Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The trial will be performed to evaluate if BIBF 1120 in combination with standard pemetrexed therapy is more effective than placebo (inactive capsule) plus standard pemetrexed therapy in patients with stage IIIB, IV or recurrent NSCLC. Safety information about BIBF1120/pemetrexed will be obtained.
Interventions
DRUGNintedanib (BIBF1120)
starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.
DRUGPemetrexed
500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.
DRUGpemetrexed
500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.
DRUGB12
1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed
DRUGdexamethasone (or corticosteroid equivalent)
4 mg PO bid the day before, the day of and the day after each pemetrexed infusion
DRUGplacebo
starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.
DRUGFolic Acid
400 ug once daily starting 1-2 weeks prior to the first dose of pemetrexed and continuing for at least 3 weeks after stopping pemetrexed.
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. Male or female patient aged 18 years or older. 2. Histologically or cytologically confirmed Stage IIIB, IV (according to AJCC) or recurrent non small cell lung cancer (NSCLC) (non squamous histologies) 3. Relapse or failure of one first line chemotherapy (in the case of recurrent disease one additional prior regimen is allowed for adjuvant, neoadjuvant or neoadjuvant plus adjuvant therapy). 4. At least one target tumor lesion that has not been irradiated within the past three months and that can accurately be measured by magnetic resonance imaging (MRI) or computed tomography (CT) in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT. 5. Life expectancy of at least three months. 6. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. 7. Patient has given written informed consent which must be consistent with the International Conference on Harmonization, Good Clinical Practice (ICH-GCP) and local legislation.
Exclusion criteria
1. Previous therapy with other vascular endothelial growth factor (VEGF) inhibitors (other than bevacizumab) or pemetrexed for treatment of NSCLC 2. Treatment with other investigational drugs or treatment in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial 3. Chemotherapy, hormone therapy, immunotherapy with monoclonal antibodies, treatment with tyrosine kinase inhibitors, or radiotherapy (except for treatment of extremities) within the past four weeks prior to treatment with the trial drug, i.e., the minimum time elapsed since the last anticancer therapy and the first administration of BIBF 1120 must be four weeks 4. Inability to stop intake of NSAIDS (non steroidal anti inflammatory drugs) for several days 5. Active brain metastases (e.g. stable for \<4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants). Dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomisation) 6. Radiographic evidence of cavitary or necrotic tumors 7. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels 8. History of clinically significant haemoptysis within the past 3 months 9. Therapeutic anticoagulation 10. History of major thrombotic or clinically relevant major bleeding event in the past 6 months 11. Significant cardiovascular diseases (i.e., hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, 12. Inadequate kidney, liver, blood clotting function 13. Inadequate blood count 14. Significant weight loss (\> 10 %) within the past 6 weeks prior to treatment in the present trial 15. Current peripheral neuropathy greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 except due to trauma 16. Pre-existing ascites (abdominal fluid collection) and/or clinically significant pleural effusion ( fluid collection between the lung and chest wall) 17. Major injuries and/or surgery within the past ten days prior to start of study drug 18. Incomplete wound healing 19. Active or chronic hepatitis C and/or B infection Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by Central Independent Review | From randomisation until cut-off date 9 July 2012 | Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death (whatever occurs earlier). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review | From randomisation until data cut-off (15 February 2013), Up to 30 months | Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
| Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator | From randomisation until data cut-off (15 February 2013), Up to 30 months | Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by investigator according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
| Objective Tumor Response | From randomisation until data cut-off (15 February 2013), Up to 30 months | Confirmed objective response is defined as confirmed Complete Response (CR) and Partial Response (PR) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator |
| Duration of Confirmed Objective Tumour Response | From randomisation until data cut-off (15 February 2013), Up to 30 months | The duration of objective response is the time from first documented (CR) or (PR) to the time of progression or death and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
| Time to Confirmed Objective Tumour Response | From randomisation until data cut-off (15 February 2013), Up to 30 months | Time to confirmed objective response is defined as time from randomisation to the date of first documented (CR) or (PR) and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
| Disease Control | From randomisation until data cut-off (15 February 2013), Up to 30 months | Disease control was defined as a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
| Overall Survival (Key Secondary Endpoint) | From randomisation until data cut-off (15 February 2013), Up to 30 months | Overall Survival (OS) defined as the duration from randomisation to death (irrespective of the reason of death). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
