Non-Small-Cell Lung Carcinoma
Conditions
Brief summary
The main purpose of this study is to determine whether nivolumab + chemotherapy is effective as compared to chemotherapy in the treatment of patients with EGFR mutation, NSCLC who failed first line (1L) or second-line (2L) EGFR TKI therapy.
Interventions
BIOLOGICALNivolumab
Specified dose on specified days
BIOLOGICALIpilimumab
Specified dose on specified days
DRUGPemetrexed
Specified dose on specified days
DRUGCisplatin
Specified dose on specified days
DRUGCarboplatin
Specified dose on specified days
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
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
* Confirmed stage IV or recurrent EGFR mutated NSCLC with disease progression on one or two prior lines of treatment with EGFR TKIs (allowed TKIs must be approved by the local health authority, including but not limited to erlotinib, gefitinib, afatinib, dacomitinib and osimertinib). In osimertinib treated subjects, T790 testing is not required. * No evidence of exon 20 T790M mutation obtained at progression on prior first- or second-generation EGFR TKI therapy. For participants who were treated with osimertinib, T790M testing is not required. * Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) * Available tumor sample for Programmed death-ligand 1 (PD-L1) immunohistochemical (IHC). * Participants are eligible if central nervous system (CNS) metastases are considered to be adequately controlled/treated before or during the screening period and participants are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. In addition, participants must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization). Participants with asymptomatic CNS metastasis are eligible. * Eastern Cooperative Group (ECOG) Performance Status 0-1 * Life expectancy is at least 3 months
Exclusion criteria
* Known EGFR mutation, T790M positive who failed 1L first- or second-generation TKI should receive osimertinib first as the standard of care (SOC). These participants are only eligible if they fail osimertinib as 2L. * who have progressed within 3 months of the first dose of 1L or 2L EGFR TKI. * Carcinomatous meningitis * Active, known or suspected autoimmune disease are excluded * ALK translocation * Known SCLC transformation * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR) | From randomization to the date of first documented tumor progression or death (approximately 58 months) | PFS is defined as the time between the date of randomization and the date of first documented tumor progression, as determined by BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Participants who died without reported progression will be considered to have progressed on the date of their death. Subsequent therapy was accounted for by censoring at the last evaluable tumor assessment on or prior to the date of subsequent therapy. Progression is the appearance of one or more new lesions. RECIST - response evaluation criteria in solid tumors is a standard system to measure tumor response to treatment. Based on Kaplan-Meier estimates |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to the date of death due to any cause (up to approximately 67 months) | Overall Survival (OS) is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a participant was known to be alive. Median based on Kaplan-Meier Estimates |
| Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR) | From randomization to the date of objectively documented progression, date of death, or the date of subsequent therapy (up to approximately 67 months) | ORR is number of randomized participants who have confirmed best overall response (BOR) of complete response (CR) or partial response (PR) using RECIST v1.1 criteria by BICR assessment. BOR is the best response designation, between randomization and objectively documented progression per RECIST v1.1 criteria by BICR or the date of subsequent anti-cancer therapy, whichever occurs first. PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to \<10 mm (whether target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. CR+PR, confidence interval based on the Clopper and Pearson method. |
| Duration of Response (DOR) by Blinded Independent Centralized Review (BICR) | From randomization to the date of first documented disease progression or death due to any cause (approximately 67 months) | DOR is the time between the date of first response (CR or PR) and the date of first documented disease progression as determined by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) or death due to any cause (death occurring after re-treatment or randomization to new combination treatment was not included), whichever occurred first. PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to \<10 mm (whether target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. Participants who neither progress nor die were censored on the date of their last assessment. Median computed using Kaplan-Meier method |
| 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 9 months after first treatment dose | The PFSR at 9 months is defined as the percent of treated participants remaining progression free and surviving at 9 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses. |
| 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 12 Months after first treatment dose | The PFSR at 12 months is defined as the percent of treated participants remaining progression free and surviving at 12 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses. |
Countries
Canada, China, France, Hong Kong, Japan, Singapore, South Korea, Spain, Taiwan, United States
Participant flow
Pre-assignment details
Arm B: Nivolumab plus Ipilimumab was exploratory and closed prior to primary completion.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy Nivolumab was administered IV every 3 weeks with platinum-doublet chemotherapy (investigator's choice of cisplatin or carboplatin) IV for a maximum of 4 cycles.
