Non-Small Cell Lung Cancer
Conditions
Brief summary
The purpose of study is to compare the efficacy and safety of ONO-4538 in combination with carboplatin, paclitaxel, and bevacizumab (ONO-4538 group) to placebo in combination with carboplatin, paclitaxel, and bevacizumab (placebo group) in chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation in a multicenter, randomized, double-blind study.
Interventions
DRUGONO-4538
360 mg solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
DRUGCarboplatin
Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
DRUGPaclitaxel
Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
DRUGBevacizumab
Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
DRUGPlacebo
Placebo solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
Sponsors
Bristol-Myers Squibb
Ono Pharmaceutical Co. Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with histologically- or cytologically-confirmed non-squamous non-small cell lung cancer * Subjects who received a diagnosis of stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation according to the UICC-TNM Classification (7th edition) with no prior systemic anticancer therapy * Subjects with at least one measurable lesion by radiographic tumor assessments per RECIST 1.1 criteria * Subjects who are able to provide tumor tissue specimens. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1
Exclusion criteria
* Subjects with known EGFR mutations, including deletions in exon 19 and exon 21 (L858R) substitution mutations. * Subjects with known ALK translocations. * Complication or history of severe hypersensitivity reactions to antibody products or platinum-containing compounds * Subjects with autoimmune disease or known chronic or recurrent autoimmune disease. * Subjects with multiple cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by the Independent Radiology Review Committee (IRRC) | Approximately 32 months | PFS (as assessed by the IRRC) will be calculated using the following formula : PFS (days) = date when overall response is assessed as progressive disease (PD) or date of death (for any reason), whichever comes first - date of randomization + 1. Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approximately 32 months | — |
| Objective Response Rate (ORR [as Assessed by the IRRC]) | Approximately 32 months | ORR represents the proportion of subjects whose best overall response was assessed as complete response (CR) or partial response (PR). Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria. |
| Disease Control Rate (DCR [as Assessed by the IRRC]) | Approximately 32 months | DCR represents the proportion of subjects whose best overall response was assessed as CR, PR, or stable disease (SD). Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria. |
| Duration of Response (DOR [as Assessed by the IRRC]) | Approximately 32 months | The lower and upper limits of 95% CI for the median are censored value in the both groups. |
| Best Overall Response (BOR [as Assessed by the IRRC]) | Approximately 32 months | — |
Countries
Japan, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ONO-4538 Group ONO-4538: 360 mg solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
Chemotherapy: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. | 275 |
| Placebo Group Placebo: Placebo solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.
Chemotherapy: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. | 275 |
| Total | 550 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawal | 7 | 6 |
| Overall Study | Continued the follow-up period | 109 | 129 |
| Overall Study | Died | 82 | 93 |
| Overall Study | Missing contact | 3 | 3 |
Baseline characteristics
| Characteristic | ONO-4538 Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 66 years | 66 years |
| Age, Customized 65-74 years | 117 Participants | 131 Participants | 248 Participants |
| Age, Customized <65 years | 131 Participants | 111 Participants | 242 Participants |
| Age, Customized >=75 years | 27 Participants | 33 Participants | 60 Participants |
| Country Japan | 188 Participants | 183 Participants | 371 Participants |
| Country Korea | 62 Participants | 63 Participants | 125 Participants |
| Country Taiwan | 25 Participants | 29 Participants | 54 Participants |
| ECOG Performance Score 0 | 129 Participants | 128 Participants | 257 Participants |
| ECOG Performance Score 1 | 146 Participants | 147 Participants | 293 Participants |
| Metastasis Bone | 56 Participants | 83 Participants | 139 Participants |
| Metastasis Brain | 36 Participants | 41 Participants | 77 Participants |
| Metastasis Liver | 19 Participants | 20 Participants | 39 Participants |
| PD-L1 expression levels 1%-49% | 82 Participants | 81 Participants | 163 Participants |
| PD-L1 expression levels <1% or indeterminate | 120 Participants | 120 Participants | 240 Participants |
