Mesothelioma
Conditions
Brief summary
The purpose of this study is to test the effectiveness and tolerability of the combination of Nivolumab and Ipilimumab compared to Pemetrexed and Cisplatin or Carboplatin in patients with unresectable pleural mesothelioma.
Interventions
DRUGCarboplatin
BIOLOGICALNivolumab
BIOLOGICALIpilimumab
DRUGPemetrexed
DRUGCisplatin
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
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Males and Females at least 18 years of age * Histologically confirmed pleural malignant mesothelioma not eligible for curative surgery * ECOG Performance status of 0 or 1 * Available tumor sample for testing * Acceptable blood work
Exclusion criteria
* Primitive peritoneal, pericardial and tunica vaginalis testis mesotheliomas * Prior chemotherapy for pleural mesothelioma * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 oranti-CTLA-4 antibody * History of other malignancy unless the subject has been disease-free for at least 3 years * Active, untreated central nervous system (CNS) metastasis Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to the date of death (Up to 40 Months) | Overall Survival was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months | Disease Control Rate is defined as the percentage of all randomized participants whose Best Overall Response was complete response (CR), partial response (PR), stable disease (SD) or Non-CR/Non-PD as assessed by Blinded Independent Central Review (BICR). Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement; SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Non-CR/Non-PD: Persistence of one or more non-target lesion(s). |
| Progression Free Survival (PFS) | From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months) | Progression Free Survival is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement. |
| Objective Response Rate (ORR) | From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months) | Objective Response Rate is defined as the percentage of randomized participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement. |
| Progression Free Survival (PFS) According to PD-L1 Expression Level | From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months) | PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by progression free survival (PFS) analysis. PFS is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement. |
| Objective Response Rate (ORR) According to PD-L1 Expression Level | From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months) | PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by objective response rate (ORR) analysis. ORR is defined as the percentage of participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement. |
| Overall Survival (OS) According to PD-L1 Expression Level | From randomization date to the date of death (Up to 76 Months) | PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by overall survival (OS) analysis. OS was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive. |
Countries
Australia, Belgium, Brazil, Chile, China, Colombia, France, Germany, Greece, Italy, Japan, Mexico, Netherlands, Poland, Romania, Russia, South Africa, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment A Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W | 303 |
| Treatment B Pemetrexed 500 mg/m\^2 + Cisplatin 75 mg/m\^2 or Carboplatin 5 AUC up to 6 cycles | 302 |
| Total | 605 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-treatment | Not reported | 0 | 1 |
| Pre-treatment | Participant no longer meets study criteria | 2 | 3 |
| Pre-treatment | Participant request to discontinue study treatment | 0 | 3 |
| Pre-treatment | Participant withdrew consent | 1 | 11 |
| Treatment | Administrative reason by Sponsor | 2 | 0 |
| Treatment | Adverse Event unrelated to Study Drug | 11 | 9 |
| Treatment | Disease Progression | 182 | 43 |
| Treatment | Lost to Follow-up | 0 | 2 |
| Treatment | Maximum Clinical Benefit | 11 | 2 |
| Treatment | Not reported | 7 | 0 |
| Treatment | Other reasons | 12 | 2 |
| Treatment | Participant no longer meets Study criteria | 4 | 0 |
| Treatment | Participant request to discontinue Study treatment | 4 | 10 |
| Treatment | Participant withdrew consent | 6 | 3 |
| Treatment | Poor/Non-compliance | 1 | 0 |
| Treatment | Study Drug Toxicity | 60 | 24 |
Baseline characteristics
| Characteristic | Treatment B | Total | Treatment A |
|---|---|---|---|
| Age, Continuous | 67.8 Years STANDARD_DEVIATION 9.7 | 68.2 Years STANDARD_DEVIATION 9.1 | 68.7 Years STANDARD_DEVIATION 8.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 38 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 136 Participants | 258 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 147 Participants | 309 Participants | 162 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 39 Participants | 65 Participants | 26 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 | 9 Participants | 18 Participants | 9 Participants |
| Race (NIH/OMB) White | 250 Participants | 516 Participants | 266 Participants |
| Sex: Female, Male Female | 69 Participants | 138 Participants | 69 Participants |
| Sex: Female, Male Male | 233 Participants | 467 Participants | 234 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 251 / 303 | 259 / 302 |
| other Total, other adverse events | 277 / 300 | 264 / 284 |
| serious Total, serious adverse events | 188 / 300 | 106 / 284 |
Outcome results
Primary
Overall Survival (OS)
Overall Survival was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
Time frame: From randomization to the date of death (Up to 40 Months)
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Overall Survival (OS) | 18.07 Months |
| Treatment B | Overall Survival (OS) | 14.09 Months |
p-value: 0.00296.6% CI: [0.6, 0.91]Stratified Log Rank
Secondary
Disease Control Rate (DCR)
Disease Control Rate is defined as the percentage of all randomized participants whose Best Overall Response was complete response (CR), partial response (PR), stable disease (SD) or Non-CR/Non-PD as assessed by Blinded Independent Central Review (BICR). Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement; SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Non-CR/Non-PD: Persistence of one or more non-target lesion(s).
