Non-Squamous Non-Small Cell Lung Cancer
Conditions
Brief summary
This open-label, randomized, multicenter study will evaluate the efficacy and safety of bevacizumab (Avastin) in combination with standard of care (SOC) treatment in participants with advanced non-squamous NSCLC. Participants will be enrolled at documentation of progression of disease (PD) after 4-6 cycles of first-line treatment with bevacizumab plus a platinum doublet-containing therapy and a minimum of two cycles of bevacizumab maintenance treatment prior to PD. Participants will be randomly assigned to one of two treatment arms to receive either bevacizumab plus SOC treatment or SOC treatment alone.
Interventions
DRUGBevacizumab
Participants will receive bevacizumab 7.5 or 15 milligrams per kilogram (mg/kg) intravenously.
DRUGDocetaxel
Docetaxel 60 or 75 milligram per meter square (mg/m\^2) on Day 1 every 21 days.
DRUGErlotinib
Erlotinib 150 mg daily taken on an empty stomach at least one hour before or two hours after the ingestion of food.
DRUGPemetrexed
Pemetrexed 500 mg/m\^2 IV over 10 minutes on Day 1 every 21 days.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed non-squamous NSCLC * Documented progression of disease (locally recurrent or metastatic) per investigator assessment following first-line treatment with 4-6 cycles of Bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of 2 cycles of Bevacizumab (monotherapy) maintenance treatment prior to first progression of disease * No treatment interruption of Bevacizumab treatment greater than 2 consecutive cycles (42 days) between the start of first-line treatment to start of Cycle 1 of second line treatment * Randomization within 4 weeks of progression of disease * At least one unidimensionally measurable lesion meeting RECIST v1.1 criteria * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Participants with adequate hematological, liver, and renal function * Female participants must not be pregnant or breast-feeding. Female participants of childbearing potential and fertile male participants must agree to use a highly effective contraceptive during the trial and for a period of at least 6 months following the last administration of trial drug(s)
Exclusion criteria
* Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component * Epidermal growth factor receptor (EGFR)-mutation-positive disease according to local laboratory testing * History of hemoptysis greater than or equal to (\>/=) grade 2 within 3 months of randomization * History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding and active gastrointestinal bleeding * Major cardiac disease * Treatment with any other investigational agent within 28 days prior to randomization * Known hypersensitivity to bevacizumab or any of its excipients, or any SOC drugs foreseen * Malignancy other than NSCLC within 5 years prior to randomization and evidence of any other disease that contraindicates the use of an investigational or SOC drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to data cut-off date 24 June 2016 (approximately 5 years) | Overall survival (OS) was defined as the time from the date of randomization at first progression of disease to the date of death, regardless of the cause of death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response According to RECIST v1.1 | Up to data cut-off date 24 June 2016 (approximately 5 years) | The objective response is defined as complete response (CR) or partial response (PR) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. |
| Percentage of Participants With Disease Control According to RECIST v1.1 | Up to data cut-off date 24 June 2016 (approximately 5 years) | The disease control rate is defined as CR or PR or stable disease (SD) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started for target lesions and the persistence of 1 or more non-target lesions. |
| Duration of Response (DoR) According to RECIST v1.1 | Up to data cut-off date 24 June 2016 (approximately 5 years) | Duration of response is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than \< 10 mm. PR was defined as greater than or equal to ≥30 % decrease in sum of longest diameter of target lesions in reference to baseline sum longest diameter. |
| Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Up to data cut-off date 24 June 2016 (approximately 5 years) | PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS2 is defined as the time between randomization at PD1 and the date of PD2 or death, whichever occurs first. PFS3 is defined as the time between PD2 and the date of PD3 or death, whichever occurs first. |
| Time to Progression (TTP) According to RECIST v1.1 | Up to data cut-off date 24 June 2016 (approximately 5 years) | The time to progression was defined as the time from baseline until disease progression as determined by the RECIST v1.1. TTP2 is defined as the interval between the day of randomization at PD1 and PD2. TTP3 is defined as the interval between the day of PD2 and PD3. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 6, 12, 18 | Percentage of participants who were alive at Month 6, 12 and 18 were reported. |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to data cut-off date 24 June 2016 (approximately 5 years) | An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. |
Countries
Argentina, Austria, Belgium, Brazil, Denmark, France, Germany, Greece, Italy, Japan, Lebanon, Mexico, Netherlands, Oman, Slovakia, Spain, United Arab Emirates, United States
Participant flow
Recruitment details
This phase 3b study was conducted across 16 different countries and enrolled 485 participants. Participants were 18 years or older and had locally recurrent or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC)
Pre-assignment details
A total of 485 participants were enrolled and randomized into the study. Of these, 475 participants were treated; 243 participants received bevacizumab plus standard of care (SoC) and 232 participants received SoC alone. The study was terminated 60 months after study start, as per protocol, but was not ended prematurely.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Standard of Care Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first). | 245 |
| Standard of Care Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first). | 240 |
| Total | 485 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 190 | 187 |
| Overall Study | Lost to Follow-up | 5 | 7 |
| Overall Study | Never Started | 5 | 5 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Reason unknown | 0 | 2 |
| Overall Study | Trial termination by the Sponsor | 28 | 19 |
