Carcinoma, Squamous Cell, Head and Neck Neoplasms
Conditions
Brief summary
The primary objective of this study is to explore the efficacy of BIBW 2992 compared with cetuximab (Erbitux) in patients with metastatic or recurrent head and neck cancer after failure of platinum-containing therapy. In addition, the trial aims to clarify the influence of EGFR genotype on tumor response to the treatment regimens.
Interventions
DRUGBIBW 2992
experimental drug taken once daily orally
DRUGCetuximab
active comparator administered weekly intravenously
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Metastatic (stage IVc) or recurrent HNSCC 2. Histologically or cytologically confirmed diagnosis of squamous cell of the head and neck. Patients with well-differentiated (keratinizing) nasopharyngeal carcinomas and patients with squamous cell carcinomas metastatic to the neck from an unknown head and neck primary are eligible. 3. Patients must have documented progressive disease (PD) following receipt of prior platinum-based therapy (either as neoadjuvant, adjuvant, concomitant with radiotherapy, or for recurrent/ metastatic disease). 4. Patients must have measurable disease as defined by RECIST criteria. 5. Patients must have recovered from any therapy-related toxicities from previous chemo-, immuno-, or radiotherapies to CTC smaller or equal to Grade 1. 6. Patients must have recovered from previous surgery. 7. Life expectancy of at least three (3) months. 8. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 or 1. 9\. Patients must be eighteen (18) years of age or older. 10. Willingness and ability to give written informed consent consistent with ICH-GCP guidelines.
Exclusion criteria
1. Progressive disease within 3 months after completion of curative intent treatment for localized/locoregionally advanced disease. 2. Prior use of an EGFR or erbB2 inhibitor in the recurrent/metastatic disease setting (treatment with cetuximab (Erbitux®) or other EGFR inhibitor during radiotherapy or chemoradiotherapy is permissible). 3. More than 2 chemotherapeutic regimens given for recurrent/metastatic disease. 4. Treatment with other investigational drugs, other anti-cancer-therapy (e.g., chemotherapy, immunotherapy, radiotherapy), concomitantly with therapy on this study and/or during the last four weeks, prior to the first treatment with the trial drug 5. eliminated per Amendment #1 6. Patients with history of other malignancy (except for appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least 3 years. 7. Patients with history of decompensated heart failure. 8. Cardiac left ventricular function with resting ejection fraction \<50% or less than the institutional lower limit of normal by MUGA or echocardiogram. 9. Active infectious disease. 10. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea. 11. Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with the protocol. 12. Use of alcohol or drugs incompatible with patient participation in the study in the investigator's opinion. 13. Patients unable to comply with the protocol. 14. Patients with active/symptomatic brain metastases. Patients with a history of treated brain metastases must have stable or normal cerebral MRI scan at screening and be at least three months post-radiation or surgery. 15. Absolute neutrophile count (ANC) less than 1000/mm3. 16. Platelet count less than 75,000/mm3. 17. Bilirubin greater than 1.5 mg/dl/ Higher bilirubin values are acceptable for patients with known Gilbert's disease, approval by the PI and sponsor necessary. 18. Asparate amino transferase (AST) or alanine amino transferase (ALT) greater than 3 times the upper limit of normal. 19. Serum creatinine greater than 1.5 X upper limit of normal for the institution. 20. Patients who are sexually active and unwilling to use a medically acceptable method of contraception. 21. Pregnancy or breast-feeding. 22. Patients with known pre-existing interstitial lung disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment | From randomization until start of Stage 2 treatment, or within 28 days after the termination of Stage 1. | Tumor shrinkage before crossover was defined as the change from baseline in the smallest post-randomisation sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after randomisation but before crossover minus SLD at baseline. Baseline was the SLD measured before randomisation. A negative value means the smallest post-randomisation SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline. Mean calculated is actually the Adjusted mean. Adjusted mean is obtained from fitting an ANCOVA model including treatment, stratification factor prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance of target lesions as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment for Stage 1. |
| Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment as onset of confirmed objective response as per the independent central review (ICR) according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment as duration of confirmed objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | Best RECIST Assessment as duration of confirmed objective response and disease control as per the independent central review (ICR) according to the RECIST 1.0 criteria. |
| Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | Best RECIST Assessment as confirmed duration of objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria. |
| Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments | From baseline assessed prior to first dose of Stage 2 study medication to 28 days after termination of Stage 2 treatment. | Tumor shrinkage after crossover was defined as the change from baseline in the smallest post-crossover sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after crossover minus SLD at baseline. Baseline was the SLD measured at the time of crossover, or the closest measurement before the patient started stage 2 treatment. A negative value means the smallest post-crossover SLD was smaller than baseline (decreased after crossover), a positive value means tumor size increased after crossover. |
| Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment | From randomisation to disease progression in Stage 1 or death whichever occurred first before crossover. | PFS is defined as time from randomisation to until the occurrence of tumor progression or death, whichever occurred first, during Stage 1 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group. |
| Progression Free Survival (PFS) After Crossover Based on Investigator Assessment | From first administration of study medication after cross over to disease progression in Stage 2 or death whichever came first after crossover. | PFS is defined as time from first administration study medication after cross over until the occurrence of tumor progression or death, whichever came first, during Stage 2 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group. |
| Overall Survival (OS) | From randomisation to data cut-off date. | OS is defined as time from randomisation to death. Median is calculated from the Kaplan-Meier curve for each treatment group. |
| Time to Deterioration in HRQoL - Stage 1 | From randomisation to deterioration in HRQoL scores before crossover. | Health related Quality of Life (HRQoL) for Time to deterioration was assessed using the the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Module (H&N35). Time to deterioration in HRQoL (defined as a 10-point change towards worsening from the baseline score on a 0-100 point scale) was determined for: * global health status (Questions 29 and 30 in EORTC QLQ C30) * pain (Questions 9 and 19 in EORTC QLQ C30) * swallowing (Questions 35 to 38 in EORTC QLQ-H&N35) |
| Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | First administration of trial medication until 28 days after last drug administration | Patients with adverse events (AEs) resulting in Diarrhea, Skin Rash, dose reduction, treatment discontinuation and decreased cardiac left ventricular function Note: To asses the Decreased Cardiac left ventricular function, Left ventricular ejection fraction (LVEF) was assessed in patients treated with afatinib in Stage 1 and Stage 2 . And no patients in either group had a significant change in LVEF during Stage 1 or Stage 2 of the trial. |
| Incidence and Intensity of Adverse Events With Grading According CTCAE | First administration of trial medication until 28 days after last drug administration | Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0). |
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15) | Day 15 | Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. Note: At day 15, values for afatinib 40 mg no values reported in stage 1 and stage 2. |
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) | Day 29 | Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. Note: At day 29, values for afatinib 40 mg no values reported in stage 2. |
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) | Day 57 | Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57. |
| Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2 | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | Best RECIST Assessment as confirmed duration of disease control as per the independent central review (ICR) assessment according to the RECIST 1.0 criteria. |
Countries
Belgium, France, Spain, United States
Participant flow
Pre-assignment details
Open-label randomized, cross-over study. 124 patients were randomised. 3 patients were not treated, 1 in Afatinib arm and 2 in Cetuximab arm.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 50 mg / Cetuximab 250mg/m2 Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2. | 62 |
| Cetuximab 250 mg/m2 / Afatinib 50 mg Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2 | 62 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Stage 1 | Not treated | 1 | 2 |
| Stage 1 | Other Adverse Event | 16 | 6 |
