GSK Medicine: Study Number: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Part A Part B Part C

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Trametinib (GSK ) + Dabrafenib (GSK ) Study Number: BRF Title: An Open-Label, Dose-Escalation, Phase IB/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the BRAF Inhibitor GSK in Combination with the MEK Inhibitor GSK in Subjects with BRAF Mutant Metastatic Melanoma Rationale: The RAS/RAF/MEK/ERK pathway (also known as the MAP kinase [MAPK] pathway) is a critical proliferation pathway in many human cancers, including melanoma. Dabrafenib is a potent and selective inhibitor of B-RAF kinase activity, whereas trametinib is a potent and highly selective inhibitor of MEK1/MEK2 activation and kinase activity. Both agents have demonstrated clinical benefit as monotherapies in randomized Phase III studies in subjects with BRAF mutation-positive metastatic melanoma. The Phase I/II study BRF was designed to investigate whether the combination regimen of dabrafenib and trametinib might simultaneously overcome mechanisms of primary resistance and attenuate mechanisms of secondary, acquired resistance to BRAF inhibition while preventing the occurrence of hyperproliferative skin lesions and cutnaeous SCC, thus improving the clinical benefit and the safety of subjects with metastatic BRAFV600 melanoma. Phase: I / II Study Period: 19 March 2010 to 25 May 2012 (clinical cut-off Parts A and B); 26 March 2010 to 31 May 2012 (clinical cut-off for Part C); and 19 March 2010 to 25 September 2012 (clinical cut-off for Part D) Study Design: BRF was a Phase I/II study to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of dabrafenib in combination with trametinib, primarily in subjects with BRAF mutant metastatic melanoma: Part A was a single-arm Phase I study to investigate the effects of repeat doses of trametinib on the PK of single dose of dabrafenib, prior to evaluating combination regimens. Part B was a Phase I, dose-escalation study to explore the range of tolerated doses of the dabrafenib plus trametinib combination, using a 3+3 design. Part C was a randomized, open-label, 3-arm, Phase II study to determine the clinical activity and safety of dabrafenib and trametinib in subjects with BRAF mutant melanoma. Part D was a randomized, Phase I study to determine the single-dose and steady-state PK of dabrafenib hydroxypropyl methylcellulose (HPMC) capsules alone and in combination with trametinib dosed orally, and also to determine the safety, tolerability, and clinical activity of the combination in subjects with BRAF mutant melanoma. Centres: 2 sites in Australia and 14 sites in the US Indication: Metastatic melanoma Treatment: Part A Subjects received a single dose of dabrafenib 75 mg alone (Day 1) and with trametinib (Day 15). Repeat doses of trametinib 2 mg once daily (QD) were administered for 14 days (Day 2 through Day 15). After a washout period from Day 16 through Day 28, subjects who elected to continue participation in the study received dabrafenib at a starting dose of 100 mg two times a day (BID) on Day 29, and 150 mg BID from Day 30, with dose modifications and addition of trametinib as allowed by the protocol. Part B In Part B, subjects were enrolled in escalating dose cohorts of dabrafenib and trametinib in a traditional 3+3 design to identify the range of tolerated doses (although 4 subjects per dose level were allowed since there were 4 centers in the study). Starting with half the recommended effective dose of each single agent (75 mg BID for dabrafenib and 1.0 mg QD for trametinib), dose escalation decisions were made based on all available PK, safety and other data from the first 4 evaluable subjects in each cohort. Part C Subjects randomized to monotherapy group received dabrafenib 150 mg BID, whereas subjects randomized to the combination therapy groups received dabrafenib 150 mg BID in combination with trametinib 1.0 mg QD or 2.0 mg QD. Subjects who progressed on dabrafenib monotherapy had the option to cross over to treatment with dabrafenib 150 mg BID in combination with trametinib 2.0 mg QD. 1

2 Part D Subjects in Part D were randomized to one of 4 cohorts: 2 monotherapy cohorts who received dabrafenib monotherapy either 75 mg BID or 150 mg BID, and 2 combination therapy cohorts who received dabrafenib at either 75 mg BID or 150 mg BID, each in combination with trametinib 2.0 mg QD. Serial PK samples were taken on Day 1 (after the first, single dose of dabrafenib or dabrafenib / trametinib combination) and subsequently, on Day 21 (after the morning dose of dabrafenib or dabrafenib / trametinib combination). Subjects in the 2 monotherapy cohorts who had completed serial PK collection were allowed to continue dabrafenib at the same dose in addition with trametinib 2.0 mg QD from Day 29 onwards. Objectives: Part A Primary: To determine the PK of single dose dabrafenib (and its metabolite(s), including hydroxy-dabrafenib), alone and with repeat dose trametinib dosed orally. Secondary: To confirm steady-state exposure of trametinib. Part B Primary: To determine the safety, tolerability and range of tolerated doses of dabrafenib and trametinib dosed orally in combination in subjects with BRAF V-600 mutation positive metastatic melanoma. Secondary: To characterize the steady-state PK of dabrafenib (and its metabolite(s) including hydroxy-dabrafenib), and trametinib. To evaluate the clinical activity of the dabrafenib and trametinib combination in subjects with BRAF V-600 mutation positive metastatic melanoma. Part C Primary: To determine clinical activity of dabrafenib and trametinib in subjects with BRAF mutant metastatic melanoma. To determine the safety, tolerability and range of tolerated doses of GSK and GSK dosed orally in combination in subjects with BRAF mutant metastatic melanoma. Secondary: To characterize the population PK parameters of dabrafenib and trametinib when administered daily in subjects with BRAF mutant metastatic melanoma. To characterize the durability of response in subjects achieving clinical benefit. Part D Primary: To determine single and steady-state PK of dabrafenib HPMC capsules alone and in combination with trametinib dosed orally. To determine the safety and tolerability of dabrafenib and trametinib dosed orally in combination in subjects with BRAF V-600 mutation positive metastatic melanoma. Secondary: To determine the single dose and steady state PK of dabrafenib metabolites using HPMC capsules. To determine single dose and steady-state PK of trametinib. To evaluate clinical activity of the dabrafenib and trametinib combination in subjects with BRAF V-600 mutation positive metastatic melanoma. Primary Endpoints: Part A: Single dose PK parameters for dabrafenib (and its metabolite(s), including hydroxy-dabrafenib), including Cmax, AUC(0-t) and AUC(0- ). Part B: AEs and changes in laboratory values and vital signs. 2

3 Part C: Response rate (complete response [CR] + partial response [PR]) of dabrafenib and trametinib in BRAF mutant metastatic melanoma. Duration of response. Progression-free survival. AEs (including rate of squamous cell carcinoma [SCC]) and changes in laboratory values and vital signs. Part D: Single and steady-state PK parameters for dabrafenib HPMC capsules including Cmax, Tmax, AUC(0-t), and AUC(0- ) (single dose). AEs (including rate of squamous cell carcinoma) and changes in laboratory values and vital signs. Secondary Endpoints: Part A: Trametinib concentrations during concomitant dabrafenib. Part B: Dabrafenib (and its metabolite(s) including hydroxy-dabrafenib), and trametinib PK parameters following repeatdose (Day 15 or Day 21) administration of dabrafenib and trametinib, including AUC(0- ), C, Cmax, and tmax. Tumor response as defined by RECIST 1.1. Part C: Population PK parameters, such as oral clearance (CL/F) and oral volume of distribution (V/F) of dabrafenib and trametinib will be determined. Additional PK parameters may also be estimated. Overall survival. Part D: Single dose and steady-state PK parameters for dabrafenib metabolites using HPMC capsules including Cmax, Tmax, AUC(0-t), and AUC(0- ) (single dose), if data permits (applicable to AUC(0- ) only). Trametinib single dose and steady state PK parameters including Cmax, Tmax, AUC(0-t) during concomitant dabrafenib. Tumor response as defined by RECIST 1.1. Statistical Methods: Analysis populations for the various parameters included: Intent-to-Treat (ITT) Population: The ITT population comprised all randomized subjects regardless of whether or not treatment was administered and was the primary population for the study population and efficacy data. Classification of treatment cohorts with ITT population was based on the treatment to which the subject was randomized. Screening failure subjects who were randomized by error were not counted in the ITT population. Crossover Population: The Crossover Population comprised the subset of subjects 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. This was the primary population for summarizing data in the crossover phase. All Treated Population: The All Treated population consisted of all subjects who received at least one dose of either dabrafenib or trametinib and was the primary population for analyses of safety data for all parts and efficacy data in Part B. Classification of treatment cohorts with All Treated population was based on the actual treatment the subject received. Pharmacokinetic (PK) Population: The PK population consisted of those subjects in the All Treated population for whom a PK sample was obtained and analyzed. A subject in Part B or D was considered to have serial PK data if on a visit the subject had both pre-dose concentration measurement and at least one post-dose concentration measurement. Safety Analyses AEs were graded according to the National Cancer Institute Common Terminology Criteria for AEs version 4.0 (NCI CTCAE v4.0). For Part B, a summary of the number of subjects with dose limiting toxicities (DLT) during the determinative period (first 21 days) was presented by dose cohort. For Part C, all safety analyses were based on the All Treated or Crossover populations, as appropriate, and were conducted separately for subjects in the randomized phase and those in the crossover phase. Only AEs with post-dose start date were summarized. 3

4 PK analyses PK analyses of concentration-time data were conducted by standard non-compartmental methods. For all the derived PK parameters (except tmax), the following summary statistics were calculated: median, maximum, minimum, arithmetic mean and 95% confidence interval (CI), standard deviation, coefficient of variation, geometric mean and 95% CI, and standard deviation of logarithmically transformed data. For tmax, median, maximum, minimum, arithmetic mean and 95% CI, and standard deviation were calculated. For subjects with serial PK, derived PK parameters were summarized by analyte, dosing cohort, and visit. For population analyses, concentration data obtained in Part C were combined with Parts A, B and D, and prior monotherapy data, and analyzed using a non-linear mixed effects approach. In Part A, point estimates and corresponding 90% CIs were calculated for the comparisons of the PK of dabrafenib and its metabolites, after dabrafenib co-administered with trametinib versus administered alone. Following logetransformation, AUC(0- ), AUC(0-t), and Cmax of dabrafenib and its metabolites, were separately analyzed by a mixed effect model, fitting a fixed effect term for treatment (dabrafenib alone and combined with trametinib) and a random effect for subject. Point estimates and associated 90% CI were constructed for the differences of interest using the appropriate error term. These point estimates and CIs were then be exponentially back-transformed to obtain point estimates and 90% CIs for the ratios of interest. In Part D, point estimates of the geometric mean ratios and corresponding 90% CI are provided for comparison of combination vs. monotherapy data (2 dose levels), for dose proportionality (150 vs. 75 mg alone and in combination), and across study day (Day 1 and Day 21). To assess capsule type (HPMC versus gelatin capsules) across cohorts (Parts B and D), a linear model was constructed based on pooled analysis using all data in Parts B and D with fixed effects of capsule type (HPMC or gelatin), BRAF dose level (75 or 150 mg BID), capsule type*dose level interaction, PK Day (Day 15 or 21), and MEK dose (0, 1, 1.5, or 2 mg). The analysis was repeated using only data obtained on Day 21 in the dosing cohort dabrafenib 150 mg BID/trametinib 2 mg QD. Point estimates and 90% CIs were calculated by analyte and PK parameter for the comparison of gelatin capsules and HPMC capsules. Efficacy Analyses Progression-Free Survival (PFS): PFS was defined as the interval of time between the date of randomization and the earlier of date of disease progression or date of death due to any cause. PFS was summarized using Kaplan-Meier estimates. Median times to PFS, first and third quartiles were presented, along with 95% CI; CIs for quartiles were estimated using the Brookmeyer-Crowley method. For the PFS comparison of each combination arm with the monotherapy arm, p-value based on two-sided log rank test was calculated; the Pike estimate of treatment hazard ratios (HRs) was provided, together with a 95% CI. The progression-free rate at 12 months was also summarized. Overall Response Rate (ORR): ORR was defined as the percentage of subjects achieving either a CR or PR per RECIST 1.1. Exact 95% CI for ORR were calculated. The ORR of each combination arm was compared to the monotherapy arm using exact test; 95% CIs for the differences in ORRs were calculated using the exact method. Duration of Response: For subjects who showed confirmed PR or CR, duration of response was defined to be the date of first documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause. The median duration of response, first and third quartiles together with 95% CIs were calculated from the Kaplan-Meier estimates. Overall Survival (OS): OS was defined as the interval of time between the date of randomization/first dose and the date of death due to any cause. For each treatment group, the Kaplan-Meier estimates for the median OS, and the first and third quartiles was presented, along with 95% CIs. CIs for quartiles were estimated using the Brookmeyer-Crowley method. For the OS comparison of each combination arm with the monotherapy arm, p- value based on two-sided log rank test was calculated; the Pike estimate of treatment HRs was provided, together with a 95% CI. Study Population: Key inclusion criteria included: Male or female of non-childbearing potential; 18 years of age Tumor type criteria: o BRAF mutation-positive melanoma or colorectal cancer (i.e., V600E, V600K or V600D) as determined via relevant genetic testing (in Parts A and B, other BRAF mutation-positive tumor types may be enrolled with approval of the GSK medical monitor). Testing with the GSK BRAF mutation assay may be required for enrolment. 4

5 Part A: No archived tissue required, but must have known BRAF mutation (i.e., V600E, V600K or V600D); Part B: Must have archived tissue requested, must have BRAF mutation (i.e., V600E, V600K or V600D); Subjects in BRAF mutant CRC-Pharmacodynamic cohort must be able to provide fresh tissue at screening and Day 15 of the study. Part C: Archived tissue is required; need fresh biopsy if archived tissue is not available, must have BRAF mutation (must be V600E, V600K or V600D). Only melanoma subjects can be enrolled. Part D: Archived tissue is required; need fresh biopsy if archived tissue is not available, must have documentation of BRAF mutation (must be V600E or V600K). Only melanoma subjects can be enrolled. Measurable disease per RECIST criteria (required for Part C and Part D enrollment). Key exclusion criteria included: Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK medical monitor. Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2). Part D: Prior exposure to BRAF or MEK inhibitors. A washout period of 6 weeks is required for ipilimumab. History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). Visible retinal pathology as assessed by ophthalmic exam that was considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, new visual field defects and intraocular pressure > 21 mm Hg as measured by tonography. Subjects with brain metastases were excluded, unless all known lesions were previously treated with surgery or stereotactic radiosurgery, and brain lesion(s), if still present, were confirmed stable (i.e. no increase in lesion size) for 90 days prior to first dose on study. PART A RESULTS SUBJECT DISPOSITION Dabrafenib 75 mg (Single Dose, Day 1 and Day 15) Trametinib (QD) 2 mg (Day 2 to Day 15) Number of Subjects 8 Planned, N 6 Enrolled, N 8 Completed, n (%) 1 Total Number Subjects Withdrawn, N (%) 7 (88) Withdrawn due to Adverse Events, n (%) 0 Withdrawn due to Lack of Efficacy, n (%) 0 Withdrawn for other reasons, n (%) 7 (88) DEMOGRAPHICS Dabrafenib 75 mg (Single Dose, Day 1 and Day 15) Trametinib (QD) 2 mg (Day 2 to Day 15) N (ITT) 8 Females: Males 2:6 Mean Age, years (SD) 52.8 (16.04) Race, n (%) White 7 (88) Asian & White 1 (13) PRIMARY ENDPOINT RESULTS Single dose PK parameters for single dose of dabrafenib, administered alone or in combination with trametinib Geometric Least Squares Mean Alone Combination Dabrafenib 75 mg (Single 75 mg (Single Dose, Day 1) Dose, Day 15) Trametinib (QD) -- 2 mg (Day 2 to Combination:Alone Ratio Estimate 90% CI 5

