Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The objective of this phase III trial is to establish statistical equivalence in terms of efficacy (best overall response rate \[ORR\], proportion of patients with complete response \[CR\] plus partial response \[PR\]) until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or Avastin®.
Interventions
DRUGBI 695502
DRUGAvastin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Adult patients aged \>=18 years with histologically or cytologically confirmed advanced nonsquamous non-small cell lung cancer (nsNSCLC). Mixed tumors should be categorized according to the predominant histology. Note: NSCLC should be predominantly nonsquamous. Recurrent or metastatic disease (Stage IV) with an indication for therapy with paclitaxel + carboplatin + Avastin®. Patients harboring tumors with unknown or without activating epidermal growth factor receptor (EGFR) / anaplastic lymphoma receptor tyrosine kinase (ALK) mutation maybe included provided chemotherapy is standard of care. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on independent central review. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Adequate hepatic, renal, and bone marrow function: Life expectancy \> 6 months based on clinical judgment. Further inclusion criteria apply.
Exclusion criteria
Prior therapy with monoclonal antibodies or small molecule inhibitors against Vascular Endothelial Growth Factor (VEGF) or VEGF receptors, including Avastin®. Prior systemic therapy for metastatic disease. Prior systemic anticancer therapy or radiotherapy for locally advanced nsNSCLC if completed \<12 months prior to Screening. Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of the skin or pre-invasive cancer of the cervix. Symptomatic brain metastasis. Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung, NSCLC not specified (NS) or NSCLC not otherwise specified(NOS). Any unresolved toxicity \> Common Toxicity Criteria Grade 1 (except alopecia) from previous anticancer therapy (including radiotherapy). History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding. Thrombotic or hemorrhagic event =\< 6 months prior to Screening. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment | Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier. | ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days. | The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: * Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), * Thromboembolic events (arterial or venous), * Febrile neutropenia, * Gastrointestinal perforations, * Hypertension, * Proteinuria, * Pulmonary hemorrhage, * Other hemorrhages (not including pulmonary hemorrhages), * Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs. |
| Progression-Free Survival (PFS) Time as Determined by Investigator Assessment | Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks). | PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique. |
| Overall Survival (OS) Time | From baseline until death due to any cause, ie., up to 35 cycles (105 weeks). | OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique. |
| Duration of Response (DOR) as Determined by Investigator Assessment | Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks). | DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique. |
Countries
Argentina, Brazil, Bulgaria, Chile, Croatia, Egypt, Germany, Greece, Hungary, Italy, Japan, Malaysia, Mexico, Philippines, Poland, Portugal, Romania, Russia, Serbia, South Africa, South Korea, Spain, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
Phase III, randomized, double-blind, multicenter, active comparator, parallel 2-arm trial in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). From 21December2017, Sponsor recommended, patients to be switched from BI 695502 to reference product Avastin® (commercially available) as soon as it was available at clinical site.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 695502 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m\^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL\*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | 335 |
| Avastin® US Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m\^2 BSA, followed by carboplatin target AUC 6 mg/mL\*min, with adequate pre- and concomitant medication.
After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | 328 |
| Total | 663 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-switch Period | Adverse Event | 4 | 4 |
| Post-switch Period | Death | 3 | 2 |
| Post-switch Period | Other than listed | 4 | 5 |
| Post-switch Period | Physician Decision | 1 | 1 |
| Post-switch Period | Progressive disease | 21 | 21 |
| Post-switch Period | Study terminated by sponsor | 8 | 11 |
| Post-switch Period | Withdrawal by Subject | 1 | 2 |
| Pre-switch Period | Adverse Event | 38 | 37 |
| Pre-switch Period | Death | 26 | 26 |
| Pre-switch Period | Lost to Follow-up | 0 | 2 |
| Pre-switch Period | Other than listed | 10 | 11 |
| Pre-switch Period | Physician Decision | 6 | 18 |
| Pre-switch Period | Progressive disease | 185 | 173 |
| Pre-switch Period | Protocol Violation | 1 | 0 |
| Pre-switch Period | Withdrawal by Subject | 27 | 15 |
| Randomized Through Treatment Start | Not treated | 3 | 5 |
Baseline characteristics
| Characteristic | Avastin® US | Total | BI 695502 |
|---|---|---|---|
| Age, Continuous | 61.3 Years STANDARD_DEVIATION 9.22 | 61.2 Years STANDARD_DEVIATION 9.55 | 61.2 Years STANDARD_DEVIATION 9.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 77 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 285 Participants | 569 Participants | 284 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 17 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 135 Participants | 64 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 20 Participants | 12 Participants |
| Race (NIH/OMB) White | 248 Participants | 506 Participants | 258 Participants |
| Sex: Female, Male Female | 125 Participants | 246 Participants | 121 Participants |
| Sex: Female, Male Male | 203 Participants | 417 Participants | 214 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 193 / 335 | 184 / 328 | 3 / 42 | 2 / 46 |
| other Total, other adverse events | 293 / 335 | 288 / 328 | 20 / 42 | 22 / 46 |
| serious Total, serious adverse events | 108 / 335 | 89 / 328 | 5 / 42 | 2 / 46 |
Outcome results
Primary
Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment
ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks.
