Trial Outcomes & Findings for GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma (NCT NCT01245062)

Last Updated: 2018-04-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

322 participants

Primary outcome timeframe

Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Results posted on

2018-04-05

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.	Cross-over From Chemotherapy to Trametinib Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.
Randomization and Crossover Phase STARTED	214	108	0
Randomization and Crossover Phase COMPLETED	173	77	0
Randomization and Crossover Phase NOT COMPLETED	41	31	0
Cross-over Phase STARTED	0	0	70
Cross-over Phase COMPLETED	0	0	53
Cross-over Phase NOT COMPLETED	0	0	17

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	Cross-over From Chemotherapy to Trametinib Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.
Randomization and Crossover Phase Lost to Follow-up	4	2	0
Randomization and Crossover Phase Physician Decision	2	4	0
Randomization and Crossover Phase Withdrew Consent	12	11	0
Randomization and Crossover Phase Study closed/ terminated	23	14	0
Cross-over Phase Lost to Follow-up	0	0	1
Cross-over Phase Physician Decision	0	0	1
Cross-over Phase Withdrew Consent	0	0	4
Cross-over Phase Study closed/ terminated	0	0	11

Baseline Characteristics

GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trametinib n=214 Participants 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.	Chemotherapy n=108 Participants 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.	Total n=322 Participants Total of all reporting groups
Age, Continuous	54.3 Years STANDARD_DEVIATION 12.97 • n=99 Participants	52.8 Years STANDARD_DEVIATION 13.56 • n=107 Participants	53.8 Years STANDARD_DEVIATION 13.17 • n=206 Participants
Sex: Female, Male Female	94 Participants n=99 Participants	55 Participants n=107 Participants	149 Participants n=206 Participants
Sex: Female, Male Male	120 Participants n=99 Participants	53 Participants n=107 Participants	173 Participants n=206 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · White - Arabic/North African Heritage	2 Participants n=99 Participants	0 Participants n=107 Participants	2 Participants n=206 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · White - White/Caucasian/European Heritage	212 Participants n=99 Participants	107 Participants n=107 Participants	319 Participants n=206 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · White - Mixed Race	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants

PRIMARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

Outcome measures

Outcome measures
Measure	Trametinib n=178 Participants 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.	Chemotherapy n=95 Participants 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.
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 Interval 3.5 to 4.9	1.4 Months Interval 1.4 to 2.7
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 Interval 4.5 to 5.1	1.6 Months Interval 1.4 to 2.8

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=214 Participants 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.	Chemotherapy n=108 Participants 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.
Progression-free Survival in All Participants Investigator-Assessed	4.9 Months Interval 4.5 to 5.0	1.5 Months Interval 1.4 to 2.8
Progression-free Survival in All Participants Independent radiologist assessed-Assessed	4.9 Months Interval 4.6 to 5.0	1.5 Months Interval 1.4 to 2.8

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=114 Participants 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.	Chemotherapy n=62 Participants 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.
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 Interval 3.4 to 5.0	1.4 Months Interval 1.4 to 1.7

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

Outcome measures

Outcome measures
Measure	Trametinib n=64 Participants 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.	Chemotherapy n=33 Participants 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.
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 Interval 2.9 to 4.9	2.7 Months Interval 1.4 to 2.9

SECONDARY outcome

Timeframe: Day 1 until death due to any cause (average of 20.3 months)

Population: ITT Population

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Trametinib n=214 Participants 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.	Chemotherapy n=108 Participants 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.
Overall Survival in All Participants	15.6 Months Interval 13.5 to 17.3	11.3 Months Interval 7.2 to 14.8

SECONDARY outcome

Timeframe: Day 1 until death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=178 Participants 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.	Chemotherapy n=95 Participants 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.
Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases	NA Months At the time of this report, there was limited follow-up for survival; therefore, the median and the confidence interval (CI) could not be estimated.	NA Months Interval 6.8 to At the time of this report, there was limited follow-up for survival; therefore, the median and the upper limit (UL) of the CI could not be estimated.

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=178 Participants 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.	Chemotherapy n=95 Participants 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.
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	7 Participants
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	0 Participants
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	0 Participants
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	3 Participants

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=214 Participants 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.	Chemotherapy n=108 Participants 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.
Number of Participants With OR as Assessed by the Investigator and Independent Review Independent Review: CR	0 Participants	1 Participants
Number of Participants With OR as Assessed by the Investigator and Independent Review Investigator-Assessed: CR	8 Participants	2 Participants
Number of Participants With OR as Assessed by the Investigator and Independent Review Investigator-Assessed: PR	53 Participants	8 Participants
Number of Participants With OR as Assessed by the Investigator and Independent Review Independent Review: PR	41 Participants	4 Participants

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=184 Participants 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.	Chemotherapy n=97 Participants 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.
Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator V600E Mutation, CR	4 Participants	0 Participants
Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator V600E Mutation, PR	40 Participants	7 Participants

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=29 Participants 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.	Chemotherapy n=11 Participants 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.
Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator V600K Mutation, PR	3 Participants	2 Participants
Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator V600K Mutation, CR	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Trametinib n=70 Participants 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.	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.
Number of Participants With OR Following Cross-over to Trametinib CR	2 Participants	—
Number of Participants With OR Following Cross-over to Trametinib PR	29 Participants	—

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=43 Participants 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.	Chemotherapy n=7 Participants 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.
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 Interval 4.9 to 5.9	NA Months Interval 3.5 to There were too few events to provide an estimable median or UL of the CI.

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: Primary Efficacy Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=33 Participants 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.	Chemotherapy n=3 Participants 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.
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 Interval 3.8 to 5.9	NA Months Interval 3.5 to There were too few events to provide an estimable median or UL of the CI.

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=47 Participants 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.	Chemotherapy n=9 Participants 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.
DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review	5.5 Months Interval 4.1 to 5.9	NA Months Interval 5.0 to There were too few events to provide an estimable median or UL of the CI.

SECONDARY outcome

Timeframe: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Trametinib n=41 Participants 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.	Chemotherapy n=5 Participants 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.
DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review	5.6 Months Interval 4.1 to 5.9	NA Months Interval 5.0 to There were too few events to provide an estimable median or UL of the CI.

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Trametinib n=13 Participants 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.	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.
DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator	2.7 Months Interval 1.3 to There were too few events to provide an estimable UL of the CI.	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Trametinib n=70 Participants 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.	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.
PFS Following Cross-over to Trametinib as Assessed by the Investigator	3.0 Months Interval 2.7 to 4.8	—

Adverse Events

Trametinib

Serious events: 52 serious events

Other events: 207 other events

Deaths: 172 deaths

Chemotherapy

Serious events: 19 serious events

Other events: 88 other events

Deaths: 22 deaths

Cross-over From Chemotherapy to Trametinib

Serious events: 18 serious events

Other events: 66 other events

Deaths: 53 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER