LUX-Lung 5: Afatinib Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following Afatinib Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01085136
• Collaborator: (none)
• Enrollment: 1,154
• Locations: 98
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 11.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this randomized, open-label, active-controlled, multi-center trial is to determine the efficacy of BIBW 2992 given as an add-on to chemotherapy in patients with NSCLC Stage IIIb or IV progressing after BIBW 2992 monotherapy compared to chemotherapy alone in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up. Additional information on the health-related quality of life (HRQOL) will be collected.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Investigator´s choice of chemotherapy; Drug: BIBW 2992	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1154 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Randomized Trial of BIBW 2992 Plus Weekly Paclitaxel Versus Investigator's Choice of Chemotherapy Following BIBW 2992 Monotherapy in Non-small Cell Lung Cancer Patients Failing Previous Erlotinib or Gefitinib Treatment (LUX Lung 5)
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Investigator's choice of chemotherapy Patients will be treated with investigator's choice of chemotherapy	Drug: Investigator´s choice of chemotherapy; BIBW 2992 in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy
Experimental: BIBW 2992 and Paclitaxel Patients will be treated with BIBW 2992daily with a medium dose and weekly administration of Paclitaxel at a dose of 80 mg/m2	Drug: BIBW 2992; BIBW 2992 will be given in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (Part B) [From randomization until disease progression or death; Up to 32 months]

   Progression free survival (PFS) time as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 from day of randomization until disease progression or death for patients randomised to combination therapy with afatinib plus paclitaxel or to investigator's choice of chemotherapy. Median was calculated from the Kaplan-Meier curve.

Secondary Outcome Measures

1. Progression Free Survival (Part A) [From first dose administration until disease progression or death; Up to 51 months]

   Progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A. Median was calculated from the Kaplan-Meier curve.

2. Overall Survival (Part B) [From randomization until death; Up to 32 months]

   Overall survival (OS) as determined by the time from randomization to death in part B. Median was calculated from the Kaplan-Meier curve.

3. Objective Response (Part A) [Post baseline tumour-imaging was performed at every 6 weeks thereafter until disease progression; upto 51 months]

   Objective response defined as the best overall response of complete response [CR]: disappearance of all target lesion & partial response [PR]: ≥30% decrease in the sum of the longest diameter of target lesions , taking as reference the baseline sum longest diameter of Afatinib monotherapy according to RECIST 1.1 for Part A.

4. Objective Response (Part B) [Post baseline tumour-imaging was performed at every 8 weeks thereafter until disease progression; up to 32 Months]

   Objective response (CR, PR) of Afatinib/paclitaxel combination therapy and comparator chemotherapy in Part B after progression in Part A according to RECIST 1.1 .

5. Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. [From first administration of treatment until 28 days after last drug administration, up to 51 Months (Part A) and from randomization until 28 days after last drug administration of Trial medication, up to 32 Months (Part B)]

   Safety of Afatinib as indicated by intensity and incidence of adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0 both for Part A and Part B. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

Part A

1. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV who have failed treatment with erlotinib (Tarceva) or gefitinib (Iressa).

2. Patients should have received and failed at least one line of cytotoxic chemotherapy including a platinum-based regimen in patients eligible for platinum-based therapy and pemetrexed in pemetrexed eligible patients (unless pemetrexed is not considered a regulatory or clinical standard of care e.g. no label indication, no availability or no coverage by 3rd party payer(s)) for advanced or metastatic disease and have progressive disease following at least 12 weeks of treatment with erlotinib or gefitinib

3. Patients pretreated with taxane-based chemotherapy for advanced or metastatic disease must have experienced stable disease, partial or complete response as best response

4. Eastern Cooperative Oncology Group performance Score 0 or 1.

5. Patients with at least one tumor lesion that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension with longest diameter to be recorded as 10 mm but no less than double the slice thickness according to RESIST 1.1.

6. Male and female patients no less than 18 years of age.

7. Life expectancy of at least three (3) months.

8. Written informed consent that is consistent with ICH-GCP guidelines. Part B 1) Clinical benefit (disease stabilization or antitumor response) of 12 weeks duration in Part A of the trial determined on the second tumour assessment.

2.) Patients should have progressed in Part A according to RECIST 1.1 3.) New informed consent, including consent to biomarker sampling, must be signed before patients enter Part B of the trial

Exclusion criteria:

1. Previous treatment with BIBW 2992

2. Chemo-, hormone- (other than megestrol acetate, steroids required for maintenance non-cancer therapy or as premedication before chemotherapy) or immunotherapy within the past 4 weeks; except for TKI pretreatment (2 weeks only)

3. Active/symptomatic brain metastases including leptomeningeal disease. Patients with a history of treated brain metastasis must have a stable or normal brain MRT/CT scan at screening and be at least 4 weeks post-radiation or surgery for brain metastasis. Dexamethasone therapy will be allowed if administered as a stable dose for at least one month before randomization.

4. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade >2 diarrhea of any etiology at baseline

5. Patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the Investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug

6. Other malignancies diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer)

7. Radiotherapy within the past 2 weeks prior to treatment with the trial drug

8. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New york Heart Association (NYHA) functional classification of 3, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to entering the trial.

9. Cardiac left ventricular function with resting ejection fraction of less than 50% measured by multigated blood pool imaging of the heart (MUGA scan) or echocardiogram .

10. Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) at or greater than 400 mg/m2

11. Absolute neutrophil count (ANC) at or less than 1500 / mm3

12. Platelet count at or less than 100,000 / mm3

13. Bilirubin at or greater than 1.5 mg / dL (>26 mol / L, SI unit equivalent)

14. Aspartate amino transferase (AST) or alanine amino transferase (ALT) at or greater than three times the upper limit of normal (if related to liver metastases at or greater than five times the upper limit of normal)

15. Serum creatinine at or greater 1.5 times the upper normal limit or calculated/measured creatinine clearance at or less than 45 mL/min

16. Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial

17. Pregnancy or breast feeding

18. Patients unable to comply with the protocol

19. Patients with any serious active infection including known human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C

20. Known or suspected active drug or alcohol abuse

21. Pre-existing or current Interstitial lung disease (ILD) 22.)

22. Peripheral polyneuropathy of > Grade 2

23. Requirement for treatment with any of the pohibited concomitant medication listed in section 4.2.2.1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Ciudad Autonoma de Buenos Aires		Argentina
2	Boehringer Ingelheim Investigational Site	Kingswood	New South Wales	Australia
3	Boehringer Ingelheim Investigational Site	South Brisbane	Queensland	Australia
4	Boehringer Ingelheim Investigational Site	Box Hill	Victoria	Australia
5	Boehringer Ingelheim Investigational Site	Fitzroy	Victoria	Australia
6	Boehringer Ingelheim Investigational Site	Wodonga	Victoria	Australia
7	Boehringer Ingelheim Investigational Site	Salzburg		Austria
8	Boehringer Ingelheim Investigational Site	Aalst		Belgium
9	Boehringer Ingelheim Investigational Site	Bruxelles		Belgium
10	Boehringer Ingelheim Investigational Site	Duffel		Belgium
11	Boehringer Ingelheim Investigational Site	La Louvière		Belgium
12	Boehringer Ingelheim Investigational Site	Liège		Belgium
13	Boehringer Ingelheim Investigational Site	Middelheim		Belgium
14	Boehringer Ingelheim Investigational Site	Ottignies		Belgium
15	Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
16	Boehringer Ingelheim Investigational Site	Beijing		China
17	Boehringer Ingelheim Investigational Site	Changchun		China
18	Boehringer Ingelheim Investigational Site	Chengdu		China
19	Boehringer Ingelheim Investigational Site	Fuzhou		China
20	Boehringer Ingelheim Investigational Site	Guangzhou		China
21	Boehringer Ingelheim Investigational Site	Hangzhou		China
22	Boehringer Ingelheim Investigational Site	Nanjing		China
23	Boehringer Ingelheim Investigational Site	Shanghai		China
24	Boehringer Ingelheim Investigational Site	Helsinki		Finland
25	Boehringer Ingelheim Investigational Site	Bayonne		France
26	Boehringer Ingelheim Investigational Site	Caen Cedex 5		France
27	Boehringer Ingelheim Investigational Site	Dijon		France
28	Boehringer Ingelheim Investigational Site	La Tronche		France
29	Boehringer Ingelheim Investigational Site	Lyon Cedex 08		France
30	Boehringer Ingelheim Investigational Site	Paris cedex 20		France
31	Boehringer Ingelheim Investigational Site	Paris		France
32	Boehringer Ingelheim Investigational Site	Saint-Herblain cedex		France
33	Boehringer Ingelheim Investigational Site	Villejuif Cedex		France
34	Boehringer Ingelheim Investigational Site	Berlin		Germany
35	Boehringer Ingelheim Investigational Site	Essen		Germany
36	Boehringer Ingelheim Investigational Site	Esslingen		Germany
37	Boehringer Ingelheim Investigational Site	Gauting		Germany
38	Boehringer Ingelheim Investigational Site	Hamburg		Germany
39	Boehringer Ingelheim Investigational Site	Hannover		Germany