Time frame: From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months
Population: All Randomized Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment A | Disease Control Rate (DCR) | 76.6 Percentage of Participants |
| Treatment B | Disease Control Rate (DCR) | 85.8 Percentage of Participants |
Secondary
Objective Response Rate (ORR)
Objective Response Rate is defined as the percentage of randomized participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
Time frame: From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months)
Population: All Randomized Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment A | Objective Response Rate (ORR) | 39.3 Percentage of Participants |
| Treatment B | Objective Response Rate (ORR) | 44.4 Percentage of Participants |
Secondary
Objective Response Rate (ORR) According to PD-L1 Expression Level
PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by objective response rate (ORR) analysis. ORR is defined as the percentage of participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
Time frame: From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months)
Population: All PD-L1 evaluable participants with baseline expression \<1% or ≥1%
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A | Objective Response Rate (ORR) According to PD-L1 Expression Level | <1% PD-L1 | 21.1 Percentage of Participants |
| Treatment A | Objective Response Rate (ORR) According to PD-L1 Expression Level | ≥1% PD-L1 | 43.1 Percentage of Participants |
| Treatment B | Objective Response Rate (ORR) According to PD-L1 Expression Level | <1% PD-L1 | 41.0 Percentage of Participants |
| Treatment B | Objective Response Rate (ORR) According to PD-L1 Expression Level | ≥1% PD-L1 | 45.7 Percentage of Participants |
Secondary
Overall Survival (OS) According to PD-L1 Expression Level
PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by overall survival (OS) analysis. OS was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
Time frame: From randomization date to the date of death (Up to 76 Months)
Population: All PD-L1 evaluable participants with baseline expression \<1% or ≥1%
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Overall Survival (OS) According to PD-L1 Expression Level | <1% PD-L1 | 17.3 Months |
| Treatment A | Overall Survival (OS) According to PD-L1 Expression Level | ≥1% PD-L1 | 18.0 Months |
| Treatment B | Overall Survival (OS) According to PD-L1 Expression Level | <1% PD-L1 | 16.6 Months |
| Treatment B | Overall Survival (OS) According to PD-L1 Expression Level | ≥1% PD-L1 | 13.3 Months |
Comparison: \<1% PD-L195% CI: [0.64, 1.32]
Comparison: ≥1% PD-L195% CI: [0.59, 0.88]
Secondary
Progression Free Survival (PFS)
Progression Free Survival is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
Time frame: From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months)
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Progression Free Survival (PFS) | 6.77 Months |
| Treatment B | Progression Free Survival (PFS) | 7.23 Months |
95% CI: [0.77, 1.13]
Secondary
Progression Free Survival (PFS) According to PD-L1 Expression Level
PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by progression free survival (PFS) analysis. PFS is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
Time frame: From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months)
Population: All PD-L1 evaluable participants with baseline expression \<1% or ≥1%
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Progression Free Survival (PFS) According to PD-L1 Expression Level | <1% PD-L1 | 4.1 Months |
| Treatment A | Progression Free Survival (PFS) According to PD-L1 Expression Level | ≥1% PD-L1 | 7.0 Months |
| Treatment B | Progression Free Survival (PFS) According to PD-L1 Expression Level | <1% PD-L1 | 8.3 Months |
| Treatment B | Progression Free Survival (PFS) According to PD-L1 Expression Level | ≥1% PD-L1 | 7.1 Months |
Comparison: \< 1% PD-L195% CI: [1.22, 2.63]
Comparison: ≥1% PD-L195% CI: [0.61, 0.96]
Post Hoc
Extended Collection: Overall Survival (OS)
Overall Survival was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
Time frame: From randomization date to the date of death (Up to 76 Months)
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Extended Collection: Overall Survival (OS) | 18.07 Months |
| Treatment B | Extended Collection: Overall Survival (OS) | 14.09 Months |
p-value: 0.000895% CI: [0.62, 0.88]Stratified Log Rank