LUX-Head&Neck 1: A Phase III Trial of Afatinib (BIBW2992) Versus Methotrexate for the Treatment of Recurrent and/or Metastatic (R/M) Head and Neck Squamous Cell Cancer After Platinum Based Chemotherapy

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ClinicalTrials.gov Identifier: NCT01345682

Recruitment Status : Completed

First Posted : May 2, 2011

Results First Posted : April 14, 2015

Last Update Posted : February 15, 2018

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Sponsor:

Information provided by (Responsible Party):

Boehringer Ingelheim

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Head and Neck Neoplasms Carcinoma, Squamous Cell
Interventions	Drug: Afatinib Drug: Methotrexate
Enrollment	483

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Period Title: Overall Study
Started	322 ^[1]	161 ^[1]
Completed	0	0
Not Completed	322	161
Reason Not Completed
Progressive disease per RECIST	226	93
Worsening of underlying cancer disease	23	12
Adverse Event	51	41
Non-compliance with protocol	0	1
Lost to Follow-up	0	1
Refused to continue trial medication	16	9
Not treated	2	1
Reason other than those specified above	4	3
[1] Randomised

Baseline Characteristics

Arm/Group Title		Afatinib (BIBW 2992)	Methotrexate	Total
Arm/Group Description		Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...	Total of all reporting groups
Arm/Group Description		Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Total of all reporting groups
Overall Number of Baseline Participants		322	161	483
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The randomised set (RS) included all patients who were randomised to receive treatment, whether treated or not
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	322 participants	161 participants	483 participants
		60.0 (8.8)	59.3 (9.7)	59.8 (9.1)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	322 participants	161 participants	483 participants
	Female	47 14.6%	24 14.9%	71 14.7%
	Male	275 85.4%	137 85.1%	412 85.3%

Outcome Measures

1.Primary Outcome


Title	Progression-free Survival (PFS) Based on Central Independent Review
Description	PFS was defined as the time from the date of randomisation to disease ...
Description	PFS was defined as the time from the date of randomisation to disease progression or death, whichever occurred first. The primary analysis of PFS considered PFS events as assessed by central independent review, including all data collected until the study completion date (06 December 2016). The date of disease progression was recorded based on RECIST version 1.1. Unequivocal progression of disease was determined if at least one of the following criteria applied: At least 20% increase in the Sum of Diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm Appearance of one or more new lesions Unequivocal progression of existing non-target lesions
Time Frame	From randomization until disease progression, death or study completion date (06Dec2016); Up to 60 months

Outcome Measure Data

Analysis Population Description

Randomised set (RS)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Median (95% Confidence Interval) Unit of Measure: months
	2.63 (2.10 to 2.73)	1.74 (1.48 to 2.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0257
	Comments	Log-rank test stratified by baseline Eastern Cooperative Oncology Group (ECOG) Performance score (PS)(0 or 1) and prior use of Epidermal Growth Factor Receptor (EGFR)-targeted antibody in the Recurrent and/or Metastatic (R/M) setting (Yes or No).
	Method	Stratified Log-rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.792
	Confidence Interval	(2-Sided) 95% 0.643 to 0.977
	Estimation Comments	Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

2.Secondary Outcome


Title	Overall Survival (OS)
Description	Overall survival (OS) was a key secondary endpoint of this trial. OS w...
Description	Overall survival (OS) was a key secondary endpoint of this trial. OS was defined as the time from randomisation to death (irrespective of the cause of death). Patients for whom there was no evidence of death at the study completion date (06 December 2016) were to be censored on the date that they were last known to be alive.
Time Frame	From randomization until death or study completion date (06Dec2016); Up to 60 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Median (95% Confidence Interval) Unit of Measure: months
	6.87 (6.14 to 7.79)	6.01 (5.16 to 7.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6755
	Comments	Log-rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No).
	Method	Stratified Log-rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.958
	Confidence Interval	(2-Sided) 95% 0.786 to 1.169
	Estimation Comments	Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

3.Secondary Outcome


Title	Objective Response (OR)
Description	OR is defined as the best overall response of complete response (CR) a...
Description	OR is defined as the best overall response of complete response (CR) and partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-Progressive Disease (PD) in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.
Time Frame	Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	10.2 (7.16 to 14.09)	5.6 (2.58 to 10.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1010
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95% 0.88 to 4.14
	Estimation Comments	Odds ratio, 95% Confidence Interval (CI) and p-value (two-sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