| Overall Study | Withdrawal by Subject | 15 | 17 |
Baseline characteristics
| Characteristic | Bevacizumab + Standard of Care | Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 9.61 | 61.8 Years STANDARD_DEVIATION 9.29 | 61.6 Years STANDARD_DEVIATION 9.44 |
| Sex: Female, Male Female | 90 Participants | 102 Participants | 192 Participants |
| Sex: Female, Male Male | 155 Participants | 138 Participants | 293 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 226 / 243 | 215 / 232 |
| serious Total, serious adverse events | 126 / 243 | 86 / 232 |
Outcome results
Primary
Overall Survival (OS)
Overall survival (OS) was defined as the time from the date of randomization at first progression of disease to the date of death, regardless of the cause of death.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Standard of Care | Overall Survival (OS) | 11.86 Months |
| Standard of Care | Overall Survival (OS) | 10.22 Months |
Comparison: The stratification factors for Log-Rank test and Hazard Ratio (HR) are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to first PD and smoking status.p-value: 0.104490% CI: [0.71, 1]Stratified Log-Rank test
Secondary
Duration of Response (DoR) According to RECIST v1.1
Duration of response is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than \< 10 mm. PR was defined as greater than or equal to ≥30 % decrease in sum of longest diameter of target lesions in reference to baseline sum longest diameter.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Standard of Care | Duration of Response (DoR) According to RECIST v1.1 | 7.46 Months |
| Standard of Care | Duration of Response (DoR) According to RECIST v1.1 | 6.24 Months |
Comparison: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.0690% CI: [0.09, 0.9]Stratified Log-Rank test
Secondary
Percentage of Participants Who Are Alive at Month 6, 12, and 18
Percentage of participants who were alive at Month 6, 12 and 18 were reported.
Time frame: Month 6, 12, 18
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab + Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 6 | 0.8 Percentage of Participants |
| Bevacizumab + Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 12 | 0.5 Percentage of Participants |
| Bevacizumab + Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 18 | 0.4 Percentage of Participants |
| Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 6 | 0.7 Percentage of Participants |
| Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 12 | 0.4 Percentage of Participants |
| Standard of Care | Percentage of Participants Who Are Alive at Month 6, 12, and 18 | Month 18 | 0.3 Percentage of Participants |
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: The safety population included all participants who had received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab + Standard of Care | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 97.5 Percentage of Participants |
| Bevacizumab + Standard of Care | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 51.9 Percentage of Participants |
| Standard of Care | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 96.1 Percentage of Participants |
| Standard of Care | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 37.1 Percentage of Participants |
Secondary
Percentage of Participants With Disease Control According to RECIST v1.1
The disease control rate is defined as CR or PR or stable disease (SD) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started for target lesions and the persistence of 1 or more non-target lesions.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Standard of Care | Percentage of Participants With Disease Control According to RECIST v1.1 | 80.2 Percentage of Participants |
| Standard of Care | Percentage of Participants With Disease Control According to RECIST v1.1 | 77.0 Percentage of Participants |
Comparison: The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.021890% CI: [-0.0288, 0.094]Stratified Cochran-Mantel-Haenszel test
Secondary
Percentage of Participants With Objective Response According to RECIST v1.1
The objective response is defined as complete response (CR) or partial response (PR) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Standard of Care | Percentage of Participants With Objective Response According to RECIST v1.1 | 8.6 Percentage of Participants |
| Standard of Care | Percentage of Participants With Objective Response According to RECIST v1.1 | 6.3 Percentage of Participants |
Comparison: The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.08190% CI: [-0.0156, 0.063]Stratified Cochran-Mantel-Haenszel test
Secondary
Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS2 is defined as the time between randomization at PD1 and the date of PD2 or death, whichever occurs first. PFS3 is defined as the time between PD2 and the date of PD3 or death, whichever occurs first.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bevacizumab + Standard of Care | Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | PFS 2 | 5.45 Months |
| Bevacizumab + Standard of Care | Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | PFS 3 | 4.01 Months |
| Standard of Care | Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | PFS 2 | 3.98 Months |
| Standard of Care | Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | PFS 3 | 2.60 Months |
Comparison: PFS 2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.057390% CI: [0.7, 0.98]Stratified Log-Rank test
Comparison: PFS 3: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.004590% CI: [0.49, 0.83]Stratified Log-Rank test
Secondary
Time to Progression (TTP) According to RECIST v1.1
The time to progression was defined as the time from baseline until disease progression as determined by the RECIST v1.1. TTP2 is defined as the interval between the day of randomization at PD1 and PD2. TTP3 is defined as the interval between the day of PD2 and PD3. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bevacizumab + Standard of Care | Time to Progression (TTP) According to RECIST v1.1 | TTP2 | 5.55 Months |
| Bevacizumab + Standard of Care | Time to Progression (TTP) According to RECIST v1.1 | TTP3 | 4.07 Months |
| Standard of Care | Time to Progression (TTP) According to RECIST v1.1 | TTP2 | 4.21 Months |
| Standard of Care | Time to Progression (TTP) According to RECIST v1.1 | TTP3 | 2.73 Months |
Comparison: TTP2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.031190% CI: [0.65, 0.95]Stratified Log-Rank test
Comparison: TTP3: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.p-value: 0.032690% CI: [0.52, 0.92]Stratified Log-Rank test