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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01523587
• Collaborator: (none)
• Enrollment: 795
• Locations: 192
• Arms: 2
• Actual Duration (Months): 69.7
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomised, open-label phase III trial will be performed in patients with advanced squamous cell carcinoma of the lung requiring second-line treatment after receiving first-line platinum-based chemotherapy. The primary objective of this trial is to compare the efficacy of BIBW 2992 to erlotinib as second-line treatment in this group of patients.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: afatinib; Drug: erlotinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 795 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: LUX-Lung 8: A Randomized, Open-label Phase III Trial of Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung as Second-line Therapy Following First-line Platinum-based Chemotherapy
• Actual Study Start Date: Mar 5, 2012
• Actual Primary Completion Date: Oct 21, 2013
• Actual Study Completion Date: Dec 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afatinib Patients receive afatinib tablets once daily	Drug: afatinib; Afatinib taken once daily, continuously until disease progression or unacceptable toxicity.
Active Comparator: Erlotinib Patients receive erlotinib tablets once daily	Drug: erlotinib; erlotinib taken once daily

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 [First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).]

   Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Overall Survival [From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).]

   Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.

2. Number of Participants With Objective Response According to RECIST 1.1 [First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).]

   A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

3. Number of Participants With Disease Control According to RECIST 1.1 [First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).]

   Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

4. Tumour Shrinkage [First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).]

   Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race.

5. Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire [From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).]

   Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.

6. Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. [From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).]

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

7. Change in Score Over Time in Coughing,Dyspnoea and Pain [From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).]

   Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Diagnosis of advanced stage NSCLC squamous histology.

2. Platinum-based doublet chemotherapy as 1st line treatment of Stage IIIB/IV NSCLC.

3. Eligible to receive 2nd line therapy in the opinion of the investigator.

4. Measurable disease according to RECIST 1.1.

5. Adequate Performance Status.

6. Availability of tumour tissue material for correlative studies. Archived tumour tissue is acceptable.

7. Adequate organ function.

8. Age = 18 years and above.

9. Written informed consent that is consistent with International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines.

Exclusion criteria:

1. Prior treatment with Epidermal Growth Factor Receptor (EGFR) directed small molecules or antibodies.

2. Radiotherapy within 4 weeks prior to randomization.

3. Active brain metastases .

4. Any other current malignancy or malignancy diagnosed within the past three (3) years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer).

5. Known pre-existing interstitial lung disease.

6. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom

7. Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.

8. Women of child-bearing potential 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.

9. Female patients of childbearing potential (see Section 4.2.3.3) who:

10. are nursing or

11. are pregnant or

12. are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study and/or do not agree to submit to pregnancy testing required by this protocol.

13. Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.

14. Known or suspected active drug or alcohol abuse in the opinion of the investigator.

15. Any contraindications for therapy with afatinib or erlotinib.

16. Known hypersensitivity to erlotinib, afatinib or the excipients of any of the trial drugs.

17. Major surgery within 4 weeks of starting study treatment.

18. Prior participation in an afatinib clinical study, even if not assigned to afatinib.

19. Use of any investigational drug within 4 weeks of randomisation (unless a longer time period is required by local regulations or by the guidelines for the investigational product).