40	Boehringer Ingelheim Investigational Site	Heidelberg		Germany
41	Boehringer Ingelheim Investigational Site	Mainz		Germany
42	Boehringer Ingelheim Investigational Site	Münster		Germany
43	Boehringer Ingelheim Investigational Site	Budapest		Hungary
44	Boehringer Ingelheim Investigational Site	Pecs		Hungary
45	Boehringer Ingelheim Investigational Site	Törökbálint		Hungary
46	Boehringer Ingelheim Investigational Site	Chennai		India
47	Boehringer Ingelheim Investigational Site	Jaipur		India
48	Boehringer Ingelheim Investigational Site	Maharashtra		India
49	Boehringer Ingelheim Investigational Site	Mumbai		India
50	Boehringer Ingelheim Investigational Site	Nashik, Maharashtra		India
51	Boehringer Ingelheim Investigational Site	Kfar Saba		Israel
52	Boehringer Ingelheim Investigational Site	Petach Tikva		Israel
53	Boehringer Ingelheim Investigational Site	Tel Hashomer		Israel
54	Boehringer Ingelheim Investigational Site	Avellino		Italy
55	Boehringer Ingelheim Investigational Site	Aviano (PN)		Italy
56	Boehringer Ingelheim Investigational Site	Bergamo		Italy
57	Boehringer Ingelheim Investigational Site	Genova		Italy
58	Boehringer Ingelheim Investigational Site	Milano		Italy
59	Boehringer Ingelheim Investigational Site	Monza (mi)		Italy
60	Boehringer Ingelheim Investigational Site	Ravenna		Italy
61	Boehringer Ingelheim Investigational Site	Roma		Italy
62	Boehringer Ingelheim Investigational Site	Goyang		Korea, Republic of
63	Boehringer Ingelheim Investigational Site	Hwasun		Korea, Republic of
64	Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
65	Boehringer Ingelheim Investigational Site	Distrito Federal		Mexico
66	Boehringer Ingelheim Investigational Site	Maastricht		Netherlands
67	Boehringer Ingelheim Investigational Site	Nieuwegein		Netherlands
68	Boehringer Ingelheim Investigational Site	Arequipa		Peru
69	Boehringer Ingelheim Investigational Site	La Victoria		Peru
70	Boehringer Ingelheim Investigational Site	Gdansk		Poland
71	Boehringer Ingelheim Investigational Site	Olsztyn		Poland
72	Boehringer Ingelheim Investigational Site	Otwock		Poland
73	Boehringer Ingelheim Investigational Site	Warszawa		Poland
74	Boehringer Ingelheim Investigational Site	Obninsk		Russian Federation
75	Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
76	Boehringer Ingelheim Investigational Site	A Coruña		Spain
77	Boehringer Ingelheim Investigational Site	Barcelona		Spain
78	Boehringer Ingelheim Investigational Site	Madrid		Spain
79	Boehringer Ingelheim Investigational Site	Mataró		Spain
80	Boehringer Ingelheim Investigational Site	Málaga		Spain
81	Boehringer Ingelheim Investigational Site	Valencia		Spain
82	Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
83	Boehringer Ingelheim Investigational Site	Taichung		Taiwan
84	Boehringer Ingelheim Investigational Site	Tainan		Taiwan
85	Boehringer Ingelheim Investigational Site	Taipei		Taiwan
86	Boehringer Ingelheim Investigational Site	Taoyuan		Taiwan
87	Boehringer Ingelheim Investigational Site	Dnipropetrovks		Ukraine
88	Boehringer Ingelheim Investigational Site	Donetsk		Ukraine
89	Boehringer Ingelheim Investigational Site	Kharkiv		Ukraine
90	Boehringer Ingelheim Investigational Site	Kyiv		Ukraine
91	Boehringer Ingelheim Investigational Site	Brighton		United Kingdom
92	Boehringer Ingelheim Investigational Site	Dundee		United Kingdom
93	Boehringer Ingelheim Investigational Site	Exeter		United Kingdom
94	Boehringer Ingelheim Investigational Site	London		United Kingdom
95	Boehringer Ingelheim Investigational Site	Maidstone		United Kingdom
96	Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
97	Boehringer Ingelheim Investigational Site	Sutton, Surrey		United Kingdom
98	Boehringer Ingelheim Investigational Site	Truro, Cornwall		United Kingdom

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: NCT01085136
• Other Study ID Numbers: 1200.42; 2009-014563-39
• First Posted: Mar 11, 2010
• Last Update Posted: Apr 4, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Afatinib

Study Results

Participant Flow

Pre-assignment Detail	PD = Progression Disease

Arm/Group Title	Afatinib Monotherapy (Part A)	Afatinib Plus Paclitaxel (Part B)	Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).	Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).	Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
Period Title: Part A
STARTED	1154	0	0
Randomized to Part B	206	0	0
COMPLETED	831	0	0
NOT COMPLETED	323	0	0
Period Title: Part A
STARTED	0	138	68
COMPLETED	0	87	42
NOT COMPLETED	0	51	26

