BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00949650
• Collaborator: (none)
• Enrollment: 345
• Locations: 133
• Arms: 2
• Actual Duration (Months): 91
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung; Adenocarcinoma	Drug: Pemetrexed; Drug: BIBW 2992; Drug: Cisplatin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 345 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients With Stage IIIB or IV Adenocarcinoma of the Lung Harbouring an EGFR Activating Mutation
• Actual Study Start Date: Aug 14, 2009
• Actual Primary Completion Date: Feb 9, 2012
• Actual Study Completion Date: Mar 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIBW 2992 BIBW 2992 tablet once daily until progression	Drug: BIBW 2992; BIBW 2992 once daily until progression
Active Comparator: Cisplatin/Pemetrexed Cisplatin and Pemetrexed IV once every 3 weeks for up to 6 cycles	Drug: Pemetrexed; Pemetrexed IV given once every 3 weeks for up to 6 cycles; Drug: Cisplatin; Cisplatin IV given once every 3 weeks for up to 6 cycles

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Time [Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression]

   PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.

Secondary Outcome Measures

1. Percentage of Patients With Objective Response (OR) [Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression]

   OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.

2. Percentage of Participants With Disease Control (DC) [Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression]

   DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.

3. Overall Survival (OS) Time [From randomisation to cut-off date (17MAR2017).]

   OS was defined as time from randomisation to death.

4. Tumour Shrinkage [Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression]

   Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.

5. Change From Baseline in Body Weight [Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.]

   Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [Throughout the trial until progression (every 3 weeks), up to 28 months.]

   ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. Dead.

7. Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing [Throughout the trial until progression (every 3 weeks).]

   HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

8. HRQOL: Time to Deterioration in Dyspnoea [Throughout the trial until progression (every 3 weeks).]

   HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

9. HRQOL: Time to Deterioration in Pain [Throughout the trial until progression (every 3 weeks).]

   HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

10. Trough Plasma Concentrations of Afatinib at Day 22 [Day 22.]

    Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

11. Trough Plasma Concentrations of Afatinib at Day 29 [Day 29.]

    Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

12. Trough Plasma Concentrations of Afatinib at Day 43 [Day 43.]

    Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.

• Epidermal Growth Factor Receptor mutation detected by central laboratory analysis of tumour biopsy material.

• Measurable disease according to RECIST 1.1.

• Eastern Cooperative Oncology Group score of 0 or 1.

• Age >/= 18 years.

• Life expectancy of at least three months.

• Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice guidelines.

Exclusion criteria:

• Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and randomisation.

• Prior treatment with Epidermal Growth Factor Receptor targeting small molecules or antibodies.

• Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomisation.

• Active brain metastases

• Any other current malignancy or malignancy diagnosed within the past five years

• Known pre-existing interstitial lung disease.

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

• History or presence of clinically relevant cardiovascular abnormalities.

• Any other concomitant serious illness or organ system dysfunction.

