Adenocarcinoma, Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.
Interventions
DRUGPemetrexed
Pemetrexed IV given once every 3 weeks for up to 6 cycles
DRUGBIBW 2992
BIBW 2992 once daily until progression
DRUGCisplatin
Cisplatin IV given once every 3 weeks for up to 6 cycles
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
* Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. * Epidermal Growth Factor Receptor mutation detected by central laboratory analysis of tumour biopsy material. * Measurable disease according to RECIST 1.1. * Eastern Cooperative Oncology Group score of 0 or 1. * Age \>/= 18 years. * Life expectancy of at least three months. * Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice guidelines.
Exclusion criteria
* Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and randomisation. * Prior treatment with Epidermal Growth Factor Receptor targeting small molecules or antibodies. * Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomisation. * Active brain metastases * Any other current malignancy or malignancy diagnosed within the past five years * Known pre-existing interstitial lung disease. * Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom. * History or presence of clinically relevant cardiovascular abnormalities. * Any other concomitant serious illness or organ system dysfunction. * Adequate absolute neutrophil count and platelet count * Adequate liver and kidney function * Active hepatitis B infection, active hepatitis C infection or known HIV carrier.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Time | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Control (DC) | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1. |
| Overall Survival (OS) Time | From randomisation to cut-off date (17MAR2017). | OS was defined as time from randomisation to death. |
| Tumour Shrinkage | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race. |
| Change From Baseline in Body Weight | Baseline and throughout the trial until progression (every 3 weeks), up to 28 months. | Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm. |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Throughout the trial until progression (every 3 weeks), up to 28 months. | ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. 1. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. 2. Ambulatory (\>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. 3. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. 4. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 5. Dead. |
| Percentage of Patients With Objective Response (OR) | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1. |
| HRQOL: Time to Deterioration in Dyspnoea | Throughout the trial until progression (every 3 weeks). | HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. |
| HRQOL: Time to Deterioration in Pain | Throughout the trial until progression (every 3 weeks). | HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. |
| Trough Plasma Concentrations of Afatinib at Day 22 | Day 22. | Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. |
| Trough Plasma Concentrations of Afatinib at Day 29 | Day 29. | Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. |
| Trough Plasma Concentrations of Afatinib at Day 43 | Day 43. | Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. |
| Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing | Throughout the trial until progression (every 3 weeks). | HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, France, Germany, Hong Kong, Hungary, Ireland, Italy, Japan, Malaysia, Peru, Philippines, Romania, Russia, South Korea, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison. 345 patients were randomised, 5 patients were not treated: 4 patients were not eligible for treatment and 1 patient in the chemotherapy arm refused to take study medication.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily. | 230 |
| Pemetrexed/Cisplatin Chemotherapy Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles. | 115 |
| Total | 345 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Completed 6 courses of chemotherapy | 0 | 60 |
| Overall Study | Not treated | 1 | 4 |
| Overall Study | Other Adverse Event (AE) | 28 | 17 |
| Overall Study | Other not specified above | 5 | 0 |
| Overall Study | Progressive disease | 188 | 19 |
| Overall Study | Protocol Violation | 1 | 4 |
| Overall Study | Refusal to continue medication | 7 | 11 |
Baseline characteristics
| Characteristic | Afatinib 40 mg | Pemetrexed/Cisplatin Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 60.5 Years STANDARD_DEVIATION 10.1 | 59.9 Years STANDARD_DEVIATION 10 | 60.3 Years STANDARD_DEVIATION 10.1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0 (baseline) | 92 Participants | 41 Participants | 133 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1 (baseline) | 138 Participants | 73 Participants | 211 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2 (baseline) | 0 Participants | 1 Participants | 1 Participants |
| Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: Deletion Exon 19 | 112 Participants | 57 Participants | 169 Participants |
| Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: L858R | 91 Participants | 47 Participants | 138 Participants |
| Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: Other | 27 Participants | 11 Participants | 38 Participants |
| Race/Ethnicity, Customized Asian | 166 Participants | 83 Participants | 249 Participants |
| Race/Ethnicity, Customized Non-Asian | 64 Participants | 32 Participants | 96 Participants |
| Sex: Female, Male Female | 147 Participants | 77 Participants | 224 Participants |
| Sex: Female, Male Male | 83 Participants | 38 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 229 / 229 | 108 / 111 |
| serious Total, serious adverse events | 72 / 229 | 25 / 111 |
Outcome results
Primary
Progression-Free Survival (PFS) Time
PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.