6 Day 15) N 8 8 Cmax (ng/ml) (0.79, 1.34) AUC(0-t) (ng hr/ml) (0.85, 1.19) AUC(0- ) (ng hr/ml) 3128 a (0.82, 1.08) a. Data could not be reported in 1 subject. PK parameters for dabrafenib metabolites following administration of single dose of dabrafenib, alone or in combination with trametinib Repeat dose administration of trametinib did not have a clinically significant effect on the single dose PK of dabrafenib metabolites. SECONDARY ENDPOINT RESULTS Trametinib concentrations during concomitant dabrafenib Median predose concentrations of trametinib were 9.7 and 10.6 ng/ml on Day 15 and 16, respectively. SAFETY RESULTS Most Frequent Adverse Events On-Therapy (AEs Reported by More Than 1 Subject) Dabrafenib 75 mg (Single Dose, Day 1 and Day 15) Trametinib (QD) 2 mg (Day 2 to Day 15) N 8 n (%) Subjects with any AE(s) 8 (100) Rash 6 (75) Fatigue 5 (63) Nausea 5 (63) Vomiting 5 (63) Decreased appetite 4 (50) Chills 3 (38) Cough 3 (38) Diarrhoea 3 (38) Pyrexia 3 (38) Skin papilloma 3 (38) Arthralgia 2 (25) Cellulitis 2 (25) Dermatitis acneiform 2 (25) Erythema 2 (25) Myalgia 2 (25) Neck pain 2 (25) Pain 2 (25) Pruritus 2 (25) Staphylococcal infection 2 (25) Vision blurred 2 (25) All Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib 75 mg (Single Dose, Day 1 and Day 15) Trametinib (QD) 2 mg (Day 2 to Day 15) N 8 n (%) [related] Subjects with any SAE(s) 5 (63) Nausea 2 (25) [0] Cellulitis 1 (13) [0] Convulsion 1 (13) [0] Diplopia 1 (13) [0] Dysphagia 1 (13) [0] Hemorrhage intracranial 1 (13) [0] Headache 1 (13) [0] 6

7 Neck pain 1 (13) [0] Pericarditis 1 (13) [0] Rectal hemorrhage 1 (13) [0] SCC 1 (13) [1] Upper airway obstruction 1 (13) [0] Vision blurred 1 (13) [0] Vomiting 1 (13) [0] Wound infection 1 (13) [0] Abbreviation: SCC=Squamous cell carcinoma. Fatal Serious Adverse Events On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib 75 mg (Single Dose, Day 1 and Day 15) Trametinib (QD) 2 mg (Day 2 to Day 15) N 8 n (%) [related] Subjects with any fatal SAE(s) 1 (13) [0] Convulsion 1 (13 [0] PART B RESULTS SUBJECT DISPOSITION Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose Number of Subjects Planned, N Enrolled, N Completed, n (%) Total Number Subjects Withdrawn, N (%) 1 (17) 3 (13) 6 (22) 15 (19) 21 (16) Withdrawn due to Adverse Events n (%) Withdrawn due to Lack of Efficacy n (%) Withdrawn for other reasons n (%) 1 (17) 3 (13) 6 (22) 15 (19) 21 (16) DEMOGRAPHICS Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N (ITT) Females: Males 2:4 10:13 12:15 44:35 68:67 Mean Age, years (SD) 48.2 (7.28) 54.2 (13.24) 52.2 (12.09) 51.5 (12.82) 52.0 (12.51) Race, n (%) White 6 (100) 22 (96) 26 (96) 77 (97) 131 (97) Asian (3) 2 (1) African American (4) 0 1 (<1) Missing 0 1 (4) (<1) PRIMARY ENDPOINT RESULTS Dose Limiting Toxicities and AEs Incidence of DLTs and AEs in Part B are reported in the Safety Results section. SECONDARY ENDPOINT RESULTS PK Results Plasma dabrafenib PK parameters following repeat dosing of dabrafenib 75 mg and 150 mg BID (gelatin capsules) administered in combination with trametinib 1.0, 1.5, or 2.0 mg QD Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Day 15 PK N tmax (hr) a 2.00 (1.03, 2.00) 2.00 (1.03, 6.00) 2.00 (1.00, 2.10) 1.50 (1.00, 2.00) 7

8 Cmax (ng/ml) b 640 (49.8) (390, 1048) 906 (109) (221, 3717) 1306 (53.6) (700, 2437) 1046 (42.8) (545, 2011) AUC(0-8) (ng*hr/ml) b 2177 (49.7) (1329, 3565) 3112 (63.3) (1237, 7834) 4507 (28.7) (3180, 6389) 3673 (61.6) (1490, 9054) AUC(0- ) (ng*hr/ml) b 2466 (53.4) (1458, 4171) 3539 (54.6) (1634, 7666) 5187 (26.9) (3737, 7199) 4114 (67.1) (1560, 10848) C (ng/ml) b 59.8 (151) (19.1, 187) 44.6 (66.3) (17.1, 117) 115 (163) (27.8, 472) 73.7 (191) (10.3, 528) CL/F (L/hr) b 30.4 (53.4) (18.0, 51.5) 42.4 (51.6) (19.6, 91.8) 28.9 (26.9) (20.8, 40.1) 36.5 (67.1) (13.8, 96.2) Day 21 PK N NA c tmax (hr) a NA c 1.54 (1.00, 2.00) 1.53 (1.00, 2.03) 2.04 (1.00, 4.03) Cmax (ng/ml) b NA c 1263 (48.0) (863, 1848) 1346 (50.0) (997, 1817) 1391 (40.8) (1002, 1932) AUC(0-8) (ng*hr/ml) b NA c 3892 (21.4) (3276, 4624) 3991 (40.1) (3123, 5100) 4901 (45.9) (3400, 7065) AUC(0- ) (ng*hr/ml) b NA c 4656 (21.4) (3901, 5557) 4528 (37.2) (3602, 5692) 5518 (49.5) (3732, 8158) C (ng/ml) b NA c 185 (132) (79.7, 428) 102 (115) (57.1, 184) 79.9 (150) (32.2, 198) CL/F (L/hr) b NA c 32.2 (21.4) (27.0, 38.5) 33.1 (37.2) (26.4, 41.6) 27.2 (49.5) (18.4, 40.2) Predose concentration was used as 12 hr concentrations to calculate AUC(0- ). Subject 270 in 150 mg/1 mg cohort received prohibited medication phenytoin and the Day 21 exposure from this subject was excluded from the summary statistics. Geometric mean Cmax and AUC(0- τ) were 1073 ng/ml and 4184 ng*hr/ml, respectively, including Subject 270. a. tmax reported as median (range) b. Data reported as geometric mean (CVb%) and (95%CI) c. NA: not applicable Plasma trametinib PK parameters following repeat dosing of trametinib 1.0, 1.5, or 2.0 mg QD in combination with dabrafenib 75 or 150 mg BID Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Day 15 PK N tmax (hr) a 2.00 (1.03, 1.00) 2.00 (1.00, 8.00) 2.00 (1.00, 8.00) 1.52 (1.00, 2.00) Cmax (ng/ml) b 10.2 (34.2) (7.18, 14.4) 8.08 (39.0) (5.06, 12.9) 11.5 (53.8) (6.16, 21.5) 22.4 (30.0) (14.0, 35.6) AUC(0-8) (ng*hr/ml) b 65.9 (38.5) (44.6, 97.3) 55.0 (36.6) (35.4, 85.4) 79.1 (42.7) (47.6, 131) 154 (31.9) (93.7, 252) AUC(0- ) (ng*hr/ml) b 169 (39.5) (113, 252) 147 (30.4) (101, 212) 217 (37.0) (139, 338) 394 (35.1) (229, 679) C (ng/ml) b 5.56 (39.3) (3.74, 8.28) 5.05 (22.9) (3.81, 6.69) 7.62 (28.5) (5.38, 10.8) 12.4 (42.3) (6.50, 23.6) CL/F (L/hr) b 5.91 (39.5) (3.96, 8.82) 6.83 (30.4) (4.72, 9.87) 6.93 (37.0) (4.44, 10.8) 5.07 (35.1) (2.95, 8.73) Day 21 PK N NA c tmax (hr) a NA c 2.00 (0.93, 8.00) 2.00 (1.00, 2.00) 2.00 (1.00, 8.15) Cmax (ng/ml) b NA c 10.2 (25.3) (8.50, 12.1) 18.0 (31.7) (14.9, 21.7) 22.6 (36.3) (18.1, 28.2) AUC(0-8) (ng*hr/ml) b NA c 65.7 (21.6) (22.9) 139 (34.2) 8

