Melanoma
Conditions
Keywords
MEK inhibitor, trametinib, Oncology, adjuvant melanoma, dabrafenib, dabrafenib and trametinib combination therapy, BRAF mutation-positive melanoma, BRAF inhibitor
Brief summary
This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus 2 placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk (Stage IIIa \[lymph node metastasis \>1 mm\], IIIb or IIIc) cutaneous melanoma were screened for eligibility. Approximately 852 patients were planned to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, IIIb, IIIc). Patients received either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]) combination therapy or 2 matching placebos (one each for dabrafenib and trametinib) for 12 months or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent. Patients were followed for disease recurrence and survival during and after the treatment period. The study did not permit crossover. Doses of study treatment could be modified and/or interrupted for management of toxicities associated with study treatment.
Detailed description
The study periods were follows: 1. Screening: Assessments were to be completed within 28 days of randomization. 2. Treatment: The treatment period was 12 months. Discontinuation of study treatment could occur earlier than 12 months for disease recurrence, death, unacceptable toxicity or withdrawal of consent. 3. Post treatment follow-up (before recurrence): Patients were to be followed for disease recurrence every 3 months after the end of treatment until Month 24, every 6 months after Month 24 and annually after Month 60 (365 days +/- 14 days from last visit). 4. Post treatment follow-up (after recurrence): After disease recurrence patients remained on study for follow-up assessments every 3 months until Month 24, every 6 months after Month 24, and annually after Month 60 (365 days +/- 14 days from last visit).
Interventions
DRUGDabrafenib
Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)
DRUGTrametinib
Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
DRUGPlacebos
The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * At least 18 years of age * Completely resected histologically confirmed high-risk (Stage IIIa \[lymph node metastasis \> 1 mm\], IIIb or IIIc) cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX) THxID BRAF Assay by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible * Must be surgically rendered free of disease (defined as the date of the most recent surgery) no more than 12 weeks before randomization * Recovered from definitive surgery (e.g., no uncontrolled wound infections or indwelling drains) * ECOG Performance Status of 0-1 * Had adequate hematologic, hepatic, renal and cardiac function. Key
Exclusion criteria
* Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases * Evidence of distant metastatic disease on Screening evaluation * Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) including radiotherapy for melanoma. Prior surgery for melanoma was allowed * History of another malignancy including melanoma or a concurrent malignancy. Patients who previously had Stage III melanoma or any malignancy with confirmed activating RAS mutation at any time were not eligible. Exceptions to this include: * Patients with a history of any malignancy that had been disease-free for at least 5 years were eligible except those with confirmed activating RAS mutations * Patients with a history of completely resected non-melanoma skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma) were eligible irrespective of the time since the resection * Patients with successfully treated in situ carcinoma were eligible * Patients presenting with multiple primary melanomas were eligible only if the lesions were concurrent. Patients who had concurrent multiple primary melanomas that were "distant" were eligible provided each lesion was considered local disease or resectable regional disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Relapse-free Survival (RFS) Events | Approximately 4 years | Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses. |
| Relapse-free Survival (RFS) | Approximately 4 years | Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Survival (OS) Events | Approximately 10 years | Censoring was performed using the date of last known contact for those who were alive at the time of analysis. |
| Overall Survival (OS) | Approximately 10 years | Overall Survival (OS) was defined as the interval from randomization to the date of death, irrespective of the cause of death. Censoring was performed using the date of last known contact for those who were alive at the time of analysis. |
| Percentage of Participants With Distant Metastasis-free Survival (DMFS) Events | Approximately 4 years | Distant metastasis-free survival (DMFS) was defined as the time from randomization to the first occurrence of distant metastasis or death, whichever occurred first, if death preceded documented recurrence. Patients who remained alive and free of distant metastasis were censored at the date of their last assessment. |
| Distant Metastasis-free Survival (DMFS) | Approximately 4 years | Distant metastasis-free survival (DMFS) was defined as the time from randomization to the first occurrence of distant metastasis or death, whichever occurred first, if death preceded documented recurrence. Patients who remained alive and free of distant metastasis were censored at the date of their last assessment. |
| Percentage of Participants With Freedom From Relapse (FFR) Events | Approximately 4 years | The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death. |
| Freedom From Relapse (FFR) | Approximately 4 years | Freedom from relapse (FFR) was defined as the interval from randomization to local or distant recurrence with censoring of patients dying from causes other than melanoma or treatment -related toxicity at the date of death. The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Netherlands, New Zealand, Norway, Poland, Russia, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
The study was conducted in 169 centers across 25 countries.
Pre-assignment details
Patients were planned to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, IIIb, IIIc).