| Change From Baseline in Tumour Size | From randomisation until data cut-off (15 February 2013), Up to 30 months | Percentage change from baseline in tumour size is defined as decrease in the sum of the longest diameter of the target lesion. Presented means are in fact adjusted best means percentage changes generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) This endpoint was analysed based on the central independent reviewer as well as the investigator. |
| Clinical Improvement. | From randomisation until data cut-off (15 February 2013), Up to 30 months | Clinical improvement was defined as the time from randomisation to deterioration in body weight and/or Eastern Cooperative Oncology group performance score (ECOG PS) whichever occurred first. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
| Quality of Life (QoL) | From randomisation until data cut-off (15 February 2013), Up to 30 months | QoL was measured by standardised questionnaires (EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC13). The EORTC QLQ-C30 comprises of 30 questions, using both multi-item scales and single-item measures. EORTC LC-13 comprises of 13 questions incorporating 1 multi-item scale and a series of single items. The following were the main points of interest: Time to deterioration of cough (QLQ-LC13 question 1), Time to deterioration of dyspnoea (QLQ-LC13, composite of questions 3 to 5), Time to deterioration of pain (QLQ- C30, composite of questions 9 and 19). Time to deterioration of cough, dyspnoea and pain was defined as the time to a 10-point increase from the baseline score. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. |
| Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Before the administration of nintedanib or placebo and between a window of 30 mins to an hour after administration of trial drug during Course 2 and between 1 and 3 hours after administration of trial drug during Course 3 | Geometric mean of dose normalised predose plasma concentration (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide evaluated at steady state based on course 2 and 3. If only one value was available and valid, then this value was used for calculation of Cpre,ss,norm. |
| Incidence and Intensity of Adverse Events | From the first drug administration until 28 days after the last drug administration, up to 36 months | Incidence and intensity of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The worst CTCAE grade per patient is reported and MedDRA version 15.1 used. Serious signs and symptoms of progressive disease were reported as an adverse event in analysis of this endpoint. |
| Duration of Disease Control | From randomisation until data cut-off (15 February 2013), Up to 30 months | The duration of disease control was defined as the time from randomisation to the date of disease progression or death (which ever occurs first) for patients with disease control. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
Countries
Argentina, Australia, Bosnia and Herzegovina, Brazil, Canada, Chile, Colombia, Ecuador, Germany, Hong Kong, Hungary, Ireland, Latvia, Malaysia, Mexico, Moldova, Netherlands, New Zealand, North Macedonia, Panama, Peru, Philippines, Poland, Romania, Serbia, South Korea, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Pre-assignment details
5 patients at one investigator site were excluded from the enrollment count because of site non-compliance.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Plus Pemetrexed Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 353 |
| Placebo Plus Pemetrexed Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 360 |
| Total | 713 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Not treated | 6 | 3 |
| Overall Study | Other AE | 38 | 40 |
| Overall Study | progressive disease (modified RECIST ) | 217 | 216 |
| Overall Study | Protocol Violation | 9 | 4 |
| Overall Study | Reasons other than stated above | 25 | 41 |
| Overall Study | Withdrawal by Subject | 32 | 29 |
| Overall Study | Worsening or AE of underlying disease | 18 | 25 |
Baseline characteristics
| Characteristic | Nintedanib Plus Pemetrexed | Placebo Plus Pemetrexed | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 10.3 | 58.7 years STANDARD_DEVIATION 10.9 | 59.0 years STANDARD_DEVIATION 10.6 |
| Gender Female | 158 Participants | 152 Participants | 310 Participants |
| Gender Male | 195 Participants | 208 Participants | 403 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 320 / 347 | 312 / 357 |
| serious Total, serious adverse events | 104 / 347 | 117 / 357 |
Outcome results
Primary
Progression Free Survival (PFS) as Assessed by Central Independent Review
Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death (whatever occurs earlier). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until cut-off date 9 July 2012
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Pemetrexed | Progression Free Survival (PFS) as Assessed by Central Independent Review | 4.4 months |
| Placebo Plus Pemetrexed | Progression Free Survival (PFS) as Assessed by Central Independent Review | 3.6 months |
Comparison: HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).p-value: 0.043595% CI: [0.7, 0.99]Regression, Cox
Secondary
Change From Baseline in Tumour Size
Percentage change from baseline in tumour size is defined as decrease in the sum of the longest diameter of the target lesion. Presented means are in fact adjusted best means percentage changes generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Change From Baseline in Tumour Size | Central independent review (N=298, 305) | -10.10 percentage of change in tumor size in mm |
| Nintedanib Plus Pemetrexed | Change From Baseline in Tumour Size | Investigator assessment (N=322, 325) | -15.60 percentage of change in tumor size in mm |
| Placebo Plus Pemetrexed | Change From Baseline in Tumour Size | Central independent review (N=298, 305) | -7.53 percentage of change in tumor size in mm |
| Placebo Plus Pemetrexed | Change From Baseline in Tumour Size | Investigator assessment (N=322, 325) | -11.28 percentage of change in tumor size in mm |
Comparison: Analysis based on the central independent reviewp-value: 0.1558ANOVA
Comparison: Analysis based on the investigator's assessmentp-value: 0.0565ANOVA
Secondary
Clinical Improvement.