4.Secondary Outcome


Title	Disease Control (DC)
Description	DC is defined as the best overall response of CR, PR, stable disease (...
Description	DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.
Time Frame	Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	49.1 (43.48 to 54.67)	38.5 (30.95 to 46.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0353
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95% 1.03 to 2.26
	Estimation Comments	Odds ratio, 95% CI and p-value (two-sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

5.Secondary Outcome


Title	Tumour Shrinkage
Description	Tumour shrinkage, defined as the maximum decrease from baseline in the...
Description	Tumour shrinkage, defined as the maximum decrease from baseline in the sum of diameters of the target lesions, as measured by central imaging. The longest diameter of target lesions was recorded, except for lymph nodes, which were measured by their short axis. Negative values indicate a reduction in the sum of target lesion diameters and positive values an increase. Percentage of Participants with Tumour shrinkage as per the categories (>=20% increase, >=0 - <20% increase, >0 - <30% decrease, >=30 - <50% decrease, >=50% decrease) are presented.
Time Frame	Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	248	121
Measure Type: Number Unit of Measure: percentage of participants
>=20% increase	16.5	21.1
>=0 - <20% increase	24.2	31.1
>0 - <30% decrease	23.6	16.1
>=30 - <50% decrease	6.2	4.3
>=50% decrease	5.0	1.9

6.Secondary Outcome


Title	Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time
Description	The HRQOL analyses focused on pain, swallowing, and global health stat...
Description	The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	265	117
Mean (Standard Error) Unit of Measure: scores on a scale
	11.8 (3.16)	16.2 (3.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG performance score (PS) and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0300
	Comments	Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR-targeted antibody for R/M HNSCC (Yes or No).
	Method	longitudinal models
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 95% -8.31 to -0.42
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.01
	Estimation Comments	Afatinib (BIBW 2992) vs Methotrexate

7.Secondary Outcome


Title	Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time
Description	The HRQOL analyses focused on pain, swallowing, and global health stat...
Description	The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	257	112
Mean (Standard Error) Unit of Measure: scores on a scale
	20.0 (3.40)	20.1 (3.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG PS and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9773
	Comments	Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR-targeted antibody for R/M HNSCC (Yes or No).
	Method	longitudinal models
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95% -4.30 to 4.18
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.16
	Estimation Comments	Afatinib (BIBW 2992) vs Methotrexate

8.Secondary Outcome


Title	Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time
Description	The HRQOL analyses focused on pain, swallowing, and global health stat...
Description	The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	267	117
Mean (Standard Error) Unit of Measure: scores on a scale
	28.7 (3.54)	28.2 (3.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG PS and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7767
	Comments	Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR-targeted antibody for R/M HNSCC (Yes or No).
	Method	longitudinal models
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95% -3.28 to 4.39
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.95
	Estimation Comments	Afatinib (BIBW 2992) vs Methotrexate

9.Secondary Outcome


Title	Status Change in Pain Scale
Description	Distribution of patients with improved, stable or worsened HRQOL: Impr...
Description	Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	265	117
Measure Type: Number Unit of Measure: percentage of participants
Improved	26.4	23.1
Stable	32.1	31.6
Worsened	41.5	45.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.494
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95% 0.717 to 1.990
	Estimation Comments	Odds ratio, 95% CI and p-value (two-sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

10.Secondary Outcome


Title	Status Change in Swallowing Scale
Description	Distribution of patients with improved, stable or worsened HRQOL: Impr...
Description	Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	257	112
Measure Type: Number Unit of Measure: percentage of participants
Improved	26.1	23.2
Stable	34.2	29.5
Worsened	39.7	47.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.584
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95% 0.687 to 1.950
	Estimation Comments	Odds ratio, 95% CI and p-value (two-sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

11.Secondary Outcome


Title	Status Change in Global Health Status Scale
Description	Distribution of patients with improved, stable or worsened HRQOL: Impr...
Description	Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description

RS (Only patients with observed cases (OC) values were analysed)


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	267	117
Measure Type: Number Unit of Measure: percentage of participants
Improved	30.3	29.1
Stable	26.6	25.6
Worsened	43.1	45.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.816
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95% 0.657 to 1.705
	Estimation Comments	Odds ratio, 95% CI and p-value (two-sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

12.Secondary Outcome


Title	Time to Deterioration in Pain
Description	The time to deterioration was defined as the time from randomisation t...
Description	The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Median (95% Confidence Interval) Unit of Measure: months
	3.02 (2.83 to 3.75)	2.30 (1.64 to 3.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0217
	Comments	Log-rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No).
	Method	Stratified Log-rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.55 to 0.96
	Estimation Comments	Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No).