Treatment administered was either Nivolumab 360 mg IV, followed by pemetrexed (500 mg/m2) with cisplatin (75 mg/m2) administered on Day 1 of each cycle OR Nivolumab 360 mg IV, followed by pemetrexed (500 mg/m2) with carboplatin (AUC 5 or 6) administered on Day 1 of each cycle.
Following completion of the fourth cycle of nivolumab/chemotherapy, all participants who did not experience disease progression should have continued nivolumab 360 mg IV and pemetrexed (500 mg/m2) every 3 weeks until the progression of disease, discontinuation due to toxicity, withdrawal of consent, or study closure, whichever comes first. Nivolumab should only be administered for a maximum of 24 months (96 weeks) from the first study treatment. | 144 |
| Arm B: Nivolumab Plus Ipilimumab Nivolumab 3 mg/kg IV was administered every 2 weeks and ipilimumab 1 mg/kg IV was administered every 6 weeks until the progression of disease, discontinuation due to toxicity, withdrawal of consent, a maximum of 24 months (96 weeks) from the first study treatment, or study closure. | 73 |
| Arm C: Platinum Doublet Chemotherapy Platinum-doublet chemotherapy (investigator's choice of cisplatin or carboplatin) was administered IV in 3-week cycles for up to a maximum of 4 cycles.
Participants received either Pemetrexed (500 mg/m2) with cisplatin (75 mg/m2) administered on Day 1 of each cycle OR Pemetrexed (500 mg/m2) with carboplatin (AUC 5 or 6) administered on Day 1 of each cycle.
Platinum-doublet chemotherapy continued until disease progression, unacceptable toxicity, or completion of the 4 cycles, whichever came first.
Participants who had stable disease or response after 4 cycles of pemetrexed with cisplatin or carboplatin should have continued pemetrexed alone as maintenance therapy until disease progression, or unacceptable toxicity. | 150 |
| Total | 367 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Pre-Treatment | Adverse Event Unrelated to Study drug | 1 | 0 | 0 |
| Pre-Treatment | Other Reasons | 0 | 1 | 1 |
| Pre-Treatment | Participant no Longer Meets Study Criteria | 2 | 1 | 2 |
| Pre-Treatment | Withdrawal by Participant | 0 | 0 | 4 |
| Treatment | Administrative Reason by Sponsor | 1 | 0 | 0 |
| Treatment | Adverse Event Unrelated to Study Drug | 1 | 1 | 6 |
| Treatment | Death | 0 | 2 | 3 |
| Treatment | Disease Progression | 109 | 52 | 101 |
| Treatment | Maximum Clinical Benefit | 1 | 0 | 1 |
| Treatment | Other Reasons | 1 | 1 | 4 |
| Treatment | Participant no Longer Meets Study Criteria | 0 | 1 | 0 |
| Treatment | Participant Requested to Discontinue Study Treatment | 8 | 0 | 5 |
| Treatment | Study Drug Toxicity | 9 | 4 | 10 |
| Treatment | Withdrawal by Participant | 8 | 5 | 13 |
Baseline characteristics
| Characteristic | Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | Arm B: Nivolumab Plus Ipilimumab | Arm C: Platinum Doublet Chemotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 10.6 | 61.9 Years STANDARD_DEVIATION 10.6 | 60.7 Years STANDARD_DEVIATION 10.1 | 61.6 Years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 39 Participants | 73 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 85 Participants | 34 Participants | 77 Participants | 196 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 136 Participants | 68 Participants | 139 Participants | 343 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 7 Participants | 3 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Female | 83 Participants | 37 Participants | 94 Participants | 214 Participants |
| Sex: Female, Male Male | 61 Participants | 36 Participants | 56 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 92 / 144 | 55 / 73 | 105 / 150 |
| other Total, other adverse events | 136 / 141 | 62 / 71 | 140 / 143 |
| serious Total, serious adverse events | 77 / 141 | 46 / 71 | 55 / 143 |
Outcome results
Primary
Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR)
PFS is defined as the time between the date of randomization and the date of first documented tumor progression, as determined by BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Participants who died without reported progression will be considered to have progressed on the date of their death. Subsequent therapy was accounted for by censoring at the last evaluable tumor assessment on or prior to the date of subsequent therapy. Progression is the appearance of one or more new lesions. RECIST - response evaluation criteria in solid tumors is a standard system to measure tumor response to treatment. Based on Kaplan-Meier estimates
Time frame: From randomization to the date of first documented tumor progression or death (approximately 58 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR) | 5.59 Months |
| Arm B: Nivolumab Plus Ipilimumab | Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR) | 1.54 Months |
| Arm C: Platinum Doublet Chemotherapy | Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR) | 5.45 Months |
p-value: 0.052895% CI: [0.56, 1]Log Rank
95% CI: [1.43, 2.99]
Secondary
12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)
The PFSR at 12 months is defined as the percent of treated participants remaining progression free and surviving at 12 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses.
