasia	1/160 (0.6%)		0/159 (0%)
Bone marrow failure	0/160 (0%)		1/159 (0.6%)
Cardiac disorders
Acute coronary syndrome	1/160 (0.6%)		0/159 (0%)
Angina pectoris	1/160 (0.6%)		0/159 (0%)
Atrial fibrillation	0/160 (0%)		1/159 (0.6%)
Coronary artery disease	1/160 (0.6%)		1/159 (0.6%)
Myocardial infarction	2/160 (1.3%)		0/159 (0%)
Pericardial effusion	1/160 (0.6%)		3/159 (1.9%)
Coronary artery occlusion	0/160 (0%)		1/159 (0.6%)
Ear and labyrinth disorders
Sudden hearing loss	1/160 (0.6%)		0/159 (0%)
Endocrine disorders
Cushing's syndrome	1/160 (0.6%)		0/159 (0%)
Eye disorders
Macular degeneration	0/160 (0%)		1/159 (0.6%)
Gastrointestinal disorders
Abdominal pain	0/160 (0%)		1/159 (0.6%)
Abdominal pain lower	0/160 (0%)		1/159 (0.6%)
Anal haemorrhage	0/160 (0%)		1/159 (0.6%)
Constipation	2/160 (1.3%)		0/159 (0%)
Diarrhoea	11/160 (6.9%)		2/159 (1.3%)
Gastrointestinal haemorrhage	0/160 (0%)		1/159 (0.6%)
Ileus	1/160 (0.6%)		0/159 (0%)
Intestinal obstruction	1/160 (0.6%)		0/159 (0%)
Nausea	0/160 (0%)		1/159 (0.6%)
Pancreatitis acute	1/160 (0.6%)		0/159 (0%)
Stomatitis	3/160 (1.9%)		0/159 (0%)
Vomiting	1/160 (0.6%)		3/159 (1.9%)
Haemorrhoids	0/160 (0%)		1/159 (0.6%)
Pancreatitis	1/160 (0.6%)		0/159 (0%)
General disorders
Asthenia	4/160 (2.5%)		2/159 (1.3%)
Chest pain	1/160 (0.6%)		0/159 (0%)
Death	1/160 (0.6%)		0/159 (0%)
Fatigue	0/160 (0%)		1/159 (0.6%)
General physical health deterioration	1/160 (0.6%)		3/159 (1.9%)
Pain	0/160 (0%)		2/159 (1.3%)
Pyrexia	1/160 (0.6%)		0/159 (0%)
Multiple organ dysfunction syndrome	1/160 (0.6%)		1/159 (0.6%)
Hepatobiliary disorders
Cholecystitis acute	1/160 (0.6%)		0/159 (0%)
Cholelithiasis	1/160 (0.6%)		0/159 (0%)
Hepatic failure	0/160 (0%)		1/159 (0.6%)
Hepatic haemorrhage	1/160 (0.6%)		0/159 (0%)
Hepatitis	0/160 (0%)		1/159 (0.6%)
Infections and infestations
Bronchitis	1/160 (0.6%)		0/159 (0%)
Clostridium difficile colitis	1/160 (0.6%)		0/159 (0%)
Empyema	1/160 (0.6%)		0/159 (0%)
Encephalitis	1/160 (0.6%)		0/159 (0%)
Erysipelas	1/160 (0.6%)		0/159 (0%)
Gastroenteritis	1/160 (0.6%)		0/159 (0%)
Infection	2/160 (1.3%)		1/159 (0.6%)
Influenza	1/160 (0.6%)		0/159 (0%)
Lung infection	0/160 (0%)		1/159 (0.6%)
Pneumonia	7/160 (4.4%)		5/159 (3.1%)
Sepsis	1/160 (0.6%)		4/159 (2.5%)
Skin bacterial infection	1/160 (0.6%)		0/159 (0%)
Upper respiratory tract infection	2/160 (1.3%)		0/159 (0%)
Urinary tract infection	0/160 (0%)		2/159 (1.3%)
Urosepsis	1/160 (0.6%)		0/159 (0%)
Lower respiratory tract infection	1/160 (0.6%)		0/159 (0%)
Large intestine infection	1/160 (0.6%)		0/159 (0%)
Injury, poisoning and procedural complications
