Malignant Melanoma
Conditions
Brief summary
This open-label, single-arm, multicenter study will evaluate the efficacy and safety in participants with metastatic melanoma who developed brain metastases. Participants may or may not have received prior systemic treatment for metastatic melanoma \[except treatment with v-raf murine sarcoma viral oncogene homolog B (BRAF) or mitogen-activated protein kinase (MEK) inhibitors\]. Participants will receive oral doses of 960 mg vemurafenib twice daily until disease progression, unacceptable toxicity or consent withdrawal.
Interventions
DRUGVemurafenib
960 mg oral doses twice daily until disease progression, unacceptable toxicity or consent withdrawal.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult participants, \>/= 18 years of age * Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) with BRAF V600 mutation (cobas 4800 BRAF V600 Mutation Test) * Measurable brain metastases, defined as lesions that were accurately measured in at least one dimension (longest diameter to be recorded) as ≥0.5 cm in the brain MRI with contrast, treated or untreated * Participants may or may not have received prior systemic therapy for metastatic melanoma and either a) have received no prior treatment for brain metastases or b) have received prior treatment for brain metastases and have progressed * Participants may or may not have symptoms related to their brain metastases * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Participants must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma
Exclusion criteria
* Increasing corticosteroid dose during the 7 days prior to first dose of study drug * Leptomeningeal involvement in participants with no prior treatment for brain metastases * Previous malignancy requiring active treatment within the past 2 years, except for treated and controlled basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix * Concurrent administration of any anticancer therapies other than those administered in the study * Treatment with any cytotoxic, investigational drug or targeted therapy 4 weeks prior to first dose of study drug. Radiation therapy ≤1 week prior to first administration of vemurafenib; and stereotactic radiotherapy ≤1 day prior to prior to first administration of vemurafenib * Prior treatment with BRAF or MEK inhibitors * Clinically significant cardiovascular disease or event within the 6 months prior to first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST]) | Baseline up to the disease progression or death from any cause (approximately 4 years) | BORR assessed by IRC is defined as percentage of participants who were responders \[with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)\]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be \>=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is \>=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Baseline up to the disease progression or death from any cause (approximately 4 years) | BORR within brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Best Overall Response Rate Outside the Brain (Assessed by IRC) | Baseline up to the disease progression or death from any cause (approximately 4 years) | BORR outside of brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Duration of Response (DOR) (Assessed by Investigator and IRC) | Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years) | Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For participants who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date. |
| Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator) | Baseline up to the disease progression or death from any cause (approximately 4 years) | Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first. |
| Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator ) | Baseline up to the disease progression or death from any cause (approximately 4 years) | Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first. |
| Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Baseline up to the disease progression or death from any cause (approximately 4 years) | Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Overall Survival | Baseline up to the disease progression or death from any cause (approximately 4 years) | Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date. |
| Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Baseline up to the disease progression or death from any cause (approximately 4 years) | Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator) | Baseline up to the disease progression or death from any cause (approximately 4 years) | Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response \[CR\] or partial response \[PR\]) were reported. |
| Percentage of Participants With Adverse Events (AE) | From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 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. |
| Time to Development of New Brain Metastases in Responders | Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years) | Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Participants who were known to be free of new lesions were censored on the date of last tumor assessment. |
Countries
Australia, Canada, France, Germany, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Previously Untreated Participants Participants who had not received previous treatment for brain metastases \[i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases\] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor. | 90 |
| Cohort 2: Previously Treated Participants Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor. | 56 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 77 | 46 |
| Overall Study | Investigator Request | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 1 |
| Overall Study | Withdrew Consent | 4 | 3 |
Baseline characteristics
| Characteristic | Cohort 1: Previously Untreated Participants | Cohort 2: Previously Treated Participants | Total |
|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 12.73 | 52.7 years STANDARD_DEVIATION 13.85 | 54.5 years STANDARD_DEVIATION 13.2 |
| Sex: Female, Male Female | 34 Participants | 22 Participants | 56 Participants |
| Sex: Female, Male Male | 56 Participants | 34 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 77 / 90 | 46 / 56 |
| other Total, other adverse events | 85 / 90 | 53 / 56 |
| serious Total, serious adverse events | 37 / 90 | 27 / 56 |
Outcome results
Primary
Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST])
BORR assessed by IRC is defined as percentage of participants who were responders \[with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)\]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be \>=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is \>=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The intent to treat (ITT) population included all participants who were enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST]) | 17.8 percentage of participants |
Secondary
Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1
BORR within brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | 17.9 percentage of participants |
Secondary
Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1
Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Partial Response | 15.6 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Progressive Disease | 32.2 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Stable Disease | 43.3 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Unevaluable | 6.7 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Complete Response | 2.2 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Unevaluable | 7.1 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Complete Response | 0.0 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Partial Response | 17.9 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Stable Disease | 41.1 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 | Progressive Disease | 33.9 percentage of participants |
Secondary
Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator)
Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study. Here, 'n' indicates the number participants who were evaluable for within brain assessment and who had measurable disease outside brain at baseline for outside brain assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Complete Response (Within Brain) (n=90, 56) | 2.2 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Partial Response (Within Brain) (n=90, 56) | 26.7 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Stable Disease (Within Brain) (n=90, 56) | 40.0 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Progressive Disease (Within Brain) (n=90, 56) | 27.8 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Unevaluable (Within Brain) (n=90, 56) | 3.3 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Complete Response (Outside Brain) (n=79, 40) | 0.0 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Partial Response (Outside Brain) (n=79, 40) | 31.6 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Stable Disease (Outside Brain) (n=79, 40) | 49.4 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Progressive Disease (Outside Brain) (n=79, 40) | 11.4 percentage of participants |
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Unevaluable (Outside Brain) (n=79, 40) | 7.6 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Stable Disease (Outside Brain) (n=79, 40) | 52.5 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Complete Response (Within Brain) (n=90, 56) | 0.0 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Complete Response (Outside Brain) (n=79, 40) | 5.0 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Partial Response (Within Brain) (n=90, 56) | 23.2 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Unevaluable (Outside Brain) (n=79, 40) | 5.0 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Stable Disease (Within Brain) (n=90, 56) | 53.6 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Partial Response (Outside Brain) (n=79, 40) | 22.5 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Progressive Disease (Within Brain) (n=90, 56) | 19.6 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Progressive Disease (Outside Brain) (n=79, 40) | 15.0 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) | Unevaluable (Within Brain) (n=90, 56) | 3.6 percentage of participants |
Secondary
Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator)
Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response \[CR\] or partial response \[PR\]) were reported.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator) | 18.9 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator) | 17.9 percentage of participants |
Secondary
Best Overall Response Rate Outside the Brain (Assessed by IRC)
BORR outside of brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study. Here, number participants analyzed is the total number of participants who had measurable disease outside brain at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Best Overall Response Rate Outside the Brain (Assessed by IRC) | 32.9 percentage of participants |
| Cohort 2: Previously Treated Participants | Best Overall Response Rate Outside the Brain (Assessed by IRC) | 22.5 percentage of participants |
Secondary
Duration of Response (DOR) (Assessed by Investigator and IRC)
Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For participants who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date.
Time frame: Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years)
Population: The ITT population included all participants who were enrolled in the study. Here, 'n' indicates number of participants who were responders within brain or outside brain assessed by investigator or IRC.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Previously Untreated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | Investigator: DOR (Within Brain) (n=26, 13) | 4.67 months |
| Cohort 1: Previously Untreated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | Investigator: DOR (Outside Brain) (n=25, 11) | 5.55 months |
| Cohort 1: Previously Untreated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | IRC: DOR (Within Brain) (n=16, 10) | 4.60 months |
| Cohort 1: Previously Untreated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | IRC: DOR (Outside Brain) (n=26, 9) | 7.72 months |
| Cohort 2: Previously Treated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | IRC: DOR (Outside Brain) (n=26, 9) | 11.07 months |
| Cohort 2: Previously Treated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | Investigator: DOR (Within Brain) (n=26, 13) | 6.64 months |
| Cohort 2: Previously Treated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | IRC: DOR (Within Brain) (n=16, 10) | 6.64 months |
| Cohort 2: Previously Treated Participants | Duration of Response (DOR) (Assessed by Investigator and IRC) | Investigator: DOR (Outside Brain) (n=25, 11) | 10.74 months |
Secondary
Overall Survival
Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Overall Survival | 8.87 months |
| Cohort 2: Previously Treated Participants | Overall Survival | 9.63 months |
Secondary
Percentage of Participants With Adverse Events (AE)
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.
Time frame: From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 years)
Population: The safety population included all participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Percentage of Participants With Adverse Events (AE) | 97.8 percentage of participants |
| Cohort 2: Previously Treated Participants | Percentage of Participants With Adverse Events (AE) | 94.6 percentage of participants |
Secondary
Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator)
Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator) | 3.65 months |
| Cohort 2: Previously Treated Participants | Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator) | 3.71 months |
Secondary
Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator )
Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
Time frame: Baseline up to the disease progression or death from any cause (approximately 4 years)
Population: The ITT population included all participants who were enrolled in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator ) | 3.68 months |
| Cohort 2: Previously Treated Participants | Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator ) | 4.04 months |
Secondary
Time to Development of New Brain Metastases in Responders
Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Participants who were known to be free of new lesions were censored on the date of last tumor assessment.
Time frame: Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years)
Population: The ITT population included all participants who were enrolled in the study. Here, number of participants analyzed is the participants who were responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Previously Untreated Participants | Time to Development of New Brain Metastases in Responders | 14.92 months |
| Cohort 2: Previously Treated Participants | Time to Development of New Brain Metastases in Responders | 14.52 months |