• Adequate absolute neutrophil count and platelet count

• Adequate liver and kidney function

• Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
2	Clinical Trials and Research Associates Inc	Montebello	California	United States	90640
3	Innovative Medical Research of South Florida	Miami	Florida	United States	33179
4	Crescent City Research Consortiom	Marrero	Louisiana	United States	70072
5	Interlakes Foundation, Incorporated	Rochester	New York	United States	14623
6	Lehigh Valley Hospital / Lehigh Valley Health Network	Allentown	Pennsylvania	United States	18103
7	South Texas Institute of Cancer, Northwest Cancer Center	Corpus Christi	Texas	United States	78410
8	Instituto de Medicina Nuclear de Bahía Blanca	Bahía Blanca		Argentina	B8000FJI
9	Hospital Alemán	Capital Federal		Argentina	C1118AAT
10	Imcaba S.R.L.	Capital Federal		Argentina	C1185AAT
11	IMAI Research	Capital Federal		Argentina	C1425AWC
12	Instituto Alexander Fleming	Capital Federal		Argentina	C1426ANZ
13	Hospital Militar Central	Capital Federal		Argentina	C1426BOR
14	PALIAR	Capital Federal		Argentina	C1430ERF
15	Centro Oncológico de Rosario	Rosario		Argentina	S2000KZE
16	Lifehouse	Camperdown	New South Wales	Australia	2050
17	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
18	Calvary Mater Newcastle Hospital	Waratah	New South Wales	Australia	2298
19	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
20	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
21	The Burnside War Memorial Hospital	Toorak Gardens	South Australia	Australia	5065
22	Box Hill Hospital	Box Hill	Victoria	Australia	3128
23	St. Vincents Hospital (MEL)	Fitzroy	Victoria	Australia	3065
24	Mount Medical Centre	Perth	Western Australia	Australia	6000
25	KH d. Elisabethinen Linz	Linz		Austria	4010
26	Klinikum Wels - Grieskirchen GmbH	Wels		Austria	4600
27	SMZ Baumgartner Hoehe Otto Wagner Spital	Wien		Austria	1140
28	Brussels - UNIV St-Pierre	Bruxelles		Belgium	1000
29	UNIV UZ Gent	Gent		Belgium	9000
30	Brussels - UNIV UZ Brussel	Jette		Belgium	1090
31	UZ Leuven	Leuven		Belgium	3000
32	Centre Hospitalier Universitaire de Liège	Liège		Belgium	4000
33	Centro de Pesquisa do Hospital Lifecenter	Belo Horizonte		Brazil
34	Centro de Pesquisas Clínicas em Oncología	Cachoeiro de Itapemirim		Brazil	29308-014
35	Insituto de Oncologia do Paraná	Curitiba		Brazil	80530-010
36	Hospital São Lucas da Pontifícia Universidade Católica	Porto Alegre		Brazil	90610-000
37	UNIFESP Departamento de Medicina de Pneumologia	Sao Paulo		Brazil	04023-900
38	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
39	Cross Cancer Institute (University of Alberta)	Edmonton	Alberta	Canada	T6G 1Z2
40	Charles LeMoyne Hospital	Greenfield Park	Migration Data	Canada	J4V 2H1
41	Hematologiste et oncologue medical CHUM - Hopital Notre-Dame	Montreal	Migration Data	Canada	H2L 4M1
42	McGill University, Department of Oncology	Montreal	Migration Data	Canada	H2W 1S6
43	Hospital Dirección de Previsión de Carabineros	Los Condes		Chile	760-0746
44	Instituto Oncológico Limitada Viña del Mar	Reñaca		Chile	2540364
45	Instituto Clínico Oncológico del Sur - ICOS	Temuco		Chile
46	HOP d'Angers	Angers		France	49933
47	HOP Côte de Nacre	Caen Cedex 5		France	14033
48	HOP Nord Michallon	La Tronche		France	38700
49	HOP Croix Rousse, Pneumo, Lyon	Lyon Cedex 4		France	69317
50	INS Curie	Paris Cedex 05		France	75248
51	CTR René Gauducheau	Saint Herblain		France	44805
52	HOP Sud-Réunion, Pneumo, Saint Pierre	Saint Pierre - La Réunion		France	97448
53	HOP - HIA Sainte Anne	Toulon		France	83041
54	HOP, Pneumo, Villefranche sur Saône	Villefranche Sur Saône		France	69655
55	Universitätsklinikum Benjamin Franklin, Berlin	Berlin		Germany	12200
56	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen		Germany	45122
57	Medizinische Hochschule Hannover	Hannover		Germany	30625
58	Lungenklinik Hemer	Hemer		Germany	58675
59	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55101
60	Universitätsklinikum Münster	Münster		Germany	48149
61	Pius-Hospital, Oldenburg	Oldenburg		Germany	26121
62	National Taiwan University Hospital	Taipei		Germany	100
63	Queen Mary Hospital	Hong Kong		Hong Kong
64	Prince of Wales Hospital	Shatin		Hong Kong
65	Szent György Hospital, Szekesfehervar	Szekesfehervar		Hungary	8000
66	Markusovszky County Hospital, Szombathely	Szombathely		Hungary	9700
67	Zala County Hospital, Zalaegerszeg	Zalaegerszeg		Hungary	8900
68	St James's Hospital	Dublin 8		Ireland
69	Ospedale San Donato di Arezzo	Arezzo		Italy	52100