Time frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Population: Randomised set (RS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg | Progression-Free Survival (PFS) Time | 11.17 Months. |
| Pemetrexed/Cisplatin Chemotherapy | Progression-Free Survival (PFS) Time | 6.90 Months. |
p-value: 0.0002Log Rank
p-value: 0.000295% CI: [0.426, 0.778]Regression, Cox
Secondary
Change From Baseline in Body Weight
Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.
Time frame: Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.
Population: RS. Only patients with baseline and at least one post-baseline assessment were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 40 mg | Change From Baseline in Body Weight | Change from baseline at lowest value | -3.95 Kg. | Standard Deviation 3.91 |
| Afatinib 40 mg | Change From Baseline in Body Weight | Change from baseline at last value | -1.19 Kg. | Standard Deviation 5.36 |
| Pemetrexed/Cisplatin Chemotherapy | Change From Baseline in Body Weight | Change from baseline at last value | -0.29 Kg. | Standard Deviation 4.02 |
| Pemetrexed/Cisplatin Chemotherapy | Change From Baseline in Body Weight | Change from baseline at lowest value | -2.68 Kg. | Standard Deviation 2.9 |
Secondary
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. 1. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. 2. Ambulatory (\>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. 3. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. 4. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 5. Dead.
Time frame: Throughout the trial until progression (every 3 weeks), up to 28 months.
Population: RS. Only patients with baseline and at least one post-baseline assessment were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 40 mg | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 0 (last value) | 92 Participants |
| Afatinib 40 mg | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 1 (last value) | 138 Participants |
| Afatinib 40 mg | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 2 (last value) | 0 Participants |
| Pemetrexed/Cisplatin Chemotherapy | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 0 (last value) | 41 Participants |
| Pemetrexed/Cisplatin Chemotherapy | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 1 (last value) | 73 Participants |
| Pemetrexed/Cisplatin Chemotherapy | Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS 2 (last value) | 1 Participants |
Secondary
Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing
HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time frame: Throughout the trial until progression (every 3 weeks).
Population: RS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg | Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing | 26.97 Months. |
| Pemetrexed/Cisplatin Chemotherapy | Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing | 8.02 Months. |
p-value: 0.0062Log Rank
p-value: 0.213395% CI: [0.401, 0.866]Regression, Cox
Secondary
HRQOL: Time to Deterioration in Dyspnoea
HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time frame: Throughout the trial until progression (every 3 weeks).
Population: RS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg | HRQOL: Time to Deterioration in Dyspnoea | 10.41 Months. |
| Pemetrexed/Cisplatin Chemotherapy | HRQOL: Time to Deterioration in Dyspnoea | 2.86 Months. |
p-value: 0.0129Log Rank
p-value: 0.007895% CI: [0.499, 0.927]Regression, Cox
Secondary
HRQOL: Time to Deterioration in Pain
HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time frame: Throughout the trial until progression (every 3 weeks).
Population: RS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg | HRQOL: Time to Deterioration in Pain | 4.17 Months. |
| Pemetrexed/Cisplatin Chemotherapy | HRQOL: Time to Deterioration in Pain | 3.09 Months. |
p-value: 0.1882Log Rank
p-value: 0.042795% CI: [0.618, 1.104]Regression, Cox
Secondary
Overall Survival (OS) Time
OS was defined as time from randomisation to death.
Time frame: From randomisation to cut-off date (17MAR2017).
Population: RS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg | Overall Survival (OS) Time | 28.16 Months. |
| Pemetrexed/Cisplatin Chemotherapy | Overall Survival (OS) Time | 28.22 Months. |
p-value: 0.7916Log Rank
p-value: 0.38595% CI: [0.66, 1.174]Regression, Cox
Secondary
Percentage of Participants With Disease Control (DC)
DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.
Time frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Population: RS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 40 mg | Percentage of Participants With Disease Control (DC) | 90.4 Percentage of participants with DC. |
| Pemetrexed/Cisplatin Chemotherapy | Percentage of Participants With Disease Control (DC) | 80.9 Percentage of participants with DC. |
p-value: 0.011895% CI: [1.202, 4.356]Regression, Logistic
Secondary
Percentage of Patients With Objective Response (OR)
OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.
Time frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Population: RS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 40 mg | Percentage of Patients With Objective Response (OR) | 56.5 Percentage of patients with OR. |
| Pemetrexed/Cisplatin Chemotherapy | Percentage of Patients With Objective Response (OR) | 22.6 Percentage of patients with OR. |
p-value: <0.000195% CI: [2.855, 8.075]Regression, Logistic
Secondary
Trough Plasma Concentrations of Afatinib at Day 22
Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time frame: Day 22.
Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed/Cisplatin Chemotherapy | Trough Plasma Concentrations of Afatinib at Day 22 | 21.8 ng/mL. | Geometric Coefficient of Variation 36.6 |
| Afatinib 40 mg | Trough Plasma Concentrations of Afatinib at Day 22 | 28.0 ng/mL. | Geometric Coefficient of Variation 85 |
| Afatinib 50 mg | Trough Plasma Concentrations of Afatinib at Day 22 | 29.9 ng/mL. | Geometric Coefficient of Variation 46.1 |
Secondary
Trough Plasma Concentrations of Afatinib at Day 29
Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time frame: Day 29.
Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed/Cisplatin Chemotherapy | Trough Plasma Concentrations of Afatinib at Day 29 | 28.0 ng/mL. | Geometric Coefficient of Variation 82.4 |
| Afatinib 40 mg | Trough Plasma Concentrations of Afatinib at Day 29 | 25.8 ng/mL. | Geometric Coefficient of Variation 69.5 |
| Afatinib 50 mg | Trough Plasma Concentrations of Afatinib at Day 29 | 29.6 ng/mL. | Geometric Coefficient of Variation 79.2 |
Secondary
Trough Plasma Concentrations of Afatinib at Day 43
Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time frame: Day 43.
Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 40 mg | Trough Plasma Concentrations of Afatinib at Day 43 | 24.4 ng/mL. | Geometric Coefficient of Variation 260 |
| Pemetrexed/Cisplatin Chemotherapy | Trough Plasma Concentrations of Afatinib at Day 43 | 24.7 ng/mL. | Geometric Coefficient of Variation 63.9 |
| Afatinib 40 mg | Trough Plasma Concentrations of Afatinib at Day 43 | 23.5 ng/mL. | Geometric Coefficient of Variation 66.2 |
| Afatinib 50 mg | Trough Plasma Concentrations of Afatinib at Day 43 | 27.5 ng/mL. | Geometric Coefficient of Variation 64.4 |
Secondary
Tumour Shrinkage
Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.
Time frame: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Population: RS. There were only 203 patients in the Afatinib 40 mg arm and 101 patients in the Pemetrexed/Cisplatin Chemotherapy with tumour measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 40 mg | Tumour Shrinkage | 33.19 mm. | Standard Error 1.12 |
| Pemetrexed/Cisplatin Chemotherapy | Tumour Shrinkage | 43.00 mm. | Standard Error 1.59 |
p-value: <0.000195% CI: [-13.64, -5.99]ANCOVA