Time frame: 12 Months after first treatment dose
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 21.2 Percent of Participants |
| Arm B: Nivolumab Plus Ipilimumab | 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 12.2 Percent of Participants |
| Arm C: Platinum Doublet Chemotherapy | 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 15.9 Percent of Participants |
Secondary
9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)
The PFSR at 9 months is defined as the percent of treated participants remaining progression free and surviving at 9 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses.
Time frame: 9 months after first treatment dose
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 25.9 Percent of Participants |
| Arm B: Nivolumab Plus Ipilimumab | 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 12.2 Percent of Participants |
| Arm C: Platinum Doublet Chemotherapy | 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR) | 19.8 Percent of Participants |
Secondary
Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)
DOR is the time between the date of first response (CR or PR) and the date of first documented disease progression as determined by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) or death due to any cause (death occurring after re-treatment or randomization to new combination treatment was not included), whichever occurred first. PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to \<10 mm (whether target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. Participants who neither progress nor die were censored on the date of their last assessment. Median computed using Kaplan-Meier method
Time frame: From randomization to the date of first documented disease progression or death due to any cause (approximately 67 months)
Population: Randomized participants with CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | Duration of Response (DOR) by Blinded Independent Centralized Review (BICR) | 6.67 Months |
| Arm B: Nivolumab Plus Ipilimumab | Duration of Response (DOR) by Blinded Independent Centralized Review (BICR) | 50.04 Months |
| Arm C: Platinum Doublet Chemotherapy | Duration of Response (DOR) by Blinded Independent Centralized Review (BICR) | 5.55 Months |
Secondary
Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR)
ORR is number of randomized participants who have confirmed best overall response (BOR) of complete response (CR) or partial response (PR) using RECIST v1.1 criteria by BICR assessment. BOR is the best response designation, between randomization and objectively documented progression per RECIST v1.1 criteria by BICR or the date of subsequent anti-cancer therapy, whichever occurs first. PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to \<10 mm (whether target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. CR+PR, confidence interval based on the Clopper and Pearson method.
Time frame: From randomization to the date of objectively documented progression, date of death, or the date of subsequent therapy (up to approximately 67 months)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR) | 30.6 Percent of Participants |
| Arm B: Nivolumab Plus Ipilimumab | Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR) | 13.7 Percent of Participants |
| Arm C: Platinum Doublet Chemotherapy | Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR) | 26.7 Percent of Participants |
95% CI: [0.75, 2.16]
Secondary
Overall Survival (OS)
Overall Survival (OS) is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a participant was known to be alive. Median based on Kaplan-Meier Estimates
Time frame: From randomization to the date of death due to any cause (up to approximately 67 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivolumab Plus Platinum-doublet Chemotherapy | Overall Survival (OS) | 19.35 Months |
| Arm B: Nivolumab Plus Ipilimumab | Overall Survival (OS) | 17.12 Months |
| Arm C: Platinum Doublet Chemotherapy | Overall Survival (OS) | 15.90 Months |
p-value: 0.21895% CI: [0.62, 1.12]Log Rank
95% CI: [0.75, 1.52]