70	Az. USL 4 di Prato	Prato		Italy	59100
71	Azienda Ospedaliera Sant'Andrea-Università di Roma La Sapienza	Roma		Italy	00189
72	Osp. Silvestrin	Sant'Andrea Delle Fratte (PG)		Italy	06132
73	National Hospital Organization Nagoya Medical Center	Aichi, Nagoya		Japan	460-0001
74	Aichi Cancer Center Hospital	Aichi, Nagoya		Japan	464-8681
75	National Cancer Center Hospital East	Chiba, Kashiwa		Japan	277-8577
76	National Hospital Organization Shikoku Cancer Center	Ehime, Matsuyama		Japan	791-0280
77	National Hospital Organization Kyushu Cancer Center	Fukuoka, Fukuoka		Japan	811-1395
78	Hokkaido University Hospital	Hokkaido, Sapporo		Japan	060-8648
79	Institute of Biomedical Research and Innovation Hospital	Hyogo, Kobe		Japan	650-0047
80	Kanazawa University Hospital	Ishikawa, Kanazawa		Japan	920-8641
81	Kanagawa Cardiovascular and Respiratory Center	Kanagawa, Yokohama		Japan	236-0051
82	Niigata Cancer Center Hospital	Niigata, Niigata		Japan	951-8566
83	Kurashiki Central Hospital	Okayama, Kurashiki		Japan	710-8602
84	Okayama University Hospital	Okayama, Okayama		Japan	700-8558
85	Kindai University Hospital	Osaka, Osaka-Sayama		Japan	589-8511
86	Osaka City Hospital Organization Osaka City General Hospital	Osaka, Osaka		Japan	534-0021
87	National Hospital Organization Kinki-Chuo Chest Medical Center	Sakai, Osaka		Japan	591-8555
88	Shizuoka Cancer Center	Shizuoka, Sunto-gun		Japan	411-8777
89	Chungbuk National University Hospital	Cheongju		Korea, Republic of	361-771
90	Chonnam National University Hwasun Hospital	Hwasun		Korea, Republic of	519-763
91	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	13620
92	Asan Medical Center	Seoul		Korea, Republic of	138-736
93	Ulsan University Hospital	Ulsan		Korea, Republic of	682-714
94	Hospital Pulau Pinang	Palau Pinang		Malaysia	10990
95	Pusat Perubatan University Kebangsaan Malaysia	Wilayah Persekutuan		Malaysia	5600
96	University Malaya Medical Centre	Wilayah Persekutuan		Malaysia	59100
97	Hospital Nacional Guillermo Almenara Irigoyen	La Victoria		Peru
98	Clínica Anglo Americana	San Isidro		Peru	27
99	Instituto Nacional de Enfermedades Neoplásicas	Surquillo		Peru	34
100	Perpetual Succour Hospital (Cebu)	Cebu City		Philippines	6000
101	Makati Medical Center	Makati City		Philippines	1229
102	St. Luke Medical Centre	Quezon		Philippines	1102
103	Institutul Oncologic "Prof. Dr. Ion Chiricuta"	Cluj Napoca		Romania	400015
104	ONCOLAB SRL, Craiova	Craiova		Romania	200535
105	Republic Clinical Oncology Dispensary, Dept. Chemotherapy	Kazan		Russian Federation	420029
106	FSBSI "N.N Blokhin Medical Research Center of Oncology"	Moscow		Russian Federation	115478
107	Medical Radiology Science Centre	Obninsk		Russian Federation	249020
108	First Pavlov State Medical University Saint Petersburg	St. Petersburg		Russian Federation	197022
109	SPb SBIH "City Clinical Oncological Dispensary"	St. Petersburg		Russian Federation	197022
110	FSBI "N.N. Petrov National Medical Research Center of Oncology" of MoH of RF	St. Petersburg		Russian Federation	197758
111	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
112	Chang Gung Memorial Hospital Kaohsiung	Kaohsiung		Taiwan	833
113	China Medical University Hospital	Taichung		Taiwan	40447
114	Taichung Veterans General Hospital	Taichung		Taiwan	40705
115	NCKUH	Tainan		Taiwan	704
116	Taipe Veterans General Hospital	Taipei		Taiwan	112
117	Tri-Service General Hospital	Taipei		Taiwan	114
118	Chang Gung Memorial Hospital(TaoYuan)	Taoyuan		Taiwan	33305
119	Ramathibodi Hospital	Bangkok		Thailand	10400
120	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai		Thailand	50200
121	Srinagarind Hospital	Khonkaen		Thailand	40002
122	Songklanagarind Hospital	Songkla		Thailand	90110
123	City Clinical Hospital #4, Dnipropetrovsk State Medical Academy	Dnipropetrovsk		Ukraine	49102
124	Donetsk Regional Antitumor Centre	Donetsk		Ukraine	83000
125	Kharkiv Regional Clinical Oncology Center	Kharkiv		Ukraine	16070
126	Lviv State Oncological Regional Treatment & Diagnostic CTR	Lviv		Ukraine	79031
127	Royal Devon and Exeter Hospital	Exeter		United Kingdom	EX2 5DW
128	Royal Surrey County Hospital	Guildford		United Kingdom	GU2 7XX
129	The Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
130	Maidstone Hospital, Kent Oncology Centre	Maidstone		United Kingdom	ME16 9QQ
131	Scunthorpe General Hospital, Oncology	Scunthorpe		United Kingdom	DN15 7BH
132	The Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT
133	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3LJ