| Stage 1 | Other than stated above | 1 | 7 |
| Stage 1 | Patient refused to continue study meds | 8 | 3 |
| Stage 1 | Progressive disease | 4 | 8 |
| Stage 2 | Other Adverse Event | 3 | 10 |
| Stage 2 | Other than stated above | 0 | 2 |
| Stage 2 | Patient refused to continue study meds | 2 | 0 |
| Stage 2 | Progressive disease | 27 | 24 |
Baseline characteristics
| Characteristic | Afatinib 50 mg / Cetuximab 250mg/m2 | Cetuximab 250 mg/m2 / Afatinib 50 mg | Total |
|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 9.4 | 58.8 years STANDARD_DEVIATION 8.7 | 58.3 years STANDARD_DEVIATION 9 |
| Baseline sum of longest diameters (SLD) of target lesions by investigator assessments | 71.4 millimeters STANDARD_DEVIATION 44.6 | 65.4 millimeters STANDARD_DEVIATION 44.2 | 68.4 millimeters STANDARD_DEVIATION 44.3 |
| Prior chemotherapies (CT)for recurrent/metastatic disease (R/M) No | 20 Number of participants | 21 Number of participants | 41 Number of participants |
| Prior chemotherapies (CT)for recurrent/metastatic disease (R/M) Yes | 42 Number of participants | 41 Number of participants | 83 Number of participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 17 Participants |
| Sex: Female, Male Male | 55 Participants | 52 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 59 / 60 | 34 / 36 | 29 / 32 | 61 / 61 |
| serious Total, serious adverse events | 26 / 60 | 18 / 36 | 13 / 32 | 36 / 61 |
Outcome results
Primary
Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment
Tumor shrinkage before crossover was defined as the change from baseline in the smallest post-randomisation sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after randomisation but before crossover minus SLD at baseline. Baseline was the SLD measured before randomisation. A negative value means the smallest post-randomisation SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline. Mean calculated is actually the Adjusted mean. Adjusted mean is obtained from fitting an ANCOVA model including treatment, stratification factor prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance of target lesions as covariates.
Time frame: From randomization until start of Stage 2 treatment, or within 28 days after the termination of Stage 1.
Population: Randomised Set (RS). The randomised set includes all patients who were randomised to receive treatment, whether treated or not. However, patients without baseline or post-baseline tumor measurements were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment | -3.86 millimeter | Standard Error 3.62 |
| Cetuximab 250 mg/m2 - Stage 1 | Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment | -2.37 millimeter | Standard Error 3.47 |
p-value: 0.760695% CI: [-11.188, 8.202]ANCOVA
Secondary
Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1
Best RECIST Assessment as duration of confirmed objective response and disease control as per the independent central review (ICR) according to the RECIST 1.0 criteria.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised Set (RS)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Duration of objective response (N=5; N=6) | 28.0 Weeks | Standard Deviation 12.6 |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Duration of disease control(N=29; N=30) | 22.8 Weeks | Standard Deviation 11 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Duration of objective response (N=5; N=6) | 55.1 Weeks | Standard Deviation 76.6 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Duration of disease control(N=29; N=30) | 28.8 Weeks | Standard Deviation 38.1 |
Secondary
Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2
Best RECIST Assessment as confirmed duration of disease control as per the independent central review (ICR) assessment according to the RECIST 1.0 criteria.
Time frame: Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Population: patients treated in stage 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2 | 17.4 Weeks | Standard Deviation 5 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2 | 18.4 Weeks | Standard Deviation 10 |
Secondary
Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1
Best RECIST Assessment as duration of confirmed objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised Set (RS)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Duration of objective response (N=10; N=4) | 21.4 Weeks | Standard Deviation 12.2 |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Duration of disease control(N=31; N=35) | 25.1 Weeks | Standard Deviation 13.9 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Duration of objective response (N=10; N=4) | 58.9 Weeks | Standard Deviation 98.1 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Duration of disease control(N=31; N=35) | 30.3 Weeks | Standard Deviation 35.8 |
Secondary
Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2
Best RECIST Assessment as confirmed duration of objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.
Time frame: Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Population: patients treated in stage 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Duration of objective response (N=1; N=2) | 24.7 Weeks | Standard Deviation 0 |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Duration of disease control(N=14; N=6) | 21.8 Weeks | Standard Deviation 6.1 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Duration of objective response (N=1; N=2) | 19.4 Weeks | Standard Deviation 21.1 |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Duration of disease control(N=14; N=6) | 21.5 Weeks | Standard Deviation 12.3 |
Secondary
Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1
Best RECIST Assessment as onset of confirmed objective response as per the independent central review (ICR) according to the RECIST 1.0 criteria.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised set (RS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 4 (Day 1 - 42) | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 8 (Day 43 - 84) | 2 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 16 (Day 85 - 140) | 2 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 24 (Day 141 - 196) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 24 (Day 141 - 196) | 1 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 4 (Day 1 - 42) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 16 (Day 85 - 140) | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Week 8 (Day 43 - 84) | 3 Number of participants |
Secondary
Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1
Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment for Stage 1.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised set (RS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 4 (Day 1 - 42) | 3 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 8 (Day 43 - 84) | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 16 (Day 85 - 140) | 4 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 24 (Day 141 - 196) | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 24 (Day 141 - 196) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 4 (Day 1 - 42) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 16 (Day 85 - 140) | 1 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Week 8 (Day 43 - 84) | 3 Number of participants |
Secondary
Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2
Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment according to the RECIST 1.0 criteria.
Time frame: Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Population: Patients treated in Stage 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 2 (Day 1 - 14) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 4 (Day 15 - 56) | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 12 (Day 57 - 112) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 2 (Day 1 - 14) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 4 (Day 15 - 56) | 1 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Week 12 (Day 57 - 112) | 1 Number of participants |
Secondary
Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment).
Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised set (RS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Missing | 10 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Objective response (CR,PR) | 5 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Complete response (CR) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Partial response (PR) | 5 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Stable disease (SD) | 24 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Progressive disease (PD) | 21 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Not evaluable | 2 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Disease control (CR, PR, SD) | 29 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Progressive disease (PD) | 21 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Disease control (CR, PR, SD) | 30 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Stable disease (SD) | 24 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Objective response (CR,PR) | 6 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Missing | 8 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Complete response (CR) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Not evaluable | 3 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Partial response (PR) | 6 Number of participants |
Secondary
Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)
Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria.
Time frame: Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Population: Patients treated in Stage 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Disease control (CR, PR, SD) | 12 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Objective response | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Complete response (CR) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Partial response (PR) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Stable disease (SD) | 12 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Progressive disease (PD) | 18 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Not evaluable | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Missing | 5 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Missing | 1 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Disease control (CR, PR, SD) | 6 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Stable disease (SD) | 6 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Objective response | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Not evaluable | 4 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Complete response (CR) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Progressive disease (PD) | 21 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Partial response (PR) | 0 Number of participants |
Secondary
Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment).
Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria.
Time frame: Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Population: Randomised set (RS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Disease control (CR, PR, SD) | 31 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Complete response (CR) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Progressive disease (PD) | 16 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Objective response (CR, PR) | 10 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Not evaluable | 5 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Partial response (PR) | 10 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Missing | 10 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Stable disease (SD) | 21 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Missing | 7 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Disease control (CR, PR, SD) | 35 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Objective response (CR, PR) | 4 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Complete response (CR) | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Partial response (PR) | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Stable disease (SD) | 31 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Progressive disease (PD) | 19 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Not evaluable | 1 Number of participants |
Secondary
Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)
Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria.
