Supplementary Appendix

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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367: DOI: /NEJMoa (PDF updated January 3, 2013.)

2 Supplementary Appendix Supplement to: Flaherty KT, Infante JI, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations Contents Acknowledgments page 2 Supplementary methods page 2 Supplementary figure 1 page 6 Supplementary figure 2a page 7 Supplementary figure 2b page 8 Supplementary figure 3 page 9 Supplementary figure 4 page 10 Supplementary table 1 page 11 Supplementary table 2 page 12 Supplementary table 3 page 13 Supplementary table 4 page 14 Supplementary table 5 page 15 1

3 Acknowledgements We also thank our investigators and study staff who contributed to the study (listed in alphabetical order by country): Australia: Ludwig Institute for Cancer Research, Austin Hospital- Miles Andrews; Westmead-Arthur Clements, the staff of Sydney West Cancer Trials Centre, and the Surgical, Dermatology and Anatomical Pathology staff of Westmead Hospital and Melanoma Institute Australia; USA: University of Pennsylvania Abramson Cancer Center- Ravi Amaravadi, Lydia Giles; Vanderbilt University- Kristin Ancell; Angeles Clinic- Peter Boasberg; U.T. MD Anderson Cancer Center- Wen-Jen Hwu; University of Colorado Denver-Amanda Iman; University of California San Francisco- Andrea Kantor; Massachusetts General Hospital- Donald Lawrence; Mayo Clinic- Robert McWilliams; Sarah Cannon Research Institute/Tennessee Oncology- Salah Nabhan; Dana Farber Cancer Institute- Geoffrey Shapiro; Johns Hopkins Sidney Kimmel Cancer Center at Green Spring Station- William Sharfman; Yale Medical Center- Mario Sznol; Moffitt Cancer Center- Patricia Urbas. Supplementary methods Eligibility Brain metastases were considered stable if they met the following criteria: asymptomatic with no corticosteroids and/or enzyme-inducing anticonvulsants for 30 days, confirmed stable with two consecutive magnetic resonance imaging (MRI) or computed tomography (CT) scans 90 days apart, and previously treated with surgery or stereotactic radiosurgery; those with untreated brain metastases were excluded. 2

4 Patients with a history of cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy were also excluded. Assessments A baseline disease assessment, using CT scan or MRI of chest, abdomen and pelvis, was performed and repeated every 8 weeks. Responses were assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST; 1.1). Adverse events, graded using the Common Terminology Criteria for Adverse Events (CTCAE; version 4.0), were assessed throughout the study and for 14 days after treatment was discontinued. Demographic data and disease characteristics were recorded at baseline. Patients also underwent a physical examination, which included electrocardiogram (ECG) and echocardiogram (ECHO), and ophthalmologic evaluation at baseline. In addition, patients vital signs and ECOG-PS were recorded at this time. Physical examinations and assessment of ECOG-PS were repeated at every cycle, ECG and ECHO assessments were repeated at Week 4, and then every 12 weeks, while ophthalmologic evaluations were repeated as clinically indicated. Chemistry and hematology were assessed every 4 weeks. A baseline disease assessment, using CT scan or MRI of chest, abdomen and pelvis, was performed and repeated every 8 weeks. Responses were assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST; 1.1). Adverse events, graded using the Common Terminology Criteria for Adverse Events 3

5 (CTCAE; version 4.0), were assessed throughout the study and for 14 days post treatment. Pharmacokinetics Samples for PK analyses were obtained at timed intervals up to 24 hours after a single dose of dabrafenib on Day 1 and with trametinib on Day 15 in Part A; on Day 15, or Day 21 using serial samples up to 8 hours post-dose in Part B; and pre-dose on Day 15, and then every 8 weeks in Part C. Plasma concentrations of dabrafenib and its metabolites, and trametinib were analyzed using validated methods. Statistical methods PFS was defined as the time from first dose (Part B) or randomization (Part C) to the first documented radiological progression or death, based on investigator assessment. PFS and OS were estimated using the Kaplan Meier method and comparisons utilized a log-rank test. RR and duration of response are reported for each treatment group, along with the 95% confidence interval (CI), and between-group comparisons were conducted. Safety analyses included all patients who had received 1 dose of study medication and are summarized by frequency and proportion of the total population. Serious adverse events and those leading to treatment discontinuation are summarized separately. Study Oversight This study (NCT ) was funded, administrated, and sponsored by GlaxoSmithKline. The original protocol was designed by Keith Flaherty, M.D. and the 4