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: NCT00949650
• Other Study ID Numbers: 1200.32; 2008-005615-18
• First Posted: Jul 30, 2009
• Last Update Posted: Apr 6, 2018
• Last Verified: Mar 1, 2018

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

Study Results

Participant Flow

Pre-assignment Detail	Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison. 345 patients were randomised, 5 patients were not treated: 4 patients were not eligible for treatment and 1 patient in the chemotherapy arm refused to take study medication.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Period Title: Overall Study
STARTED	230	115
COMPLETED	0	0
NOT COMPLETED	230	115

Baseline Characteristics

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy	Total
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Total of all reporting groups
Overall Participants	230	115	345
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.5 (10.1)	59.9 (10.0)	60.3 (10.1)
Sex: Female, Male (Count of Participants)
Female	147 63.9%	77 67%	224 64.9%
Male	83 36.1%	38 33%	121 35.1%
Race/Ethnicity, Customized (Number) [Number]
Asian	166 72.2%	83 72.2%	249 72.2%
Non-Asian	64 27.8%	32 27.8%	96 27.8%
Epidermal Growth Factor Receptor (EGFR) mutation group (Number) [Number]
EGFR mutation category: L858R	91 39.6%	47 40.9%	138 40%
EGFR mutation category: Deletion Exon 19	112 48.7%	57 49.6%	169 49%
EGFR mutation category: Other	27 11.7%	11 9.6%	38 11%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Number) [Number]
ECOG PS 0 (baseline)	92 40%	41 35.7%	133 38.6%
ECOG PS 1 (baseline)	138 60%	73 63.5%	211 61.2%
ECOG PS 2 (baseline)	0 0%	1 0.9%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Time
Description	PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

Randomised set (RS)

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Median (95% Confidence Interval) [Months.]	11.17	6.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Regression, Cox
	Comments	Cox Proportional Hazard (PH) regression stratified by epidermal growth factor receptor (EGFR) mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.576
	Confidence Interval	() 95%; 0.426 to 0.778
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg versus Pemetrexed/Cisplatin Chemotherapy.

