Malignant Melanoma
Conditions
Keywords
Zelboraf, vemurafenib, RG7204, PLX4032, Genentech MEK inhibitor, Genentech BRAF inhibitor, Roche MEK inhibitor, Roche BRAF inhibitor, RO5185426, metastatic melanoma, BRAF positive melanoma, BRAF mutant melanoma, advanced melanoma, Genentech RAF inhibitor, Roche RAF inhibitor, BRAF V600E kinase inhibitor, Oncogenic BRAF inhibitor, BRAF kinase inhibitor, GDC-0973, XL518, melanoma
Brief summary
To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.
Interventions
DRUGPlacebo
Placebo supplied as tablets
DRUGVemurafenib
Vemurafenib supplied as tablets
DRUGCobimetinib
Cobimetinib supplied as tablets
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist * Participants must be naïve to treatment for locally advanced unresectable or metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed * Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test * Measurable disease per RECIST v1.1 * Eastern Clinical Oncology Group performance status of 0 or 1 * Consent to provide archival for biomarker analyses * Consent to undergo tumor biopsies for biomarker analyses * Life expectancy greater than or equal to (≥) 12 weeks * Adequate hematologic and end organ function
Exclusion criteria
* History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase pathway inhibitor treatment * Palliative radiotherapy within 14 days prior to the first dose of study treatment * Major surgery or traumatic injury within 14 days prior to first dose of study treatment * Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Participants with a previous malignancy within the past 3 years are excluded except for participants with resected basal cell carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast * History of or evidence of retinal pathology on ophthalmological examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion, or neovascular macular degeneration * Uncontrolled glaucoma with intraocular pressure * Serum cholesterol ≥ Grade 2 * Hypertriglyceridemia ≥ Grade 2 * Hyperglycemia (fasting) ≥ Grade 2 * History of clinically significant cardiac dysfunction * Participants with active central nervous system (CNS) lesions (including carcinomatous meningitis) are excluded. However, participants are eligible if: 1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND 2. There has been no evidence of clinical and radiographic disease progression in the CNS for ≥ 3 weeks after radiotherapy or surgery * Current severe, uncontrolled systemic disease * History of malabsorption or other condition that would interfere with absorption of study drugs * Pregnant, lactating, or breast feeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | Overall survival was defined as the time from randomization until the date of death from any cause. |
| Percentage of Participants With an Objective Response | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions. |
| Duration of Response | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, New Zealand, Norway, Russia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.
Participants by arm
| Arm | Count |
|---|---|
| Cobimetinib + Vemurafenib Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. | 247 |
| Placebo + Vemurafenib Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. | 248 |
| Total | 495 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intent to Treat | Death | 157 | 167 |
| Intent to Treat | Lost to Follow-up | 4 | 8 |
| Intent to Treat | Other | 2 | 4 |
| Intent to Treat | Physician Decision | 4 | 1 |
| Intent to Treat | Study terminated by Spon6sor | 59 | 48 |
| Intent to Treat | Withdrawal by Subject | 21 | 20 |
| Safety Population | Death | 158 | 165 |
| Safety Population | Lost to Follow-up | 4 | 8 |
| Safety Population | Other | 2 | 4 |
| Safety Population | Physician Decision | 4 | 1 |
| Safety Population | Study Terminated By Sponsor | 60 | 47 |
| Safety Population | Withdrawal by Subject | 20 | 20 |
Baseline characteristics
| Characteristic | Placebo + Vemurafenib | Cobimetinib + Vemurafenib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 69 Participants | 64 Participants | 133 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants | 183 Participants | 362 Participants |
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 13.8 | 54.9 Years STANDARD_DEVIATION 14 | 55.1 Years STANDARD_DEVIATION 13.9 |
| Race/Ethnicity, Customized Asian | 0 Count of Participants | 1 Count of Participants | 1 Count of Participants |
| Race/Ethnicity, Customized Black or African American | 0 Count of Participants | 0 Count of Participants | 0 Count of Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 12 Count of Participants | 14 Count of Participants | 26 Count of Participants |
| Race/Ethnicity, Customized More than one race | 1 Count of Participants | 1 Count of Participants | 2 Count of Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islande | 1 Count of Participants | 0 Count of Participants | 1 Count of Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 223 Count of Participants | 213 Count of Participants | 436 Count of Participants |
