Trial Outcomes & Findings for Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. (NCT NCT01336634)

Last Updated: 2022-04-04

Results Overview

ORR was defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment as per RECIST v1 .1 criteria. Specifically, ORR = (number of subjects with a confirmed best overall response of CR or PR) divided by the total number of subjects in the corresponding analysis population.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

177 participants

Primary outcome timeframe

From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months

Results posted on

2022-04-04

Participant Flow

The study was conducted in 50 sites across 11 countries: Netherlands(2), United States(15), Germany(4), Spain(7), France(8), Italy(3), Taiwan(2), South Korea(3), United Kingdom(3), Japan(2), Norway(1)

Participant milestones

Participant milestones
Measure	Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.
Overall Study STARTED	84	57	36
Overall Study 2nd Line Plus All Treated	78	57	0
Overall Study 1st Line All Treated	6	2	34
Overall Study Crossover	20	0	0
Overall Study COMPLETED	70	49	27
Overall Study NOT COMPLETED	14	8	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.
Overall Study Study closed/terminated	5	6	6
Overall Study Lost to Follow-up	2	1	1
Overall Study Physician Decision	1	1	0
Overall Study Withdrawal by Subject	6	0	2

Baseline Characteristics

Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID n=84 Participants Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=57 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=36 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Total n=177 Participants Total of all reporting groups
Age, Continuous	64.8 Years STANDARD_DEVIATION 10.51 • n=5 Participants	65.1 Years STANDARD_DEVIATION 10.14 • n=7 Participants	67.8 Years STANDARD_DEVIATION 11.00 • n=5 Participants	65.5 Years STANDARD_DEVIATION 10.50 • n=4 Participants
Sex: Female, Male Female	44 Participants n=5 Participants	28 Participants n=7 Participants	22 Participants n=5 Participants	94 Participants n=4 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	29 Participants n=7 Participants	14 Participants n=5 Participants	83 Participants n=4 Participants
Race/Ethnicity, Customized White	64 Participants n=5 Participants	49 Participants n=7 Participants	30 Participants n=5 Participants	143 Participants n=4 Participants
Race/Ethnicity, Customized Asian	18 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	25 Participants n=4 Participants
Race/Ethnicity, Customized African American Heritage	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific islander	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
ECOG Performance Status Grade 0	20 Participants n=5 Participants	17 Participants n=7 Participants	13 Participants n=5 Participants	50 Participants n=4 Participants
ECOG Performance Status Grade 1	52 Participants n=5 Participants	35 Participants n=7 Participants	22 Participants n=5 Participants	109 Participants n=4 Participants
ECOG Performance Status Grade 2	12 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	18 Participants n=4 Participants

PRIMARY outcome

Timeframe: From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months

Population: All Treated Population (ATP).

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=36 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD n=20 Participants Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=78 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=57 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Overall Response Rate (ORR)	23 Participants	4 Participants	27 Participants	39 Participants

SECONDARY outcome

Timeframe: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 113 months

Population: All Treated Population (ATP). Only participants with an evaluable PFS events were included in the analysis.

Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=28 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD n=18 Participants Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=65 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=48 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Progression Free Survival (PFS) Based on Local Investigator Assessment	10.8 Months Interval 7.0 to 14.5	11.0 Months Interval 3.0 to 18.7	5.4 Months Interval 2.8 to 6.9	10.2 Months Interval 6.9 to 16.7

SECONDARY outcome

Timeframe: From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 113 months

Population: All Treated Population (ATP). Only responders (PR or CR) were included in the analysis.

Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=23 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD n=4 Participants Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=27 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=39 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Duration of Response (DoR) Based on Local Investigator Assessment	10.2 Months Interval 8.3 to 15.2	13.4 Months Interval 7.6 to 19.3	11.8 Months Interval 5.4 to 23.5	9.8 Months Interval 6.9 to 18.3

SECONDARY outcome

Timeframe: From study treatment start date until date of of death from any cause, assessed up to approximately 113 months

Population: All Treated Population (ATP). No separate OS analysis was conducted for cross over patient, as they were included in Cohort A (Dabrafenib Monotherapy Second-Line Plus).