20. Patients without Progression of their lung cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ironwood Cancer and Research Centers	Chandler	Arizona	United States	85224
2	University of California	La Jolla	California	United States	92093
3	Sutter Medical Group	Sacramento	California	United States	95816
4	Boca Raton Reginl Hospital-Lynn Cancer Institute	Boca Raton	Florida	United States	33486
5	Memorial Healthcare System	Hollywood	Florida	United States	22021
6	Cancer Care of North Florida, PA	Lake City	Florida	United States	32024
7	Illinois Cancer Specialists	Niles	Illinois	United States	60714
8	Orchard Healthcare Research Inc	Skokie	Illinois	United States	60076
9	University of Louisville	Louisville	Kentucky	United States	40202
10	West Jefferson General Hospital and Cancer Clinic	Marrero	Louisiana	United States	70072
11	Lahey Clinic	Burlington	Massachusetts	United States	01805
12	Commonwealth Hematology-Oncology, PC	Lawrence	Massachusetts	United States	01841
13	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
14	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
15	Billings Clinic Cancer Center	Billings	Montana	United States	59101
16	Montefiore Medical Center	Bronx	New York	United States	10461
17	Montefiore Medical Center	Bronx	New York	United States	10467
18	Queens Medical Associates	Fresh Meadows	New York	United States	11366
19	SUNY Upstate Medical University	Syracuse	New York	United States	13210
20	Cleveland Clinic	Cleveland	Ohio	United States	44195
21	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43201
22	Mid Ohio Oncology/Hematology, Inc	Columbus	Ohio	United States	43219
23	Kaiser Permanente Northwest	Portland	Oregon	United States	97227
24	Oncology Hematology Associates of Norhtern Pennsylvania, PC	DuBois	Pennsylvania	United States	15801
25	Kimmel Cancer Center	Philadelphia	Pennsylvania	United States	19107
26	Temple University Cancer Center	Philadelphia	Pennsylvania	United States	19140
27	Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303
28	Cancer Center of Cookeville Regional Medical Center	Cookeville	Tennessee	United States	38501
29	Paris Cancer Center (PCC), Texas Oncology	Paris	Texas	United States	75460
30	Cancer Therapy and Research at UTHSCSA	San Antonio	Texas	United States	78229
31	Fletcher Allen Health Care	Burlington	Vermont	United States	05401
32	Blue Ridge Cancer Care	Christiansburg	Virginia	United States	24382
33	Virginia Oncology Associates	Norfolk	Virginia	United States	23502
34	Instituto Medico Especializado Alexander Fleming	Ciudad Autonoma de Bs As		Argentina	C1426ANZ
35	Instituto Oncologico de Cordoba	Cordoba		Argentina	X5000HXL
36	Clínica Colombo S.A.	Cordoba		Argentina	X5002AOQ
37	Centro Oncologico de Rosario	Rosario		Argentina	S2000KZE
38	Centro Oncologico CAIPO	San Miguel de Tucuman		Argentina	T4000GTB
39	Medical University of Innsbruck	Innsbruck		Austria	6020
40	LKH Leoben	Leoben		Austria	8700
41	AKH d. Stadt Linz, Pulmologie	Linz		Austria	4020
42	SMZ Baumgartner Hoehe Otto Wagner Spital	Wien		Austria	1140
43	BC Cancer Agency - Fraser Valley Centre	Surrey	British Columbia	Canada	V3V 1Z2
44	Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
45	The Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
46	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
47	Montreal General Hospital - McGill University Health Centre	Montreal	Quebec	Canada	H3G 1A4
48	Centro Oncologico Antofagasta	Antofagasta		Chile	1720421
49	Instituto de Terapias Oncologicas Providencia	Providencia, Santiago		Chile	7501088
50	Centro Internacional de Estudios Clinicos - CIEC	Recoleta, Santiago De Chile		Chile	8420383
51	Orlandi Oncologia	Vitacura		Chile	7630457
52	Beijing Cancer Hospital	Beijing		China	100036
53	Beijing Hospital	Beijing		China	100730
54	First Hospital of Jilin University	Changchun		China	130021
55	Xiangya Hospital, Central South University	Changsha		China	410008
56	Sun Yat-Sen University Cancer Center	Guangzhou		China	510060
57	the 81th Hospital of PLA	Nanjing		China	210002
58	Jiangsu Cancer Hospital	Nanjing		China	210009
59	Shanghai Chest Hospital	Shanghai		China	200030
60	Shanghai Pulmonary Hospital	Shanghai		China	200433
61	Herlev Hospital	Herlev		Denmark	2730
62	Næstved Sygehus	Næstved		Denmark	4700
63	Odense Universitetshospital	Odense C		Denmark	5000
64	HOP d'Angers	Angers		France	49 933
65	INS Bergonié	Bordeaux		France	33076
66	HOP Côte de Nacre	Caen		France	14033
67	HOP de Chauny	Chauny		France	02303
68	HOP Gabriel-Montpied	Clermont Ferrand		France	63003
69	HOP de Creteil, Pneumo, Creteil	Creteil		France	94010
70	HOP Le Mans	Le Mans		France	72037
71	CTR Oscar Lambret, Cancéro, Lille	Lille		France	59020
72	HOP Calmette	Lille		France	59037
73	HOP Nord	Marseille Cedex 20		France	13915
74	INS Paoli-Calmettes	Marseille		France	13273
75	HOP de Mulhouse, Onco, Mulhouse	Mulhouse		France	68070
76	HOP Cochin	Paris		France	75014
77	HOP Val de Grâce, Onco, Paris	Paris		France	75230
78	INS Jean Godinot, Onco, Reims	Reims		France	51056
79	HOP de Rennes, Pneumo, Rennes	Rennes		France	35033
80	HOP Saint Quentin, Onco, Saint Quentin	Saint Quentin		France	02321
81	HOP Civil	Strasbourg		France	67091
82	HOP Foch	Suresnes		France	92151
83	INS Gustave Roussy	Villejuif		France	94805
84	Zentralklinik Bad Berka GmbH	Bad Berka		Germany	99437
85	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen		Germany	45147
86	Klinikum Esslingen GmbH	Esslingen		Germany	73730
87	Universitätsklinikum Frankfurt	Frankfurt am Main		Germany	60590
88	Universitätsklinikum Freiburg	Freiburg		Germany	79106
89	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
90	Lungenklinik Hemer	Hemer		Germany	58675
91	Universitätsklinikum Mannheim GmbH	Mannheim		Germany	68167
92	Universitätsklinikum Münster	Münster		Germany	48149
93	Mathias-Spital Rheine	Rheine		Germany	48431
94	"Hippokratio" Hospital of Athens, 2nd Internal Medicine Clin	Athens		Greece	11527
95	General Hospital of Chest Diseases Sotiria	Athens		Greece	11527
96	University General Hospital of Heraklion	Heraklion		Greece	71110
97	University Hospital of Larisa, Oncology Clinic	Larisa		Greece	41110
98	General Hospital of Larissa	Larisa		Greece	41221
