Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The present trial will be performed to evaluate whether BIBF 1120 in combination with standard therapy of docetaxel in patients with stage IIIB/IV or recurrent NSCLC is more effective as compared to placebo in combination with standard therapy of docetaxel. A secondary aim is to obtain safety information as well as information on quality of life of patients treated with BIBF 1120 in combination to standard therapy with docetaxel. In addition, blood will be collected for pharmacokinetic analysis.
Interventions
placebo matching BIBF 1120 2 times daily along with standard therapy of docetaxel
DRUGBIBF 1120 plus docetaxel
BIBF 1120 2 times daily along with standard therapy of docetaxel
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
* male or female patient aged 18 years or older; * histologically or cytologically confirmed, locally advanced and/or metastatic NSCLC of stage IIIB or IV or recurrent NSCLC; * relapse or failure of one first line prior chemotherapy; * at least one target tumour lesion that has not been irradiated within the past three months and that can accurately be measured ; * life expectancy of at least three months; * Eastern Cooperative Oncology group (ECOG) score of 0 or 1; * patient has given written informed consent
Exclusion criteria
* more than one prior chemotherapy regimen for advanced and/or metastatic or recurrent NSCLC; * more than one chemotherapy treatment regimen (either neoadjuvant or adjuvant or neoadjuvant plus adjuvant) prior to first line chemotherapy; * previous therapy with other VEGFR inhibitors (other than bevacizumab) or docetaxel for treatment of NSCLC; * persistence of clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy; * treatment with other investigational drugs or other anti-cancer therapy or treatment in another clinical trial within the past four weeks before start of - therapy or concomitantly with this trial ; * radiotherapy (except extremities and brain) within the past three months prior to baseline imaging; * active brain metastases or leptomeningeal disease; * radiographic evidence of cavitary or necrotic tumours; * centrally located tumours with radiographic evidence (CT or MRI) of local invasion of major blood vessels; * history of clinically significant haemoptysis within the past 3 months; * therapeutic anticoagulation (except low dose heparin) or antiplatelet therapy; * history of major thrombotic or clinically relevant major bleeding event in the past 6 months; * known inherited predisposition to bleeding or thrombosis; * significant cardiovascular diseases ; * inadequate safety laboratory parameters; * significant weight loss (\> 10 %) within the past 6 weeks; * current peripheral neuropathy greater than CTCAE grade 2 except due to trauma; * preexisting ascites and/or clinically significant pleural effusion; * major injuries and/or surgery within the past ten days prior to randomisation with incomplete wound healing; * serious infections requiring systemic antibiotic therapy; * decompensated diabetes mellitus or other contraindication to high dose corticosteroid therapy; * gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug; * active or chronic hepatitis C and/or B infection; * serious illness or concomitant non-oncological disease or laboratory abnormality that may increase the risk associated with study participation or study drug administration; * patients who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for at least twelve months after end of active therapy; * pregnancy or breast feeding; * psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; * patients unable to comply with the protocol; * active alcohol or drug abuse; * other malignancy within the past three years other than basal cell skin cancer, or carcinoma in situ of the cervix; * any contraindications for therapy with docetaxel; * history of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80 (Tween 80); * hypersensitivity to BIBF 1120 and/or the excipients of the trial drugs; * hypersensitivity to contrast media
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by Central Independent Review | From randomisation until cut-off date 2 November 2010 (when 713 PFS events were observed) | Progression Free Survival (PFS) as assessed by central independent review according to the modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) . 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 cut-off date 15 February 2013 | 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 cut-off date 15 February 2013 | 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 Tumour Response | From randomisation until cut-off date 15 February 2013 | 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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
| Clinical Improvement | From randomisation until cut-off date 15 February 2013 | 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. |