9 (56.4, 76.5) (95.3, 125) (112, 171) AUC(0- ) (ng*hr/ml) b NA c 169 (20.0) (146, 194) 269 (20.5) (238, 304) 351 (33.9) (284, 432) C (ng/ml) b NA c 5.57 (20.8) (4.80, 6.45) 8.51 (17.9) (7.65, 9.48) 10.8 (33.6) (8.75, 13.3) CL/F (L/hr) b NA c 5.93 (20.0) (5.15, 6.83) 5.58 (20.5) (4.94, 6.31) 5.70 (33.9) (4.63, 7.03) Predose concentration was used as 24 hr concentrations to calculate AUC(0- ). a. tmax reported as median (range) b. Data reported as geometric mean (CVb%) and (95%CI) c. NA: not applicable Steady-state PK of dabrafenib metabolites The PK parameters for dabrafenib metabolites were generally similar after repeat dosing of dabrafenib for 15 and 21 days across all doses investigated, suggesting that steady state was achieved by Day 15. The increase in plasma exposure of dabrafenib metabolites (Cmax and AUCs) was less than dose-proportional from 75 to 150 mg BID dabrafenib. The systemic exposure of dabrafenib metabolites were similar following repeat dosing of 150 mg BID dabrafenib in combination with different doses of trametinib (1.0, 1.5, and 2.0 mg QD). Geometric means (%CVb) of metabolite to parent ratios were (18.5%), 10.3 (25.8%) and (37.4%) for hydroxy-, carboxy- and desmethyl-dabrafenib, respectively, following administration of dabrafenib 150 mg BID and trametinib 2.0 mg daily (Day 21). Clinical Activity Results Investigator-Assessed ORR Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N Best Response, n (%) CR 0 4 (18) 0 2 (8) 6 (8) PR 4 (67) 10 (45) 11 (44) 13 (54) 38 (49) SD 2 (33) 7 (32) 11 (44) 9 (38) 29 (38) Non-CR/Non-PD (4) 0 1 (1) PD 0 1 (5) 2 (8) 0 3 (4) ORR CR+PR, n (%) 4 (67) 14 (64) 11 (44) 15 (63) 44 (57) 95% CI a (22.3, 95.7) (40.7, 82.8) (24.4, 65.1) (40.6, 81.2) (45.4, 68.4) Abbreviations: CR=Complete response; PD=Progressive disease; PR=Partial response; SD=Stable disease. a. CI calculated using the exact method. Investigator-Assessed Duration of Confirmed Response Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N N Progressed or Died (event), n (%) 3 (75) 9 (64) 6 (55) 8 (53) 26 (59) Censored, Follow-up ended, n (%) (7) 1 (2) Censored, Follow-up ongoing, n (%) 1 (25) 5 (36) 5 (45) 6 (40) 17 (39) Duration of response, months 1st Quartile (95% CI) 6.9 (3.7, 14.9) 5.5 (3.6, 9.2) 6.5 (3.7, 12.6) 9.1 (3.7, 16.9) 6.5 (3.9, 10.0) Median (95% CI) (3.7, 14.9) (5.5, -) 3rd Quartile (95% CI) (10.0,14.9) (7.6, -) a. Confidence interval calculated from the Kaplan-Meier estimates. Investigator-Assessed PFS (6.5, -) - (11.1, -) (9.1, 16.9) 16.9 (11.3, 16.9) Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg (9.2, 16.9) - (14.9, -) 9

10 Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N N Progressed or Died (event), n (%) 5 (83) 17 (77) 20 (80) 17 (71) 59 (77) Censored, Follow-up ended, n (%) (4) 1 (1) Censored, Follow-up ongoing, n (%) 1 (17) 5 (23) 5 (20) 6 (25) 17 (22) Estimates for PFS, months 1st Quartile (95%CI) a 5.3 (3.4, 11.8) 4.3 (3.5,7.3) 3.3 (2.9,4.5) 3.6 (3.5,9.1) 3.6 (3.5,5.3) Median (95%CI) a (5.3, 16.6) (5.4, 11.0) 3rd Quartile (95%CI) a (5.6, -) (9.2, -) a. Confidence interval calculated from the Kaplan-Meier estimates. SAFETY RESULTS Dose Limiting Toxicities (Primary Endpoint in Part B) (3.5, 12.8) 12.9 (5.5, -) (5.3, 14.4) 18.6 (11.3, 18.6) (5.5, 11.0) 14.8 (11.8, -) No DLTs were observed in the first 4 subjects of the first 3 dosing cohorts: o dabrafenib 75 mg BID / trametinib 1.0 mg QD o dabrafenib 150 mg BID / trametinib 1.0 mg QD o dabrafenib 150 mg BID / trametinib 1.5 mg QD One subject in the fourth cohort (dabrafenib 150 mg BID / trametinib 2.0 mg QD) experienced a DLT (Grade 1 neutrophilic panniculitis; considered drug-related by investigator) on Day 16. Dose escalation did not proceed beyond the fourth cohort (dabrafenib 150 mg BID / trametinib 2.0 mg QD); these doses represent the recommended single-agent doses for dabrafenib and trametinib monotherapy. Incidences of AEs in Part B (also a primary endpoint) are reported below. Most Frequent Adverse Events On-Therapy (AEs Reported by 15% of All Subjects) Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N n (%) Subjects with any AE(s) 6 (100) 23 (100) 27 (100) 79 (100) 135 (100) Pyrexia 4 (67) 12 (52) 14 (52) 55 (70) 85 (63) Fatigue 4 (67) 13 (57) 12 (44) 39 (49) 68 (50) Chills 3 (50) 10 (43) 11 (41) 38 (48) 62 (46) Nausea 2 (33) 10 (43) 11 (41) 39 (49) 62 (46) Headache 3 (50) 10 (43) 8 (30) 25 (32) 46 (34) Vomiting 2 (33) 6 (26) 10 (37) 28 (35) 46 (34) Diarrhoea 2 (33) 9 (39) 6 (22) 22 (28) 39 (29) Rash 2 (33) 5 (22) 9 (33) 21 (27) 37 (27) Cough 3 (50) 3 (13) 9 (33) 20 (25) 35 (26) Constipation 1 (17) 7 (30) 5 (19) 21 (27) 34 (25) Edema peripheral 0 5 (22) 6 (22) 19 (24) 30 (22) Arthralgia 2 (33) 4 (17) 5 (19) 16 (20) 27 (20) Decreased appetite 3 (50) 1 (4) 4 (15) 19 (24) 27 (20) Dizziness 1 (17) 3 (13) 5 (19) 17 (22) 26 (19) Night sweats 1 (17) 3 (13) 6 (22) 16 (20) 26 (19) Anemia 0 4 (17) 2 (7) 16 (20) 22 (16) Asthenia 0 6 (26) 4 (15) 11 (14) 21 (16) Hypotension 1 (17) 3 (13) 3 (11) 13 (16) 20 (15) Urinary tract infection 0 3 (13) 4 (15) 13 (16) 20 (15) All Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg 10