Participants by arm
| Arm | Count |
|---|---|
| Dabrafenib and Trametinib Combination Therapy Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. | 438 |
| Dabrafenib and Trametinib Placebos Subjects received matching placebos orally for 12 months | 432 |
| Total | 870 |
Baseline characteristics
| Characteristic | Dabrafenib and Trametinib Combination Therapy | Dabrafenib and Trametinib Placebos | Total |
|---|---|---|---|
| Age, Continuous | 50.4 Years STANDARD_DEVIATION 14.17 | 50.5 Years STANDARD_DEVIATION 13.14 | 50.4 Years STANDARD_DEVIATION 13.66 |
| Race/Ethnicity, Customized Asian | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 432 Participants | 427 Participants | 859 Participants |
| Sex: Female, Male Female | 195 Participants | 193 Participants | 388 Participants |
| Sex: Female, Male Male | 243 Participants | 239 Participants | 482 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 438 | 1 / 432 | 121 / 431 | 135 / 431 |
| other Total, other adverse events | 414 / 435 | 343 / 432 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 155 / 435 | 44 / 432 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Relapse-free Survival (RFS)
Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.
Time frame: Approximately 3.5 years
Population: Intent-to-Treat (ITT) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabrafenib and Trametinib Combination Therapy | Relapse-free Survival (RFS) | Died | 3 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Relapse-free Survival (RFS) | Relapsed (event) | 163 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Relapse-free Survival (RFS) | Censored, follow-up ended | 43 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Relapse-free Survival (RFS) | Censored, follow-up ongoing | 229 Participants with events |
| Dabrafenib and Trametinib Placebos | Relapse-free Survival (RFS) | Censored, follow-up ongoing | 149 Participants with events |
| Dabrafenib and Trametinib Placebos | Relapse-free Survival (RFS) | Censored, follow-up ended | 35 Participants with events |
| Dabrafenib and Trametinib Placebos | Relapse-free Survival (RFS) | Relapsed (event) | 247 Participants with events |
| Dabrafenib and Trametinib Placebos | Relapse-free Survival (RFS) | Died | 1 Participants with events |
Comparison: The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.p-value: <0.000195% CI: [0.39, 0.58]Log Rank
Secondary
Distant Metastasis-free Survival
Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.
Time frame: approximately 3.5 years
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabrafenib and Trametinib Combination Therapy | Distant Metastasis-free Survival | Number of Subjects - Relapsed | 106 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Distant Metastasis-free Survival | Number of Subjects - died | 4 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Distant Metastasis-free Survival | Number of Subjects - censored, follow-up ended | 99 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Distant Metastasis-free Survival | Number of Subjects - follow-up ongoing | 229 Participants with events |
| Dabrafenib and Trametinib Placebos | Distant Metastasis-free Survival | Number of Subjects - follow-up ongoing | 149 Participants with events |
| Dabrafenib and Trametinib Placebos | Distant Metastasis-free Survival | Number of Subjects - Relapsed | 150 Participants with events |
| Dabrafenib and Trametinib Placebos | Distant Metastasis-free Survival | Number of Subjects - censored, follow-up ended | 131 Participants with events |
| Dabrafenib and Trametinib Placebos | Distant Metastasis-free Survival | Number of Subjects - died | 2 Participants with events |
Comparison: Hazard ratio is estimated using Pike estimator.95% CI: [0.4, 0.65]
Secondary
Freedom From Relapse
Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.
Time frame: approximately 3.5 years
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabrafenib and Trametinib Combination Therapy | Freedom From Relapse | Number of Subjects - died | 2 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Freedom From Relapse | Number of Subjects - relapsed | 163 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Freedom From Relapse | Number of Subjects - censored, follow-up ended | 44 Participants with events |
| Dabrafenib and Trametinib Combination Therapy | Freedom From Relapse | Number of Subjects - censored, follow-up ongoing | 229 Participants with events |
| Dabrafenib and Trametinib Placebos | Freedom From Relapse | Number of Subjects - censored, follow-up ongoing | 149 Participants with events |
| Dabrafenib and Trametinib Placebos | Freedom From Relapse | Number of Subjects - censored, follow-up ended | 36 Participants with events |
| Dabrafenib and Trametinib Placebos | Freedom From Relapse | Number of Subjects - relapsed | 247 Participants with events |
| Dabrafenib and Trametinib Placebos | Freedom From Relapse | Number of Subjects - died | 0 Participants with events |
Comparison: Hazard ratio is estimated using Pike estimator.95% CI: [0.39, 0.57]
Secondary
Overall Survival
Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo
Time frame: approximately 3.5 years
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabrafenib and Trametinib Combination Therapy | Overall Survival | Died (event) | 60 Participants |
| Dabrafenib and Trametinib Combination Therapy | Overall Survival | Censored, follow-up ended | 47 Participants |
| Dabrafenib and Trametinib Combination Therapy | Overall Survival | Censored, follow-up ongoing | 331 Participants |
| Dabrafenib and Trametinib Placebos | Overall Survival | Died (event) | 93 Participants |
| Dabrafenib and Trametinib Placebos | Overall Survival | Censored, follow-up ended | 62 Participants |
| Dabrafenib and Trametinib Placebos | Overall Survival | Censored, follow-up ongoing | 277 Participants |
Comparison: Hazard ratio is obtained from the stratified Pike estimator.p-value: 0.00695% CI: [0.42, 0.79]Log Rank