Baseline Characteristics

Arm/Group Title	Afatinib Monotherapy (Part A)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).
Overall Participants	1154
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	741 64.2%
>=65 years	413 35.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.1 (10.9)
Sex: Female, Male (Count of Participants)
Female	654 56.7%
Male	500 43.3%
Race/Ethnicity, Customized (Number) [Number]
Eastern Asian	491 42.5%
Caucasian	459 39.8%
Other	29 2.5%
Unknown	175 15.2%
Baseline Eastern Cooperative Oncology Group (ECOG) performance score (Number) [Number]
0	341 29.5%
1	691 59.9%
2	122 10.6%
Smoking history (Number) [Number]
Never smoked	615 53.3%
<15 pack years & stopped >1 year before diagnosis	132 11.4%
Other current or ex-smoker	407 35.3%
Histologic classification (Number) [Number]
Adenocarcinoma	985 85.4%
Squamous	90 7.8%
Other	78 6.8%
Missing	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (Part B)
Description	Progression free survival (PFS) time as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 from day of randomization until disease progression or death for patients randomised to combination therapy with afatinib plus paclitaxel or to investigator's choice of chemotherapy. Median was calculated from the Kaplan-Meier curve.
Time Frame	From randomization until disease progression or death; Up to 32 months

Outcome Measure Data

Analysis Population Description

Randomised Set: This analysis set consist of all randomised patients irrespective of whether treated or not.

Arm/Group Title	Afatinib Plus Paclitaxel (Part B)	Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).	Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
Measure Participants	138	68
Median (95% Confidence Interval) [Months]	5.55	2.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib Plus Paclitaxel (Part B), Investigators Choice of Chemotherapy (Part B)
	Comments	Hazard ratio is calculated from Cox proportional hazard model with treatment as the only factor, stratified by gender and maximum duration of erlotinib or gefitinib (<6 months vs >=6 months).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments	P-value is calculated from two-sided stratified log-rank test
	Method	stratified log-rank test
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival (Part A)
Description	Progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A. Median was calculated from the Kaplan-Meier curve.
Time Frame	From first dose administration until disease progression or death; Up to 51 months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Afatinib Monotherapy (Part A)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).
Measure Participants	1154
Median (95% Confidence Interval) [Months]	3.15

3. Secondary Outcome

Title	Overall Survival (Part B)
Description	Overall survival (OS) as determined by the time from randomization to death in part B. Median was calculated from the Kaplan-Meier curve.
Time Frame	From randomization until death; Up to 32 months

Outcome Measure Data

Analysis Population Description

Randomised Set

Arm/Group Title	Afatinib Plus Paclitaxel (Part B)	Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).	Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
Measure Participants	138	68
Median (95% Confidence Interval) [Months]	12.25	13.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib Plus Paclitaxel (Part B), Investigators Choice of Chemotherapy (Part B)
	Comments	Hazard ratio was calculated from Cox proportional hazard model with treatment as the only factor, stratified by gender and maximum duration of erlotinib or gefitinib (<6 months vs >=6 months).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7905
	Comments
	Method	Stratified log-rank test.
	Comments	P-value is calculated from two-sided stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Objective Response (Part A)
Description	Objective response defined as the best overall response of complete response [CR]: disappearance of all target lesion & partial response [PR]: ≥30% decrease in the sum of the longest diameter of target lesions , taking as reference the baseline sum longest diameter of Afatinib monotherapy according to RECIST 1.1 for Part A.
Time Frame	Post baseline tumour-imaging was performed at every 6 weeks thereafter until disease progression; upto 51 months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Afatinib Monotherapy (Part A)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).
Measure Participants	1154
Number (95% Confidence Interval) [Percentage of participants]	8.5 0.7%

5. Secondary Outcome

Title	Objective Response (Part B)
Description	Objective response (CR, PR) of Afatinib/paclitaxel combination therapy and comparator chemotherapy in Part B after progression in Part A according to RECIST 1.1 .
Time Frame	Post baseline tumour-imaging was performed at every 8 weeks thereafter until disease progression; up to 32 Months

Outcome Measure Data

Analysis Population Description

Randomized Set

Arm/Group Title	Afatinib Plus Paclitaxel (Part B)	Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).	Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
Measure Participants	138	68
Number (95% Confidence Interval) [Percentage of participants]	31.2 2.7%	13.2 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib Plus Paclitaxel (Part B), Investigators Choice of Chemotherapy (Part B)
	Comments	Odds ratio, 95% Confidence Interval (CI) and p-value (two-sided) from logistic regression stratified for maximum treatment duration of prior erlotinib or gefitinib (>=6 months vs <6 months) and gender.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0065
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.980
	Confidence Interval	(2-Sided) 95%; 1.357 to 6.543
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Intensity and Incidence of Adverse Events (AEs) for Part A & Part B.
Description	Safety of Afatinib as indicated by intensity and incidence of adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0 both for Part A and Part B. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time Frame	From first administration of treatment until 28 days after last drug administration, up to 51 Months (Part A) and from randomization until 28 days after last drug administration of Trial medication, up to 32 Months (Part B)