| Duration of Confirmed Objective Tumour Response | From randomisation until cut-off date 15 February 2013 | 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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. 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 cut-off date 15 February 2013 | 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. |
| Overall Survival (Key Secondary Endpoint) | From randomisation until cut-off date 15 February 2013 (approximately 48 months or 1151 deaths among all patients ) | 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. A fixed-sequence-testing was implemented for key secondary endpoint if both the primary and the follow-up analysis showed a treatment benefit (P\<0.05) of nintedanib over placebo. In this case, the OS would be tested using hierarchical testing of statistical hypotheses in (1) patients with adenocarcinoma and \<9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been. |
| Duration of Disease Control | From randomisation until cut-off date 15 February 2013 | 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. |
| Change From Baseline in Tumour Size | From randomisation until cut-off date 15 February 2013 | 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 (squamous vs non-squamous), 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. |
| Quality of Life (QoL) | From randomisation until cut-off date 15 February 2013 | Quality of life (QoL) was measured by standardised questionnaires (Health Status Self-Assessment Questionnaire (EQ-5D), EORTC Quality of life questionnaire - Core 30 (EORTC QLQ-C30), Quality of life questionnaire - lung cancer module (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 (EORTC 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 42 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. |
| Disease Control | From randomisation until cut-off date 15 February 2013 | 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. As per RECIST v1.0 for target lesions : Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. This endpoint was analysed based on the central independent reviewer as well as the investigator. |
Countries
Austria, Belarus, Belgium, Bulgaria, China, Croatia, Czechia, Denmark, France, Georgia, Germany, Greece, India, Israel, Italy, Lithuania, Poland, Portugal, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Switzerland, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Plus Docetaxel Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 milligram (mg)/square meter (m2) once every 3 weeks administered via intravenous infusion over 1 hour (h). | 655 |
| Placebo Plus Docetaxel Placebo soft gelatin capsule matching that of nintedanib 2 times daily plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h). | 659 |
| Total | 1,314 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Not treated | 3 | 4 |
| Overall Study | Other AE | 84 | 73 |
| Overall Study | Progressive disease (modified RECIST) | 404 | 435 |
| Overall Study | Protocol Violation | 9 | 9 |
| Overall Study | Reasons other than stated above | 20 | 16 |
| Overall Study | Withdrawal by Subject | 60 | 42 |
| Overall Study | Worsening or AE of underlying disease | 64 | 70 |
Baseline characteristics
| Characteristic | Nintedanib Plus Docetaxel | Placebo Plus Docetaxel | Total |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 9.7 | 59.8 years STANDARD_DEVIATION 9 | 59.7 years STANDARD_DEVIATION 9.3 |
| Number of patients with adenocarcinoma and time since first line therapy in categories <9 month | 206 Participants | 199 Participants | 405 Participants |
| Number of patients with adenocarcinoma and time since first line therapy in categories >=9 month | 112 Participants | 134 Participants | 246 Participants |
| Number of patients with adenocarcinoma and time since first line therapy in categories Missing | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 179 Participants | 180 Participants | 359 Participants |
| Sex: Female, Male Male | 476 Participants | 479 Participants | 955 Participants |
| Tumour histology Adenocarcinoma | 322 Participants | 336 Participants | 658 Participants |
| Tumour histology Other | 57 Participants | 44 Participants | 101 Participants |
| Tumour histology Squamous cell carcinoma | 276 Participants | 279 Participants | 555 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 107 / 652 | 77 / 655 |
| other Total, other adverse events | 569 / 652 | 547 / 655 |
| serious Total, serious adverse events | 224 / 652 | 206 / 655 |
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 Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) . 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 2 November 2010 (when 713 PFS events were observed)
Population: Randomised Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Docetaxel | Progression Free Survival (PFS) as Assessed by Central Independent Review | 3.4 months |
| Placebo Plus Docetaxel | Progression Free Survival (PFS) as Assessed by Central Independent Review | 2.7 months |
Comparison: HR, Confidence Interval (CI) and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)p-value: 0.001995% CI: [0.68, 0.92]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 (squamous vs non-squamous), 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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Change From Baseline in Tumour Size | central independent reviewer | -4.87 percentage of change in tumor size in mm |