Time frame: Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Population: Patients treated in Stage 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Disease control (CR, PR, SD) | 14 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Objective response (CR,PR) | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Complete response (CR) | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Partial response (PR) | 0 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Stable disease (SD) | 13 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Progressive disease (PD) | 16 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Not evaluable | 1 Number of participants |
| Afatinib 50 mg - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Missing | 5 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Missing | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Disease control (CR, PR, SD) | 6 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Stable disease (SD) | 4 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Objective response (CR,PR) | 2 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Not evaluable | 4 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Complete response (CR) | 0 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Progressive disease (PD) | 20 Number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Partial response (PR) | 2 Number of participants |
Secondary
Incidence and Intensity of Adverse Events With Grading According CTCAE
Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time frame: First administration of trial medication until 28 days after last drug administration
Population: Treated Set in Stage 1 : This analysis set included the randomized patients who took at least 1 dose of the randomized treatment (61 afatinib and 60 cetuximab patients. Treated set in Stage 2: This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 24.6 percentage of participants |
| Afatinib 50 mg - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 3.3 percentage of participants |
| Afatinib 50 mg - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 39.3 percentage of participants |
| Afatinib 50 mg - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 24.6 percentage of participants |
| Afatinib 50 mg - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 8.2 percentage of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 28.3 percentage of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 5.0 percentage of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 41.7 percentage of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 6.7 percentage of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 16.7 percentage of participants |
| Afatinib 50 mg - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 25.0 percentage of participants |
| Afatinib 50 mg - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 5.6 percentage of participants |
| Afatinib 50 mg - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 30.6 percentage of participants |
| Afatinib 50 mg - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 13.9 percentage of participants |
| Afatinib 50 mg - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 25.0 percentage of participants |
| Cetuximab mg/m2 - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 9.4 percentage of participants |
| Cetuximab mg/m2 - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 25.0 percentage of participants |
| Cetuximab mg/m2 - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 9.4 percentage of participants |
| Cetuximab mg/m2 - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 15.6 percentage of participants |
| Cetuximab mg/m2 - Stage 2 | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 37.5 percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as time from randomisation to death. Median is calculated from the Kaplan-Meier curve for each treatment group.
Time frame: From randomisation to data cut-off date.
Population: Randomised set (RS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg - Stage 1 | Overall Survival (OS) | 35.86 Weeks |
| Cetuximab 250 mg/m2 - Stage 1 | Overall Survival (OS) | 47.14 Weeks |
p-value: 0.75895% CI: [0.708, 1.608]Regression, Cox
Secondary
Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function
Patients with adverse events (AEs) resulting in Diarrhea, Skin Rash, dose reduction, treatment discontinuation and decreased cardiac left ventricular function Note: To asses the Decreased Cardiac left ventricular function, Left ventricular ejection fraction (LVEF) was assessed in patients treated with afatinib in Stage 1 and Stage 2 . And no patients in either group had a significant change in LVEF during Stage 1 or Stage 2 of the trial.
Time frame: First administration of trial medication until 28 days after last drug administration
Population: Treated Set in Stage 1 : This analysis set included the randomized patients who took at least 1 dose of the randomized treatment (61 afatinib and 60 cetuximab patients. Treated set in Stage 2: This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to Diarrhea | 49 number of participants |
| Afatinib 50 mg - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to skin rash | 48 number of participants |
| Afatinib 50 mg - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to dose reduction | 18 number of participants |
| Afatinib 50 mg - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to treatment discontinuation | 23 number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to skin rash | 46 number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to dose reduction | 2 number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to treatment discontinuation | 11 number of participants |
| Cetuximab 250 mg/m2 - Stage 1 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to Diarrhea | 15 number of participants |
| Afatinib 50 mg - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to dose reduction | 11 number of participants |
| Afatinib 50 mg - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to skin rash | 23 number of participants |
| Afatinib 50 mg - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to treatment discontinuation | 8 number of participants |
| Afatinib 50 mg - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to Diarrhea | 22 number of participants |
| Cetuximab mg/m2 - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to treatment discontinuation | 6 number of participants |
| Cetuximab mg/m2 - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to skin rash | 14 number of participants |
| Cetuximab mg/m2 - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to Diarrhea | 2 number of participants |
| Cetuximab mg/m2 - Stage 2 | Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | With AE leading to dose reduction | 0 number of participants |
Secondary
Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15)
Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. Note: At day 15, values for afatinib 40 mg no values reported in stage 1 and stage 2.
Time frame: Day 15
Population: Pharmacokinetic Set (PK): The PK analysis was based on all patients who were treated with afatinib and who had evaluable plasma concentration data, which consisted of data for 60 patients in Stage 1 and 35 patients in Stage 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15) | 39.3 ng/mL | Geometric Coefficient of Variation 70.1 |
| Cetuximab 250 mg/m2 - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15) | 46.6 ng/mL | Geometric Coefficient of Variation 81.4 |
Secondary
Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29)
Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. Note: At day 29, values for afatinib 40 mg no values reported in stage 2.
Time frame: Day 29
Population: Pharmacokinetic Set (PK)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) | 8.84 ng/mL | Geometric Coefficient of Variation 206 |
| Cetuximab 250 mg/m2 - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) | 31.7 ng/mL | Geometric Coefficient of Variation 97.7 |
| Afatinib 50 mg - Stage 2 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) | 45.9 ng/mL | Geometric Coefficient of Variation 48.9 |
Secondary
Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57)
Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.
Time frame: Day 57
Population: Pharmacokinetic Set (PK)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) | 32.7 ng/mL | Geometric Coefficient of Variation 25.3 |
| Cetuximab 250 mg/m2 - Stage 1 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) | 19.9 ng/mL | Geometric Coefficient of Variation 94.4 |
| Afatinib 50 mg - Stage 2 | Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) | 46.5 ng/mL | Geometric Coefficient of Variation 67.2 |
Secondary
Progression Free Survival (PFS) After Crossover Based on Investigator Assessment
PFS is defined as time from first administration study medication after cross over until the occurrence of tumor progression or death, whichever came first, during Stage 2 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group.
Time frame: From first administration of study medication after cross over to disease progression in Stage 2 or death whichever came first after crossover.
Population: Patients treated in stage 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg - Stage 1 | Progression Free Survival (PFS) After Crossover Based on Investigator Assessment | 7.93 weeks |
| Cetuximab 250 mg/m2 - Stage 1 | Progression Free Survival (PFS) After Crossover Based on Investigator Assessment | 6.43 weeks |
p-value: 0.21995% CI: [0.434, 1.212]Regression, Cox
Secondary
Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment
PFS is defined as time from randomisation to until the occurrence of tumor progression or death, whichever occurred first, during Stage 1 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group.
Time frame: From randomisation to disease progression in Stage 1 or death whichever occurred first before crossover.
Population: Randomised set (RS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg - Stage 1 | Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment | 15.86 weeks |
| Cetuximab 250 mg/m2 - Stage 1 | Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment | 15.14 weeks |
p-value: 0.76495% CI: [0.64, 1.387]Regression, Cox
Secondary
Time to Deterioration in HRQoL - Stage 1
Health related Quality of Life (HRQoL) for Time to deterioration was assessed using the the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Module (H&N35). Time to deterioration in HRQoL (defined as a 10-point change towards worsening from the baseline score on a 0-100 point scale) was determined for: * global health status (Questions 29 and 30 in EORTC QLQ C30) * pain (Questions 9 and 19 in EORTC QLQ C30) * swallowing (Questions 35 to 38 in EORTC QLQ-H&N35)
Time frame: From randomisation to deterioration in HRQoL scores before crossover.
Population: Randomised Set (RS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | global health status (N=37; N=38) | 2.83 months |
| Afatinib 50 mg - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | pain (N=34; N=33) | 2.73 months |
| Afatinib 50 mg - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | swallowing (N=33; N=34) | 5.59 months |
| Cetuximab 250 mg/m2 - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | global health status (N=37; N=38) | 3.94 months |
| Cetuximab 250 mg/m2 - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | pain (N=34; N=33) | 4.63 months |
| Cetuximab 250 mg/m2 - Stage 1 | Time to Deterioration in HRQoL - Stage 1 | swallowing (N=33; N=34) | 6.60 months |
Secondary
Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments
Tumor shrinkage after crossover was defined as the change from baseline in the smallest post-crossover sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after crossover minus SLD at baseline. Baseline was the SLD measured at the time of crossover, or the closest measurement before the patient started stage 2 treatment. A negative value means the smallest post-crossover SLD was smaller than baseline (decreased after crossover), a positive value means tumor size increased after crossover.
Time frame: From baseline assessed prior to first dose of Stage 2 study medication to 28 days after termination of Stage 2 treatment.
Population: Patients treated in stage 2 : This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg - Stage 1 | Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments | 2 millimeters | Standard Deviation 15 |
| Cetuximab 250 mg/m2 - Stage 1 | Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments | 16 millimeters | Standard Deviation 30 |