Clinical improvement was defined as the time from randomisation to deterioration in body weight and/or Eastern Cooperative Oncology group performance score (ECOG PS) whichever occurred first. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Pemetrexed | Clinical Improvement. | 7.2 Months |
| Placebo Plus Pemetrexed | Clinical Improvement. | 7.5 Months |
Comparison: HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).p-value: 0.506895% CI: [0.74, 1.16]Regression, Cox
Secondary
Disease Control
Disease control was defined as a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Disease Control | Central independent review (N=215, 192) | 60.9 % of participants |
| Nintedanib Plus Pemetrexed | Disease Control | Investigator assessment (N=233, 217) | 66.0 % of participants |
| Placebo Plus Pemetrexed | Disease Control | Central independent review (N=215, 192) | 53.3 % of participants |
| Placebo Plus Pemetrexed | Disease Control | Investigator assessment (N=233, 217) | 60.3 % of participants |
Comparison: Analysis based on the central independent reviewp-value: 0.038795% CI: [1.02, 1.85]Regression, Logistic
Comparison: Analysis based on investigator's assessmentp-value: 0.107195% CI: [0.95, 1.75]Regression, Logistic
Secondary
Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide
Geometric mean of dose normalised predose plasma concentration (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide evaluated at steady state based on course 2 and 3. If only one value was available and valid, then this value was used for calculation of Cpre,ss,norm.
Time frame: Before the administration of nintedanib or placebo and between a window of 30 mins to an hour after administration of trial drug during Course 2 and between 1 and 3 hours after administration of trial drug during Course 3
Population: Pharmacokinetic set- all patients in the treated set who were documented to have received at least 1 dose of nintedanib and who had at least 1 valid drug plasma concentration available
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1120 (N=188, 39) | 0.0883 ng/mL/mg | Geometric Coefficient of Variation 66.4 |
| Nintedanib Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1202 (N=188, 40) | 0.131 ng/mL/mg | Geometric Coefficient of Variation 123 |
| Nintedanib Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1202 glucuronide (N=184, 39) | 1.40 ng/mL/mg | Geometric Coefficient of Variation 169 |
| Placebo Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1120 (N=188, 39) | 0.103 ng/mL/mg | Geometric Coefficient of Variation 72.9 |
| Placebo Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1202 (N=188, 40) | 0.151 ng/mL/mg | Geometric Coefficient of Variation 125 |
| Placebo Plus Pemetrexed | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | Nintedanib BIBF 1202 glucuronide (N=184, 39) | 1.72 ng/mL/mg | Geometric Coefficient of Variation 185 |
Secondary
Duration of Confirmed Objective Tumour Response
The duration of objective response is the time from first documented (CR) or (PR) to the time of progression or death and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Duration of Confirmed Objective Tumour Response | central independent reviewer (N=32, 30) | 6.9 Months |
| Nintedanib Plus Pemetrexed | Duration of Confirmed Objective Tumour Response | Investigator assessment (N=53, 48) | 6.5 Months |
| Placebo Plus Pemetrexed | Duration of Confirmed Objective Tumour Response | central independent reviewer (N=32, 30) | 4.4 Months |
| Placebo Plus Pemetrexed | Duration of Confirmed Objective Tumour Response | Investigator assessment (N=53, 48) | 7.2 Months |
Secondary
Duration of Disease Control
The duration of disease control was defined as the time from randomisation to the date of disease progression or death (which ever occurs first) for patients with disease control. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Duration of Disease Control | Central independent review (N=215, 192) | 7.4 Months |
| Nintedanib Plus Pemetrexed | Duration of Disease Control | Investigator assessment (N=233, 217) | 6.9 Months |
| Placebo Plus Pemetrexed | Duration of Disease Control | Central independent review (N=215, 192) | 6.8 Months |
| Placebo Plus Pemetrexed | Duration of Disease Control | Investigator assessment (N=233, 217) | 6.8 Months |
Secondary
Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review
Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Pemetrexed | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review | 4.4 Months |
| Placebo Plus Pemetrexed | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review | 3.4 Months |
Comparison: HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)p-value: 0.050695% CI: [0.7, 1]Regression, Cox
Secondary
Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator
Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by investigator according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Pemetrexed | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator | 5.3 Months |
| Placebo Plus Pemetrexed | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator | 4.3 Months |
Comparison: HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)p-value: 0.086595% CI: [0.73, 1.02]Regression, Cox
Secondary
Incidence and Intensity of Adverse Events
Incidence and intensity of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The worst CTCAE grade per patient is reported and MedDRA version 15.1 used. Serious signs and symptoms of progressive disease were reported as an adverse event in analysis of this endpoint.