2. Secondary Outcome

Title	Percentage of Patients With Objective Response (OR)
Description	OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Number (95% Confidence Interval) [Percentage of patients with OR.]	56.5	22.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression stratified for EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.802
	Confidence Interval	() 95%; 2.855 to 8.075
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

3. Secondary Outcome

Title	Percentage of Participants With Disease Control (DC)
Description	DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Number (95% Confidence Interval) [Percentage of participants with DC.]	90.4 39.3%	80.9 70.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression stratified for EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.288
	Confidence Interval	() 95%; 1.202 to 4.356
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

4. Secondary Outcome

Title	Overall Survival (OS) Time
Description	OS was defined as time from randomisation to death.
Time Frame	From randomisation to cut-off date (17MAR2017).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Median (95% Confidence Interval) [Months.]	28.16	28.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7916
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3850
	Comments
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.880
	Confidence Interval	() 95%; 0.660 to 1.174
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

5. Secondary Outcome

Title	Tumour Shrinkage
Description	Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS. There were only 203 patients in the Afatinib 40 mg arm and 101 patients in the Pemetrexed/Cisplatin Chemotherapy with tumour measurements.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	203	101
Mean (Standard Error) [mm.]	33.19 (1.12)	43.00 (1.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline SoD, EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.82
	Confidence Interval	() 95%; -13.64 to -5.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

6. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.
Time Frame	Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.

Outcome Measure Data

Analysis Population Description

RS. Only patients with baseline and at least one post-baseline assessment were included.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	224	109
Change from baseline at lowest value	-3.95 (3.91)	-2.68 (2.90)
Change from baseline at last value	-1.19 (5.36)	-0.29 (4.02)

7. Secondary Outcome

Title	Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Description	ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. Dead.
Time Frame	Throughout the trial until progression (every 3 weeks), up to 28 months.

Outcome Measure Data

Analysis Population Description

RS. Only patients with baseline and at least one post-baseline assessment were included.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	228	111
ECOG PS 0 (last value)	92 40%	41 35.7%
ECOG PS 1 (last value)	138 60%	73 63.5%
ECOG PS 2 (last value)	0 0%	1 0.9%

8. Secondary Outcome

Title	Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing
Description	HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Median (95% Confidence Interval) [Months.]	26.97	8.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0062
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2133
	Comments
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.589
	Confidence Interval	() 95%; 0.401 to 0.866
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

9. Secondary Outcome

Title	HRQOL: Time to Deterioration in Dyspnoea
Description	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Median (95% Confidence Interval) [Months.]	10.41	2.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0129
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.680
	Confidence Interval	() 95%; 0.499 to 0.927
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

10. Secondary Outcome

Title	HRQOL: Time to Deterioration in Pain
Description	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Measure Participants	230	115
Median (95% Confidence Interval) [Months.]	4.17	3.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1882
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0427
	Comments
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.826
	Confidence Interval	() 95%; 0.618 to 1.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

11. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 22
Description	Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 22.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Measure Participants	0	11	165	3
Geometric Mean (Geometric Coefficient of Variation) [ng/mL.]	21.8 (36.6)	28.0 (85.0)	29.9 (46.1)

12. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 29
Description	Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 29.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Measure Participants	0	25	143	16
Geometric Mean (Geometric Coefficient of Variation) [ng/mL.]	28.0 (82.4)	25.8 (69.5)	29.6 (79.2)

13. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 43
Description	Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 43.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Measure Participants	2	39	126	14
Geometric Mean (Geometric Coefficient of Variation) [ng/mL.]	24.4 (260)	24.7 (63.9)	23.5 (66.2)	27.5 (64.4)