| Nintedanib Plus Docetaxel | Change From Baseline in Tumour Size | investigator assessment | -10.34 percentage of change in tumor size in mm |
| Placebo Plus Docetaxel | Change From Baseline in Tumour Size | central independent reviewer | 0.58 percentage of change in tumor size in mm |
| Placebo Plus Docetaxel | Change From Baseline in Tumour Size | investigator assessment | -2.14 percentage of change in tumor size in mm |
Comparison: Analysis based on the central independent reviewp-value: <0.0001ANOVA
Comparison: Analysis based on the investigator's assessmentp-value: <0.0001ANOVA
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 cut-off date 15 February 2013
Population: Randomised set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Docetaxel | Clinical Improvement | 5.9 months |
| Placebo Plus Docetaxel | Clinical Improvement | 5.2 months |
p-value: 0.728295% CI: [0.87, 1.21]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. As per RECIST v1.0 for target lesions : Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Disease Control | central independent reviewer | 54.0 % of participants |
| Nintedanib Plus Docetaxel | Disease Control | investigator assessment | 63.4 % of participants |
| Placebo Plus Docetaxel | Disease Control | central independent reviewer | 41.3 % of participants |
| Placebo Plus Docetaxel | Disease Control | investigator assessment | 51.4 % of participants |
Comparison: Analysis based on the central independent reviewp-value: <0.000195% CI: [1.35, 2.09]Regression, Logistic
Comparison: Analysis based on investigator's assessmentp-value: <0.000195% CI: [1.31, 2.05]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 Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | nintedanib | 0.0707 ng/mL/mg | Geometric Coefficient of Variation 77.7 |
| Nintedanib Plus Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | metabolite BIBF 1202 | 0.0907 ng/mL/mg | Geometric Coefficient of Variation 127 |
| Nintedanib Plus Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | metabolite BIBF 1202 glucuronide | 1.04 ng/mL/mg | Geometric Coefficient of Variation 153 |
| Placebo Plus Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | nintedanib | 0.106 ng/mL/mg | Geometric Coefficient of Variation 52.6 |
| Placebo Plus Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | metabolite BIBF 1202 | 0.190 ng/mL/mg | Geometric Coefficient of Variation 152 |
| Placebo Plus Docetaxel | Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide | metabolite BIBF 1202 glucuronide | 1.94 ng/mL/mg | Geometric Coefficient of Variation 135 |
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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. 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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Duration of Confirmed Objective Tumour Response | central independent reviewer | 4.3 months |
| Nintedanib Plus Docetaxel | Duration of Confirmed Objective Tumour Response | investigator assessment | 5.7 months |
| Placebo Plus Docetaxel | Duration of Confirmed Objective Tumour Response | central independent reviewer | 4.3 months |
| Placebo Plus Docetaxel | Duration of Confirmed Objective Tumour Response | investigator assessment | 5.5 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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Duration of Disease Control | central independent reviewer | 5.6 months |
| Nintedanib Plus Docetaxel | Duration of Disease Control | investigator assessment | 5.7 months |
| Placebo Plus Docetaxel | Duration of Disease Control | investigator assessment | 5.6 months |
| Placebo Plus Docetaxel | Duration of Disease Control | central independent reviewer | 5.6 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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Docetaxel | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review | 3.5 months |
| Placebo Plus Docetaxel | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review | 2.7 months |
p-value: 0.00795% CI: [0.75, 0.96]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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib Plus Docetaxel | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator | 4.2 months |
| Placebo Plus Docetaxel | Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator | 3.0 months |
p-value: 0.001295% CI: [0.73, 0.93]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 42 months
Population: Treated set- 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 Docetaxel | Incidence and Intensity of Adverse Events | Grade 2 | 16.6 % of participants |
| Nintedanib Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 4 | 33.7 % of participants |
| Nintedanib Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 3 | 21.2 % of participants |
| Nintedanib Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 5 | 16.4 % of participants |
| Nintedanib Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 1 | 5.7 % of participants |
