Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

Pharmacokinetic (PK) Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.

PK Population

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

All Treated Participants (ATP) Population: all participants who received at least one dose of either dabrafenib or trametinib

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury [mmHg]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented.

ATP Population

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeters [mm] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.

ITT Population

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.

Crossover Population: participants who were randomized to and received at least one dose of dabrafenib monotherapy, and who elected to crossover to combination therapy following disease progression while on monotherapy

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

ITT Population

PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants received anti-cancer therapy prior to the date of documented events, and censored at the last adequate assessment, prior to the initiation of therapy. If the participant did not have a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

Crossover Population

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the BICR according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment

ITT Population

Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

ITT Population. Only those participants who had a CR or PR were analyzed for duration of response.

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

ATP Population

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

ATP Population. Only those participants who were available at the indicated time points were analyzed.

Hematology parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury [mmHg]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented.

ATP Population

The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

PK Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

tmax is defined as the time of occurenceof Cmax. Blood samples for PK analysis of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.

PK Population. Only participants available at the indicated timepoints were analyzed.

The PK parameters were determined for area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration AUC (0-tau) and from time zero (pre-dose) extrapolated to infinite time AUC (0-inf). Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour only on Day 1) post-dose administration.

PK Population. Only participants available at the indicated timepoints were analyzed.

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event for possible drug-induced liver injury.

ATP Population

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.

Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury [mmHg]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heartbeats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented

ATP Population

The steady state plasma concentration (Css) of trametinib with concomitant dabrafenib administration was assessed at Day 15 and Day 16. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated.

PK Population

Area under the concentration-time curve from time zero (predose) until the last time of quantifiable concentration (AUC [0-tau]) was assessed. Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time point were analyzed.

Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma dabrafenib (DAB) following repeat dosing of DAB administered in combination with trametinib (T). The trough concentration is defined as the plasma level of a pharmaceutical product measured just before the next dose. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time points were analyzed.

The tmax is defined as the time of occurenceof Cmax. Tha tmax was assessed for plasma dabrafenib (DAB) following repeat dosing of dabrafenib 75 and 150 mg BID administered in combination with trametinib. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time points were analyzed.

AUC (0-tau) is defined as area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration. AUC (0-tau) was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time points were analyzed.

Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time point were analyzed.

The tmax is defined as the time of occurrence of Cmax. The PK parameter for tmax was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.

PK Population. Only those participants who were available at the indicated time point were analyzed.

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 milimeter [mm] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.

All Treated Population

Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.

All Treated Population. Only those participants who had a CR or PR were analyzed.

PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve were the participants with BRAF-mutation positive melanoma who had not received prior therapy with a BRAF-inhibitor..

All Treated Population.

OS is defined as the interval of time between the first dose of study medication until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.

All Treated Population.

p-ERK and p-AKT, biomarkers in tumor biopsies, were assessed for participants with BRAF mutant colorectal cancer. The H-score, which is a composite score that comprises intensity and percentage of staining, is a method of assessing the amount of protein or phospho-protein present in a biopsy sample. The score is obtained by the formula: (3 * percentage of strongly staining nuclei) + (2 * percentage of moderately staining nuclei) + (percentage of weakly staining nuclei). The H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.

Biomarker Population: participants with H-score data for pre- and post-biopsy pairs

OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact. When calculating overall survival, deaths following crossover were included.

ITT Population

Plasma concentrations of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were assesed following daily dose of dabrafenib and trametinib.

PK Population. Only those participants who were available at the indicated time points were analyzed.

Plasma concentrations of trametinib was assessed following daily dose of dabrafenib and trametinib.

PK Population. Only those participants who were available at the indicated time points were analyzed.

Oral clearance (CL/F) of dabrafenib and trametinib were assessed using a population approach. Oral clearance (CL/F) is defined as the apparent volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. For dabrafenib, population CL/F is defined as inducible and non-inducible CL/F. As dabrafenib induces its own metabolism, total oral clearance at steady state includes a non-induced (Day 1) component and an induced component, as estimated by a population PK model.

PK Population

Oral volume of distribution (V/F) of dabrafenib and trametinib were assessed using a population approach. Oral volume of distribution (V/F) is defined as the apparent volume of distribution in the central compartment.

PK Population

The maximum concentration (Cmax) of dabrafenib metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

The time to Cmax (tmax) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measuered at Day 1 and Day 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

Area under the concentration-time curve (AUC) from pre-dose to dosing interval (AUC[0-tau]), from pre-dose to the last time of quantifable concentration (AUC[0-tau]), and from pre-dose extrapolated to infinity (AUC[0-inf]) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

Cmax of trametinib after single and repeat dose in combination with DAB was observed at Day 1 and Day 21. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, Cmax was not analyzed in these participants at Days 1 and 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

The tmax of trametinib after single and repeat dose in combination with dabrafenib (DAB) was observed at Day 1 and Day 21. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, tmax was not analyzed in these participants at Days 1 and 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

AUC(0-tau) after single and repeat dose of teametinib alone and in combination with dabrafenib was observed at Day 1 and Day 21. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, AUC(0-tau) was not analyzed in these participants at Days 1 and 21.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 milimeter [mm] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment should be performed no less than 28 days after the criteria for response are first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

ITT Population

Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

ITT Population. Only those participants who had CR or PR were considered.

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

ITT Population

OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.

ITT Population