11 Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N n (%) [related] Subjects with any SAE(s) 0 12 (52) [8] 12 (44) [6] 44 (56) [27] 68 (50) [41] Pyrexia 0 4 (17) [2] 6 (22) [5] 19 (24) [18] 29 (21) [25] Chills 0 1 (4) [1] 2 (7) [2] 13 (16) [13] 16 (12) [16] Hypotension 0 1 (4) [1] 2 (7) [1] 5 (6) [0] 8 (6) [2] Dehydration 0 1 (4) [0] 2 (7) [1] 4 (5) [2] 7 (5) [3] Ejection fraction decreased (4) [1] 4 (5) [3] 5 (4) [4] SCC of skin 0 2 (9) [2] 2 (7) [1] 1 (1) [1] 5 (4) [4] Asthenia 0 2 (9) [1] 1 (4) [0] 1 (1) [0] 4 (3) [1] Basal cell carcinoma (4) [1] 3 (2) [1] Confusional state (7) [0] 1 (1) [1] 3 (2) [1] Convulsion (7) [0] 1 (1) [0] 3 (2) [0] Dizziness (7) [2] 1 (1) [0] 3 (2) [2] Influenza like illness 0 1 (4) [1] 1 (4) [1] 1 (1) [1] 3 (2) [3] Nausea 0 1 (4) [0] 1 (4) [1] 1 (1) [1] 3 (2) [2] Abdominal pain 0 1 (4) [0] 1 (4) [0] 0 2 (1) [0] Anaemia (3) [0] 2 (1) [0] Atrial fibrillation (4) [0] 1 (1) [0] 2 (1) [0] Back pain (4) [0] 1 (1) [0] 2 (1) [0] Dyspnoea (3) [0] 2 (1) [0] Failure to thrive (3) [0] 2 (1) [0] Hemiparesis 0 1 (4) [0] 1 (4) [0] 0 2 (1) [0] Hyperbilirubinaemia (3) [2] 2 (1) [2] Hyponatraemia (4) [0] 1 (1) [0] 2 (1) [0] Partial seizures (3) [0] 2 (1) [0] Pneumonia (4) [0] 1 (1) [0] 2 (1) [0] Pulmonary embolism (3) [0] 2 (1) [0] Renal failure acute (4) [0] 1 (1) [0] 2 (1) [0] SCC 0 1 (4) [1] 0 1 (1) [1] 2 (1) [2] Syncope 0 1 (4) [1] 0 1 (1) [0] 2 (1) [1] Vomiting 0 1 (4) [0] 0 1 (1) [1] 2 (1) [1] Abdominal distension 0 1 (4) [0] (<1) [0] Abdominal hernia (1) [0] 1 (<1) [0] Abdominal pain upper (1) [1] 1 (<1) [1] Abscess neck (1) [0] 1 (<1) [0] Addison's disease (1) [1] 1 (<1) [1] Appendicitis (4) [0] 0 1 (<1) [0] Cytokine release syndrome (1) [1] 1 (<1) [1] Device related sepsis (1) [0] 1 (<1) [0] Diarrhoea (4) [1] 0 1 (<1) [1] Diverticulitis 0 1 (4) [0] (<1) [0] Duodenal stenosis (4) [0] 0 1 (<1) [0] Fatigue (4) [0] 0 1 (<1) [0] Febrile neutropenia (1) [1] 1 (<1) [1] Flank pain (1) [0] 1 (<1) [0] Gastric ulcer haemorrhage (1) [0] 1 (<1) [0] Haemoptysis (1) [1] 1 (<1) [1] Headache (4) [0] 0 1 (<1) [0] Hepatic enzyme increased (1) [1] 1 (<1) [1] Hepatic infection (4) [0] 0 1 (<1) [0] Hypoglycaemia (1) [0] 1 (<1) [0] Large intestinal obstruction (1) [0] 1 (<1) [0] Large intestine perforation 0 1 (4) [0] (<1) [0] 11

12 Leukocytosis (1) [1] 1 (<1) [1] Leukopenia (1) [1] 1 (<1) [1] Melaena (1) [0] 1 (<1) [0] Mental status changes (4) [0] 0 1 (<1) [0] Metastases to spine (1) [0] 1 (<1) [0] Neuritis 0 1 (4) [0] (<1) [0] Neutropenia (4) [1] 0 1 (<1) [1] Obstructive airways disorder (1) [0] 1 (<1) [0] Oedema peripheral 0 1 (4) [0] (<1) [0] Pain (1) [0] 1 (<1) [0] Peritonitis (1) [0] 1 (<1) [0] Pharyngitis (4) [1] 0 1 (<1) [1] Rash (1) [1] 1 (<1) [1] Rash maculo-papular 0 1 (4) [0] (<1) [0] Sepsis (1) [0] 1 (<1) [0] Tachycardia (4) [0] 0 1 (<1) [0] VIIth nerve paralysis (1) [1] 1 (<1) [1] Vena cava thrombosis (1) [0] 1 (<1) [0] Ventricular arrhythmia (1) [1] 1 (<1) [1] WBC decreased 0 1 (4) [0] (<1) [0] Abbreviations: SCC=Squamous cell carcinoma; WBC=White blood cell. Fatal Serious Adverse Events On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib (BID) 75 mg 150 mg 150 mg 150 mg Trametinib (QD) 1 mg 1 mg 1.5 mg 2 mg Any Dose N n (%) [related] Subjects with any fatal SAE(s) (3) [1] 2 (2) [1] Hyponatremia (1) [0] 1 (<1) [0] Ventricular arrhythmia (1) [1] 1 (<1) [1] PART C RESULTS SUBJECT DISPOSITION Dabrafenib (BID) 150 mg 150 mg 150 mg Trametinib (QD) -- 1 mg 2 mg Number of Subjects Planned, N Randomised, N Completed, n (%) Total Number Subjects Withdrawn, N (%) 0 4 (7) 0 Withdrawn due to Adverse Events n (%) Withdrawn due to Lack of Efficacy n (%) Withdrawn for other reasons n (%) 0 4 (7) 0 DEMOGRAPHICS Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg N (ITT) Females: Males 25:29 24:30 20:34 Mean Age, years (SD) 51.8 (15.19) 49.9 (14.70) 55.9 (11.85) Race, n (%) White 52 (100) a 54 (100) 53 (98) Asian (2) a. Race information was not available for 2 subjects; the denominator is the number of subjects with race information entered. PRIMARY ENDPOINT RESULTS 12

