Melanoma
Conditions
Keywords
MEK inhibitor, Cancer, Metastatic Melanoma, BRAF mutant metastatic melanoma, GSK1120212
Brief summary
This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.
Interventions
DRUGGSK1120212
MEK inhibitor
DRUGChemotherapy
Investigator Choice of DTIC or paclitaxel
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory * Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. Prior treatment with immunotherapy (with the exception of prior ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy, biological or vaccine regimen is permitted. Prior use of sorafenib is allowed * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) * Women of childbearing potential and men with reproductive potential must agree to use effective contraception during the study. Additionally women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 * Adequate screening organ function
Exclusion criteria
* Any prior use of BRAF inhibitors or MEK inhibitors. * Subjects who have received dacarbazine or paclitaxel prior to randomization will not be eligible to receive the same chemotherapy as study medication (i.e. a subject who received prior dacarbazine cannot receive dacarbazine on this trial and would thus receive paclitaxel if randomized to the control arm) * History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above * Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed) * Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor: All known lesions must be previously treated with surgery or stereotactic radiosurgery, and Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to randomization (must be documented with two consecutive MRI or CT scans using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization * History or evidence of cardiovascular risk including any of the following: * QTcB ≥ 480 msec. * History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for \>30 days prior to randomization are eligible * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. * History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association * History of interstitial lung disease or pneumonitis * History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): * History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). * Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as: * Evidence of new optic disc cupping. * Intraocular pressure \> 21 mm Hg as measured by tonography
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. |
| PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. |
| Overall Survival in All Participants | Day 1 until death due to any cause (average of 20.3 months) | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. |
| Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases | Day 1 until death due to any cause (average of 20.3 months) | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available. |
| Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1. |
| Number of Participants With OR as Assessed by the Investigator and Independent Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1. |
| Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1. |
| Progression-free Survival in All Participants | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered. |
| Number of Participants With OR Following Cross-over to Trametinib | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population. |
| Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. |
| DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. |
| DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. |
| DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. |
| DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. |
| PFS Following Cross-over to Trametinib as Assessed by the Investigator | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. |
| Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Italy, New Zealand, Norway, Poland, Russia, Sweden, Switzerland, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This was a randomized open-label, multi-center Phase III study to evaluate the efficacy and safety of single agent trametinib compared with chemotherapy (CT) (dacarbazine or paclitaxel). Participants (par.) were enrolled by 86 sites in 19 countries from December 2010 to July 2011. Results as of 16 December 2016 data-cut have been presented.
Pre-assignment details
Participants (par.) were stratified for lactate dehydrogenase and prior CT for advanced or metastatic disease. 1059 par. were screened and 322 were enrolled to receive trametinib (214 par.) or CT (108 par.) until disease progression, death, or withdrawal. Par. randomized to CT were allowed to cross-over to trametinib if disease progressed.
Participants by arm
| Arm | Count |
|---|---|
| Trametinib Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal. | 214 |
| Chemotherapy Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal. | 108 |
| Total | 322 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cross-over Phase | Lost to Follow-up | 0 | 0 | 1 |
| Cross-over Phase | Physician Decision | 0 | 0 | 1 |
| Cross-over Phase | Study closed/ terminated | 0 | 0 | 11 |
| Cross-over Phase | Withdrew Consent | 0 | 0 | 4 |
| Randomization and Crossover Phase | Lost to Follow-up | 4 | 2 | 0 |
| Randomization and Crossover Phase | Physician Decision | 2 | 4 | 0 |
| Randomization and Crossover Phase | Study closed/ terminated | 23 | 14 | 0 |
| Randomization and Crossover Phase | Withdrew Consent | 12 | 11 | 0 |
Baseline characteristics
| Characteristic | Trametinib | Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 54.3 Years STANDARD_DEVIATION 12.97 | 52.8 Years STANDARD_DEVIATION 13.56 | 53.8 Years STANDARD_DEVIATION 13.17 |
| Race/Ethnicity, Customized Race/Ethnicity, Customized White - Arabic/North African Heritage | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized White - Mixed Race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 212 Participants | 107 Participants | 319 Participants |
| Sex: Female, Male Female | 94 Participants | 55 Participants | 149 Participants |
| Sex: Female, Male Male | 120 Participants | 53 Participants | 173 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 172 / 211 | 22 / 99 | 53 / 70 |
| other Total, other adverse events | 207 / 211 | 88 / 99 | 66 / 70 |
| serious Total, serious adverse events | 52 / 211 | 19 / 99 | 18 / 70 |
Outcome results
Primary
Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review
Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Trametinib | Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review | Investigator-Assessed | 4.8 Months |
| Trametinib | Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review | Independent Review | 4.9 Months |
| Chemotherapy | Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review | Investigator-Assessed | 1.4 Months |
| Chemotherapy | Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review | Independent Review | 1.6 Months |
p-value: <0.000195% CI: [0.31, 0.64]Log Rank
p-value: <0.000195% CI: [0.29, 0.6]Log Rank
Secondary
DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review
DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review | 5.6 Months |
| Chemotherapy | DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review | NA Months |
Secondary
DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review
DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review | 5.6 Months |
| Chemotherapy | DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review | NA Months |
Secondary
DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review
DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review | 5.5 Months |
| Chemotherapy | DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review | NA Months |
Secondary
DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator
DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.