99	Metropolitan Hospital, Oncology Clinic	Neo Faliro, Athens		Greece	18547
100	General Hospital "G. Papageorgiou"	Thessaloniki		Greece	56429
101	National Koranyi TBC and Pulm. Internal Med. Clinic	Budapest		Hungary	1121
102	Semmelweis University	Budapest		Hungary	1125
103	Institute of Chest Diseases Csongrad County,Dpt. Pulmonology	Deszk		Hungary	6772
104	Pulmonology Institute of Veszprem County, Farkasgyepu	Farkasgyepü		Hungary	8582
105	Aladar Petz County Teaching Hospital, Dept. Pulmonology	Györ		Hungary	9023
106	Lung Hospital of Matra, Dept. Pulmonology	Matrahaza		Hungary	3233
107	Josa Andras Korhaz, Nyiregyhaza	Nyiregyhaza		Hungary	4400
108	University of Pecs, 1st internal Med. Dept., Pulmonology	Pecs		Hungary	7623
109	Pest County Lung Hospital, Department No. 3	Törökbalint		Hungary	2045
110	Vikram Hospital	Bangalore		India	560052
111	V S Hospital	Chennai		India	600031
112	Dr. Kamakshi Memorial Hospital	Chennai		India	600100
113	Sri Ramachandra Medical College & Research Institute	Chennai		India	600116
114	M.S. Patel Cancer Hospital	Karamsad		India	388325
115	B. P .Poddar Hospital & Medical Research Ltd.	Kolkata, West Bengal		India	700053
116	Tata Memorial Hospital	Mumbai		India	400012
117	Ruby Hall Clinic	Pune		India	411001
118	St James's Hospital	Dublin 8		Ireland	Dublin
119	P.O. Bellaria IRCCS Istituto delle scienze Neurologiche di Bologna	Bologna		Italy	40139
120	ASST di Cremona	Cremona		Italy	26100
121	Spedali Riuniti di Livorno	Livorno		Italy	57100
122	Istituto Nazionale Tumori Fondazione Pascale	Napoli		Italy	80131
123	Istituto Oncologico Veneto IRCCS	Padova		Italy	35128
124	Azienda Ospedaliera di Parma	Parma		Italy	43100
125	Azienda Ospedaliera Universitaria Pisana	Pisa		Italy	56126
126	Istituto Clinico Humanitas	Rozzano (MI)		Italy	20089
127	Ospedale San Vincenzo	Taormina (ME)		Italy	98039
128	Ospedale Molinette, AO Città della Salute e della	Torino		Italy	10126
129	A. O. S. Maria della Misericordia	Udine		Italy	33100
130	Chungbuk National University Hospital	Cheongju		Korea, Republic of	361-711
131	Gachon University Gil Medical Center	Incheon		Korea, Republic of	405-760
132	Gyeongsang National University Hospital	Jinju		Korea, Republic of	660-702
133	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	13620
134	Asan Medical Center	Seoul		Korea, Republic of	05505
135	Samsung Medical Center	Seoul		Korea, Republic of	130-710
136	The Catholic University of Korea, Seoul St.Mary's Hospital	Seoul		Korea, Republic of	137-701
137	The Catholic University of Korea, St.Vincent's Hospital	Suwon		Korea, Republic of	442-723
138	Ulsan University Hospital	Ulsan		Korea, Republic of	682-714
139	Instituto Nacional de Cancerologia	Mexico		Mexico	14080
140	Hospital y Clínica OCA S. A. de C. V.	Monterrey		Mexico	64000
141	Centro Hemato-Oncologico Privado de Toluca S.A. de C.V.	Toluca		Mexico	50080
142	Jeroen Bosch Ziekenhuis-Hertogenbosch	's-HERTOGENBOSCH		Netherlands	5223 GZ
143	Rijnstate Hospital	Arnhem		Netherlands	6815 AD
144	Amphia Ziekenhuis	Breda		Netherlands	4818 CK
145	Catharina Ziekenhuis	Eindhoven		Netherlands	5623 EJ
146	METC Academisch Ziekenhuis Maastricht/Universiteit van Maastricht	Maastricht		Netherlands	6229 HX
147	St. Antonius ziekenhuis, locatie Nieuwegein	Nieuwegein		Netherlands	3435 CM
148	Erasmus Medisch Centrum	Rotterdam		Netherlands	3015 CD
149	CHUC - Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra		Portugal	3041-801
150	CHLN, EPE - Hospital de Santa Maria	Lisboa		Portugal	1064-035
151	IPO Lisboa Francisco Gentil, EPE	Lisboa		Portugal	1099-023
152	IPO Porto Francisco Gentil, EPE	Porto		Portugal	4200-072
153	Centro Hospitalar São João,EPE	Porto		Portugal	4200-319
154	Centro Hospitalar de Vila Nova de Gaia	Vila Nova de Gaia		Portugal	4434-502
155	National Cancer Centre	Singapore		Singapore	169610
156	Johns Hopkins Singapore International Medical Centre	Singapore		Singapore	308433
157	Hospital A Coruña	A Coruña		Spain	15006
158	Hospital Vall d'Hebron	Barcelona		Spain	08035
159	Hospital Santa Creu i Sant Pau	Barcelona		Spain	08041
160	Hospital Clínico San Carlos	Madrid		Spain	28040
161	Hospital La Paz	Madrid		Spain	28046
162	Hospital Regional Universitario de Málaga	Malaga		Spain	29010
163	Hospital Virgen de la Victoria	Malaga		Spain	29010
164	Hospital Clínico de Valencia	Valencia		Spain	46010
165	Hospital Clínico Universitario Lozano Blesa	Zaragoza		Spain	50009
166	Chang Gung Memorial Hospital Chiayi	Chiayi		Taiwan	613
167	Buddhist Tzu Chi General Hospital	Chiayi		Taiwan	622
168	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung		Taiwan	833
169	China Medical University Hospital	Taichung		Taiwan	404
170	Taichung Veterans General Hospital	Taichung		Taiwan	407
171	National Taiwan University Hospital	Taipei		Taiwan	100
172	Koo Foundation Sun Yet-Sen Cancer Center	Taipei		Taiwan	112
173	Taipe Veterans General Hospital	Taipei		Taiwan	112
174	Chang Gung Memorial Hospital(TaoYuan)	Taoyuan		Taiwan	330
175	Akdeniz Universitesi Tip Fakultesi	Antalya		Turkey	07070
176	Uludag Universitesi Tip Fakultesi, Bursa	Bursa		Turkey	16045
177	Dicle Universitesi Tip Fakultesi	Diyarbakir		Turkey
178	Gaziantep Univ. Tip Fakultesi Tibbi Onkoloji Bilim Dali	Gaziantep		Turkey	27310
179	Kartal Egitim Ve Arastirma Hastanesi	Istanbul		Turkey
180	Yedikule Gog. Hst. EAH	Istanbul		Turkey
181	Ege Universitesi Tip Fakultesi Tibbi Onkoloji Bilim Dali	Izmir		Turkey	35100
182	Dr.Suat Seren EAH	Izmir		Turkey	35120
183	Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
184	Royal Devon and Exeter Hospital	Exeter		United Kingdom	EX2 5DW
185	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
186	Harrogate District Hospital	Harrogate		United Kingdom	HG2 7SX
187	Royal Free Hospital	London		United Kingdom	NW3 2QG
188	The Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
189	Maidstone Hospital, Kent Oncology Centre	Maidstone		United Kingdom	ME16 9QQ
190	Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB
191	Scarborough Hospital	Scarborough		United Kingdom	YO12 6QL
192	The Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Jun 24, 2016
• Statistical Analysis Plan - Apr 18, 2012