13 Investigator-Assessed PFS Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg Progressed or Died (event), n (%) 47 (87) 39 (72) 31 (57) Censored, Follow-up ended, n (%) 1 (2) 2 (4) 3 (6) Censored, Follow-up ongoing, n (%) 6 (11) 13 (24) 20 (37) Hazard ratio Estimate (95% CI) (0.37, 0.87) 0.39 (0.25, 0.62) Log rank p-value < Kaplan-Meier Estimates for PFS, months 1st Quartile (95% CI) 3.8 (3.6, 5.5) 5.5 (3.7, 6.5) 5.8 (5.3, 8.7) Median (95% CI) 5.8 (4.6, 7.4) 9.2 (6.4, 11.0) 9.4 (8.6, 16.7) 3rd Quartile (95% CI) 9.1 (7.4, 9.4) 12.9 (11.0, -) 16.7 (12.4, 16.7) Kaplan-Meier Estimates for PFS at 12 months, % Estimate (95% CI) 9 (3, 20) 26 (15, 39) 41 (27, 54) Note: P-values are based on 2-sided log rank test. The censoring method included censoring for extended loss to follow-up, new anti-cancer therapy, and excluding symptomatic progression. a. HRs were estimated using the Pike estimator. A HR <1 indicates a lower risk with this treatment compared with the monotherapy group. b. Confidence intervals were estimated using the Brookmeyer Crowley method. Investigator-Assessed ORR Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg Best Response, n (%) CR 2 (4) 3 (6) 5 (9) PR 27 (50) 24 (44) 36 (67) SD 22 (41) 24 (44) 13 (24) PD 3 (6) 2 (4) 0 NE 0 1 (2) 0 ORR CR+PR, n (%) 29 (54) 27 (50) 41 (76) 95% CI a (39.6, 67.4) (36.1, 63.9) (62.4, 86.5) Difference in ORR Difference -- 4% 22% 95% CI a -- (-23.1, 15.9) (2.5, 40.7) P-value a Abbreviations: CR=Complete response; NE=Not evaluable; PD=Progressive disease; PR=Partial response; SD=Stable disease. Note: Subject 555 (150/1 combination therapy group [V600E, no prior brain metastases]) was NE due to death occurring before the first post-dose assessment. a. P-values and 95% CIs were calculated based on the unconditional exact method. Investigator-Assessed Duration of Confirmed Response Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg N Progressed or died (event), n (%) 25 (86) 15 (56) 21 (51) Censored, follow-up ended, n (%) 0 1 (4) 1 (2) Censored, follow-up ongoing, n (%) 4 (14) 11 (41) 19 (46) Duration of response, months 1st Quartile (95% CI) 3.9 (3.7, 5.5) 5.5 (3.7, 9.2) 6.3 (3.7, 8.1) Median (95% CI) 5.6 (4.5, 7.4) 9.5 (7.4, -) 10.5 (7.4, 14.9) 3rd Quartile (95% CI) 7.6 (5.6, 11.3) - (9.5, -) 14.9 (-, -) a. CIs were estimated using the Brookmeyer Crowley method. Incidence Rate of Cutaneous SCC 13

14 Incidence rates of SCC in the different treatment groups are presented in the Safety Results section. SECONDARY ENDPOINT RESULTS Population PK Results Population PK parameters: oral clearance (CL/F) and oral volume of distribution (V/F) of dabrafenib and trametinib Typical CL/F (non-inducible) and V/F values for dabrafenib were 19.4 L/hr and 80.8 L, respectively. The effect of concomitant trametinib resulted in a decrease in the inducible clearance (CLIND,SS/F of 20.0 L/hr) of dabrafenib with a ratio (90% CI) of (0.654, 0.724). Inducible clearance represents approximately half of the total oral clearance, and thus administration of the combination resulted in an increase in AUC(0- ) of 19%, relative to monotherapy. Dabrafenib exposure following administration of dabrafenib HPMC capsules in combination with trametinib was 46% and 33% higher for Cmax and AUC(0- ), respectively, relative to gelatin capsules. Typical CL/F and V/F for trametinib were 5.07 L/hr and 184 L, respectively. The effect of concomitant dabrafenib resulted in a decrease in oral bioavailability of trametinib with a ratio (90% CI) of (0.797, 0.887). Clinical Activity Results Overall Survival Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg Died (event), n (%) 19 (35) 18 (33) 14 (26) Censored, follow-up ended, n (%) 0 4 (7) 0 Censored, follow-up ongoing, n (%) 35 (65) 32 (59) 40 (74) Hazarad Ratio Estimate (95% CI) (0.51, 1.87) 0.67 (0.34, 1.34) Log rank p-value Kaplan-Meier Estimates for Overall Survival, months 1st Quartile (95% CI) 10.7 (7.9, 13.4) 10.3 (9.1, -) 12.7 (9.6, -) Median (95% CI) - (13.4, -) - (14.5, -) - (-, -) 3rd Quartile (95% CI) - (-, -) - (-, -) - (-, -) Estimated Survival at 12 months, % Rate (95% CI) 70 (55, 80) 68 (54, 79) 79 (66, 88) SAFETY RESULTS Incidence Rate of Cutaneous SCC (Primary Endpoint in Part C) Dabrafenib (BID) 150 mg 150 mg BID 150 mg Trametinib (QD) -- 1 mg 2 mg Number of events Incidence rate (proportion of subjects with 10 (19) 1 (2) 4 (7) events), n (%) Difference in incidence rate Difference -- 17% 12% P-value (2-sided) a,b a. P-values were based on the Fishers Exact test. b. Per protocol, 1-sided p-values for the differences in incidence rate were also calculated: p= for the 150/1 combination therapy group vs dabrafenib monotherapy, and p= for the 150/2 combination therapy group vs dabrafenib monotherapy. Most Frequent Adverse Events On-Therapy (AEs Reported by 15% of All Subjects) Dabrafenib (BID) 150 mg 150 mg 150 mg Trametinib (QD) -- 1 mg 2 mg N n (%) Subjects with any AE(s) 53 (100) 53 (98) 55 (100) Pyrexia 14 (26) 37 (69) 39 (71) Chills 9 (17) 27 (50) 32 (58) Fatigue 21 (40) 31 (57) 29 (53) 14

15 Nausea 11 (21) 25 (46) 24 (44) Vomiting 8 (15) 23 (43) 22 (40) Diarrhoea 15 (28) 14 (26) 20 (36) Cough 11 (21) 6 (11) 16 (29) Headache 15 (28) 20 (37) 16 (29) Oedema peripheral 9 (17) 13 (24) 16 (29) Arthralgia 18 (34) 24 (44) 15 (27) Rash 19 (36) 11 (20) 15 (27) Night sweats 3 (6) 8 (15) 13 (24) Constipation 6 (11) 9 (17) 12 (22) Decreased appetite 10 (19) 16 (30) 12 (22) Myalgia 12 (23) 13 (24) 12 (22) Back pain 6 (11) 6 (11) 10 (18) Dry skin 3 (6) 5 (9) 10 (18) Insomnia 4 (8) 6 (11) 10 (18) Abdominal pain upper 4 (8) 4 (7) 9 (16) Dermatitis acneiform 2 (4) 6 (11) 9 (16) Dizziness 5 (9) 7 (13) 9 (16) Muscle spasms 2 (4) 1 (2) 9 (16) Pain in extremity 10 (19) 6 (11) 9 (16) Abdominal pain 7 (13) 8 (15) 8 (15) Actinic keratosis 5 (9) 4 (7) 8 (15) Erythema 1 (2) 3 (6) 8 (15) Neutropenia 1 (2) 5 (9) 8 (15) Anaemia 3 (6) 11 (20) 7 (13) ALT increased 1 (2) 11 (20) 5 (9) AST increased 1 (2) 10 (19) 5 (9) Blood ALKP increased 1 (2) 12 (22) 5 (9) GGT increased 1 (2) 11 (20) 5 (9) Hyperkeratosis 16 (30) 3 (6) 5 (9) Influenza like illness 4 (8) 11 (20) 5 (9) PPES 9 (17) 4 (7) 4 (7) Alopecia 18 (34) 5 (9) 3 (5) Skin papilloma 8 (15) 4 (7) 2 (4) Pruritus generalised 8 (15) 3 (6) 0 Abbreviations: ALK-P=Alkaline phosphatise; ALT=Alanine aminotransferase; AST=Aspartate aminotransferase; GGT=Gamma glutamyltransferase; PPES=Palmar-plantar erythrodysaesthesia syndrome. All Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib (BID) 150 mg 150 mg 150 mg Trametinib (QD) -- 1 mg 2 mg N n (%) [related] Subjects with any SAE(s) 13 (25) [10] 20 (37) [16] 34 (62) [23] Pyrexia 1 (2) [1] 10 (19) [8] 14 (25) [13] Chills 1 (2) [1] 8 (15) [6] 10 (18) [9] Dehydration 0 1 (2) [1] 2 (4) [0] Ejection fraction decreased 0 1 (2) [1] 2 (4) [1] Pneumonia 1 (2) [0] 1 (2) [0] 2 (4) [1] Pulmonary embolism (4) [0] Renal failure acute 0 1 (2) [1] 2 (4) [2] SCC 3 (6) [3] 1 (2) [0] 2 (4) [2] Abdominal pain 1 (2) [0] 0 1 (2) [0] Back pain (2) [0] Brain stem haemorrhage (2) [0] 15