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Afatinib Monotherapy (Part A)	Afatinib Plus Paclitaxel (Part B)	Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).	Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).	Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
Measure Participants	1154	134	60
Grade 1	8.6 0.7%	4.5 NaN	8.3 NaN
Grade 2	28.0 2.4%	26.1 NaN	26.7 NaN
Grade 3	41.1 3.6%	44.0 NaN	38.3 NaN
Grade 4	4.9 0.4%	9.7 NaN	6.7 NaN
Grade 5	16.6 1.4%	12.7 NaN	6.7 NaN

Adverse Events

Time Frame	From first administration of treatment until 28 days after last drug administration, upto 51 Months (Part A) and from randomization until 28 days after last drug administration of Trial medication, upto 32 Months (Part B).
Adverse Event Reporting Description	Part A-events that started within the period defined by the first administration of afatinib until randomization into Part B or 28 days after the last administration of afatinib, whichever occurred first. Part B-events that started within the period from randomization through 28 days after the last administration of trial medication.
Arm/Group Title	Afatinib Monotherapy (Part A)		Afatinib Plus Paclitaxel (Part B)		Investigators Choice of Chemotherapy (Part B)
Arm/Group Description	Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme).		Afatinib 40 mg film-coated tablet dose was orally administered once daily of each 28-day treatment course, with dose reductions to 30 mg/day and 20 mg/day (following the protocol defined dose reduction scheme) plus paclitaxel 80 mg/m2 administered via intravenous infusion once weekly (7 weeks on/1 week off; 2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).		Reference therapy for Part B dose: Depending on schedule Intravenous or oral administration (2 dose reductions were allowed following the protocol defined dose reduction scheme and the current local summary of product characteristics).
All Cause Mortality
	Afatinib Monotherapy (Part A)		Afatinib Plus Paclitaxel (Part B)		Investigators Choice of Chemotherapy (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Afatinib Monotherapy (Part A)		Afatinib Plus Paclitaxel (Part B)		Investigators Choice of Chemotherapy (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	471/1154 (40.8%)		54/134 (40.3%)		19/60 (31.7%)
Blood and lymphatic system disorders
Anaemia	4/1154 (0.3%)		1/134 (0.7%)		0/60 (0%)
Febrile neutropenia	0/1154 (0%)		1/134 (0.7%)		1/60 (1.7%)
Leukopenia	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Neutropenia	0/1154 (0%)		1/134 (0.7%)		1/60 (1.7%)
Disseminated intravascular coagulation	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Thrombocytopenia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Cardiac disorders
Arrhythmia	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Acute coronary syndrome	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Acute left ventricular failure	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Atrial fibrillation	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Atrioventricular block complete	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Bradycardia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Cardiac failure	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Cardiac tamponade	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Cardiopulmonary failure	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Coronary artery disease	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Left ventricular dysfunction	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Myocardial infarction	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Pericardial effusion	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Tachycardia	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Ear and labyrinth disorders
Vertigo	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Eye disorders
Diplopia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Retinal detachment	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Vision blurred	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Gastrointestinal disorders
Abdominal pain	6/1154 (0.5%)		2/134 (1.5%)		1/60 (1.7%)
Ascites	4/1154 (0.3%)		1/134 (0.7%)		0/60 (0%)
Diarrhoea	59/1154 (5.1%)		6/134 (4.5%)		0/60 (0%)
Gastrointestinal disorder	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Gingival bleeding	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Haemorrhoids	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Nausea	8/1154 (0.7%)		1/134 (0.7%)		0/60 (0%)
Pancreatitis	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Rectal haemorrhage	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Rectal prolapse	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Vomiting	18/1154 (1.6%)		1/134 (0.7%)		0/60 (0%)
Abdominal pain upper	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Constipation	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Duodenal ulcer	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Dysphagia	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Epigastric discomfort	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Gastritis haemorrhagic	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Gastrointestinal hypomotility	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Gastrooesophageal reflux disease	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Haematemesis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Ileus	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Ileus paralytic	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Intestinal obstruction	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Jejunal perforation	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pancreatitis acute	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Peritoneal haemorrhage	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Small intestinal obstruction	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Stomatitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Vomiting projectile	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
General disorders
