Lung Neoplasms
Conditions
Brief summary
This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.
Interventions
DRUGAfatinib
afatinib once daily
DRUGgefitinib
Gefitinib 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 90 Years
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed diagnosis of Stage IIIB / IV adenocarcinoma of the lung. 2. Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues. 3. At least one measurable lesion according to response evaluation criteria in solid tumours version 1.1 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 5. Age \>= 18 years. 6. Adequate organ function as defined by the following criteria: Serum aspartate transaminase(AST) and serum alanine transaminase(ALT) =\< 3 x upper limit of normal (ULN), or AST and ALT =\<5 x ULN if liver function abnormalities are due to underlying malignancy Total serum bilirubin =\<1.5 x ULN Absolute neutrophil count (ANC) \>=1.5 x 109/L Creatinine clearance \> 45ml / min Platelets \>= 75 x 109/L
Exclusion criteria
1. Prior systemic chemotherapy for stage IIIB or IV non-small cell lung cancer. Neo-/adjuvant chemotherapy, chemoradiation or radiotherapy is permitted if at least 12 months has elapsed prior to disease progression. 2. Prior treatment with epidermal growth factor receptor targeting small molecules or antibodies. 3. Major surgery within 4 weeks of study randomisation. 4. Active brain metastases 5. Meningeal carcinomatosis. 6. Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured in the opinion of investigator. 7. Known pre-existing interstitial lung disease. 8. Clinically relevant cardiovascular abnormalities as judged by the investigator. 9. Cardiac left ventricular function with resting ejection fraction of less than institutional lower limit of normal. 10. Women of child-bearing potential (WOCBP) 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. 11. Pregnancy or breast-feeding. 12. Active hepatitis and/or known HIV carrier 13. Any prohibited concomitant medications for therapy with afatinib or gefitinib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days. | Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment. |
| Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | From first drug administration until last drug administration, up to 1482 days | Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason. |
| Overall Survival | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days. | Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days. | Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment. |
| Duration of Disease Control | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days. | Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment. |
| Objective Response Rate | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days. | Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment. |
| Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | Every 8 weeks, up to 56 weeks | Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks. |
| Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | From first drug administration until last drug administration, up to 1482 days | Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size. |
| Time to Objective Response | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days. | Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment. |
| Duration of Objective Response | From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days. | Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment. |
Countries
Australia, Canada, China, France, Germany, Hong Kong, Ireland, Norway, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom
Participant flow
Recruitment details
Two-arm, randomised (1:1 ratio), open-label, parallel group trial. In the study disease response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal. | 160 |
| Gefitinib Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal. | 159 |
| Total | 319 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other adverse event | 19 | 18 |
| Overall Study | Other reason not defined above | 10 | 8 |
| Overall Study | Progressive Disease (RECIST 1.1) | 120 | 127 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Refused continuation of trial medication | 4 | 3 |
| Overall Study | Worsening of underlying cancer disease | 5 | 2 |
Baseline characteristics
| Characteristic | Afatinib | Gefitinib | Total |
|---|---|---|---|
| Age, Continuous | 61.7 Years STANDARD_DEVIATION 11.5 | 63.0 Years STANDARD_DEVIATION 10.4 | 62.4 Years STANDARD_DEVIATION 11 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 94 Participants | 88 Participants | 182 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 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 | 17 Participants | 17 Participants | 34 Participants |
| Race (NIH/OMB) White | 48 Participants | 54 Participants | 102 Participants |
| Sex: Female, Male Female | 91 Participants | 106 Participants | 197 Participants |
| Sex: Female, Male Male | 69 Participants | 53 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 126 / 160 | 132 / 159 |
| other Total, other adverse events | 157 / 160 | 159 / 159 |
| serious Total, serious adverse events | 75 / 160 | 64 / 159 |
Outcome results
Primary
Overall Survival
Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.
Population: Randomised set which included all patients randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Overall Survival | 27.86 Months |
| Gefitinib | Overall Survival | 24.54 Months |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.234395% CI: [0.674, 1.101]Log Rank
Primary
Progression-free Survival
Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
Population: Randomised set which included all patients randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Progression-free Survival | 12.78 Months |
| Gefitinib | Progression-free Survival | 11.17 Months |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.089195% CI: [0.655, 1.032]Log Rank
Primary
Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016)
Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.