16 Cerebral haemorrhage (2) [0] Chorioretinopathy (2) [1] Colonic obstruction (2) [0] Cytokine release syndrome (2) [1] Endocarditis bacterial (2) [0] Febrile neutropenia (2) [0] Gastric haemorrhage (2) [0] Haemoptysis (2) [0] Haemorrhage intracranial (2) [0] Hyperhidrosis (2) [1] Hyponatraemia 0 1 (2) [0] 1 (2) [1] Influenza (2) [1] Intestinal perforation (2) [0] Intracranial hypotension (2) [0] Myalgia (2) [0] Neutropenia (2) [1] Parkinson's disease (2) [1] Pseudomonal sepsis (2) [1] Renal cell carcinoma (2) [0] Renal failure (2) [1] Respiratory failure (2) [0] Streptococcal sepsis (2) [0] Thrombocytopenia (2) [1] Viral infection (2) [0] Wound infection (2) [0] Abdominal distension 1 (2) [0] 0 0 Anaemia 1 (2) [0] 2 (4) [1] 0 Ascites 0 1 (2) [1] 0 Atrial fibrillation 1 (2) [1] 0 0 Basal cell carcinoma 1 (2) [1] 0 0 Cardiac failure 0 1 (2) [1] 0 Cholangitis 0 1 (2) [0] 0 Colitis 0 1 (2) [0] 0 Constipation 0 1 (2) [0] 0 Drug hypersensitivity 0 1 (2) [0] 0 Facial paresis 0 1 (2) [1] 0 Hyperbilirubinaemia 0 1 (2) [1] 0 Hypercalcaemia 0 1 (2) [1] 0 Influenza like illness 0 1 (2) [1] 0 Keratoacanthoma 2 (4) [2] 0 0 Mental status changes 0 1 (2) [0] 0 Muscular weakness 0 1 (2) [1] 0 Nausea 0 2 (4) [2] 0 Night sweats 0 1 (2) [1] 0 Pancreatitis 0 1 (2) [0] 0 Pancreatitis acute 0 1 (2) [0] 0 Pathological fracture 1 (2) [0] 0 0 Pleural effusion 1 (2) [0] 0 0 Presyncope 1 (2) [0] 0 0 Pyelonephritis 0 1 (2) [0] 0 Rash generalised 0 1 (2) [0] 0 Sepsis 0 1 (2) [0] 0 Skin infection 0 1 (2) [0] 0 Spinal compression fracture 1 (2) [0] 0 0 SCC of skin 4 (8) [4]

17 Streptococcal infection 0 1 (2) [0] 0 Urinary tract infection 1 (2) [0] 0 0 Urosepsis 1 (2) [0] 0 0 Vomiting 0 2 (4) [1] 0 Abbreviation: SCC=Squamous cell carcinoma. Fatal Serious Adverse Events On-Therapy n (%) [n considered by the investigator to be related to study medication] Dabrafenib (BID) 150 mg 150 mg 150 mg Trametinib (QD) -- 1 mg 2 mg N n (%) [related] Subjects with any fatal SAE(s) 0 1 (2) [0] 3 (5) [0] Brain stem haemorrhage (2) [0] Cerebral haemorrhage (2) [0] Haemorrhage intracranial (2) [0] Pulmonary embolism (2) [0] Sepsis 0 1 (2) [0] 0 PART D RESULTS SUBJECT DISPOSITION Dabrafenib (BID) 75 mg a 150 mg b 75 mg 150 mg Trametinib (QD) 2 mg a 2 mg b 2 mg 2 mg Any Dose Number of Subjects Planned, N Randomised, N Completed, n (%) Total Number Subjects Withdrawn, N (%) (7) 0 3 (3) Withdrawn due to Adverse Events n (%) Withdrawn due to Lack of Efficacy n (%) Withdrawn for other reasons n (%) (7) 0 3 (3) a. Subjects in this cohort received dabrafenib monotherapy (75 mg BID) for the first 28 days; subjects who had finished Day 21 serial PK sampling were subsequently allowed to receive dabrafenib 75 mg BID in combination with trametinib 2 mg QD from Day 29. b. Subjects in this cohort received dabrafenib monotherapy (150 mg BID) for the first 28 days; subjects who had finished Day 21 serial PK sampling were subsequently allowed to receive dabrafenib 150 mg BID in combination with trametinib 2 mg QD. DEMOGRAPHICS Dabrafenib (BID) 75 mg a 150 mg b 75 mg 150 mg Any Dose Trametinib (QD) 2 mg a 2 mg b 2 mg 2 mg N (ITT) Females: Males 6:6 8:8 18:25 14:25 46:64 Mean Age, years (SD) 51.8 (12.39) 53.1 (17.04) 52.8 (14.57) 56.7 (14.08) 54.1 (14.50) Race, n (%) White 12 (100) 16 (100) 43 (100) 39 (100) 110 (100) a. Subjects in this cohort received dabrafenib monotherapy (75 mg BID) for the first 28 days, followed by dabrafenib 75 mg BID in combination with trametinib 2 mg QD. b. Subjects in this cohort received dabrafenib monotherapy (150 mg BID) for the first 28 days, followed by dabrafenib 150 mg BID in combination with trametinib 2 mg QD. PRIMARY ENDPOINT RESULTS Dabrafenib plasma PK parameters following single- and repeat-dosing of dabrafenib 75 mg and 150 mg BID (HPMC capsules) administered alone and in combination with trametinib Dabrafenib (BID) 75 mg 150 mg 75 mg 150 mg Trametinib (QD) -- 2 mg -- 2 mg Day 1 PK N d 15 17