Time frame: From the first drug administration until 28 days after the last drug administration, up to 36 months
Population: Treated set uncut - all randomised patients who were documented to have taken at least 1 dose of study medication . Patients were allocated to the treatment groups according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 2 | 22.2 % of participants |
| Nintedanib Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 4 | 12.4 % of participants |
| Nintedanib Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 3 | 46.1 % of participants |
| Nintedanib Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 5 | 9.8 % of participants |
| Nintedanib Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 1 | 4.9 % of participants |
| Placebo Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 5 | 12.0 % of participants |
| Placebo Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 1 | 9.2 % of participants |
| Placebo Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 2 | 30.5 % of participants |
| Placebo Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 3 | 34.5 % of participants |
| Placebo Plus Pemetrexed | Incidence and Intensity of Adverse Events | CTCAE grade 4 | 7.8 % of participants |
Secondary
Objective Tumor Response
Confirmed objective response is defined as confirmed Complete Response (CR) and Partial Response (PR) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: Randomised Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Objective Tumor Response | Central independent reviewer | 9.1 % of participants |
| Nintedanib Plus Pemetrexed | Objective Tumor Response | Investigator assessment | 15.0 % of participants |
| Placebo Plus Pemetrexed | Objective Tumor Response | Central independent reviewer | 8.3 % of participants |
| Placebo Plus Pemetrexed | Objective Tumor Response | Investigator assessment | 13.3 % of participants |
Comparison: Analysis based on the central independent reviewp-value: 0.727995% CI: [0.65, 1.85]Regression, Logistic
Comparison: Analysis based on the investigator's assessmentp-value: 0.51895% CI: [0.75, 1.76]Regression, Logistic
Secondary
Overall Survival (Key Secondary Endpoint)
Overall Survival (OS) defined as the duration from randomisation to death (irrespective of the reason of death). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Pemetrexed | Overall Survival (Key Secondary Endpoint) | 12.0 months |
| Placebo Plus Pemetrexed | Overall Survival (Key Secondary Endpoint) | 12.7 months |
Comparison: HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).p-value: 0.89495% CI: [0.85, 1.21]Regression, Cox
Secondary
Quality of Life (QoL)
QoL was measured by standardised questionnaires (EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC13). The EORTC QLQ-C30 comprises of 30 questions, using both multi-item scales and single-item measures. EORTC LC-13 comprises of 13 questions incorporating 1 multi-item scale and a series of single items. The following were the main points of interest: Time to deterioration of cough (QLQ-LC13 question 1), Time to deterioration of dyspnoea (QLQ-LC13, composite of questions 3 to 5), Time to deterioration of pain (QLQ- C30, composite of questions 9 and 19). Time to deterioration of cough, dyspnoea and pain was defined as the time to a 10-point increase from the baseline score. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of cough | 6.0 Months |
| Nintedanib Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of dyspnoea | 2.4 Months |
| Nintedanib Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of pain | 2.8 Months |
| Placebo Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of cough | 4.3 Months |
| Placebo Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of dyspnoea | 2.0 Months |
| Placebo Plus Pemetrexed | Quality of Life (QoL) | Time to deterioration of pain | 2.7 Months |
Comparison: Analysis evaluating the time to deterioration of cough. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs \>=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)p-value: 0.118195% CI: [0.66, 1.05]Regression, Cox
Comparison: Analysis evaluating the time to deterioration of dyspnoea. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs \>=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).p-value: 0.426495% CI: [0.77, 1.12]Regression, Cox
Comparison: Analysis evaluating the time to deterioration of pain. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs \>= 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).p-value: 0.892995% CI: [0.84, 1.23]Regression, Cox
Secondary
Time to Confirmed Objective Tumour Response
Time to confirmed objective response is defined as time from randomisation to the date of first documented (CR) or (PR) and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until data cut-off (15 February 2013), Up to 30 months
Population: RS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Pemetrexed | Time to Confirmed Objective Tumour Response | Central independent review (N=32, 30) | 2.6 Months |
| Nintedanib Plus Pemetrexed | Time to Confirmed Objective Tumour Response | Investigator assessment (N=53, 48) | 2.6 Months |
| Placebo Plus Pemetrexed | Time to Confirmed Objective Tumour Response | Central independent review (N=32, 30) | 2.7 Months |
| Placebo Plus Pemetrexed | Time to Confirmed Objective Tumour Response | Investigator assessment (N=53, 48) | 2.8 Months |