13.Secondary Outcome


Title	Time to Deterioration in Swallowing
Description	The time to deterioration was defined as the time from randomisation t...
Description	The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Median (95% Confidence Interval) Unit of Measure: months
	3.75 (2.83 to 4.30)	2.10 (1.48 to 3.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0040
	Comments	Log-rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No).
	Method	Stratified Log-rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95% 0.50 to 0.89
	Estimation Comments	Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

14.Secondary Outcome


Title	Time to Deterioration in Global Health Status
Description	The time to deterioration was defined as the time from randomisation t...
Description	The time to deterioration was defined as the time from randomisation to a score decreased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
Time Frame	From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description:	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description:	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed	322	161
Median (95% Confidence Interval) Unit of Measure: months
	3.25 (2.83 to 4.01)	2.69 (1.61 to 2.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib (BIBW 2992), Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0268
	Comments	Log-rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No).
	Method	Stratified Log-rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.56 to 0.97
	Estimation Comments	Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR-targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate

Adverse Events

Time Frame	From first administration of study medication (afatinib or methotrexate) and within 28 days after the last administration of study medication (study completion date is 06Dec2016); Up to 60 months
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Afatinib (BIBW 2992)	Methotrexate
Arm/Group Description	Oral administration of Afatinib (fi...	Intravenous bolus injection of Meth...
Arm/Group Description	Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.	Intravenous bolus injection of Methotrexate Starting dose 40 milligram per square meter mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
All-Cause Mortality
	Afatinib (BIBW 2992)	Methotrexate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Afatinib (BIBW 2992)	Methotrexate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	168/320 (52.50%)	73/160 (45.63%)
Blood and lymphatic system disorders
Anaemia ^† 1	3/320 (0.94%)	8/160 (5.00%)
Febrile neutropenia ^† 1	2/320 (0.63%)	2/160 (1.25%)
Neutropenia ^† 1	1/320 (0.31%)	3/160 (1.88%)
Pancytopenia ^† 1	0/320 (0.00%)	3/160 (1.88%)
Thrombocytopenia ^† 1	3/320 (0.94%)	1/160 (0.63%)
Cardiac disorders
Atrial fibrillation ^† 1	0/320 (0.00%)	1/160 (0.63%)
Atrial tachycardia ^† 1	1/320 (0.31%)	0/160 (0.00%)
Left ventricular dysfunction ^† 1	1/320 (0.31%)	0/160 (0.00%)
Myocardial infarction ^† 1	0/320 (0.00%)	1/160 (0.63%)
Tachycardia ^† 1	1/320 (0.31%)	0/160 (0.00%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula ^† 1	3/320 (0.94%)	0/160 (0.00%)
Eye disorders
Blindness unilateral ^† 1	1/320 (0.31%)	0/160 (0.00%)
Keratitis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Gastrointestinal disorders