18 Tmax (hr) 2.00 ( ) 2.00 ( ) 2.00 ( ) 1.50 ( ) Cmax (ng/ml) 1117 (37.5) 1277 (63.7) 1669 (92.7) 2289 (68.8) AUC(0- ) (ng*hr/ml) 3593 (33.0) 4618 (51.8) 6507 (78.1) b 7331 (61.6) AUC(0- ) (ng*hr/ml) 3982 (32.0) b 5321 (41.1) c 7291 (76.9) b 8152 (62.2) b t1/2 (hr) 3.8 (23.3) b 3.9 (21.0) c 4.1 (19.9) b 3.6 (36.4) b Day 21 PK N 14 d 14 d 11 e 12 f Tmax (hr) 1.50 ( ) 1.75 ( ) 1.55 ( ) 1.50 ( ) Cmax (ng/ml) 1050 (47.0) 1217 (57.2) 1746 (40.5) 2052 (56.0) AUC(0- ) (ng*hr/ml) a 3020 (42.2) 3434 (45.1) 4663 (44.2) 5886 (40.0) C (ng/ml) 28.0 (175) 63.3 (149) 77.4 (215) 72.1 (106) Day 21:Day 1 Ratios AUC(0- ) Ratio 0.85 (38.6) 0.71 (34.6) 0.65 (79.5) b 0.73 (42.7) Note: PK parameters reported as geometric mean (%CV) except Tmax reported as median (min - max). a. Predose concentration was used as 12 hr concentrations to calculate AUC(0- ). b. Parameter could not be determined in 1 subject. c. Parameter could not be determined in 2 subjects. d. Parameters were available in 14 out of 15 subjects included in the PK population. e. Parameters were available in 11 out of 15 subjects included in the PK population. f. Parameters were available in 12 out of 15 subjects included in the PK population. Trametinib plasma PK parameters following single- and repeat-dosing of trametinib 2.0 mg QD in combination with dabrafenib 75 mg and 150 mg BID Dabrafenib (BID) 150 mg 150 mg Trametinib (QD) 2 mg 2 mg Day 1 PK N Tmax (hr) 2.00 ( ) 1.50 ( ) Cmax (ng/ml) 6.8 (74.9) 6.6 (85.7) AUC(0- ) (ng*hr/ml) 53.4 (57.8) 50.7 (46.8) Day 21 PK N Tmax (hr) 2.00 ( ) 2.00 ( ) Cmax (ng/ml) 24.1 (30.2) 22.6 (24.8) AUC(0- ) (ng*hr/ml) a 366 (32.3) 356 (19.3) C (ng/ml) 11.2 (34.3) 10.9 (22.6) Day 21:Day 1 Ratios AUC(0- ) Ratio 6.5 (34.4) 7.2 (42.8) PK parameters reported as geometric mean (%CV) except Tmax reported as median (min - max). a. Predose concentration was used as 24 hr concentrations to calculate AUC(0- ). SECONDARY ENDPOINT RESULTS PK Results Hydroxy-dabrafenib plasma PK parameters following single- and repeat-dosing of dabrafenib 75 mg and 150 mg BID (HPMC capsules) administered alone and in combination with trametinib Dabrafenib (BID) 75 mg 150 mg 75 mg 150 mg Trametinib (QD) -- 2 mg -- 2 mg Day 1 PK n Tmax (hr) 3.00 ( ) 3.00 ( ) 3.51 ( ) 2.07 ( ) Cmax (ng/ml) 525 (37.8) 597 (43.6) 1055 (79.3) 1363 (87.0) AUC(0- ) (ng*hr/ml) 3134 (39.9) 3694 (45.6) 5950 (71.0) b 6524 (74.3) AUC(0- ) (ng*hr/ml) 3963 (41.6) b 5026 (44.4) b 7415 (73.2) b 7907 (72.5) b t1/2 (hr) 4.3 (12.7) b 4.7 (19.8) b 4.3 (16.3) b 4.0 (17.7) b Day 21 PK n 14 d 14 d 11 e 12 f 18

19 Tmax (hr) 2.00 ( ) 2.00 ( ) 2.00 ( ) 2.00 ( ) Cmax (ng/ml) 596 (30.8) 696 (42.4) 1203 (44.2) 1120 (77.3) AUC(0- ) (ng*hr/ml) a 2568 (36.1) 2919 (41.3) b 4262 (55.6) 4216 (58.5) C (ng/ml) 47.7 (123) 80.8 (114) 109 (118) 83.3 (101) Ratio M:P (35.6) (26.8) b (38.5) (29.7) Day 21:Day 1 Ratios AUC(0- ) Ratio 0.83 (29.3) 0.72 (35.6) b 0.64 (97.1) b 0.59 (63.2) Note: PK parameters reported as geometric mean (%CV) except Tmax reported as median (min - max). a. Predose concentration was used as 12 hr concentrations to calculate AUC(0- ). b. Parameter could not be determined in 1 subject. c. Parameter could not be determined in 2 subjects. d. Parameters were available in 14 out of 15 subjects included in the PK population. e. Parameters were available in 11 out of 15 subjects included in the PK population. f. Parameters were available in 12 out of 15 subjects included in the PK population. Carboxy-dabrafenib plasma PK parameters following single- and repeat-dosing of dabrafenib 75 mg and 150 mg BID (HPMC capsules) administered alone and in combination with trametinib Dabrafenib (BID) 75 mg 150 mg 75 mg 150 mg Trametinib (QD) -- 2 mg -- 2 mg Day 1 PK N Tmax (hr) 10.0 ( ) 10.0 ( ) 8.93 ( ) 8.00 ( ) Cmax (ng/ml) 1475 (30.7) 1478 (39.4) 2268 (67.0) 2551 (75.9) AUC(0- ) (ng*hr/ml) (38.5) b 9575 (56.8) (82.3) (105) c AUC(0-t) (ng*hr/ml) (50.7) (39.3) (65.2) (126) Day 21 PK N 14 d 14 d 11 e 12 f Tmax (hr) 5.00 ( ) 5.98 ( ) 4.00 ( ) 4.00 ( ) Cmax (ng/ml) 3637 (27.1) 4158 (52.0) 6743 (42.4) 6319 (48.3) AUC(0- ) (ng*hr/ml) a (28.4) (54.9) (44.5) (45.2) C (ng/ml) 1998 (35.2) 2534 (67.6) 3622 (48.9) 2764 (39.6) Ratio M:P 10.7 (53.8) 10.9 (61.7) 12.0 (19.2) 8.5 (31.2) Day 21:Day 1 Ratios AUC(0- ) Ratio 3.3 (32.0) 4.2 (73.5) 3.6 (104) b 2.0 (32.6) c Note: PK parameters reported as geometric mean (%CV) except Tmax reported as median (min - max). a. Predose concentration was used as 12 hr concentrations to calculate AUC(0- ). b. Parameter could not be determined in 1 subject. c. Parameter could not be determined in 2 subjects. d. Parameters were available in 14 out of 15 subjects included in the PK population. e. Parameters were available in 11 out of 15 subjects included in the PK population. f. Parameters were available in 12 out of 15 subjects included in the PK population. Desmethyl-dabrafenib plasma PK parameters following single- and repeat-dosing of dabrafenib 75 mg and 150 mg BID (HPMC capsules) administered alone and in combination with trametinib Dabrafenib (BID) 75 mg 150 mg 75 mg 150 mg Trametinib (QD) -- 2 mg -- 2 mg Day 1 PK N 13 d Tmax (hr) 24.0 ( ) 24.0 ( ) 24.0 ( ) 24.0 ( ) Cmax (ng/ml) 50.1 (105) 61.2 (81.7) 68.6 (141) 86.3 (143) AUC(0- ) (ng*hr/ml) 132 (95.0) b 88.8 (97.4) 190 (129) b 354 (78.2) g AUC(0-t) (ng*hr/ml) 500 (135) 614 (80.1) 737 (147) 1316 (90.7) c Day 21 PK N 14 d 14 d 11 e 12 f Tmax (hr) 0.75 ( ) 2.00 ( ) 2.00 ( ) 1.75 ( ) Cmax (ng/ml) 210 (57.4) 289 (69.9) 355 (43.7) 440 (63.9) 19