Adverse Events

Time Frame	First administration of trial medication until 28 days after last administration of trial medication.
Arm/Group Title	Afatinib 40 mg		Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.		Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
All Cause Mortality
	Afatinib 40 mg		Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Afatinib 40 mg		Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/229 (31.4%)		25/111 (22.5%)
Blood and lymphatic system disorders
Anaemia	0/229 (0%)		2/111 (1.8%)
Thrombocytopenia	0/229 (0%)		1/111 (0.9%)
Cardiac disorders
Atrial fibrillation	0/229 (0%)		1/111 (0.9%)
Mitral valve incompetence	1/229 (0.4%)		0/111 (0%)
Myocardial infarction	0/229 (0%)		1/111 (0.9%)
Pericardial effusion	1/229 (0.4%)		0/111 (0%)
Eye disorders
Cataract	1/229 (0.4%)		0/111 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/229 (0.4%)		0/111 (0%)
Abdominal pain upper	1/229 (0.4%)		0/111 (0%)
Diarrhoea	15/229 (6.6%)		0/111 (0%)
Gastritis	1/229 (0.4%)		0/111 (0%)
Gastrooesophageal reflux disease	1/229 (0.4%)		0/111 (0%)
Haemorrhoids	1/229 (0.4%)		0/111 (0%)
Nausea	0/229 (0%)		2/111 (1.8%)
Pancreatitis acute	1/229 (0.4%)		0/111 (0%)
Stomatitis	1/229 (0.4%)		1/111 (0.9%)
Vomiting	11/229 (4.8%)		3/111 (2.7%)
General disorders
Abasia	0/229 (0%)		1/111 (0.9%)
Asthenia	1/229 (0.4%)		2/111 (1.8%)
Death	2/229 (0.9%)		1/111 (0.9%)
Disease progression	2/229 (0.9%)		0/111 (0%)
Fatigue	3/229 (1.3%)		1/111 (0.9%)
General physical health deterioration	1/229 (0.4%)		1/111 (0.9%)
Hernia	1/229 (0.4%)		0/111 (0%)
Malaise	0/229 (0%)		1/111 (0.9%)
Mucosal inflammation	2/229 (0.9%)		0/111 (0%)
Pyrexia	2/229 (0.9%)		1/111 (0.9%)
Hepatobiliary disorders
Cholecystitis acute	2/229 (0.9%)		0/111 (0%)
Jaundice	1/229 (0.4%)		0/111 (0%)
Infections and infestations
Cellulitis	1/229 (0.4%)		1/111 (0.9%)
Device related infection	1/229 (0.4%)		0/111 (0%)
Lower respiratory tract infection	2/229 (0.9%)		0/111 (0%)
Lung infection	1/229 (0.4%)		0/111 (0%)
Meningitis aseptic	1/229 (0.4%)		0/111 (0%)
Meningoencephalitis herpetic	0/229 (0%)		1/111 (0.9%)
Pneumonia	4/229 (1.7%)		1/111 (0.9%)
Sepsis	1/229 (0.4%)		0/111 (0%)
Upper respiratory tract infection	2/229 (0.9%)		0/111 (0%)
Urinary tract infection	2/229 (0.9%)		0/111 (0%)
Injury, poisoning and procedural complications
Femur fracture	1/229 (0.4%)		0/111 (0%)
Lower limb fracture	1/229 (0.4%)		0/111 (0%)
Splenic rupture	1/229 (0.4%)		0/111 (0%)
Synovial rupture	0/229 (0%)		1/111 (0.9%)
Thoracic vertebral fracture	1/229 (0.4%)		0/111 (0%)
Tibia fracture	1/229 (0.4%)		0/111 (0%)
Investigations
Alanine aminotransferase increased	0/229 (0%)		1/111 (0.9%)
Aspartate aminotransferase increased	0/229 (0%)		1/111 (0.9%)
Blood sodium decreased	0/229 (0%)		1/111 (0.9%)
Liver function test abnormal	1/229 (0.4%)		0/111 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/229 (0.9%)		0/111 (0%)
