Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This randomized, double-blind, multi-center Phase IIb/III trial will be performed in patients with NSCLC who have received previous treatment with at least one but not more than two lines of cytotoxic chemotherapy (one line must have been a platinum-containing regimen) and either gefitinib or erlotinib for a period of at least 12 weeks and then progressed. The primary objective of this randomized trial is to determine the efficacy of BIBW 2992 as a single agent (Arm A) as compared to a matching placebo (Arm B) in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up.
Interventions
DRUGplacebo
Patients receive placebo once daily
DRUGBIBW 2992
Patients receive afatinib tablets once daily, and can reduce dose for adverse event management. Afatinib is given once daily, continuously until disease progression or unacceptable toxicity.
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. Patients with pathologic confirmation of NSCLC Stage III-B (with pleural effusion) or Stage IV adenocarcinoma who have failed at least one but not more than two lines of cytotoxic chemotherapy (including adjuvant chemotherapy). One of the chemotherapy regimens must have been platinum-based. 2. Progressive disease following at least 12 weeks of treatment with erlotinib (Tarceva®) or gefitinib (Iressa®) 3. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance Score 0, 1 or 2 4. Patients with at least one tumor lesion that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension with longest diameter to be recorded as \>20 mm using conventional techniques or \>10 mm with spiral CT scan 5. Male and female patients age \>18 years 6. Life expectancy of at least three (3) months 7. Written informed consent that is consistent with ICH-GCP guidelines
Exclusion criteria
1. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within 14 days of treatment Day 1 2. Chemo-, hormone- (other than megestrol acetate or steroids required for maintenance non-cancer therapy) or immunotherapy within the past 4 weeks 3. Active brain metastases 4. Significant or recent acute gastrointestinal disorders with diarrhea 5. Patients who have any other life-threatening illness or organ system dysfunction, 6. Other malignancies diagnosed within the past five (5) years 7. Radiotherapy within the past 2 weeks prior to treatment 8. History of clinically significant or uncontrolled cardiac disease 9. Adequate ANC and platelet count 10. Adequate liver and kidney function 11. Patients with any serious active infection including known HIV, active hepatitis B or active hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until death or the last patient out date, an average of 12 months | Overall survival was the duration from the date of randomization to the date of death. Patients who were alive were censored at the last contact date prior to the database lock. For the primary analysis 11 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Primary analysis data cut-off date was 08 July 2010. For the final analysis 13 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Final analysis data cut-off date was 04 October 2013. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months | PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0). |
| Objective Response Rate (OR) | From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months | OR is defined as complete response (CR) and partial response (PR). Assessed by central independent review according to RECIST 1.0. |
Countries
Belgium, Canada, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States
Participant flow
Pre-assignment details
Two-arm, randomised (2:1 ratio), double-blind , placebo-controlled, multi-centre trial. 585 patients were randomised. All patients randomized received at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Plus Best Supportive Care (BSC) Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm. | 195 |
| Afatinib 50 mg/Day Plus Best Supportive Care (BSC) Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0). | 390 |
| Total | 585 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other Adverse Event | 5 | 51 |
| Overall Study | Patient refused to take study medication | 7 | 10 |
| Overall Study | Progressive disease | 177 | 322 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Unknown and others | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo Plus Best Supportive Care (BSC) | Afatinib 50 mg/Day Plus Best Supportive Care (BSC) | Total |
|---|---|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 10.4 | 58 years STANDARD_DEVIATION 10.8 | 58 years STANDARD_DEVIATION 10.6 |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 0 | 53 Number of participants | 92 Number of participants | 145 Number of participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 1 | 127 Number of participants | 268 Number of participants | 395 Number of participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 2 | 15 Number of participants | 30 Number of participants | 45 Number of participants |
| Race/Ethnicity, Customized Caucasian | 72 Number of participants | 121 Number of participants | 193 Number of participants |
| Race/Ethnicity, Customized Eastern Asian | 110 Number of participants | 227 Number of participants | 337 Number of participants |
| Race/Ethnicity, Customized Other | 1 Number of participants | 4 Number of participants | 5 Number of participants |
| Race/Ethnicity, Customized Other Asian | 12 Number of participants | 38 Number of participants | 50 Number of participants |
| Sex: Female, Male Female | 117 Participants | 231 Participants | 348 Participants |
| Sex: Female, Male Male | 78 Participants | 159 Participants | 237 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 167 / 195 | 383 / 390 |
| serious Total, serious adverse events | 36 / 195 | 136 / 390 |
Outcome results
Primary
Overall Survival
Overall survival was the duration from the date of randomization to the date of death. Patients who were alive were censored at the last contact date prior to the database lock. For the primary analysis 11 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Primary analysis data cut-off date was 08 July 2010. For the final analysis 13 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Final analysis data cut-off date was 04 October 2013.
Time frame: From randomization until death or the last patient out date, an average of 12 months
Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Plus Best Supportive Care (BSC) | Overall Survival | Primary analysis (358 deaths) | 11.96 Months |
| Placebo Plus Best Supportive Care (BSC) | Overall Survival | Final analysis (526 deaths) | 11.73 Months |
| Afatinib 50 mg/Day Plus Best Supportive Care (BSC) | Overall Survival | Primary analysis (358 deaths) | 10.78 Months |
| Afatinib 50 mg/Day Plus Best Supportive Care (BSC) | Overall Survival | Final analysis (526 deaths) | 10.87 Months |
Comparison: Primary analysis was performed after 358 deaths were observed among randomized patients. The data cut-off date for the primary analysis was 08 July 2010.p-value: 0.742895% CI: [0.862, 1.346]Regression, Cox
Comparison: Final analysis was performed after 526 deaths were observed among randomized patients. The data cut-off date for the final analysis was 04 October 2013.p-value: 0.395595% CI: [0.814, 1.17]Regression, Cox
Secondary
Objective Response Rate (OR)
OR is defined as complete response (CR) and partial response (PR). Assessed by central independent review according to RECIST 1.0.
Time frame: From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months
Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Plus Best Supportive Care (BSC) | Objective Response Rate (OR) | 0.5 Percentage of patients with OR |
| Afatinib 50 mg/Day Plus Best Supportive Care (BSC) | Objective Response Rate (OR) | 7.4 Percentage of patients with OR |
p-value: 0.007195% CI: [2.1, 115]Regression, Logistic
Secondary
Progression-free Survival (PFS)
PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0).
Time frame: From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months
Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Plus Best Supportive Care (BSC) | Progression-free Survival (PFS) | 1.08 Months |
| Afatinib 50 mg/Day Plus Best Supportive Care (BSC) | Progression-free Survival (PFS) | 3.29 Months |
p-value: <0.000195% CI: [0.306, 0.475]Regression, Cox