Adverse drug reaction	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Asthenia	8/1154 (0.7%)		1/134 (0.7%)		0/60 (0%)
Chest pain	8/1154 (0.7%)		1/134 (0.7%)		1/60 (1.7%)
Extravasation	0/1154 (0%)		0/134 (0%)		1/60 (1.7%)
General physical health deterioration	45/1154 (3.9%)		7/134 (5.2%)		1/60 (1.7%)
Pyrexia	9/1154 (0.8%)		1/134 (0.7%)		1/60 (1.7%)
Chest discomfort	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Death	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Fatigue	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Gravitational oedema	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hyperthermia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Local swelling	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Malaise	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Mucosal inflammation	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Multi-organ failure	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Oedema	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pain	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Performance status decreased	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Sudden death	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Hepatobiliary disorders
Bile duct obstruction	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Cholangitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Cholestasis	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Hepatic failure	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hepatic mass	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hepatic pain	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hepatitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Liver injury	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Infections and infestations
Bacterial infection	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Bronchitis	2/1154 (0.2%)		2/134 (1.5%)		0/60 (0%)
Cellulitis	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Empyema	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Infectious pleural effusion	1/1154 (0.1%)		1/134 (0.7%)		0/60 (0%)
Lower respiratory tract infection	5/1154 (0.4%)		2/134 (1.5%)		0/60 (0%)
Nasopharyngitis	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Pneumonia	42/1154 (3.6%)		4/134 (3%)		3/60 (5%)
Pneumonia bacterial	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Respiratory tract infection	5/1154 (0.4%)		3/134 (2.2%)		0/60 (0%)
Urinary tract infection	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Aspergillus infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Catheter site infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Device related infection	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Endocarditis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Erysipelas	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Escherichia sepsis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Fungal infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Gastroenteritis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Herpes zoster	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Infection	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Kidney infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Laryngitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Lobar pneumonia	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Localised infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Lung abscess	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Lung infection	11/1154 (1%)		0/134 (0%)		0/60 (0%)
Lymphangitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Meningitis bacterial	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Paronychia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Peritonitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Respiratory tract infection viral	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Sepsis	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Septic shock	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Skin bacterial infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Staphylococcal infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Staphylococcal skin infection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Upper respiratory tract infection	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Urosepsis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Injury, poisoning and procedural complications
Fracture displacement	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Overdose	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Compression fracture	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Fall	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Femoral neck fracture	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Femur fracture	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Ligament sprain	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pelvic fracture	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Post procedural complication	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Road traffic accident	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Spinal compression fracture	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Investigations
Biopsy lymph gland abnormal	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Gene mutation identification test	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Weight decreased	0/1154 (0%)		2/134 (1.5%)		0/60 (0%)
Glomerular filtration rate decreased	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Haemoglobin decreased	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Oxygen saturation decreased	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Staphylococcus test positive	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Metabolism and nutrition disorders
Decreased appetite	12/1154 (1%)		2/134 (1.5%)		0/60 (0%)
Dehydration	15/1154 (1.3%)		1/134 (0.7%)		0/60 (0%)