Time frame: From first drug administration until last drug administration, up to 1482 days
Population: Randomised set which included all patients randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | 13.67 Months |
| Gefitinib | Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | 11.53 Months |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.013695% CI: [0.595, 0.944]Log Rank
Secondary
Disease Control
Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
Population: Randomised set which included all patients randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Disease Control | 94.4 Percentage of participants |
| Gefitinib | Disease Control | 93.7 Percentage of participants |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.785695% CI: [0.447, 2.896]Regression, Logistic
Secondary
Duration of Disease Control
Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
Population: All participants in the randomised set with disease control, that is, with best overall response of complete response or partial response or stable disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Duration of Disease Control | 12.88 Months |
| Gefitinib | Duration of Disease Control | 11.73 Months |
Secondary
Duration of Objective Response
Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
Population: Participants in the randomised set with objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Duration of Objective Response | 11.86 Months |
| Gefitinib | Duration of Objective Response | 11.07 Months |
Secondary
Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015)
Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.
Time frame: Every 8 weeks, up to 56 weeks
Population: All randomised subjects with health-related quality of life data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Afatinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-VAS utility score | 74.5 Units on a scale |
| Afatinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-5D UK utility score | 0.77 Units on a scale |
| Afatinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-5D Belgium utility score | 0.74 Units on a scale |
| Gefitinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-5D UK utility score | 0.80 Units on a scale |
| Gefitinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-5D Belgium utility score | 0.77 Units on a scale |
| Gefitinib | Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015) | EQ-VAS utility score | 76.0 Units on a scale |
Comparison: EQ-5D UK utility score.~Exploratory trial, no formal hypotheses were tested.p-value: 0.142295% CI: [-0.06, 0.01]Mixed Models Analysis
Comparison: EQ-5D Belgium utility score.~Exploratory trial, no formal hypotheses were tested.p-value: 0.05495% CI: [-0.06, 0]Mixed Models Analysis
Comparison: EQ-VAS utility score.~Exploratory trial, no formal hypotheses were tested.p-value: 0.203295% CI: [-3.9, 0.8]Mixed Models Analysis
Secondary
Objective Response Rate
Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
Population: Randomised set which included all patients randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Objective Response Rate | 79.4 Percentage of participants |
| Gefitinib | Objective Response Rate | 74.8 Percentage of participants |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.323595% CI: [0.768, 2.223]Regression, Logistic
Secondary
Time to Objective Response
Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
Time frame: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
Population: All participants in the randomised set with objective response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib | Time to Objective Response | Week 8 | 112 Participants |
| Afatinib | Time to Objective Response | Week 32 | 125 Participants |
| Afatinib | Time to Objective Response | Week 4 | 81 Participants |
| Afatinib | Time to Objective Response | Week 40 | 126 Participants |
| Afatinib | Time to Objective Response | Week 16 | 119 Participants |
| Afatinib | Time to Objective Response | Week 48 | 127 Participants |
| Afatinib | Time to Objective Response | Week 24 | 122 Participants |
| Gefitinib | Time to Objective Response | Week 48 | 119 Participants |
| Gefitinib | Time to Objective Response | Week 4 | 74 Participants |
| Gefitinib | Time to Objective Response | Week 8 | 107 Participants |
| Gefitinib | Time to Objective Response | Week 24 | 118 Participants |
| Gefitinib | Time to Objective Response | Week 32 | 118 Participants |
| Gefitinib | Time to Objective Response | Week 40 | 118 Participants |
| Gefitinib | Time to Objective Response | Week 16 | 117 Participants |
Secondary
Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016)
Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.
Time frame: From first drug administration until last drug administration, up to 1482 days
Population: Participants in the randomised set with tumour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Afatinib | Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | 34.79 millimetre (mm) |
| Gefitinib | Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016) | 38.25 millimetre (mm) |
Comparison: Exploratory trial, no formal hypotheses were tested.p-value: 0.065795% CI: [-7.13, 0.23]ANCOVA