6 sponsor. The sponsor collected and analyzed the data and vouches for such data and analysis. All authors had access to all study data. The lead authors (K.T.F., J.R.I., and J.W.) developed the first draft of the manuscript in collaboration with the sponsor. All authors reviewed subsequent drafts and are responsible for the decision to publish. 5

7 Supplemental Figure 1 - CONSORT diagram * * One patient was randomized to dabrafenib monotherapy but received 150/2 combination. As a result, a total of 55 subjects received combination 150/2 in Part C 6

8 Supplemental Figure 2a - Dabrafenib Pharmacokinetics in Part B Patients 7

9 Supplemental Figure 2b - Trametinib Pharmacokinetics in Part B Patients 8

10 Supplemental Figure 3 - Overall Survival in Part C 9

11 Supplemental Figure 4 - Independent Review Committee Assessed Progression Free Survival in Part C 10

12 Supplementary Tables Table S1. Part C - Study medication exposure, dose interruptions, and dose reductions Part C/randomized Phase II (n=162) Dabrafenib Monotherapy (n=53) Combination 150 mg/1 mg (n=54) Combination 150mg/ 2 mg (n=55) Exposure Median duration on study treatment, months (min, max) 6.1 (1.8, 15.2) 10.5 (0.9, 16.4) 11.0 (2.1, 17.3) Dose Interruptions due to toxicity any dose interruption, n (%) 15 (28) 32 (59) 37 (67) dabrafenib dose interruption, n (%) 15 (28) 31 (57) 34 (62) trametinib dose interruption, n (%) NA 29 (54) 35 (64) Dose Reductions due to toxicity any dose reduction 10 (19) 27 (50) 32 (58) dabrafenib dose reduction, n (%) 10 (19) 27 (50) 30 (55) re-escalation, n(%)* 9 (90) 20 (74) 28 (93) trametinib dose reduction, n (%) NA 1 (2) 12 (22) re-escalation, n(%)** NA 0 4 (33) * For percentage calculation, the denominator is the number of subjects with dabrafenib reduction. ** For percentage calculation, the denominator is the number of subjects with trametinib dose reduction. One subject was randomized to dabrafenib monotherapy but received combination 150/2. This subject was included in combination 150/2 safety analyses. 11

13 Table S2. Part A - Assessment of repeat-dose trametinib on single-dose dabrafenib pharmacokinetics Dabrafenib PK parameter Number of patients (Day 1/Day 15) Geometric Least-Squares Mean Ratio for Day 15/Day 1 (90% CI) AUC (0-t) (ng.hr/ml) 8/ (0.85, 1.19) AUC (0-inf) (ng.hr/ml) 7/ (0.82, 1.08) C max (ng/ml) 8/ (0.79, 1.34) 12

14 Table S3. Parts A and B - Patient characteristics at baseline Characteristic Parts A and B* (n=85) All doses Median age, years (range) 52.8 (25-80) Male gender, n (%) 53 (62%) White race, n (%) 83 (98%) ECOG performance status, n (%) 0 1 M status, n (%) M0 M1a M1b M1c 45 (53%) 40 (47%) 0 6 (7%) 11 (13%) 68 (80%) Disease sites 3, n (%) 60 (71%) History of brain metastases, n (%) 22 (26%) LDH > upper limit of normal, n (%) 41 (48%) BRAF mutation status, n (%) V600E V600K 77 (91) 7 (8) Previous chemotherapy, n (%) 49 (58%) Previous immunotherapy, n (%) 26 (31%) *Other patients included in Part B (dose escalation) were: BRAF inhibitor-treated melanoma (n=26), colorectal (n=28), other tumor types (n=4, 1 non-small cell lung, 1 thyroid, 1 salivary ductal carcinoma, and 1 large cell neuroendocrine carcinoma). One patient in Part A/B was V600R. 13