Fluid retention	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypokalaemia	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Hyponatraemia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypophosphataemia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypoproteinaemia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypovolaemia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
Back pain	11/1154 (1%)		1/134 (0.7%)		0/60 (0%)
Musculoskeletal chest pain	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Osteoporosis	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Spinal pain	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Arthralgia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Bone pain	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Intervertebral disc protrusion	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Mobility decreased	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Muscular weakness	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Musculoskeletal pain	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Neck pain	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Osteonecrosis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pain in extremity	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pathological fracture	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	46/1154 (4%)		2/134 (1.5%)		0/60 (0%)
Metastases to central nervous system	7/1154 (0.6%)		3/134 (2.2%)		1/60 (1.7%)
Metastases to meninges	2/1154 (0.2%)		2/134 (1.5%)		0/60 (0%)
Metastasis	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Neoplasm progression	19/1154 (1.6%)		2/134 (1.5%)		2/60 (3.3%)
Pericarditis malignant	1/1154 (0.1%)		1/134 (0.7%)		0/60 (0%)
Brain neoplasm	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Lung neoplasm	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Malignant ascites	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Malignant neoplasm of pleura	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Malignant pleural effusion	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Metastases to bone	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Metastases to liver	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Metastases to peritoneum	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Metastases to pleura	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Metastases to spine	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Metastatic pain	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Non-small cell lung cancer	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Parathyroid tumour benign	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Tumour compression	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Tumour pain	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Nervous system disorders
Cognitive disorder	1/1154 (0.1%)		1/134 (0.7%)		0/60 (0%)
Headache	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Hydrocephalus	0/1154 (0%)		0/134 (0%)		1/60 (1.7%)
Intracranial pressure increased	3/1154 (0.3%)		1/134 (0.7%)		0/60 (0%)
Nervous system disorder	1/1154 (0.1%)		0/134 (0%)		1/60 (1.7%)
Seizure	6/1154 (0.5%)		1/134 (0.7%)		1/60 (1.7%)
Altered state of consciousness	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Ataxia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Brain oedema	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Cerebral haemorrhage	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Cerebrovascular accident	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Cervicobrachial syndrome	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Dizziness	5/1154 (0.4%)		0/134 (0%)		0/60 (0%)
Dysarthria	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Epilepsy	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Monoplegia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Paraparesis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Reversible ischaemic neurological deficit	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Sciatica	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Somnolence	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Speech disorder	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Spinal cord compression	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Syncope	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Psychiatric disorders
Completed suicide	1/1154 (0.1%)		0/134 (0%)		1/60 (1.7%)
Confusional state	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Depression	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Mental status changes	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Renal and urinary disorders
Acute kidney injury	9/1154 (0.8%)		1/134 (0.7%)		0/60 (0%)
Renal failure	4/1154 (0.3%)		1/134 (0.7%)		0/60 (0%)
Anuria	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Haematuria	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Renal colic	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Urinary retention	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	67/1154 (5.8%)		5/134 (3.7%)		3/60 (5%)
Haemoptysis	7/1154 (0.6%)		1/134 (0.7%)		0/60 (0%)
Hypercapnia	0/1154 (0%)		0/134 (0%)		1/60 (1.7%)
Interstitial lung disease	6/1154 (0.5%)		1/134 (0.7%)		1/60 (1.7%)
Lung disorder	1/1154 (0.1%)		2/134 (1.5%)		0/60 (0%)
Pleural effusion	49/1154 (4.2%)		3/134 (2.2%)		1/60 (1.7%)
Pneumothorax	6/1154 (0.5%)		2/134 (1.5%)		0/60 (0%)
Pulmonary embolism	17/1154 (1.5%)		4/134 (3%)		1/60 (1.7%)
Respiratory arrest	1/1154 (0.1%)		1/134 (0.7%)		0/60 (0%)
Respiratory failure	13/1154 (1.1%)		1/134 (0.7%)		0/60 (0%)
Acute pulmonary oedema	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Acute respiratory distress syndrome	8/1154 (0.7%)		0/134 (0%)		0/60 (0%)