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01523587
• Other Study ID Numbers: 1200.125; 2011-002380-24
• First Posted: Feb 1, 2012
• Last Update Posted: Feb 15, 2019
• Last Verified: Feb 1, 2019

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

Study Results

Participant Flow

Recruitment Details	Open-Label Phase-III trial to compare the efficacy of afatinib with erlotinib for the second-line treatment of patients with advanced non-small cell lung cancer, who completed at least 4 cycles of platinum-based doublet chemotherapy. Randomization ratio was 1:1. Stratification was based on race.
Pre-assignment Detail	Patients screened to ensure that they met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met. Tumor assessments at screening were completed within 21 days and other screening assessments were completed within 28 days, of randomization.

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Period Title: Overall Study
STARTED	398	397
Treated	392	395
COMPLETED	0	0
NOT COMPLETED	398	397

Baseline Characteristics

Arm/Group Title	Afatinib	Erlotinib	Total
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.	Total of all reporting groups
Overall Participants	398	397	795
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.9 (8.39)	63.4 (8.98)	64.1 (8.72)
Sex: Female, Male (Count of Participants)
Female	63 15.8%	66 16.6%	129 16.2%
Male	335 84.2%	331 83.4%	666 83.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.5%	2 0.5%	4 0.5%
Asian	97 24.4%	94 23.7%	191 24%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 1.8%	8 2%	15 1.9%
White	288 72.4%	291 73.3%	579 72.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 1%	2 0.5%	6 0.8%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1
Description	Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Outcome Measure Data

Analysis Population Description

Randomized Set (RS): All patients who were randomized, regardless of whether they received investigational treatment.

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Median (95% Confidence Interval) [Months]	2.63	1.94

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	A Cox proportional hazards model without the randomization stratification variable was used for each subgroup category, along with the corresponding log-rank test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments	P-value from log-rank stratified by Race (two-sided). Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazards model stratified by Race.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.814
	Confidence Interval	(2-Sided) 95%; 0.693 to 0.956
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.
Time Frame	From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Median (95% Confidence Interval) [Months]	7.82	6.77

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	A Cox proportional-hazards model, stratified by race, was used to estimate the hazard ratio and 95% confidence interval (CI) between the two treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0193
	Comments	P-value from log-rank stratified by Race (two-sided). Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazards model stratified by Race.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.841
	Confidence Interval	(2-Sided) 95%; 0.727 to 0.973
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Objective Response According to RECIST 1.1
Description	A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Number [Participants]	22 5.5%	11 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0551
	Comments	Odds ratio (Afatinib vs Erlotinib), 95% CI and p-value (two-sided) from logistic regression stratified by race.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.06
	Confidence Interval	(2-Sided) 95%; 0.98 to 4.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Disease Control According to RECIST 1.1
Description	Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Number [Participants]	201 50.5%	157 39.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio (Afatinib vs Erlotinib), 95% CI and p-value (two-sided) from logistic regression stratified by race.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 95%; 1.18 to 2.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Tumour Shrinkage
Description	Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race.
Time Frame	First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Outcome Measure Data

Analysis Population Description

Patients from the randomised set with tumour assessments are considered for the analysis of this endpoint.