Colitis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Diarrhoea ^† 1	16/320 (5.00%)	1/160 (0.63%)
Duodenal ulcer ^† 1	1/320 (0.31%)	0/160 (0.00%)
Dysphagia ^† 1	9/320 (2.81%)	3/160 (1.88%)
Gastric ulcer ^† 1	1/320 (0.31%)	0/160 (0.00%)
Gastrointestinal haemorrhage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Gastrooesophageal reflux disease ^† 1	1/320 (0.31%)	0/160 (0.00%)
Haematemesis ^† 1	1/320 (0.31%)	1/160 (0.63%)
Intestinal obstruction ^† 1	2/320 (0.63%)	0/160 (0.00%)
Large intestine perforation ^† 1	1/320 (0.31%)	0/160 (0.00%)
Melaena ^† 1	0/320 (0.00%)	1/160 (0.63%)
Mouth haemorrhage ^† 1	5/320 (1.56%)	0/160 (0.00%)
Nausea ^† 1	5/320 (1.56%)	1/160 (0.63%)
Odynophagia ^† 1	2/320 (0.63%)	0/160 (0.00%)
Oesophageal fistula ^† 1	1/320 (0.31%)	0/160 (0.00%)
Oesophageal stenosis ^† 1	1/320 (0.31%)	1/160 (0.63%)
Retroperitoneal haemorrhage ^† 1	0/320 (0.00%)	1/160 (0.63%)
Stomatitis ^† 1	3/320 (0.94%)	1/160 (0.63%)
Vomiting ^† 1	10/320 (3.13%)	1/160 (0.63%)
General disorders
Asthenia ^† 1	6/320 (1.88%)	1/160 (0.63%)
Complication associated with device ^† 1	1/320 (0.31%)	0/160 (0.00%)
Death ^† 1	1/320 (0.31%)	1/160 (0.63%)
Face oedema ^† 1	1/320 (0.31%)	0/160 (0.00%)
Facial pain ^† 1	1/320 (0.31%)	0/160 (0.00%)
Fatigue ^† 1	3/320 (0.94%)	2/160 (1.25%)
General physical health deterioration ^† 1	27/320 (8.44%)	8/160 (5.00%)
Hyperpyrexia ^† 1	0/320 (0.00%)	1/160 (0.63%)
Hyperthermia ^† 1	1/320 (0.31%)	0/160 (0.00%)
Mucosal haemorrhage ^† 1	0/320 (0.00%)	1/160 (0.63%)
Mucosal inflammation ^† 1	3/320 (0.94%)	2/160 (1.25%)
Multiple organ dysfunction syndrome ^† 1	1/320 (0.31%)	1/160 (0.63%)
Pain ^† 1	2/320 (0.63%)	0/160 (0.00%)
Pyrexia ^† 1	7/320 (2.19%)	5/160 (3.13%)
Sudden death ^† 1	0/320 (0.00%)	1/160 (0.63%)
Hepatobiliary disorders
Hepatic failure ^† 1	0/320 (0.00%)	1/160 (0.63%)
Hepatic function abnormal ^† 1	0/320 (0.00%)	1/160 (0.63%)
Immune system disorders
Drug hypersensitivity ^† 1	0/320 (0.00%)	1/160 (0.63%)
Infections and infestations
Abscess oral ^† 1	0/320 (0.00%)	1/160 (0.63%)
Atypical pneumonia ^† 1	0/320 (0.00%)	1/160 (0.63%)
Bacteraemia ^† 1	0/320 (0.00%)	1/160 (0.63%)
Cellulitis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Device related infection ^† 1	4/320 (1.25%)	0/160 (0.00%)
Empyema ^† 1	1/320 (0.31%)	0/160 (0.00%)
Infection ^† 1	0/320 (0.00%)	1/160 (0.63%)
Klebsiella sepsis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Laryngitis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Lower respiratory tract infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Lung infection ^† 1	4/320 (1.25%)	2/160 (1.25%)
Oral infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Otitis media ^† 1	1/320 (0.31%)	0/160 (0.00%)
Periorbital cellulitis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pneumonia ^† 1	13/320 (4.06%)	3/160 (1.88%)
Pulmonary sepsis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Respiratory tract infection ^† 1	4/320 (1.25%)	0/160 (0.00%)
Sepsis ^† 1	3/320 (0.94%)	2/160 (1.25%)
Septic shock ^† 1	2/320 (0.63%)	2/160 (1.25%)
Skin infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Soft tissue infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Staphylococcal infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Staphylococcal sepsis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Tracheitis ^† 1	1/320 (0.31%)	1/160 (0.63%)
Tracheobronchitis ^† 1	3/320 (0.94%)	0/160 (0.00%)
Urinary tract infection ^† 1	1/320 (0.31%)	0/160 (0.00%)
Wound sepsis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Injury, poisoning and procedural complications
Cervical vertebral fracture ^† 1	0/320 (0.00%)	1/160 (0.63%)
Contusion ^† 1	0/320 (0.00%)	1/160 (0.63%)
Fall ^† 1	0/320 (0.00%)	1/160 (0.63%)
Femur fracture ^† 1	1/320 (0.31%)	0/160 (0.00%)
Foreign body aspiration ^† 1	0/320 (0.00%)	1/160 (0.63%)
Poisoning deliberate ^† 1	0/320 (0.00%)	1/160 (0.63%)
Post procedural haemorrhage ^† 1	3/320 (0.94%)	0/160 (0.00%)
Tracheal haemorrhage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Tracheal obstruction ^† 1	0/320 (0.00%)	1/160 (0.63%)
Vascular pseudoaneurysm ^† 1	1/320 (0.31%)	0/160 (0.00%)
Investigations
Blood creatinine increased ^† 1	2/320 (0.63%)	0/160 (0.00%)
Blood pressure orthostatic decreased ^† 1	1/320 (0.31%)	0/160 (0.00%)
False positive investigation result ^† 1	1/320 (0.31%)	0/160 (0.00%)
International normalised ratio increased ^† 1	1/320 (0.31%)	0/160 (0.00%)
Oxygen saturation decreased ^† 1	0/320 (0.00%)	1/160 (0.63%)
Weight decreased ^† 1	2/320 (0.63%)	2/160 (1.25%)
Metabolism and nutrition disorders
Cachexia ^† 1	1/320 (0.31%)	2/160 (1.25%)
Decreased appetite ^† 1	7/320 (2.19%)	1/160 (0.63%)
Dehydration ^† 1	9/320 (2.81%)	1/160 (0.63%)
Failure to thrive ^† 1	0/320 (0.00%)	1/160 (0.63%)
Food aversion ^† 1	1/320 (0.31%)	0/160 (0.00%)
Hypercalcaemia ^† 1	3/320 (0.94%)	1/160 (0.63%)
Hyperglycaemia ^† 1	0/320 (0.00%)	1/160 (0.63%)
Hypokalaemia ^† 1	3/320 (0.94%)	1/160 (0.63%)
Hyponatraemia ^† 1	6/320 (1.88%)	1/160 (0.63%)
Malnutrition ^† 1	5/320 (1.56%)	1/160 (0.63%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	2/320 (0.63%)	0/160 (0.00%)
Fistula ^† 1	2/320 (0.63%)	0/160 (0.00%)
Musculoskeletal chest pain ^† 1	2/320 (0.63%)	0/160 (0.00%)
Musculoskeletal pain ^† 1	0/320 (0.00%)	1/160 (0.63%)
Pain in extremity ^† 1	2/320 (0.63%)	0/160 (0.00%)
Rotator cuff syndrome ^† 1	1/320 (0.31%)	0/160 (0.00%)
Trismus ^† 1	1/320 (0.31%)	0/160 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	1/320 (0.31%)	0/160 (0.00%)
Infected neoplasm ^† 1	1/320 (0.31%)	1/160 (0.63%)
Laryngeal cancer ^† 1	0/320 (0.00%)	1/160 (0.63%)
Malignant neoplasm progression ^† 1	40/320 (12.50%)	9/160 (5.63%)
Metastases to liver ^† 1	1/320 (0.31%)	0/160 (0.00%)
Oesophageal squamous cell carcinoma ^† 1	1/320 (0.31%)	0/160 (0.00%)
Tumour associated fever ^† 1	1/320 (0.31%)	0/160 (0.00%)
Tumour haemorrhage ^† 1	11/320 (3.44%)	4/160 (2.50%)
Tumour pain ^† 1	3/320 (0.94%)	2/160 (1.25%)
Tumour ulceration ^† 1	1/320 (0.31%)	0/160 (0.00%)
Nervous system disorders
Cerebrovascular accident ^† 1	5/320 (1.56%)	0/160 (0.00%)
Cognitive disorder ^† 1	0/320 (0.00%)	1/160 (0.63%)
Dizziness ^† 1	1/320 (0.31%)	0/160 (0.00%)
Epilepsy ^† 1	1/320 (0.31%)	0/160 (0.00%)
Generalised tonic-clonic seizure ^† 1	1/320 (0.31%)	0/160 (0.00%)
Headache ^† 1	1/320 (0.31%)	0/160 (0.00%)
Ischaemic stroke ^† 1	1/320 (0.31%)	0/160 (0.00%)
Paralysis recurrent laryngeal nerve ^† 1	0/320 (0.00%)	1/160 (0.63%)
Somnolence ^† 1	1/320 (0.31%)	1/160 (0.63%)
Spinal cord compression ^† 1	1/320 (0.31%)	0/160 (0.00%)
Syncope ^† 1	2/320 (0.63%)	0/160 (0.00%)
Product Issues
Device dislocation ^† 1	0/320 (0.00%)	1/160 (0.63%)
Device leakage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Psychiatric disorders
Agitation ^† 1	1/320 (0.31%)	0/160 (0.00%)
Renal and urinary disorders
Acute kidney injury ^† 1	3/320 (0.94%)	0/160 (0.00%)
Renal failure ^† 1	6/320 (1.88%)	1/160 (0.63%)
Renal impairment ^† 1	1/320 (0.31%)	0/160 (0.00%)
Reproductive system and breast disorders
Prostatomegaly ^† 1	1/320 (0.31%)	0/160 (0.00%)
Respiratory, thoracic and mediastinal disorders
Aspiration ^† 1	1/320 (0.31%)	1/160 (0.63%)
Bronchial obstruction ^† 1	2/320 (0.63%)	0/160 (0.00%)
Bronchopneumopathy ^† 1	1/320 (0.31%)	0/160 (0.00%)
Dyspnoea ^† 1	15/320 (4.69%)	4/160 (2.50%)
Epistaxis ^† 1	0/320 (0.00%)	2/160 (1.25%)
Haemoptysis ^† 1	4/320 (1.25%)	0/160 (0.00%)
Hypoxia ^† 1	1/320 (0.31%)	0/160 (0.00%)
Increased bronchial secretion ^† 1	0/320 (0.00%)	1/160 (0.63%)
Laryngeal obstruction ^† 1	1/320 (0.31%)	1/160 (0.63%)
Laryngeal oedema ^† 1	1/320 (0.31%)	2/160 (1.25%)
Lung disorder ^† 1	1/320 (0.31%)	1/160 (0.63%)
Organising pneumonia ^† 1	1/320 (0.31%)	1/160 (0.63%)
Oropharyngeal pain ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pharyngeal haemorrhage ^† 1	1/320 (0.31%)	1/160 (0.63%)
Pharyngeal stenosis ^† 1	0/320 (0.00%)	1/160 (0.63%)
Pleural effusion ^† 1	4/320 (1.25%)	2/160 (1.25%)
Pneumonia aspiration ^† 1	3/320 (0.94%)	3/160 (1.88%)
Pneumonitis ^† 1	2/320 (0.63%)	3/160 (1.88%)
Productive cough ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pulmonary artery thrombosis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pulmonary embolism ^† 1	1/320 (0.31%)	1/160 (0.63%)
Pulmonary fibrosis ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pulmonary haemorrhage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Pulmonary hypertension ^† 1	1/320 (0.31%)	0/160 (0.00%)
Respiratory acidosis ^† 1	0/320 (0.00%)	1/160 (0.63%)
Respiratory depression ^† 1	0/320 (0.00%)	1/160 (0.63%)
Respiratory distress ^† 1	4/320 (1.25%)	0/160 (0.00%)
Respiratory failure ^† 1	6/320 (1.88%)	1/160 (0.63%)
Respiratory tract haemorrhage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Stridor ^† 1	2/320 (0.63%)	0/160 (0.00%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome ^† 1	1/320 (0.31%)	0/160 (0.00%)
Skin haemorrhage ^† 1	1/320 (0.31%)	0/160 (0.00%)
Skin reaction ^† 1	1/320 (0.31%)	0/160 (0.00%)
Surgical and medical procedures
Gastrostomy ^† 1	1/320 (0.31%)	0/160 (0.00%)
Vascular disorders
Angiopathy ^† 1	1/320 (0.31%)	0/160 (0.00%)
Deep vein thrombosis ^† 1	1/320 (0.31%)	1/160 (0.63%)
Haemorrhage ^† 1	0/320 (0.00%)	4/160 (2.50%)
Hypotension ^† 1	2/320 (0.63%)	0/160 (0.00%)
Shock haemorrhagic ^† 1	1/320 (0.31%)	0/160 (0.00%)
Superior vena cava syndrome ^† 1	0/320 (0.00%)	1/160 (0.63%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Afatinib (BIBW 2992)	Methotrexate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	309/320 (96.56%)	146/160 (91.25%)
Blood and lymphatic system disorders
Anaemia ^† 1	61/320 (19.06%)	42/160 (26.25%)
Leukopenia ^† 1	3/320 (0.94%)	13/160 (8.13%)
Neutropenia ^† 1	1/320 (0.31%)	30/160 (18.75%)
Thrombocytopenia ^† 1	2/320 (0.63%)	10/160 (6.25%)
Gastrointestinal disorders
Abdominal pain ^† 1	27/320 (8.44%)	5/160 (3.13%)
Constipation ^† 1	39/320 (12.19%)	28/160 (17.50%)
Diarrhoea ^† 1	239/320 (74.69%)	28/160 (17.50%)
Dyspepsia ^† 1	31/320 (9.69%)	4/160 (2.50%)
Dysphagia ^† 1	42/320 (13.13%)	12/160 (7.50%)
Nausea ^† 1	89/320 (27.81%)	43/160 (26.88%)
Stomatitis ^† 1	73/320 (22.81%)	28/160 (17.50%)
Vomiting ^† 1	63/320 (19.69%)	26/160 (16.25%)
General disorders
Asthenia ^† 1	66/320 (20.63%)	41/160 (25.62%)
Fatigue ^† 1	72/320 (22.50%)	42/160 (26.25%)
Mucosal inflammation ^† 1	74/320 (23.13%)	42/160 (26.25%)
Pyrexia ^† 1	38/320 (11.88%)	27/160 (16.88%)
Infections and infestations
Conjunctivitis ^† 1	25/320 (7.81%)	4/160 (2.50%)
Folliculitis ^† 1	24/320 (7.50%)	1/160 (0.63%)
Paronychia ^† 1	51/320 (15.94%)	0/160 (0.00%)
Investigations
Alanine aminotransferase increased ^† 1	4/320 (1.25%)	19/160 (11.88%)
Aspartate aminotransferase increased ^† 1	6/320 (1.88%)	20/160 (12.50%)
Weight decreased ^† 1	69/320 (21.56%)	25/160 (15.63%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	60/320 (18.75%)	39/160 (24.38%)
Hypokalaemia ^† 1	20/320 (6.25%)	10/160 (6.25%)
Hyponatraemia ^† 1	17/320 (5.31%)	4/160 (2.50%)
Musculoskeletal and connective tissue disorders
Back pain ^† 1	17/320 (5.31%)	5/160 (3.13%)
Neck pain ^† 1	17/320 (5.31%)	9/160 (5.63%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain ^† 1	25/320 (7.81%)	9/160 (5.63%)
Nervous system disorders
Headache ^† 1	26/320 (8.13%)	16/160 (10.00%)
Psychiatric disorders
Anxiety ^† 1	21/320 (6.56%)	7/160 (4.38%)
Insomnia ^† 1	27/320 (8.44%)	8/160 (5.00%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	41/320 (12.81%)	23/160 (14.37%)
Dyspnoea ^† 1	45/320 (14.06%)	21/160 (13.13%)
Epistaxis ^† 1	32/320 (10.00%)	5/160 (3.13%)
Skin and subcutaneous tissue disorders
Acne ^† 1	28/320 (8.75%)	2/160 (1.25%)
Dermatitis acneiform ^† 1	68/320 (21.25%)	4/160 (2.50%)
Dry skin ^† 1	47/320 (14.69%)	5/160 (3.13%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	19/320 (5.94%)	3/160 (1.88%)
Pruritus ^† 1	29/320 (9.06%)	1/160 (0.63%)
Rash ^† 1	134/320 (41.88%)	11/160 (6.88%)
Skin fissures ^† 1	40/320 (12.50%)	0/160 (0.00%)
Vascular disorders
Hypotension ^† 1	9/320 (2.81%)	10/160 (6.25%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Boehringer Ingelheim Call Center
Organization:	Boehringer Ingelheim
Phone:	1-800-243-0127
EMail:	clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cohen EEW, Licitra LF, Burtness B, Fayette J, Gauler T, Clement PM, Grau JJ, Del Campo JM, Mailliez A, Haddad RI, Vermorken JB, Tahara M, Guigay J, Geoffrois L, Merlano MC, Dupuis N, Kramer N, Cong XJ, Gibson N, Solca F, Ehrnrooth E, Machiels JH. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol. 2017 Oct 1;28(10):2526-2532. doi: 10.1093/annonc/mdx344.

Clement PM, Gauler T, Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Cohen EE, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Vermorken JB; LUX-H&N 1 investigators. Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial. Ann Oncol. 2016 Aug;27(8):1585-93. doi: 10.1093/annonc/mdw151. Epub 2016 Apr 15.

Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):583-94. doi: 10.1016/S1470-2045(15)70124-5. Epub 2015 Apr 16.

Layout table for additonal information

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01345682
Other Study ID Numbers:	1200.43 2011-000391-34 ( EudraCT Number: EudraCT )
First Submitted:	April 28, 2011
First Posted:	May 2, 2011
Results First Submitted:	March 13, 2015
Results First Posted:	April 14, 2015
Last Update Posted:	February 15, 2018

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