Foreign body aspiration	1/160 (0.6%)		0/159 (0%)
Lower limb fracture	1/160 (0.6%)		0/159 (0%)
Spinal compression fracture	1/160 (0.6%)		0/159 (0%)
Spinal fracture	1/160 (0.6%)		0/159 (0%)
Thermal burn	1/160 (0.6%)		0/159 (0%)
Wound haemorrhage	0/160 (0%)		1/159 (0.6%)
Hip fracture	0/160 (0%)		1/159 (0.6%)
Femur fracture	1/160 (0.6%)		0/159 (0%)
Limb injury	1/160 (0.6%)		0/159 (0%)
Skin laceration	1/160 (0.6%)		0/159 (0%)
Investigations
Blood sodium decreased	0/160 (0%)		1/159 (0.6%)
Weight decreased	0/160 (0%)		1/159 (0.6%)
Alanine aminotransferase increased	1/160 (0.6%)		0/159 (0%)
Aspartate aminotransferase increased	1/160 (0.6%)		0/159 (0%)
Blood bilirubin increased	1/160 (0.6%)		0/159 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/160 (0%)		1/159 (0.6%)
Dehydration	3/160 (1.9%)		1/159 (0.6%)
Hypokalaemia	1/160 (0.6%)		1/159 (0.6%)
Hyponatraemia	1/160 (0.6%)		0/159 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/160 (1.9%)		2/159 (1.3%)
Bone pain	1/160 (0.6%)		0/159 (0%)
Intervertebral disc protrusion	1/160 (0.6%)		0/159 (0%)
Muscular weakness	1/160 (0.6%)		1/159 (0.6%)
Musculoskeletal pain	0/160 (0%)		2/159 (1.3%)
Pain in extremity	0/160 (0%)		1/159 (0.6%)
Spinal osteoarthritis	0/160 (0%)		1/159 (0.6%)
Spinal pain	1/160 (0.6%)		0/159 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma	1/160 (0.6%)		0/159 (0%)
Malignant neoplasm progression	7/160 (4.4%)		1/159 (0.6%)
Metastases to central nervous system	0/160 (0%)		2/159 (1.3%)
Metastases to meninges	1/160 (0.6%)		3/159 (1.9%)
Renal cancer	0/160 (0%)		1/159 (0.6%)
Small cell lung cancer	1/160 (0.6%)		0/159 (0%)
Basal cell carcinoma	1/160 (0.6%)		0/159 (0%)
Cancer pain	1/160 (0.6%)		1/159 (0.6%)
Cholesteatoma	0/160 (0%)		1/159 (0.6%)
Endometrial adenocarcinoma	1/160 (0.6%)		0/159 (0%)
Nervous system disorders
Aphasia	0/160 (0%)		1/159 (0.6%)
Cerebellar haemorrhage	0/160 (0%)		1/159 (0.6%)
Cerebellar infarction	0/160 (0%)		1/159 (0.6%)
Cerebral haemorrhage	0/160 (0%)		1/159 (0.6%)
Cerebral infarction	1/160 (0.6%)		1/159 (0.6%)
Cerebrovascular accident	1/160 (0.6%)		0/159 (0%)
Cognitive disorder	0/160 (0%)		1/159 (0.6%)
Dizziness	1/160 (0.6%)		5/159 (3.1%)
Dystonia	1/160 (0.6%)		0/159 (0%)
Embolic cerebral infarction	1/160 (0.6%)		0/159 (0%)
Generalised tonic-clonic seizure	1/160 (0.6%)		0/159 (0%)
Headache	1/160 (0.6%)		3/159 (1.9%)
Hydrocephalus	0/160 (0%)		1/159 (0.6%)
Ischaemic stroke	1/160 (0.6%)		1/159 (0.6%)
Nervous system disorder	0/160 (0%)		1/159 (0.6%)
Paraneoplastic encephalomyelitis	1/160 (0.6%)		0/159 (0%)
Paraplegia	0/160 (0%)		1/159 (0.6%)
Partial seizures	1/160 (0.6%)		0/159 (0%)