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	307	311
Least Squares Mean (Standard Error) [Millimeter (mm)]	78.8 (1.26)	80.0 (1.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The analysis will compare the treatments using analysis of covariance (ANCOVA) for minimum sum of diameters, using baseline sum of diameters as a covariate. The randomization strata will be included as classification factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.500
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -4.67 to 2.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.77
	Estimation Comments	Mean was adjusted for baseline sum of diameters and race.

6. Secondary Outcome

Title	Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire
Description	Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.
Time Frame	From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Improved Cough	147 36.9%	120 30.2%
Improved Dyspnoea	174 43.7%	150 37.8%
Improved Pain Related	138 34.7%	134 33.8%
Improved Global Health Status	121 30.4%	96 24.2%

7. Secondary Outcome

Title	Summary of Time to Deterioration in Coughing, Dyspnoea and Pain.
Description	Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration.
Time Frame	From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Time to Deterioration - Coughing	4.53	3.65
Time to Deterioration - Dyspnoea	2.63	1.91
Time to Deterioration - Pain	2.50	2.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Time to Deterioration in Coughing.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2562
	Comments	p-value calculated using log rank test stratified by race.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Time to Deterioration in Dyspnoea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments	p-value calculated using log rank test stratified by race.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Time to Deterioration in Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8690
	Comments	p-value calculated using log rank test stratified by race
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (Afatinib vs Erlotinib) from Cox proportional hazard model stratified by race.

8. Secondary Outcome

Title	Change in Score Over Time in Coughing,Dyspnoea and Pain
Description	Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.
Time Frame	From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Afatinib	Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Measure Participants	398	397
Coughing	15.8 (2.40)	19.3 (2.37)
Dyspnoea	11.4 (1.83)	14.9 (1.85)
Pain	10.3 (2.13)	13.1 (2.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Change in scores over time for: Coughing.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0091
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -6.15 to -0.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.34
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Change in scores over time for: Dyspnoea.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -5.75 to -1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.15
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Afatinib, Erlotinib
	Comments	The results shown relate to Change in scores over time for: Pain.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0384
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -5.33 to -0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.32
	Estimation Comments