| PD-L1 expression levels >=50 | 73 Participants | 74 Participants | 147 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 275 Participants | 275 Participants | 550 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 70 Participants | 69 Participants | 139 Participants |
| Sex: Female, Male Male | 205 Participants | 206 Participants | 411 Participants |
| Smoking status Current | 18 Participants | 21 Participants | 39 Participants |
| Smoking status Former | 196 Participants | 200 Participants | 396 Participants |
| Smoking status Never | 61 Participants | 54 Participants | 115 Participants |
| Staging (the UICC-TNM classification, 7th edition) Recurrent | 21 Participants | 23 Participants | 44 Participants |
| Staging (the UICC-TNM classification, 7th edition) Stage IIIB | 15 Participants | 14 Participants | 29 Participants |
| Staging (the UICC-TNM classification, 7th edition) Stage IV | 239 Participants | 238 Participants | 477 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 82 / 275 | 93 / 275 |
| other Total, other adverse events | 271 / 273 | 274 / 275 |
| serious Total, serious adverse events | 154 / 273 | 118 / 275 |
Outcome results
Primary
Progression Free Survival (PFS) as Assessed by the Independent Radiology Review Committee (IRRC)
PFS (as assessed by the IRRC) will be calculated using the following formula : PFS (days) = date when overall response is assessed as progressive disease (PD) or date of death (for any reason), whichever comes first - date of randomization + 1. Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria.
Time frame: Approximately 32 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ONO-4538 Group | Progression Free Survival (PFS) as Assessed by the Independent Radiology Review Committee (IRRC) | 12.1 months |
| Placebo Group | Progression Free Survival (PFS) as Assessed by the Independent Radiology Review Committee (IRRC) | 8.1 months |
p-value: <0.000196.37% CI: [0.43, 0.71]Stratified log-rank test
Secondary
Best Overall Response (BOR [as Assessed by the IRRC])
Time frame: Approximately 32 months
Population: For best overall response to be assessed as stable disease in this study, at least one stable disease or better rather than progressive disease on or after day 43 should be obtained.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-4538 Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Not evaluable | 30 Participants |
| ONO-4538 Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Complete response | 14 Participants |
| ONO-4538 Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Partial response | 155 Participants |
| ONO-4538 Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Stable disease | 71 Participants |
| ONO-4538 Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Progressive disease | 5 Participants |
| Placebo Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Progressive disease | 11 Participants |
| Placebo Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Stable disease | 108 Participants |
| Placebo Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Complete response | 8 Participants |
| Placebo Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Not evaluable | 17 Participants |
| Placebo Group | Best Overall Response (BOR [as Assessed by the IRRC]) | Partial response | 131 Participants |
Secondary
Disease Control Rate (DCR [as Assessed by the IRRC])
DCR represents the proportion of subjects whose best overall response was assessed as CR, PR, or stable disease (SD). Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria.
Time frame: Approximately 32 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ONO-4538 Group | Disease Control Rate (DCR [as Assessed by the IRRC]) | 87.3 percentage of participants |
| Placebo Group | Disease Control Rate (DCR [as Assessed by the IRRC]) | 89.8 percentage of participants |
95% CI: [0.46, 1.31]
Secondary
Duration of Response (DOR [as Assessed by the IRRC])
The lower and upper limits of 95% CI for the median are censored value in the both groups.
Time frame: Approximately 32 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ONO-4538 Group | Duration of Response (DOR [as Assessed by the IRRC]) | 11.0 months |
| Placebo Group | Duration of Response (DOR [as Assessed by the IRRC]) | 7.0 months |
Secondary
Objective Response Rate (ORR [as Assessed by the IRRC])
ORR represents the proportion of subjects whose best overall response was assessed as complete response (CR) or partial response (PR). Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria.
Time frame: Approximately 32 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ONO-4538 Group | Objective Response Rate (ORR [as Assessed by the IRRC]) | 61.5 percentage of participants |
| Placebo Group | Objective Response Rate (ORR [as Assessed by the IRRC]) | 50.5 percentage of participants |
95% CI: [1.11, 2.17]
Secondary
Overall Survival (OS)
Time frame: Approximately 32 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ONO-4538 Group | Overall Survival (OS) | 25.4 months |
| Placebo Group | Overall Survival (OS) | 24.7 months |
95% CI: [0.63, 1.14]