Dehydration	3/229 (1.3%)		1/111 (0.9%)
Diabetes with hyperosmolarity	0/229 (0%)		1/111 (0.9%)
Hypokalaemia	4/229 (1.7%)		1/111 (0.9%)
Hyponatraemia	1/229 (0.4%)		0/111 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/229 (0%)		1/111 (0.9%)
Bone pain	1/229 (0.4%)		0/111 (0%)
Muscular weakness	0/229 (0%)		1/111 (0.9%)
Pain in extremity	1/229 (0.4%)		0/111 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	3/229 (1.3%)		2/111 (1.8%)
Metastases to central nervous system	3/229 (1.3%)		0/111 (0%)
Metastases to lung	0/229 (0%)		1/111 (0.9%)
Metastases to meninges	1/229 (0.4%)		0/111 (0%)
Neoplasm progression	2/229 (0.9%)		0/111 (0%)
Nervous system disorders
Depressed level of consciousness	1/229 (0.4%)		0/111 (0%)
Epilepsy	1/229 (0.4%)		0/111 (0%)
Headache	1/229 (0.4%)		0/111 (0%)
Intracranial pressure increased	1/229 (0.4%)		0/111 (0%)
Loss of consciousness	1/229 (0.4%)		0/111 (0%)
Partial seizures	1/229 (0.4%)		0/111 (0%)
Seizure	3/229 (1.3%)		0/111 (0%)
Syncope	0/229 (0%)		1/111 (0.9%)
Psychiatric disorders
Confusional state	3/229 (1.3%)		0/111 (0%)
Schizophreniform disorder	0/229 (0%)		1/111 (0.9%)
Renal and urinary disorders
Acute kidney injury	0/229 (0%)		1/111 (0.9%)
Acute prerenal failure	1/229 (0.4%)		1/111 (0.9%)
Renal failure	1/229 (0.4%)		0/111 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	2/229 (0.9%)		0/111 (0%)
Bronchospasm	0/229 (0%)		1/111 (0.9%)
Dyspnoea	4/229 (1.7%)		2/111 (1.8%)
Epistaxis	0/229 (0%)		1/111 (0.9%)
Haemoptysis	1/229 (0.4%)		1/111 (0.9%)
Interstitial lung disease	1/229 (0.4%)		0/111 (0%)
Pleural effusion	2/229 (0.9%)		3/111 (2.7%)
Pneumothorax	1/229 (0.4%)		1/111 (0.9%)
Pulmonary artery thrombosis	0/229 (0%)		1/111 (0.9%)
Pulmonary embolism	2/229 (0.9%)		1/111 (0.9%)
Respiratory arrest	1/229 (0.4%)		0/111 (0%)
Respiratory failure	1/229 (0.4%)		0/111 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	1/229 (0.4%)		0/111 (0%)
Vascular disorders
Deep vein thrombosis	2/229 (0.9%)		0/111 (0%)
Hypotension	1/229 (0.4%)		0/111 (0%)
Superior vena cava syndrome	1/229 (0.4%)		0/111 (0%)
Thrombosis	0/229 (0%)		1/111 (0.9%)
Venous thrombosis	1/229 (0.4%)		1/111 (0.9%)
Other (Not Including Serious) Adverse Events
	Afatinib 40 mg		Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	229/229 (100%)		108/111 (97.3%)
Blood and lymphatic system disorders
Anaemia	19/229 (8.3%)		29/111 (26.1%)
Leukopenia	6/229 (2.6%)		21/111 (18.9%)
Neutropenia	4/229 (1.7%)		35/111 (31.5%)
Thrombocytopenia	1/229 (0.4%)		8/111 (7.2%)
Eye disorders
Dry eye	14/229 (6.1%)		0/111 (0%)
Vision blurred	12/229 (5.2%)		2/111 (1.8%)
Gastrointestinal disorders
Abdominal pain	13/229 (5.7%)		5/111 (4.5%)
Abdominal pain upper	15/229 (6.6%)		8/111 (7.2%)
Cheilitis	22/229 (9.6%)		0/111 (0%)
Constipation	37/229 (16.2%)		39/111 (35.1%)