Overall Survival (OS) was defined as the time from first dose until death due to any cause. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=27 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=67 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=49 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Overall Survival (OS)	17.3 Months Interval 12.3 to 40.2	—	12.7 Months Interval 7.3 to 16.3	18.2 Months Interval 14.3 to 28.6

SECONDARY outcome

Timeframe: From study treatment start date till 30 days safety follow-up, assessed up to approximately 81 months

Population: All Treated Population (ATP)

The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=36 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD n=20 Participants Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=84 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=57 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Number of Participants With Treatment Emergent Adverse Events Treatment Emergent Adverse Events (TAEs)	36 Participants	20 Participants	82 Participants	54 Participants
Number of Participants With Treatment Emergent Adverse Events Treatment Emergent Serious Adverse Events (TESAEs)	24 Participants	9 Participants	37 Participants	38 Participants
Number of Participants With Treatment Emergent Adverse Events Deaths due to AE causally related to treatment	0 Participants	0 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 3, Week 6, Week 12 and Week 18

Population: All subjects who received at least one dose of dabrafenib in the Cohort A (Dabrafenib Monotherapy) and in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile.

Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=30 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=76 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=53 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Apparent Clearance (CL/F) of Dabrafenib	23.9 Liter/hour (L/hr) Interval 22.02 to 25.87	—	30.5 Liter/hour (L/hr) Interval 29.1 to 32.0	21.4 Liter/hour (L/hr) Interval 19.37 to 23.7

SECONDARY outcome

Timeframe: Week 3, Week 6, Week 12 and Week 18

Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of dabrafenib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=30 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=76 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=53 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Oral Volume of Distribution (V/F) of Dabrafenib	48.1 Liter (L) Interval 42.15 to 54.95	—	50.6 Liter (L) Interval 47.4 to 54.0	38.1 Liter (L) Interval 30.93 to 46.97

SECONDARY outcome

Timeframe: Week 3, Week 6, Week 12 and Week 18

Population: All subjects who received at least one dose of trametinib in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile.

Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of trametinib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=30 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=54 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Apparent Clearance (CL/F) of Trametinib	5.03 Liter/hour (L/hr) Interval 4.64 to 5.46	—	—	4.9 Liter/hour (L/hr) Interval 4.62 to 5.19

SECONDARY outcome

Timeframe: Week 3, Week 6, Week 12 and Week 18

Population: All subjects who received at least one dose of trametinib in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile.

Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of trametinib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=30 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=54 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
Oral Volume of Distribution (V/F) of Trametinib	103.48 Liter (L) Interval 84.58 to 126.59	—	—	91.98 Liter (L) Interval 78.58 to 107.66

POST_HOC outcome

Timeframe: up to 81 months (study treatment with dabrafenib and trametinib), up to approximately 9 years (study duration)

Population: Clinical database population; all treated patients.

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration with dabrafenib and trametinib of 81 months (study treatment with dabrafenib and trametinib ranged from 0.3 to 80.0 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 9 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Outcome measures

Outcome measures
Measure	Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=36 Participants Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue.	Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD n=20 Participants Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event.	Cohort A (Dabrafenib Monotherapy) n=84 Participants Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.	Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD n=57 Participants Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue.
All Collected Deaths On-treatment deaths	5 Participants	4 Participants	15 Participants	12 Participants
All Collected Deaths Post-treatment deaths	21 Participants	13 Participants	38 Participants	38 Participants
All Collected Deaths All deaths	26 Participants	17 Participants	53 Participants	50 Participants

Adverse Events

Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID

Serious events: 37 serious events

Other events: 82 other events

Deaths: 15 deaths

Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD

Serious events: 38 serious events

Other events: 54 other events

Deaths: 12 deaths

Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD

Serious events: 24 serious events

Other events: 36 other events

Deaths: 5 deaths

Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD

Serious events: 9 serious events

Other events: 20 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER