Carcinoma, Squamous Cell, Head and Neck Neoplasms
Conditions
Brief summary
This randomised, open-label, phase III study will be performed in patients with R/M head and neck squamous cell carcinoma (HNSCC) who have progressed after platinum-based therapy. The objectives of the trial are to compare the efficacy and safety of afatinib versus methotrexate
Interventions
DRUGAfatinib
Once daily
DRUGMethotrexate
Weekly
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy 2. Documented progressive disease based on investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST) following receipt of at least two cycles of cisplatin or carboplatin administered for R/M disease 3. Measurable disease according to RECIST 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Exclusion criteria
1. Progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC 2. Any other than one previous platinum based systemic regimen given for R/M disease 3. Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules 4. Pregnancy or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Based on Central Independent Review | From randomization until disease progression, death or study completion date (06Dec2016); Up to 60 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | 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 | 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'. |
| Disease Control (DC) | 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 | 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. |
| Tumour Shrinkage | 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 | 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. |
| Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
| Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
| Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
| Overall Survival (OS) | From randomization until death or study completion date (06Dec2016); Up to 60 months | 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. |
| Status Change in Swallowing Scale | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
| Status Change in Global Health Status Scale | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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 to Deterioration in Pain | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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 to Deterioration in Swallowing | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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 to Deterioration in Global Health Status | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
| Status Change in Pain Scale | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 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. |
Countries
Argentina, Austria, Belgium, Brazil, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Mexico, Russia, South Africa, Spain, Sweden, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afatinib (BIBW 2992) 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. | 322 |
| Methotrexate 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. | 161 |
| Total | 483 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 51 | 41 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance with protocol | 0 | 1 |
| Overall Study | Not treated | 2 | 1 |
| Overall Study | Progressive disease per RECIST | 226 | 93 |
| Overall Study | Reason other than those specified above | 4 | 3 |
| Overall Study | Refused to continue trial medication | 16 | 9 |
| Overall Study | Worsening of underlying cancer disease | 23 | 12 |
Baseline characteristics
| Characteristic | Afatinib (BIBW 2992) | Methotrexate | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 8.8 | 59.3 years STANDARD_DEVIATION 9.7 | 59.8 years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 47 Participants | 24 Participants | 71 Participants |
| Sex: Female, Male Male | 275 Participants | 137 Participants | 412 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 309 / 320 | 146 / 160 |
| serious Total, serious adverse events | 168 / 320 | 73 / 160 |
Outcome results
Primary
Progression-free Survival (PFS) Based on Central Independent Review
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
Population: Randomised set (RS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Progression-free Survival (PFS) Based on Central Independent Review | 2.63 months |
| Methotrexate | Progression-free Survival (PFS) Based on Central Independent Review | 1.74 months |
p-value: 0.025795% CI: [0.643, 0.977]Stratified Log-rank test
Secondary
Disease Control (DC)
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
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (BIBW 2992) | Disease Control (DC) | 49.1 percentage of participants |
| Methotrexate | Disease Control (DC) | 38.5 percentage of participants |
p-value: 0.035395% CI: [1.03, 2.26]Regression, Logistic
Secondary
Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time | 28.7 scores on a scale | Standard Error 3.54 |
| Methotrexate | Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time | 28.2 scores on a scale | Standard Error 3.76 |
Comparison: 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).p-value: 0.776795% CI: [-3.28, 4.39]longitudinal models
Secondary
Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time | 11.8 scores on a scale | Standard Error 3.16 |
| Methotrexate | Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time | 16.2 scores on a scale | Standard Error 3.43 |
Comparison: 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).p-value: 0.0395% CI: [-8.31, -0.42]longitudinal models
Secondary
Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time | 20.0 scores on a scale | Standard Error 3.4 |
| Methotrexate | Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time | 20.1 scores on a scale | Standard Error 3.66 |
Comparison: 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).p-value: 0.977395% CI: [-4.3, 4.18]longitudinal models
Secondary
Objective Response (OR)
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
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (BIBW 2992) | Objective Response (OR) | 10.2 percentage of participants |
| Methotrexate | Objective Response (OR) | 5.6 percentage of participants |
p-value: 0.10195% CI: [0.88, 4.14]Regression, Logistic
Secondary
Overall Survival (OS)
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
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Overall Survival (OS) | 6.87 months |
| Methotrexate | Overall Survival (OS) | 6.01 months |
p-value: 0.675595% CI: [0.786, 1.169]Stratified Log-rank test
Secondary
Status Change in Global Health Status Scale
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Status Change in Global Health Status Scale | Improved | 30.3 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Global Health Status Scale | Stable | 26.6 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Global Health Status Scale | Worsened | 43.1 percentage of participants |
| Methotrexate | Status Change in Global Health Status Scale | Improved | 29.1 percentage of participants |
| Methotrexate | Status Change in Global Health Status Scale | Stable | 25.6 percentage of participants |
| Methotrexate | Status Change in Global Health Status Scale | Worsened | 45.3 percentage of participants |
p-value: 0.81695% CI: [0.657, 1.705]Regression, Logistic
Secondary
Status Change in Pain Scale
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Status Change in Pain Scale | Improved | 26.4 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Pain Scale | Stable | 32.1 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Pain Scale | Worsened | 41.5 percentage of participants |
| Methotrexate | Status Change in Pain Scale | Improved | 23.1 percentage of participants |
| Methotrexate | Status Change in Pain Scale | Stable | 31.6 percentage of participants |
| Methotrexate | Status Change in Pain Scale | Worsened | 45.3 percentage of participants |
p-value: 0.49495% CI: [0.717, 1.99]Regression, Logistic
Secondary
Status Change in Swallowing Scale
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.
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Status Change in Swallowing Scale | Improved | 26.1 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Swallowing Scale | Stable | 34.2 percentage of participants |
| Afatinib (BIBW 2992) | Status Change in Swallowing Scale | Worsened | 39.7 percentage of participants |
| Methotrexate | Status Change in Swallowing Scale | Improved | 23.2 percentage of participants |
| Methotrexate | Status Change in Swallowing Scale | Stable | 29.5 percentage of participants |
| Methotrexate | Status Change in Swallowing Scale | Worsened | 47.3 percentage of participants |
p-value: 0.58495% CI: [0.687, 1.95]Regression, Logistic
Secondary
Time to Deterioration in Global Health Status
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.
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Time to Deterioration in Global Health Status | 3.25 months |
| Methotrexate | Time to Deterioration in Global Health Status | 2.69 months |
p-value: 0.026895% CI: [0.56, 0.97]Stratified Log-rank test
Secondary
Time to Deterioration in Pain
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.
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Time to Deterioration in Pain | 3.02 months |
| Methotrexate | Time to Deterioration in Pain | 2.30 months |
p-value: 0.021795% CI: [0.55, 0.96]Stratified Log-rank test
Secondary
Time to Deterioration in Swallowing
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.
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Time to Deterioration in Swallowing | 3.75 months |
| Methotrexate | Time to Deterioration in Swallowing | 2.10 months |
p-value: 0.00495% CI: [0.5, 0.89]Stratified Log-rank test
Secondary
Tumour Shrinkage
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
Population: RS (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Tumour Shrinkage | >=50% decrease | 5.0 percentage of participants |
| Afatinib (BIBW 2992) | Tumour Shrinkage | >=20% increase | 16.5 percentage of participants |
| Afatinib (BIBW 2992) | Tumour Shrinkage | >=0 - <20% increase | 24.2 percentage of participants |
| Afatinib (BIBW 2992) | Tumour Shrinkage | >0 - <30% decrease | 23.6 percentage of participants |
| Afatinib (BIBW 2992) | Tumour Shrinkage | >=30 - <50% decrease | 6.2 percentage of participants |
| Methotrexate | Tumour Shrinkage | >=30 - <50% decrease | 4.3 percentage of participants |
| Methotrexate | Tumour Shrinkage | >0 - <30% decrease | 16.1 percentage of participants |
| Methotrexate | Tumour Shrinkage | >=20% increase | 21.1 percentage of participants |
| Methotrexate | Tumour Shrinkage | >=50% decrease | 1.9 percentage of participants |
| Methotrexate | Tumour Shrinkage | >=0 - <20% increase | 31.1 percentage of participants |