Diarrhoea	216/229 (94.3%)		25/111 (22.5%)
Dyspepsia	21/229 (9.2%)		7/111 (6.3%)
Mouth ulceration	24/229 (10.5%)		3/111 (2.7%)
Nausea	65/229 (28.4%)		75/111 (67.6%)
Stomatitis	88/229 (38.4%)		10/111 (9%)
Vomiting	53/229 (23.1%)		50/111 (45%)
General disorders
Asthenia	16/229 (7%)		14/111 (12.6%)
Chest pain	16/229 (7%)		14/111 (12.6%)
Fatigue	45/229 (19.7%)		39/111 (35.1%)
Malaise	7/229 (3.1%)		6/111 (5.4%)
Mucosal inflammation	67/229 (29.3%)		5/111 (4.5%)
Oedema	7/229 (3.1%)		13/111 (11.7%)
Oedema peripheral	17/229 (7.4%)		8/111 (7.2%)
Pyrexia	28/229 (12.2%)		6/111 (5.4%)
Infections and infestations
Conjunctivitis	28/229 (12.2%)		3/111 (2.7%)
Cystitis	15/229 (6.6%)		1/111 (0.9%)
Folliculitis	12/229 (5.2%)		0/111 (0%)
Nasopharyngitis	39/229 (17%)		9/111 (8.1%)
Paronychia	132/229 (57.6%)		0/111 (0%)
Upper respiratory tract infection	29/229 (12.7%)		4/111 (3.6%)
Urinary tract infection	19/229 (8.3%)		5/111 (4.5%)
Investigations
Alanine aminotransferase increased	27/229 (11.8%)		3/111 (2.7%)
Aspartate aminotransferase increased	22/229 (9.6%)		1/111 (0.9%)
Blood creatinine increased	5/229 (2.2%)		10/111 (9%)
Haemoglobin decreased	3/229 (1.3%)		13/111 (11.7%)
Neutrophil count decreased	1/229 (0.4%)		8/111 (7.2%)
Weight decreased	44/229 (19.2%)		16/111 (14.4%)
Metabolism and nutrition disorders
Decreased appetite	70/229 (30.6%)		61/111 (55%)
Hypokalaemia	21/229 (9.2%)		4/111 (3.6%)
Hyponatraemia	4/229 (1.7%)		6/111 (5.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	21/229 (9.2%)		6/111 (5.4%)
Back pain	37/229 (16.2%)		13/111 (11.7%)
Muscle spasms	20/229 (8.7%)		0/111 (0%)
Musculoskeletal pain	21/229 (9.2%)		2/111 (1.8%)
Myalgia	12/229 (5.2%)		1/111 (0.9%)
Pain in extremity	20/229 (8.7%)		4/111 (3.6%)
Nervous system disorders
Dizziness	28/229 (12.2%)		12/111 (10.8%)
Dysgeusia	18/229 (7.9%)		9/111 (8.1%)
Headache	37/229 (16.2%)		19/111 (17.1%)
Psychiatric disorders
Insomnia	37/229 (16.2%)		10/111 (9%)
Respiratory, thoracic and mediastinal disorders
Cough	39/229 (17%)		21/111 (18.9%)
Dyspnoea	18/229 (7.9%)		12/111 (10.8%)
Epistaxis	41/229 (17.9%)		1/111 (0.9%)
Hiccups	5/229 (2.2%)		10/111 (9%)
Nasal inflammation	15/229 (6.6%)		0/111 (0%)
Oropharyngeal pain	13/229 (5.7%)		3/111 (2.7%)
Rhinorrhoea	16/229 (7%)		7/111 (6.3%)
Skin and subcutaneous tissue disorders
Acne	52/229 (22.7%)		0/111 (0%)
Alopecia	30/229 (13.1%)		20/111 (18%)
Dermatitis acneiform	32/229 (14%)		0/111 (0%)
Dry skin	72/229 (31.4%)		2/111 (1.8%)
Nail disorder	14/229 (6.1%)		0/111 (0%)
Palmar-plantar erythrodysaesthesia syndrome	19/229 (8.3%)		0/111 (0%)
Pruritus	50/229 (21.8%)		1/111 (0.9%)
Rash	145/229 (63.3%)		11/111 (9.9%)
Skin exfoliation	13/229 (5.7%)		0/111 (0%)
Skin fissures	16/229 (7%)		0/111 (0%)
Vascular disorders
Hypertension	14/229 (6.1%)		14/111 (12.6%)

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.