Peripheral sensory neuropathy	1/160 (0.6%)		0/159 (0%)
Seizure	0/160 (0%)		1/159 (0.6%)
Spinal cord compression	1/160 (0.6%)		2/159 (1.3%)
Cerebral disorder	0/160 (0%)		1/159 (0.6%)
Cerebral ischaemia	0/160 (0%)		1/159 (0.6%)
Dementia	1/160 (0.6%)		0/159 (0%)
Status epilepticus	1/160 (0.6%)		0/159 (0%)
Psychiatric disorders
Confusional state	2/160 (1.3%)		0/159 (0%)
Depression	1/160 (0.6%)		0/159 (0%)
Mental status changes	0/160 (0%)		1/159 (0.6%)
Delirium	1/160 (0.6%)		1/159 (0.6%)
Renal and urinary disorders
Acute kidney injury	3/160 (1.9%)		0/159 (0%)
Calculus bladder	0/160 (0%)		1/159 (0.6%)
Renal colic	0/160 (0%)		1/159 (0.6%)
Renal failure	0/160 (0%)		1/159 (0.6%)
Urinary tract obstruction	1/160 (0.6%)		0/159 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/160 (0%)		1/159 (0.6%)
Cervical dysplasia	0/160 (0%)		1/159 (0.6%)
Pelvic pain	0/160 (0%)		1/159 (0.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/160 (0.6%)		1/159 (0.6%)
Chronic obstructive pulmonary disease	1/160 (0.6%)		0/159 (0%)
Cough	1/160 (0.6%)		0/159 (0%)
Dyspnoea	2/160 (1.3%)		5/159 (3.1%)
Haemoptysis	0/160 (0%)		2/159 (1.3%)
Interstitial lung disease	1/160 (0.6%)		4/159 (2.5%)
Pleural effusion	9/160 (5.6%)		2/159 (1.3%)
Pleurisy	1/160 (0.6%)		0/159 (0%)
Pneumonia aspiration	1/160 (0.6%)		1/159 (0.6%)
Pneumothorax	3/160 (1.9%)		3/159 (1.9%)
Pulmonary embolism	6/160 (3.8%)		5/159 (3.1%)
Pulmonary oedema	1/160 (0.6%)		0/159 (0%)
Respiratory distress	1/160 (0.6%)		0/159 (0%)
Respiratory failure	1/160 (0.6%)		1/159 (0.6%)
Skin and subcutaneous tissue disorders
Eczema	1/160 (0.6%)		0/159 (0%)
Intertrigo	1/160 (0.6%)		0/159 (0%)
Pain of skin	1/160 (0.6%)		0/159 (0%)
Seborrhoeic dermatitis	0/160 (0%)		1/159 (0.6%)
Surgical and medical procedures
Pneumonectomy	0/160 (0%)		1/159 (0.6%)
Vascular disorders
Deep vein thrombosis	1/160 (0.6%)		0/159 (0%)
Hypertensive crisis	0/160 (0%)		1/159 (0.6%)
Superior vena cava syndrome	1/160 (0.6%)		0/159 (0%)
Other (Not Including Serious) Adverse Events
	Afatinib		Gefitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/160 (98.1%)		159/159 (100%)
Blood and lymphatic system disorders
Anaemia	14/160 (8.8%)		5/159 (3.1%)
Eye disorders
Dry eye	15/160 (9.4%)		13/159 (8.2%)
Gastrointestinal disorders
Abdominal pain	14/160 (8.8%)		11/159 (6.9%)
Abdominal pain upper	17/160 (10.6%)		17/159 (10.7%)
Constipation	29/160 (18.1%)		24/159 (15.1%)
Diarrhoea	143/160 (89.4%)		102/159 (64.2%)
Dry mouth	11/160 (6.9%)		14/159 (8.8%)
Dyspepsia	16/160 (10%)		14/159 (8.8%)
Gastrooesophageal reflux disease	6/160 (3.8%)		13/159 (8.2%)
Mouth ulceration	20/160 (12.5%)		7/159 (4.4%)