Time frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
Population: Cross-over Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator | 2.7 Months |
Secondary
Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review
DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review | 5.5 Months |
| Chemotherapy | Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review | NA Months |
Secondary
Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator
OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib | Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600E Mutation, CR | 4 Participants |
| Trametinib | Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600E Mutation, PR | 40 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600E Mutation, CR | 0 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600E Mutation, PR | 7 Participants |
Secondary
Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review
OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Investigator-Assessed: CR | 4 Participants |
| Trametinib | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Investigator-Assessed: PR | 39 Participants |
| Trametinib | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Independent Review: CR | 0 Participants |
| Trametinib | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Independent Review: PR | 33 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Independent Review: PR | 3 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Investigator-Assessed: CR | 0 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Independent Review: CR | 0 Participants |
| Chemotherapy | Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review | Investigator-Assessed: PR | 7 Participants |
Secondary
Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator
OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib | Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600K Mutation, CR | 0 Participants |
| Trametinib | Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600K Mutation, PR | 3 Participants |
| Chemotherapy | Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600K Mutation, CR | 0 Participants |
| Chemotherapy | Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | V600K Mutation, PR | 2 Participants |
Secondary
Number of Participants With OR as Assessed by the Investigator and Independent Review
OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib | Number of Participants With OR as Assessed by the Investigator and Independent Review | Investigator-Assessed: CR | 8 Participants |
| Trametinib | Number of Participants With OR as Assessed by the Investigator and Independent Review | Investigator-Assessed: PR | 53 Participants |
| Trametinib | Number of Participants With OR as Assessed by the Investigator and Independent Review | Independent Review: CR | 0 Participants |
| Trametinib | Number of Participants With OR as Assessed by the Investigator and Independent Review | Independent Review: PR | 41 Participants |
| Chemotherapy | Number of Participants With OR as Assessed by the Investigator and Independent Review | Independent Review: PR | 4 Participants |
| Chemotherapy | Number of Participants With OR as Assessed by the Investigator and Independent Review | Investigator-Assessed: CR | 2 Participants |
| Chemotherapy | Number of Participants With OR as Assessed by the Investigator and Independent Review | Independent Review: CR | 1 Participants |
| Chemotherapy | Number of Participants With OR as Assessed by the Investigator and Independent Review | Investigator-Assessed: PR | 8 Participants |
Secondary
Number of Participants With OR Following Cross-over to Trametinib
OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population.
Time frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
Population: Cross-over Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib | Number of Participants With OR Following Cross-over to Trametinib | CR | 2 Participants |
| Trametinib | Number of Participants With OR Following Cross-over to Trametinib | PR | 29 Participants |
Secondary
Overall Survival in All Participants
Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
Time frame: Day 1 until death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | Overall Survival in All Participants | 15.6 Months |
| Chemotherapy | Overall Survival in All Participants | 11.3 Months |
Secondary
Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases
Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available.
Time frame: Day 1 until death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases | NA Months |
| Chemotherapy | Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases | NA Months |
Secondary
PFS Following Cross-over to Trametinib as Assessed by the Investigator
PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
Time frame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
Population: Cross-over Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | PFS Following Cross-over to Trametinib as Assessed by the Investigator | 3.0 Months |
Secondary
PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator
PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator | 4.8 Months |
| Chemotherapy | PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator | 1.4 Months |
Secondary
PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator
PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: Primary Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib | PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator | 4.8 Months |
| Chemotherapy | PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator | 2.7 Months |
Secondary
Progression-free Survival in All Participants
PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.
Time frame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Population: ITT Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Trametinib | Progression-free Survival in All Participants | Investigator-Assessed | 4.9 Months |
| Trametinib | Progression-free Survival in All Participants | Independent radiologist assessed-Assessed | 4.9 Months |
| Chemotherapy | Progression-free Survival in All Participants | Investigator-Assessed | 1.5 Months |
| Chemotherapy | Progression-free Survival in All Participants | Independent radiologist assessed-Assessed | 1.5 Months |