Adverse Events

Time Frame	From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Adverse Event Reporting Description	All adverse events (AEs) reported for this trial are on treatment AEs.
Arm/Group Title	Afatinib		Erlotinib
Arm/Group Description	Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.		Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
All Cause Mortality
	Afatinib		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/392 (19.6%)		71/395 (18%)
Serious Adverse Events
	Afatinib		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	174/392 (44.4%)		175/395 (44.3%)
Blood and lymphatic system disorders
Anaemia	5/392 (1.3%)		2/395 (0.5%)
Febrile neutropenia	1/392 (0.3%)		1/395 (0.3%)
Leukopenia	1/392 (0.3%)		0/395 (0%)
Neutropenia	1/392 (0.3%)		0/395 (0%)
Thrombocytopenia	2/392 (0.5%)		0/395 (0%)
Cardiac disorders
Atrial fibrillation	4/392 (1%)		2/395 (0.5%)
Cardiac arrest	1/392 (0.3%)		1/395 (0.3%)
Cardiac failure	1/392 (0.3%)		3/395 (0.8%)
Cardiac failure congestive	1/392 (0.3%)		0/395 (0%)
Cardiac tamponade	0/392 (0%)		1/395 (0.3%)
Cardio-respiratory arrest	0/392 (0%)		1/395 (0.3%)
Cardiopulmonary failure	1/392 (0.3%)		1/395 (0.3%)
Myocardial infarction	0/392 (0%)		4/395 (1%)
Myocardial ischaemia	1/392 (0.3%)		0/395 (0%)
Palpitations	2/392 (0.5%)		0/395 (0%)
Pericardial effusion	0/392 (0%)		2/395 (0.5%)
Pericarditis	0/392 (0%)		1/395 (0.3%)
Sinus tachycardia	1/392 (0.3%)		0/395 (0%)
Supraventricular tachycardia	3/392 (0.8%)		0/395 (0%)
Tachycardia	1/392 (0.3%)		0/395 (0%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/392 (0.3%)		0/395 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/392 (0%)		1/395 (0.3%)
Gastrointestinal disorders
Abdominal pain	5/392 (1.3%)		5/395 (1.3%)
Abdominal pain upper	0/392 (0%)		2/395 (0.5%)
Anal fissure	1/392 (0.3%)		0/395 (0%)
Aphagia	1/392 (0.3%)		0/395 (0%)
Constipation	0/392 (0%)		1/395 (0.3%)
Diarrhoea	18/392 (4.6%)		7/395 (1.8%)
Dysphagia	0/392 (0%)		3/395 (0.8%)
Gastric perforation	0/392 (0%)		1/395 (0.3%)
Gastric ulcer	1/392 (0.3%)		2/395 (0.5%)
Gastritis	1/392 (0.3%)		0/395 (0%)
Gastrointestinal haemorrhage	1/392 (0.3%)		1/395 (0.3%)
Gastrointestinal perforation	1/392 (0.3%)		0/395 (0%)
Gastrointestinal telangiectasia	0/392 (0%)		1/395 (0.3%)
Intestinal obstruction	1/392 (0.3%)		1/395 (0.3%)
Intestinal perforation	0/392 (0%)		1/395 (0.3%)
Melaena	0/392 (0%)		1/395 (0.3%)
Nausea	2/392 (0.5%)		3/395 (0.8%)
Oesophageal stenosis	1/392 (0.3%)		1/395 (0.3%)
Pancreatic duct dilatation	0/392 (0%)		1/395 (0.3%)
Pancreatitis	0/392 (0%)		1/395 (0.3%)
Proctalgia	1/392 (0.3%)		0/395 (0%)
Small intestinal haemorrhage	0/392 (0%)		1/395 (0.3%)
Small intestinal obstruction	0/392 (0%)		1/395 (0.3%)
Stomatitis	1/392 (0.3%)		0/395 (0%)
Vomiting	4/392 (1%)		5/395 (1.3%)
General disorders
Asthenia	6/392 (1.5%)		3/395 (0.8%)
Chest discomfort	0/392 (0%)		2/395 (0.5%)
Chest pain	0/392 (0%)		6/395 (1.5%)
Condition aggravated	1/392 (0.3%)		1/395 (0.3%)
Death	4/392 (1%)		2/395 (0.5%)
Device occlusion	0/392 (0%)		1/395 (0.3%)
Discomfort	0/392 (0%)		1/395 (0.3%)
Fatigue	1/392 (0.3%)		2/395 (0.5%)
General physical health deterioration	11/392 (2.8%)		6/395 (1.5%)
Mucosal inflammation	2/392 (0.5%)		1/395 (0.3%)
Multi-organ failure	1/392 (0.3%)		1/395 (0.3%)
Necrosis	1/392 (0.3%)		0/395 (0%)
Non-cardiac chest pain	1/392 (0.3%)		0/395 (0%)
Oedema peripheral	0/392 (0%)		2/395 (0.5%)
Pain	2/392 (0.5%)		3/395 (0.8%)
Performance status decreased	0/392 (0%)		1/395 (0.3%)
Pyrexia	3/392 (0.8%)		4/395 (1%)
Sudden death	1/392 (0.3%)		1/395 (0.3%)
Hepatobiliary disorders
Hepatic function abnormal	0/392 (0%)		1/395 (0.3%)
Hepatitis toxic	0/392 (0%)		1/395 (0.3%)
Hepatomegaly	0/392 (0%)		1/395 (0.3%)
Hyperbilirubinaemia	0/392 (0%)		1/395 (0.3%)
Jaundice	0/392 (0%)		1/395 (0.3%)
Infections and infestations
Anal abscess	1/392 (0.3%)		0/395 (0%)
Bronchitis	2/392 (0.5%)		6/395 (1.5%)
Bronchopneumonia	0/392 (0%)		1/395 (0.3%)
Endocarditis	0/392 (0%)		1/395 (0.3%)
Folliculitis	1/392 (0.3%)		0/395 (0%)
Gastroenteritis	0/392 (0%)		1/395 (0.3%)