Nausea	43/160 (26.9%)		45/159 (28.3%)
Stomatitis	63/160 (39.4%)		18/159 (11.3%)
Vomiting	31/160 (19.4%)		19/159 (11.9%)
General disorders
Asthenia	21/160 (13.1%)		22/159 (13.8%)
Chest pain	20/160 (12.5%)		19/159 (11.9%)
Fatigue	34/160 (21.3%)		30/159 (18.9%)
Influenza like illness	3/160 (1.9%)		8/159 (5%)
Mucosal inflammation	32/160 (20%)		19/159 (11.9%)
Oedema peripheral	11/160 (6.9%)		10/159 (6.3%)
Pyrexia	22/160 (13.8%)		10/159 (6.3%)
Infections and infestations
Conjunctivitis	14/160 (8.8%)		10/159 (6.3%)
Folliculitis	10/160 (6.3%)		4/159 (2.5%)
Nasopharyngitis	11/160 (6.9%)		11/159 (6.9%)
Paronychia	89/160 (55.6%)		28/159 (17.6%)
Upper respiratory tract infection	16/160 (10%)		20/159 (12.6%)
Urinary tract infection	18/160 (11.3%)		9/159 (5.7%)
Investigations
Alanine aminotransferase increased	19/160 (11.9%)		44/159 (27.7%)
Aspartate aminotransferase increased	15/160 (9.4%)		38/159 (23.9%)
Weight decreased	18/160 (11.3%)		9/159 (5.7%)
Metabolism and nutrition disorders
Decreased appetite	45/160 (28.1%)		39/159 (24.5%)
Hypokalaemia	15/160 (9.4%)		7/159 (4.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/160 (6.9%)		16/159 (10.1%)
Back pain	22/160 (13.8%)		32/159 (20.1%)
Muscle spasms	13/160 (8.1%)		12/159 (7.5%)
Musculoskeletal chest pain	9/160 (5.6%)		13/159 (8.2%)
Musculoskeletal pain	14/160 (8.8%)		17/159 (10.7%)
Neck pain	3/160 (1.9%)		12/159 (7.5%)
Pain in extremity	20/160 (12.5%)		10/159 (6.3%)
Nervous system disorders
Dizziness	12/160 (7.5%)		18/159 (11.3%)
Headache	14/160 (8.8%)		22/159 (13.8%)
Psychiatric disorders
Insomnia	13/160 (8.1%)		9/159 (5.7%)
Anxiety	4/160 (2.5%)		8/159 (5%)
Renal and urinary disorders
Dysuria	7/160 (4.4%)		9/159 (5.7%)
Respiratory, thoracic and mediastinal disorders
Cough	48/160 (30%)		47/159 (29.6%)
Dysphonia	10/160 (6.3%)		5/159 (3.1%)
Dyspnoea	34/160 (21.3%)		26/159 (16.4%)
Epistaxis	30/160 (18.8%)		14/159 (8.8%)
Haemoptysis	5/160 (3.1%)		9/159 (5.7%)
Nasal dryness	12/160 (7.5%)		0/159 (0%)
Nasal inflammation	11/160 (6.9%)		1/159 (0.6%)
Oropharyngeal pain	7/160 (4.4%)		10/159 (6.3%)
Productive cough	6/160 (3.8%)		11/159 (6.9%)
Rhinorrhoea	24/160 (15%)		12/159 (7.5%)
Skin and subcutaneous tissue disorders
Acne	5/160 (3.1%)		17/159 (10.7%)
Alopecia	19/160 (11.9%)		27/159 (17%)
Dermatitis acneiform	34/160 (21.3%)		34/159 (21.4%)
Dry skin	52/160 (32.5%)		63/159 (39.6%)
Erythema	10/160 (6.3%)		4/159 (2.5%)
Nail disorder	10/160 (6.3%)		3/159 (1.9%)
Pruritus	40/160 (25%)		40/159 (25.2%)
Rash	100/160 (62.5%)		87/159 (54.7%)
Skin fissures	23/160 (14.4%)		6/159 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.