| Placebo Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 5 | 11.8 % of participants |
| Placebo Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 1 | 8.2 % of participants |
| Placebo Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 2 | 20.5 % of participants |
| Placebo Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 3 | 21.2 % of participants |
| Placebo Plus Docetaxel | Incidence and Intensity of Adverse Events | Grade 4 | 31.3 % of participants |
Secondary
Objective Tumour 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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time frame: From randomisation until cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Objective Tumour Response | central independent reviewer | 4.4 % of participants |
| Nintedanib Plus Docetaxel | Objective Tumour Response | investigator assessment | 10.4 % of participants |
| Placebo Plus Docetaxel | Objective Tumour Response | investigator assessment | 7.6 % of participants |
| Placebo Plus Docetaxel | Objective Tumour Response | central independent reviewer | 3.3 % of participants |
Comparison: Analysis based on the central independent reviewp-value: 0.306795% CI: [0.76, 2.39]Regression, Logistic
Comparison: Analysis based on the investigator's assessmentp-value: 0.076195% CI: [0.96, 2.08]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. A fixed-sequence-testing was implemented for key secondary endpoint if both the primary and the follow-up analysis showed a treatment benefit (P\<0.05) of nintedanib over placebo. In this case, the OS would be tested using hierarchical testing of statistical hypotheses in (1) patients with adenocarcinoma and \<9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been.
Time frame: From randomisation until cut-off date 15 February 2013 (approximately 48 months or 1151 deaths among all patients )
Population: Randomised Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | Adenocarcinoma and <9 months | 10.9 months |
| Nintedanib Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | Adenocarcinoma | 12.6 months |
| Nintedanib Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | All patients | 10.1 months |
| Placebo Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | Adenocarcinoma and <9 months | 7.9 months |
| Placebo Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | Adenocarcinoma | 10.3 months |
| Placebo Plus Docetaxel | Overall Survival (Key Secondary Endpoint) | All patients | 9.1 months |
Comparison: Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and \<9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected.~Overall survival for patients with adenocarcinoma and \<9 months since start of first line therapy.p-value: 0.007395% CI: [0.6, 0.92]Regression, Cox
Comparison: Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and \<9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected.~Overall survival for patients with adenocarcinoma.p-value: 0.035995% CI: [0.7, 0.99]Regression, Cox
Comparison: Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and \<9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected.~Overall survival for all patients.p-value: 0.27295% CI: [0.83, 1.05]Regression, Cox
Secondary
Quality of Life (QoL)
Quality of life (QoL) was measured by standardised questionnaires (Health Status Self-Assessment Questionnaire (EQ-5D), EORTC Quality of life questionnaire - Core 30 (EORTC QLQ-C30), Quality of life questionnaire - lung cancer module (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 (EORTC 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 cut-off date 15 February 2013
Population: Randomised set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of cough | 4.3 months |
| Nintedanib Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of dyspnoea | 2.0 months |
| Nintedanib Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of pain | 2.8 months |
| Placebo Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of cough | 3.5 months |
| Placebo Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of dyspnoea | 2.1 months |
| Placebo Plus Docetaxel | Quality of Life (QoL) | Time to deterioration of pain | 2.6 months |
Comparison: Analysis evaluating the time to deterioration of coughp-value: 0.185895% CI: [0.77, 1.05]Regression, Cox
Comparison: Analysis evaluating the time to deterioration of dyspnoeap-value: 0.520395% CI: [0.91, 1.2]Regression, Cox
Comparison: Analysis evaluating the time to deterioration of painp-value: 0.437395% CI: [0.82, 1.09]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 cut-off date 15 February 2013
Population: Randomised Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Time to Confirmed Objective Tumour Response | central independent reviewer | 1.5 months |
| Nintedanib Plus Docetaxel | Time to Confirmed Objective Tumour Response | investigator assessment | 2.6 months |
| Placebo Plus Docetaxel | Time to Confirmed Objective Tumour Response | central independent reviewer | 2.9 months |
| Placebo Plus Docetaxel | Time to Confirmed Objective Tumour Response | investigator assessment | 2.7 months |