Hepatitis C	0/392 (0%)		1/395 (0.3%)
Herpes virus infection	0/392 (0%)		1/395 (0.3%)
Infection	1/392 (0.3%)		1/395 (0.3%)
Lower respiratory tract infection	1/392 (0.3%)		3/395 (0.8%)
Lung infection	2/392 (0.5%)		5/395 (1.3%)
Oral fungal infection	0/392 (0%)		1/395 (0.3%)
Peritonitis	1/392 (0.3%)		1/395 (0.3%)
Pneumonia	26/392 (6.6%)		16/395 (4.1%)
Pneumonia bacterial	0/392 (0%)		1/395 (0.3%)
Pulmonary tuberculosis	0/392 (0%)		1/395 (0.3%)
Respiratory tract infection	2/392 (0.5%)		0/395 (0%)
Sepsis	9/392 (2.3%)		2/395 (0.5%)
Septic shock	0/392 (0%)		1/395 (0.3%)
Skin infection	1/392 (0.3%)		0/395 (0%)
Upper respiratory tract infection	1/392 (0.3%)		0/395 (0%)
Urinary tract infection	2/392 (0.5%)		1/395 (0.3%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/392 (0%)		1/395 (0.3%)
Femoral neck fracture	2/392 (0.5%)		1/395 (0.3%)
Femur fracture	0/392 (0%)		1/395 (0.3%)
Fracture	0/392 (0%)		1/395 (0.3%)
Injury	0/392 (0%)		1/395 (0.3%)
Investigations
Blood calcium increased	1/392 (0.3%)		0/395 (0%)
Blood creatinine increased	2/392 (0.5%)		1/395 (0.3%)
Blood urea increased	1/392 (0.3%)		0/395 (0%)
C-reactive protein increased	1/392 (0.3%)		0/395 (0%)
Eastern Cooperative Oncology Group performance status worsened	0/392 (0%)		1/395 (0.3%)
General physical condition abnormal	0/392 (0%)		1/395 (0.3%)
Hepatic enzyme increased	0/392 (0%)		1/395 (0.3%)
Platelet count decreased	1/392 (0.3%)		0/395 (0%)
Weight decreased	0/392 (0%)		1/395 (0.3%)
White blood cell count decreased	0/392 (0%)		1/395 (0.3%)
Metabolism and nutrition disorders
Cachexia	2/392 (0.5%)		0/395 (0%)
Decreased appetite	3/392 (0.8%)		3/395 (0.8%)
Dehydration	12/392 (3.1%)		4/395 (1%)
Hypercalcaemia	1/392 (0.3%)		6/395 (1.5%)
Hyperglycaemia	1/392 (0.3%)		2/395 (0.5%)
Hyperkalaemia	1/392 (0.3%)		0/395 (0%)
Hyperuricaemia	0/392 (0%)		1/395 (0.3%)
Hypokalaemia	2/392 (0.5%)		0/395 (0%)
Hypophagia	0/392 (0%)		1/395 (0.3%)
Malnutrition	0/392 (0%)		1/395 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/392 (0%)		1/395 (0.3%)
Back pain	3/392 (0.8%)		1/395 (0.3%)
Bone pain	1/392 (0.3%)		1/395 (0.3%)
Muscle spasms	1/392 (0.3%)		0/395 (0%)
Muscular weakness	2/392 (0.5%)		2/395 (0.5%)
Musculoskeletal chest pain	2/392 (0.5%)		0/395 (0%)
Musculoskeletal pain	1/392 (0.3%)		1/395 (0.3%)
Myalgia	1/392 (0.3%)		0/395 (0%)
Neck pain	2/392 (0.5%)		1/395 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/392 (0.3%)		0/395 (0%)
Cancer pain	0/392 (0%)		1/395 (0.3%)
Malignant neoplasm progression	23/392 (5.9%)		16/395 (4.1%)
Metastases to bone	0/392 (0%)		1/395 (0.3%)
Metastases to central nervous system	2/392 (0.5%)		6/395 (1.5%)
Metastases to liver	0/392 (0%)		1/395 (0.3%)
Metastases to meninges	1/392 (0.3%)		0/395 (0%)
Neoplasm malignant	2/392 (0.5%)		0/395 (0%)
Neoplasm progression	2/392 (0.5%)		1/395 (0.3%)
Non-small cell lung cancer	0/392 (0%)		1/395 (0.3%)
Transitional cell carcinoma	1/392 (0.3%)		0/395 (0%)
Tumour pain	2/392 (0.5%)		0/395 (0%)
Ureteric cancer	0/392 (0%)		1/395 (0.3%)
Nervous system disorders
Altered state of consciousness	0/392 (0%)		1/395 (0.3%)
Amnesia	0/392 (0%)		1/395 (0.3%)
Aphasia	1/392 (0.3%)		0/395 (0%)
Brain oedema	3/392 (0.8%)		0/395 (0%)
Cerebrovascular accident	1/392 (0.3%)		1/395 (0.3%)
Convulsion	4/392 (1%)		1/395 (0.3%)
Dizziness	2/392 (0.5%)		4/395 (1%)
Dysarthria	0/392 (0%)		1/395 (0.3%)
Haemorrhage intracranial	0/392 (0%)		1/395 (0.3%)
Hemiparesis	1/392 (0.3%)		0/395 (0%)
Hypoaesthesia	0/392 (0%)		2/395 (0.5%)
Motor dysfunction	0/392 (0%)		1/395 (0.3%)
Myoclonus	1/392 (0.3%)		0/395 (0%)
Paraparesis	0/392 (0%)		1/395 (0.3%)
Polyneuropathy	1/392 (0.3%)		0/395 (0%)
Somnolence	1/392 (0.3%)		0/395 (0%)
Spinal cord compression	0/392 (0%)		2/395 (0.5%)
Syncope	1/392 (0.3%)		1/395 (0.3%)
Psychiatric disorders
Confusional state	2/392 (0.5%)		1/395 (0.3%)
Delirium	0/392 (0%)		1/395 (0.3%)
Disorientation	0/392 (0%)		2/395 (0.5%)
Renal and urinary disorders
Acute prerenal failure	1/392 (0.3%)		0/395 (0%)
Azotaemia	0/392 (0%)		1/395 (0.3%)
Bladder mass	0/392 (0%)		1/395 (0.3%)
Calculus bladder	1/392 (0.3%)		0/395 (0%)