15 Table S4. Part B - Summary of efficacy endpoints 75 mg BID/ 1 mg QD (n=6) 150 mg BID/ 1 mg QD (n=22) 150 mg BID/ 1.5 mg QD (n=25) 150 mg BID/ 2 mg QD (n=24) Median PFS, months (95% CI) 8.7 (5.3,16.6) 8.2 (5.4, 11.0) 5.4 (3.5, 12.8) 10.8 (5.3, 14.4) PFS rate at 12 months, % (95% CI) 33 (5, 68) 27 (11, 46) 32 (15, 50) 44 (24, 63) Best Response, months (%) Complete Response (CR) 0 4 (18) 0 2 (8) Partial Response (PR) 4 (67) 10 (45) 11 (44) 13 (54) Stable Disease (SD) 2 (33) 7 (32) 11 (44) 9 (38) Non-CR/Non-PD (4) 0 Progressive Disease (PD) 0 1 (5) 2 (8) 0 Response Rate CR+PR (%) 4 (67) 14 (64) 11 (44) 15 (63) 95% CI 22.3, , , , 81.2 Median Duration of Response, months (95% CI) 12.4 (3.7, 14.9) 8.4 (5.5, NA) 12.6 (6.5, NA) 11.3 (9.1, 16.9) 14

16 Table S5. Part B - Adverse events in >20% regardless of causal relationship 75 mg BID/ 1 mg QD (n=6) 150 mg BID/ 1 mg QD (n=22) 150 mg BID/ 1.5 mg QD (n=25) 150 mg BID/ 2 mg QD (n=24) Grade 3/4 Total Grade 3/4 Total Grade 3/4 Total Grade 3/4 Total Any event 3 (50) 6 (100) 13 (59) 22 (100) 12 (48) 25 (100) 12 (50) 24 (100) Pyrexia 0 4 (67) 1 (5) 12 (55) 1 (4) 13 (52) 2 (8) 21 (88) Chills 1 (17%) 3 (50) 1 (5%) 10 (45) 0 10 (40) 1 (4) 18 (75) Fatigue 0 4 (67) 2 (9) 12 (55) 2 (8) 12 (48) 1 (4) 13 (54) Headache 0 3 (50) 0 10 (45) 0 7 (28) 0 11 (46) Nausea 0 2 (33) 1 (5) 9 (41) 0 10 (40) 0 10 (42) Cough 0 3 (50) 0 3 (14) 0 9 (36) 0 10 (42) Rash 0 2 (33) 0 4 (18) 0 8 (32) 0 10 (42) Vomiting 0 2 (33) 1 (5) 6 (27) 0 8 (32) 1 (4) 9 (38) Diarrhea 0 2 (33) 2 (9) 9 (41) 0 6 (24) 0 9 (38) Arthralgia 1 (17) 2 (33) 0 4 (18) 1 (4) 4 (16) 0 9 (38) Acneiform dermatitis (5) 0 3 (12) 0 8 (33) Night sweats 0 1 (17) 0 3 (14) 0 6 (24) 0 7 (29) Dizziness 0 1 (17) 0 3 (14) 0 4 (16) 0 7 (29) Constipation 0 1 (17) 0 6 (27) 0 5 (20) 0 6 (25) Edema peripheral (23) 0 5 (20) 0 6 (25) Decreased appetite 0 3 (50) 0 1 (5) 0 4 (16) 0 6 (25) Pain in extremity 0 1 (17) 0 4 (18) 0 1 (4) 0 5 (21) 15

17 Ejection fraction decreased (5) 0 1 (4) 0 5 (21) Oropharyngeal pain (5) 0 1 (4) 0 5 (21) Anaemia (18) 1 (4) 2 (8) 1 (4) 5 (21) Abdominal pain 0 2 (33) 1 (5) 4 (18) 1 (4) 2 (8) 0 3 (13) Asthenia (9) 6 (27) 1 (4) 4 (16) 0 2 (8) Rash generalized 1 (17) 2 (33) 0 3 (14) (4) Pain 0 2 (33) 0 2 (9) 0 2 (8) 0 0 Vision blurred 0 2 (33) 0 3 (14) 0 2 (8)

Supplementary Appendix

Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib