Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This randomised, open-label phase III trial will be performed in patients with advanced squamous cell carcinoma of the lung requiring second-line treatment after receiving first-line platinum-based chemotherapy. The primary objective of this trial is to compare the efficacy of BIBW 2992 to erlotinib as second-line treatment in this group of patients.
Interventions
DRUGafatinib
Afatinib taken once daily, continuously until disease progression or unacceptable toxicity.
DRUGerlotinib
erlotinib taken once daily
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. Diagnosis of advanced stage NSCLC squamous histology. 2. Platinum-based doublet chemotherapy as 1st line treatment of Stage IIIB/IV NSCLC. 3. Eligible to receive 2nd line therapy in the opinion of the investigator. 4. Measurable disease according to RECIST 1.1. 5. Adequate Performance Status. 6. Availability of tumour tissue material for correlative studies. Archived tumour tissue is acceptable. 7. Adequate organ function. 8. Age = 18 years and above. 9. Written informed consent that is consistent with International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines.
Exclusion criteria
1. Prior treatment with Epidermal Growth Factor Receptor (EGFR) directed small molecules or antibodies. 2. Radiotherapy within 4 weeks prior to randomization. 3. Active brain metastases . 4. Any other current malignancy or malignancy diagnosed within the past three (3) years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer). 5. Known pre-existing interstitial lung disease. 6. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom 7. Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug. 8. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended. 9. Female patients of childbearing potential (see Section 4.2.3.3) who: 1. are nursing or 2. are pregnant or 3. are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study and/or do not agree to submit to pregnancy testing required by this protocol. 10. Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier. 11. Known or suspected active drug or alcohol abuse in the opinion of the investigator. 12. Any contraindications for therapy with afatinib or erlotinib. 13. Known hypersensitivity to erlotinib, afatinib or the excipients of any of the trial drugs. 14. Major surgery within 4 weeks of starting study treatment. 15. Prior participation in an afatinib clinical study, even if not assigned to afatinib. 16. Use of any investigational drug within 4 weeks of randomisation (unless a longer time period is required by local regulations or by the guidelines for the investigational product). 17. Patients without Progression of their lung cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Response According to RECIST 1.1 | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Number of Participants With Disease Control According to RECIST 1.1 | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Tumour Shrinkage | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race. |
| Overall Survival | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint. |
| Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration. |
| Change in Score Over Time in Coughing,Dyspnoea and Pain | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race. |
| Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time. |
Countries
Argentina, Austria, Canada, Chile, China, Denmark, France, Germany, Greece, Hungary, India, Ireland, Italy, Mexico, Netherlands, Portugal, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Open-Label Phase-III trial to compare the efficacy of afatinib with erlotinib for the second-line treatment of patients with advanced non-small cell lung cancer, who completed at least 4 cycles of platinum-based doublet chemotherapy. Randomization ratio was 1:1. Stratification was based on race.
Pre-assignment details
Patients screened to ensure that they met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met. Tumor assessments at screening were completed within 21 days and other screening assessments were completed within 28 days, of randomization.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events. | 398 |
| Erlotinib Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events. | 397 |
| Total | 795 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 68 | 52 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Other than listed | 5 | 5 |
| Overall Study | Protocol Violation | 5 | 3 |
| Overall Study | Randomised but bot treated | 6 | 2 |
| Overall Study | Withdrawal by Subject | 28 | 20 |
| Overall Study | Withdrew due to Progressive disease | 265 | 279 |
| Overall Study | Worsening of underlying cancer disease | 19 | 34 |
Baseline characteristics
| Characteristic | Erlotinib | Total | Afatinib |
|---|---|---|---|
| Age, Continuous | 63.4 Years STANDARD_DEVIATION 8.98 | 64.1 Years STANDARD_DEVIATION 8.72 | 64.9 Years STANDARD_DEVIATION 8.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 94 Participants | 191 Participants | 97 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 15 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 291 Participants | 579 Participants | 288 Participants |
| Sex: Female, Male Female | 66 Participants | 129 Participants | 63 Participants |
| Sex: Female, Male Male | 331 Participants | 666 Participants | 335 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 77 / 392 | 71 / 395 |
| other Total, other adverse events | 383 / 392 | 371 / 395 |
| serious Total, serious adverse events | 174 / 392 | 175 / 395 |
Outcome results
Primary
Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1
Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Population: Randomized Set (RS): All patients who were randomized, regardless of whether they received investigational treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 | 2.63 Months |
| Erlotinib | Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 | 1.94 Months |
Comparison: A Cox proportional hazards model without the randomization stratification variable was used for each subgroup category, along with the corresponding log-rank test.p-value: 0.010395% CI: [0.693, 0.956]Log Rank
Secondary
Change in Score Over Time in Coughing,Dyspnoea and Pain
Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.
Time frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Population: RS
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Coughing | 15.8 Units on a scale | Standard Error 2.4 |
| Afatinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Dyspnoea | 11.4 Units on a scale | Standard Error 1.83 |
| Afatinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Pain | 10.3 Units on a scale | Standard Error 2.13 |
| Erlotinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Coughing | 19.3 Units on a scale | Standard Error 2.37 |
| Erlotinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Dyspnoea | 14.9 Units on a scale | Standard Error 1.85 |
| Erlotinib | Change in Score Over Time in Coughing,Dyspnoea and Pain | Pain | 13.1 Units on a scale | Standard Error 2.17 |
Comparison: The results shown relate to Change in scores over time for: Coughing.p-value: 0.009195% CI: [-6.15, -0.88]Regression, Cox
Comparison: The results shown relate to Change in scores over time for: Dyspnoea.p-value: 0.002495% CI: [-5.75, -1.25]Regression, Cox
Comparison: The results shown relate to Change in scores over time for: Pain.p-value: 0.038495% CI: [-5.33, -0.15]Regression, Cox
Secondary
Number of Participants With Disease Control According to RECIST 1.1
Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Number of Participants With Disease Control According to RECIST 1.1 | 201 Participants |
| Erlotinib | Number of Participants With Disease Control According to RECIST 1.1 | 157 Participants |
p-value: 0.00295% CI: [1.18, 2.06]Regression, Logistic
Secondary
Number of Participants With Objective Response According to RECIST 1.1
A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Number of Participants With Objective Response According to RECIST 1.1 | 22 Participants |
| Erlotinib | Number of Participants With Objective Response According to RECIST 1.1 | 11 Participants |
p-value: 0.055195% CI: [0.98, 4.32]Regression, Logistic
Secondary
Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire
Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.
Time frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Population: RS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Cough | 147 Participants |
| Afatinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Dyspnoea | 174 Participants |
| Afatinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Pain Related | 138 Participants |
| Afatinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Global Health Status | 121 Participants |
| Erlotinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Global Health Status | 96 Participants |
| Erlotinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Cough | 120 Participants |
| Erlotinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Pain Related | 134 Participants |
| Erlotinib | Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Improved Dyspnoea | 150 Participants |
Secondary
Overall Survival
Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.
Time frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Overall Survival | 7.82 Months |
| Erlotinib | Overall Survival | 6.77 Months |
Comparison: A Cox proportional-hazards model, stratified by race, was used to estimate the hazard ratio and 95% confidence interval (CI) between the two treatment groups.p-value: 0.019395% CI: [0.727, 0.973]Log Rank
Secondary
Summary of Time to Deterioration in Coughing, Dyspnoea and Pain.
Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration.
Time frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).
Population: RS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Afatinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Coughing | 4.53 Months |
| Afatinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Dyspnoea | 2.63 Months |
| Afatinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Pain | 2.50 Months |
| Erlotinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Coughing | 3.65 Months |
| Erlotinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Dyspnoea | 1.91 Months |
| Erlotinib | Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Time to Deterioration - Pain | 2.37 Months |
Comparison: The results shown relate to Time to Deterioration in Coughing.p-value: 0.256295% CI: [0.72, 1.09]Regression, Cox
Comparison: The results shown relate to Time to Deterioration in Dyspnoeap-value: 0.007895% CI: [0.66, 0.94]Regression, Cox
Comparison: The results shown relate to Time to Deterioration in Painp-value: 0.86995% CI: [0.82, 1.18]Regression, Cox
Secondary
Tumour Shrinkage
Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race.
Time frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).
Population: Patients from the randomised set with tumour assessments are considered for the analysis of this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib | Tumour Shrinkage | 78.8 Millimeter (mm) | Standard Error 1.26 |
| Erlotinib | Tumour Shrinkage | 80.0 Millimeter (mm) | Standard Error 1.24 |
Comparison: The analysis will compare the treatments using analysis of covariance (ANCOVA) for minimum sum of diameters, using baseline sum of diameters as a covariate. The randomization strata will be included as classification factors.p-value: 0.595% CI: [-4.67, 2.28]ANCOVA