Head and Neck Neoplasms
Conditions
Brief summary
This randomised, double-blind phase III trial will be performed in patients with head and neck squamous cell carcinoma (HNSCC). The objectives of the trial are to compare the efficacy and safety of afatinib (BIBW 2992) with placebo as adjuvant therapy to patients who have received definitive chemo-radiotherapy.
Interventions
DRUGPlacebo
Once daily
DRUGAfatinib
Once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed loco-regionally advanced head and neck squamous cell carcinoma (HNSCC), stage III to IVb 2. Unresected tumour prior to chemo-radiotherapy (CRT) 3. Concomitant CRT completed prior to randomisation 4. After concomitant platinum-based CRT, no evidence of disease (NED) on clinical and radiographic examinations 5. Eastern cooperative oncology group (ECOG) performance status 0 or 1
Exclusion criteria
1. Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules, EGFR-targeted antibodies, and/or any investigational agents for HNSCC 2. Patients with smoking history of less than or equal to 10 pack years and with primary tumour site of base of tongue and/or tonsil 3. Any other malignancy (except for simultaneous HNSCC primaries, appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least five years 4. Known pre-existing Interstitial Lung Disease (ILD) 5. Pregnancy or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) | Up to 5 years | Disease Free Survival defined as the time from randomisation until documented tumour recurrence/ second primary tumour (SPT) or death from any cause, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) Rate at 2 Years | Up to 2 years | Disease Free Survival (DFS) rate at 2 years. Probability of being disease free at 2 years in percentage is provided based on Kaplan-Meier method. |
| Percentage of Patient Deaths (Overall Survival (OS)) | Up to 5 years | Overall survival (OS), defined as the time from randomisation until death (regardless of cause). Due to the small event rate in both treatment arms caused by the early termination of the trial, the hazard estimate is not interpretable. Hence presented the total randomized and the percentage of patients died. |
| Patients With Improved Health Related Quality of Life (HRQOL) | Up to 5 years | HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Improvement was defined as a score that improved from baseline by at least 10 points (on the 0-100 point scale) at any time during the study. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the study. Patients who had neither improved nor worsened were considered as stable. Percentages of patients with improvement in HRQoL are presented. |
| Time to Deterioration in Health Related Quality of Life (HRQOL) | Up to 5 years | HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Time to deterioration was defined as the time from randomisation to the first 10-point worsening on the 0-100 point scale. Patients with no deterioration (including those with disease recurrence/SPT) were censored at the last available HRQoL assessment date. Patients with no post-baseline assessments were censored on the day of randomisation. |
| Health Related Quality of Life (HRQOL) Scores Over Time | Baseline and 5 years | HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Scoring of the symptom scales/items followed the European Organisation for Research and Treatment of Cancer (EORTC) scoring manual and a linear transformation of the scores to a 0-100 point scale. Higher values are better. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Denmark, Egypt, Finland, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, Portugal, Russia, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
This was a randomised, placebo-controlled, double-blind, parallel arms, multinational phase III trial in which patients were randomised 2:1 to Afatinib or Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib (BIBW 2992) Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal. | 411 |
| Placebo Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal. | 206 |
| Total | 617 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 63 | 9 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other Reasons | 111 | 60 |
| Overall Study | Primary tumour recurrence | 53 | 32 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Second primary tumour | 4 | 3 |
| Overall Study | Withdrawal by Subject | 52 | 13 |
Baseline characteristics
| Characteristic | Afatinib (BIBW 2992) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.3 Years STANDARD_DEVIATION 8.23 | 57.3 Years STANDARD_DEVIATION 8.64 | 58.0 Years STANDARD_DEVIATION 8.38 |
| Sex: Female, Male Female | 61 Participants | 28 Participants | 89 Participants |
| Sex: Female, Male Male | 350 Participants | 178 Participants | 528 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 407 / 411 | 169 / 206 |
| serious Total, serious adverse events | 80 / 411 | 51 / 206 |
Outcome results
Primary
Disease Free Survival (DFS)
Disease Free Survival defined as the time from randomisation until documented tumour recurrence/ second primary tumour (SPT) or death from any cause, whichever occurred first.