Calculus ureteric	1/392 (0.3%)		0/395 (0%)
Haematuria	0/392 (0%)		2/395 (0.5%)
Hydronephrosis	1/392 (0.3%)		0/395 (0%)
Renal failure	2/392 (0.5%)		2/395 (0.5%)
Renal failure acute	9/392 (2.3%)		1/395 (0.3%)
Renal impairment	1/392 (0.3%)		0/395 (0%)
Urinary bladder polyp	0/392 (0%)		1/395 (0.3%)
Urinary retention	0/392 (0%)		1/395 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/392 (0%)		1/395 (0.3%)
Acute respiratory distress syndrome	3/392 (0.8%)		1/395 (0.3%)
Acute respiratory failure	2/392 (0.5%)		0/395 (0%)
Atelectasis	1/392 (0.3%)		3/395 (0.8%)
Bronchial fistula	1/392 (0.3%)		0/395 (0%)
Chronic obstructive pulmonary disease	5/392 (1.3%)		4/395 (1%)
Cough	2/392 (0.5%)		3/395 (0.8%)
Dyspnoea	12/392 (3.1%)		30/395 (7.6%)
Dyspnoea exertional	2/392 (0.5%)		0/395 (0%)
Haemoptysis	5/392 (1.3%)		10/395 (2.5%)
Hypoxia	1/392 (0.3%)		1/395 (0.3%)
Interstitial lung disease	4/392 (1%)		1/395 (0.3%)
Lung disorder	1/392 (0.3%)		0/395 (0%)
Pleural effusion	3/392 (0.8%)		6/395 (1.5%)
Pleurisy	1/392 (0.3%)		0/395 (0%)
Pleuritic pain	1/392 (0.3%)		0/395 (0%)
Pneumonia aspiration	1/392 (0.3%)		0/395 (0%)
Pneumonitis	1/392 (0.3%)		3/395 (0.8%)
Pneumothorax	2/392 (0.5%)		4/395 (1%)
Pulmonary artery thrombosis	1/392 (0.3%)		0/395 (0%)
Pulmonary embolism	10/392 (2.6%)		5/395 (1.3%)
Pulmonary haemorrhage	2/392 (0.5%)		0/395 (0%)
Pulmonary hypertension	0/392 (0%)		1/395 (0.3%)
Pulmonary mass	1/392 (0.3%)		0/395 (0%)
Pulmonary oedema	1/392 (0.3%)		1/395 (0.3%)
Respiratory disorder	1/392 (0.3%)		0/395 (0%)
Respiratory distress	2/392 (0.5%)		2/395 (0.5%)
Respiratory failure	2/392 (0.5%)		12/395 (3%)
Sputum increased	1/392 (0.3%)		0/395 (0%)
Skin and subcutaneous tissue disorders
Acne	0/392 (0%)		1/395 (0.3%)
Dermatitis acneiform	1/392 (0.3%)		0/395 (0%)
Dermatomyositis	0/392 (0%)		1/395 (0.3%)
Palmar-plantar erythrodysaesthesia syndrome	1/392 (0.3%)		0/395 (0%)
Skin lesion	0/392 (0%)		1/395 (0.3%)
Vascular disorders
Arterial thrombosis	0/392 (0%)		1/395 (0.3%)
Deep vein thrombosis	2/392 (0.5%)		1/395 (0.3%)
Haemorrhage	0/392 (0%)		2/395 (0.5%)
Hypotension	1/392 (0.3%)		1/395 (0.3%)
Inferior vena cava syndrome	1/392 (0.3%)		0/395 (0%)
Ischaemia	0/392 (0%)		1/395 (0.3%)
Orthostatic hypotension	1/392 (0.3%)		0/395 (0%)
Superior vena cava syndrome	1/392 (0.3%)		1/395 (0.3%)
Thrombosis	0/392 (0%)		1/395 (0.3%)
Other (Not Including Serious) Adverse Events
	Afatinib		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	383/392 (97.7%)		371/395 (93.9%)
Blood and lymphatic system disorders
Anaemia	31/392 (7.9%)		41/395 (10.4%)
Gastrointestinal disorders
Constipation	43/392 (11%)		42/395 (10.6%)
Diarrhoea	284/392 (72.4%)		158/395 (40%)
Nausea	81/392 (20.7%)		62/395 (15.7%)
Stomatitis	54/392 (13.8%)		21/395 (5.3%)
Vomiting	48/392 (12.2%)		38/395 (9.6%)
General disorders
Asthenia	61/392 (15.6%)		48/395 (12.2%)
Chest pain	14/392 (3.6%)		20/395 (5.1%)
Fatigue	65/392 (16.6%)		67/395 (17%)
Mucosal inflammation	50/392 (12.8%)		14/395 (3.5%)
Pyrexia	32/392 (8.2%)		33/395 (8.4%)
Infections and infestations
Paronychia	41/392 (10.5%)		18/395 (4.6%)
Investigations
Weight decreased	38/392 (9.7%)		51/395 (12.9%)
Metabolism and nutrition disorders
Decreased appetite	94/392 (24%)		100/395 (25.3%)
Musculoskeletal and connective tissue disorders
Back pain	22/392 (5.6%)		25/395 (6.3%)
Musculoskeletal pain	20/392 (5.1%)		20/395 (5.1%)
Pain in extremity	14/392 (3.6%)		23/395 (5.8%)
Nervous system disorders
Dizziness	12/392 (3.1%)		21/395 (5.3%)
Psychiatric disorders
Insomnia	20/392 (5.1%)		17/395 (4.3%)
Respiratory, thoracic and mediastinal disorders
Cough	65/392 (16.6%)		67/395 (17%)
Dyspnoea	68/392 (17.3%)		69/395 (17.5%)
Epistaxis	27/392 (6.9%)		10/395 (2.5%)
Haemoptysis	44/392 (11.2%)		39/395 (9.9%)
Productive cough	14/392 (3.6%)		21/395 (5.3%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	38/392 (9.7%)		56/395 (14.2%)
Dry skin	36/392 (9.2%)		47/395 (11.9%)
Pruritus	38/392 (9.7%)		52/395 (13.2%)
Rash	196/392 (50%)		187/395 (47.3%)

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.