Time frame: Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.
Population: The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Best ORR (CR+PR) is reported for observed values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695502 | Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment | 54.0 Percentage of patients (%) |
| Avastin® US | Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment | 63.1 Percentage of patients (%) |
Comparison: Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).90% CI: [0.7697, 0.9506]Log-binomial regression
Comparison: Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).95% CI: [0.7543, 0.97]Log-binomial regression
Secondary
Duration of Response (DOR) as Determined by Investigator Assessment
DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique.
Time frame: Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks).
Population: The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Only patients with an objective response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Duration of Response (DOR) as Determined by Investigator Assessment | 7.66 Months |
| Avastin® US | Duration of Response (DOR) as Determined by Investigator Assessment | 8.94 Months |
Comparison: Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).95% CI: [0.88, 1.48]Cox-proportional hazards regression
Secondary
Overall Survival (OS) Time
OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique.
Time frame: From baseline until death due to any cause, ie., up to 35 cycles (105 weeks).
Population: The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Overall Survival (OS) Time | 15.57 Months |
| Avastin® US | Overall Survival (OS) Time | 19.48 Months |
Comparison: Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).95% CI: [1, 1.51]Cox-proportional hazards regression
Secondary
Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®
The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: * Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), * Thromboembolic events (arterial or venous), * Febrile neutropenia, * Gastrointestinal perforations, * Hypertension, * Proteinuria, * Pulmonary hemorrhage, * Other hemorrhages (not including pulmonary hemorrhages), * Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs.
Time frame: From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days.
Population: The Treated Set contained all patients who signed informed consent and who received at least one dose of trial drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Thromboembolic events | 6.60 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Hypertension | 15.50 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Infusion reactions | 16.70 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Proteinuria | 15.80 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Febrile neutropenia | 3.90 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Pulmonary haemorrhage | 1.20 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Other hemorrhages | 20.00 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | AtLeast 1 AE selected for Comparability Assessment | 52.50 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Wound-healing complications/abscess/fistulas | 2.70 Percentage of patients (%) |
| BI 695502 | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Gastrointestinal perforations | 2.10 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Wound-healing complications/abscess/fistulas | 2.10 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | AtLeast 1 AE selected for Comparability Assessment | 45.10 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Infusion reactions | 13.10 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Thromboembolic events | 5.50 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Febrile neutropenia | 3.40 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Gastrointestinal perforations | 0.60 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Hypertension | 16.20 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Proteinuria | 14.60 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Other hemorrhages | 16.20 Percentage of patients (%) |
| Avastin® US | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® | Pulmonary haemorrhage | 0.90 Percentage of patients (%) |
Comparison: At least 1 AE selected for comparability assessment, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.99, 1.37]Score exact method
Comparison: Infusion reactions, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.88, 1.88]Score exact method
Comparison: Thromboembolic events, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.64, 2.32]Score exact method
Comparison: Febrile neutropenia, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.51, 2.76]Score exact method
Comparison: Gastrointestinal perforations, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.79, 32.82]Score exact method
Comparison: Hypertension, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.66, 1.39]Score exact method
Comparison: Proteinuria, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.74, 1.57]Score exact method
Comparison: Pulmonary haemorrhage, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.28, 10.79]Score exact method
Comparison: Other hemorrhages, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.88, 1.74]Score exact method
Comparison: Wound healing complications/ abscesses/ fistulas, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.95% CI: [0.47, 3.57]Score excat method
Secondary
Progression-Free Survival (PFS) Time as Determined by Investigator Assessment
PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks).
Population: The Full Analysis Set (FAS) contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Progression-Free Survival (PFS) Time as Determined by Investigator Assessment | 8.34 Months |
| Avastin® US | Progression-Free Survival (PFS) Time as Determined by Investigator Assessment | 9.00 Months |
Comparison: Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).95% CI: [1.02, 1.45]Cox-proportional hazards regression