| Race/Ethnicity, Customized Not Stated | 10 Count of Participants | 16 Count of Participants | 26 Count of Participants |
| Race/Ethnicity, Customized Other | 2 Count of Participants | 2 Count of Participants | 4 Count of Participants |
| Race/Ethnicity, Customized Unknown | 3 Count of Participants | 4 Count of Participants | 7 Count of Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 9 Count of Participants | 16 Count of Participants | 25 Count of Participants |
| Race/Ethnicity, Customized White | 235 Count of Participants | 227 Count of Participants | 462 Count of Participants |
| Sex: Female, Male Female | 108 Participants | 101 Participants | 209 Participants |
| Sex: Female, Male Male | 140 Participants | 146 Participants | 286 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 160 / 247 | 164 / 248 |
| other Total, other adverse events | 239 / 248 | 236 / 245 |
| serious Total, serious adverse events | 105 / 248 | 71 / 245 |
Outcome results
Primary
Progression-free Survival
Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
Time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Vemurafenib | Progression-free Survival | Primary Analysis: 9 May 2014 | 9.90 Months |
| Cobimetinib + Vemurafenib | Progression-free Survival | Post hoc Efficacy Analysis: 16 January 2015 | 12.30 Months |
| Cobimetinib + Vemurafenib | Progression-free Survival | Extended 5-Year Analysis: 21 July 2019 | 12.60 Months |
| Placebo + Vemurafenib | Progression-free Survival | Primary Analysis: 9 May 2014 | 6.20 Months |
| Placebo + Vemurafenib | Progression-free Survival | Post hoc Efficacy Analysis: 16 January 2015 | 7.20 Months |
| Placebo + Vemurafenib | Progression-free Survival | Extended 5-Year Analysis: 21 July 2019 | 7.20 Months |
Comparison: Primary Analysis 9 May 2014p-value: 0.000195% CI: [0.39, 0.68]Log Rank
Comparison: Post hoc Efficacy Analysis: 16 January 2015p-value: <0.000195% CI: [0.46, 0.72]Log Rank
Comparison: Extended 5-Year Analysis: 21 July 2019p-value: <0.000195% CI: [0.53, 0.79]Log Rank
Secondary
Duration of Response
Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
Time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Vemurafenib | Duration of Response | Primary Analysis: 9 May 2014 | NA Months |
| Cobimetinib + Vemurafenib | Duration of Response | Extended 5-Year Analysis: 21 July 2019 | 14.65 Months |
| Placebo + Vemurafenib | Duration of Response | Primary Analysis: 9 May 2014 | 7.29 Months |
| Placebo + Vemurafenib | Duration of Response | Extended 5-Year Analysis: 21 July 2019 | 9.23 Months |
Secondary
Overall Survival
Overall survival was defined as the time from randomization until the date of death from any cause.
Time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Vemurafenib | Overall Survival | Primary Analysis 9 May 2014 | NA Months |
| Cobimetinib + Vemurafenib | Overall Survival | Post hoc Analysis 16 January 2015 | NA Months |
| Cobimetinib + Vemurafenib | Overall Survival | Final Analysis 28 August 2015 | 22.30 Months |
| Cobimetinib + Vemurafenib | Overall Survival | Extended 5-year Analysis 21 July 2019 | 22.50 Months |
| Placebo + Vemurafenib | Overall Survival | Extended 5-year Analysis 21 July 2019 | 17.40 Months |
| Placebo + Vemurafenib | Overall Survival | Primary Analysis 9 May 2014 | NA Months |
| Placebo + Vemurafenib | Overall Survival | Final Analysis 28 August 2015 | 17.40 Months |
| Placebo + Vemurafenib | Overall Survival | Post hoc Analysis 16 January 2015 | 17.00 Months |
Comparison: Primary Analysis 9 May 2014p-value: 0.046395% CI: [0.42, 1]Log Rank
Comparison: Post hoc Analysis 16 January 2015p-value: 0.003495% CI: [0.49, 0.87]Log Rank
Comparison: Final Analysis 28 August 2015p-value: 0.00595% CI: [0.55, 0.9]Log Rank
Secondary
Percentage of Participants With an Objective Response
An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.
Time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib + Vemurafenib | Percentage of Participants With an Objective Response | Primary Analysis: 9 May 2014 | 67.60 Percentage of participants |
| Cobimetinib + Vemurafenib | Percentage of Participants With an Objective Response | Post hoc Efficacy Analysis: 16 January 2015 | 69.60 Percentage of participants |
| Cobimetinib + Vemurafenib | Percentage of Participants With an Objective Response | Extended 5-Year Analysis: 21 July 2019 | 69.60 Percentage of participants |
| Placebo + Vemurafenib | Percentage of Participants With an Objective Response | Primary Analysis: 9 May 2014 | 44.80 Percentage of participants |
| Placebo + Vemurafenib | Percentage of Participants With an Objective Response | Post hoc Efficacy Analysis: 16 January 2015 | 50.00 Percentage of participants |
| Placebo + Vemurafenib | Percentage of Participants With an Objective Response | Extended 5-Year Analysis: 21 July 2019 | 49.60 Percentage of participants |
Comparison: Primary Analysis: 9 May 2014p-value: <0.000195% CI: [14.13, 31.58]Chi-squared
Comparison: Post hoc Efficacy Analysis: 16 January 2015p-value: <0.000195% CI: [11, 28.3]Chi-squared
Comparison: Extended 5-Year Analysis: 21 July 2019p-value: <0.000195% CI: [11.4, 28.7]Chi-squared