Time frame: Up to 5 years
Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (BIBW 2992) | Disease Free Survival (DFS) | 43.40 Months |
| Placebo | Disease Free Survival (DFS) | NA Months |
Comparison: DFS was analysed using a stratified log-rank test with nodal status (N0- N2a vs. N2b-N3) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1) being the stratification factors.p-value: 0.480695% CI: [0.809, 1.569]Log Rank
Secondary
Disease Free Survival (DFS) Rate at 2 Years
Disease Free Survival (DFS) rate at 2 years. Probability of being disease free at 2 years in percentage is provided based on Kaplan-Meier method.
Time frame: Up to 2 years
Population: Randomised Set, the number of patients from the randomized set those are disease free (or DFS) at 2 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (BIBW 2992) | Disease Free Survival (DFS) Rate at 2 Years | 67.2 Probability (%) |
| Placebo | Disease Free Survival (DFS) Rate at 2 Years | 73.5 Probability (%) |
Comparison: Kaplan-Meier (KM) curves were calculated for each treatment group, separately, and the estimates of DFS probabilities from the curves and 95% Confidence interval (CI) (using the Greenwood standard error estimate) were tabulatedp-value: 0.16195% CI: [-15.04, 2.5]Log Rank
Secondary
Health Related Quality of Life (HRQOL) Scores Over Time
HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Scoring of the symptom scales/items followed the European Organisation for Research and Treatment of Cancer (EORTC) scoring manual and a linear transformation of the scores to a 0-100 point scale. Higher values are better.
Time frame: Baseline and 5 years
Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL) Scores Over Time | Swallowing | 10.1 Unit on Scale | Standard Error 1 |
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL) Scores Over Time | Pain HN35 | 13.1 Unit on Scale | Standard Error 0.98 |
| Afatinib (BIBW 2992) | Health Related Quality of Life (HRQOL) Scores Over Time | Global health status/QoL | 29.6 Unit on Scale | Standard Error 2.23 |
| Placebo | Health Related Quality of Life (HRQOL) Scores Over Time | Swallowing | 8.8 Unit on Scale | Standard Error 1.12 |
| Placebo | Health Related Quality of Life (HRQOL) Scores Over Time | Pain HN35 | 9.9 Unit on Scale | Standard Error 1.1 |
| Placebo | Health Related Quality of Life (HRQOL) Scores Over Time | Global health status/QoL | 33.0 Unit on Scale | Standard Error 2.28 |
Comparison: Scores (swallowing scale) over time were assessed using longitudinal 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 and nodal status.p-value: 0.223295% CI: [-0.81, 3.45]Mixed Models Analysis
Comparison: Scores (pain scale) over time were assessed using longitudinal 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 and nodal status.p-value: 0.002895% CI: [1.12, 5.36]Mixed Models Analysis
Comparison: Scores (global health/QoL) over time were assessed using longitudinal 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 and nodal status.p-value: 0.000595% CI: [-5.33, -1.49]Mixed Models Analysis
Secondary
Patients With Improved Health Related Quality of Life (HRQOL)
HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Improvement was defined as a score that improved from baseline by at least 10 points (on the 0-100 point scale) at any time during the study. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the study. Patients who had neither improved nor worsened were considered as stable. Percentages of patients with improvement in HRQoL are presented.
Time frame: Up to 5 years
Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Patients With Improved Health Related Quality of Life (HRQOL) | Swallowing (Q5-Q8 from QLQ-HN35) | 34.8 Percentage of Patients |
| Afatinib (BIBW 2992) | Patients With Improved Health Related Quality of Life (HRQOL) | Pain HN35 (Q1-Q4 from QLQ-HN35) | 33.8 Percentage of Patients |
| Afatinib (BIBW 2992) | Patients With Improved Health Related Quality of Life (HRQOL) | Global health status/QoL(Q29-Q30 from QLQ-C30) | 33.6 Percentage of Patients |
| Placebo | Patients With Improved Health Related Quality of Life (HRQOL) | Swallowing (Q5-Q8 from QLQ-HN35) | 27.2 Percentage of Patients |
| Placebo | Patients With Improved Health Related Quality of Life (HRQOL) | Pain HN35 (Q1-Q4 from QLQ-HN35) | 26.2 Percentage of Patients |
| Placebo | Patients With Improved Health Related Quality of Life (HRQOL) | Global health status/QoL(Q29-Q30 from QLQ-C30) | 38.3 Percentage of Patients |
Comparison: Odds ratio and p-value from logistic regression analysis of 'improved vs. not improved' stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3) for Swallowing (Q5-Q8 from QLQ-HN35).p-value: 0.056195% CI: [0.991, 2.068]Regression, Logistic
Comparison: Odds ratio and p-value from logistic regression analysis of 'improved vs. not improved' stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3) for Pain HN35 (Q1-Q4 from QLQ-HN35).p-value: 0.052395% CI: [0.996, 2.098]Regression, Logistic
Comparison: Odds ratio and p-value from logistic regression analysis of 'improved vs. not improved' stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3) for Global health status/QoL(Q29-Q30 from QLQ-C30).p-value: 0.25795% CI: [0.577, 1.158]Regression, Logistic
Secondary
Percentage of Patient Deaths (Overall Survival (OS))
Overall survival (OS), defined as the time from randomisation until death (regardless of cause). Due to the small event rate in both treatment arms caused by the early termination of the trial, the hazard estimate is not interpretable. Hence presented the total randomized and the percentage of patients died.
Time frame: Up to 5 years
Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (BIBW 2992) | Percentage of Patient Deaths (Overall Survival (OS)) | 15.1 Percentage of patients |
| Placebo | Percentage of Patient Deaths (Overall Survival (OS)) | 11.2 Percentage of patients |
Comparison: Hazard ratio from Cox proportional hazards model stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3).p-value: 0.130195% CI: [0.895, 2.332]Log Rank
Secondary
Time to Deterioration in Health Related Quality of Life (HRQOL)
HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Time to deterioration was defined as the time from randomisation to the first 10-point worsening on the 0-100 point scale. Patients with no deterioration (including those with disease recurrence/SPT) were censored at the last available HRQoL assessment date. Patients with no post-baseline assessments were censored on the day of randomisation.
Time frame: Up to 5 years
Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Afatinib (BIBW 2992) | Time to Deterioration in Health Related Quality of Life (HRQOL) | Swallowing | 18.43 Months |
| Afatinib (BIBW 2992) | Time to Deterioration in Health Related Quality of Life (HRQOL) | Pain HN35 | 12.06 Months |
| Afatinib (BIBW 2992) | Time to Deterioration in Health Related Quality of Life (HRQOL) | Global health status/QoL | 7.59 Months |
| Placebo | Time to Deterioration in Health Related Quality of Life (HRQOL) | Swallowing | 31.44 Months |
| Placebo | Time to Deterioration in Health Related Quality of Life (HRQOL) | Pain HN35 | 31.08 Months |
| Placebo | Time to Deterioration in Health Related Quality of Life (HRQOL) | Global health status/QoL | 25.79 Months |
Comparison: For swallowing scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3).p-value: 0.059195% CI: [0.986, 1.7]Log Rank
Comparison: For pain HN35 scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3).p-value: 0.004995% CI: [1.113, 1.905]Log Rank
Comparison: For global health status/QoL scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0-N2a or N2b-N3).p-value: 0.000295% CI: [1.238, 2.079]Log Rank