Acute respiratory failure	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Asphyxia	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Atelectasis	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Choking	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Chronic obstructive pulmonary disease	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Cough	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Haemothorax	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hydrothorax	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypoxia	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Obstructive airways disorder	3/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Pleural fibrosis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pneumonia aspiration	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pneumonitis	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Productive cough	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Pulmonary haemorrhage	4/1154 (0.3%)		0/134 (0%)		0/60 (0%)
Pulmonary oedema	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Respiratory acidosis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Thoracic haemorrhage	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Petechiae	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Rash	1/1154 (0.1%)		1/134 (0.7%)		0/60 (0%)
Rash erythematous	0/1154 (0%)		1/134 (0.7%)		0/60 (0%)
Skin erosion	0/1154 (0%)		0/134 (0%)		1/60 (1.7%)
Decubitus ulcer	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Dermatitis acneiform	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Skin toxicity	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Surgical and medical procedures
Lung transplant	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Partial lung resection	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Vascular disorders
Shock	2/1154 (0.2%)		1/134 (0.7%)		0/60 (0%)
Deep vein thrombosis	6/1154 (0.5%)		0/134 (0%)		0/60 (0%)
Embolism	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Haemorrhage	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Hypotension	2/1154 (0.2%)		0/134 (0%)		0/60 (0%)
Neurogenic shock	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Phlebitis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Raynaud's phenomenon	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Superior vena cava syndrome	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Thrombosis	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Venous thrombosis limb	1/1154 (0.1%)		0/134 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Afatinib Monotherapy (Part A)		Afatinib Plus Paclitaxel (Part B)		Investigators Choice of Chemotherapy (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1129/1154 (97.8%)		128/134 (95.5%)		50/60 (83.3%)
Blood and lymphatic system disorders
Anaemia	80/1154 (6.9%)		33/134 (24.6%)		6/60 (10%)
Leukopenia	5/1154 (0.4%)		20/134 (14.9%)		7/60 (11.7%)
Neutropenia	7/1154 (0.6%)		26/134 (19.4%)		8/60 (13.3%)
Gastrointestinal disorders
Abdominal pain	90/1154 (7.8%)		11/134 (8.2%)		4/60 (6.7%)
Abdominal pain upper	65/1154 (5.6%)		19/134 (14.2%)		4/60 (6.7%)
Constipation	85/1154 (7.4%)		22/134 (16.4%)		10/60 (16.7%)
Diarrhoea	964/1154 (83.5%)		72/134 (53.7%)		4/60 (6.7%)
Nausea	252/1154 (21.8%)		28/134 (20.9%)		14/60 (23.3%)
Stomatitis	303/1154 (26.3%)		14/134 (10.4%)		2/60 (3.3%)
Vomiting	211/1154 (18.3%)		31/134 (23.1%)		4/60 (6.7%)
Mouth ulceration	91/1154 (7.9%)		2/134 (1.5%)		0/60 (0%)
General disorders
Asthenia	200/1154 (17.3%)		47/134 (35.1%)		18/60 (30%)
Chest pain	82/1154 (7.1%)		9/134 (6.7%)		2/60 (3.3%)
Fatigue	136/1154 (11.8%)		32/134 (23.9%)		10/60 (16.7%)
Mucosal inflammation	200/1154 (17.3%)		13/134 (9.7%)		0/60 (0%)
Oedema peripheral	57/1154 (4.9%)		12/134 (9%)		2/60 (3.3%)
Pyrexia	82/1154 (7.1%)		18/134 (13.4%)		7/60 (11.7%)
Infections and infestations
Bronchitis	21/1154 (1.8%)		7/134 (5.2%)		2/60 (3.3%)
Conjunctivitis	79/1154 (6.8%)		12/134 (9%)		0/60 (0%)
Nasopharyngitis	35/1154 (3%)		10/134 (7.5%)		2/60 (3.3%)
Paronychia	342/1154 (29.6%)		23/134 (17.2%)		0/60 (0%)
Pneumonia	68/1154 (5.9%)		8/134 (6%)		1/60 (1.7%)
Rhinitis	54/1154 (4.7%)		7/134 (5.2%)		4/60 (6.7%)
Upper respiratory tract infection	32/1154 (2.8%)		7/134 (5.2%)		1/60 (1.7%)
Urinary tract infection	62/1154 (5.4%)		14/134 (10.4%)		1/60 (1.7%)
Folliculitis	86/1154 (7.5%)		5/134 (3.7%)		0/60 (0%)
Investigations
Alanine aminotransferase increased	28/1154 (2.4%)		8/134 (6%)		2/60 (3.3%)
Haemoglobin decreased	11/1154 (1%)		7/134 (5.2%)		0/60 (0%)
Weight decreased	132/1154 (11.4%)		16/134 (11.9%)		3/60 (5%)
Metabolism and nutrition disorders
Decreased appetite	304/1154 (26.3%)		37/134 (27.6%)		10/60 (16.7%)
Hypokalaemia	51/1154 (4.4%)		12/134 (9%)		3/60 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	46/1154 (4%)		8/134 (6%)		2/60 (3.3%)
Back pain	94/1154 (8.1%)		8/134 (6%)		5/60 (8.3%)
Musculoskeletal pain	48/1154 (4.2%)		8/134 (6%)		0/60 (0%)
Myalgia	17/1154 (1.5%)		10/134 (7.5%)		7/60 (11.7%)
Pain in extremity	60/1154 (5.2%)		8/134 (6%)		5/60 (8.3%)
Nervous system disorders
Dizziness	60/1154 (5.2%)		13/134 (9.7%)		4/60 (6.7%)
Dysgeusia	25/1154 (2.2%)		7/134 (5.2%)		4/60 (6.7%)
Headache	56/1154 (4.9%)		16/134 (11.9%)		6/60 (10%)
Hypoaesthesia	6/1154 (0.5%)		9/134 (6.7%)		5/60 (8.3%)
Neuropathy peripheral	8/1154 (0.7%)		16/134 (11.9%)		7/60 (11.7%)
Paraesthesia	25/1154 (2.2%)		13/134 (9.7%)		2/60 (3.3%)
Peripheral sensory neuropathy	4/1154 (0.3%)		8/134 (6%)		2/60 (3.3%)
Psychiatric disorders
Insomnia	39/1154 (3.4%)		9/134 (6.7%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	194/1154 (16.8%)		32/134 (23.9%)		13/60 (21.7%)
Dysphonia	36/1154 (3.1%)		7/134 (5.2%)		2/60 (3.3%)
Dyspnoea	194/1154 (16.8%)		34/134 (25.4%)		11/60 (18.3%)
Epistaxis	151/1154 (13.1%)		19/134 (14.2%)		3/60 (5%)
Oropharyngeal pain	30/1154 (2.6%)		10/134 (7.5%)		1/60 (1.7%)
Productive cough	47/1154 (4.1%)		6/134 (4.5%)		4/60 (6.7%)
Rhinorrhoea	61/1154 (5.3%)		6/134 (4.5%)		4/60 (6.7%)
Skin and subcutaneous tissue disorders
Alopecia	39/1154 (3.4%)		47/134 (35.1%)		10/60 (16.7%)
Nail disorder	41/1154 (3.6%)		9/134 (6.7%)		2/60 (3.3%)
Pruritus	179/1154 (15.5%)		13/134 (9.7%)		3/60 (5%)
Rash	629/1154 (54.5%)		30/134 (22.4%)		7/60 (11.7%)
Skin fissures	101/1154 (8.8%)		10/134 (7.5%)		1/60 (1.7%)
Acne	87/1154 (7.5%)		5/134 (3.7%)		0/60 (0%)
Dry skin	164/1154 (14.2%)		6/134 (4.5%)		0/60 (0%)
Palmar-plantar erythrodysaesthesia syndrome	71/1154 (6.2%)		2/134 (1.5%)		0/60 (0%)

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.