Trial Outcomes & Findings for A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3) (NCT NCT01006980)

Last Updated: 2016-09-28

Results Overview

A progression-free survival (PFS) event was defined as disease progression or death due to any cause. Tumor response (progression) was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria using computed tomography (CT) scans or magnetic resonance imaging (MRI).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

675 participants

Primary outcome timeframe

From randomization (initiated January 2010) to December 30 2010.

Results posted on

2016-09-28

Participant Flow

675 participants were randomized, 337 to vemurafenib and 338 to dacarbazine. One participant randomized to dacarbazine was treated in error with vemurafenib throughout the study and is included in the Vemurafenib arm in the table below and for exposure and safety analyses and is included in the dacarbazine arm for efficacy analyses.

Participant milestones

Participant milestones
Measure	Vemurafenib Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Vemurafenib and Dacarbazine STARTED	337	338
Vemurafenib and Dacarbazine Treated	336	293
Vemurafenib and Dacarbazine COMPLETED	0	0
Vemurafenib and Dacarbazine NOT COMPLETED	337	338
Crossover: Dacarbazine to Vemurafenib STARTED	0	84
Crossover: Dacarbazine to Vemurafenib COMPLETED	0	0
Crossover: Dacarbazine to Vemurafenib NOT COMPLETED	0	84

Reasons for withdrawal

Reasons for withdrawal
Measure	Vemurafenib Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Vemurafenib and Dacarbazine Randomized but Not Treated	1	45
Vemurafenib and Dacarbazine Adverse Event	25	5
Vemurafenib and Dacarbazine Death	13	12
Vemurafenib and Dacarbazine Progression	257	218
Vemurafenib and Dacarbazine Withdrawal of Consent	4	6
Vemurafenib and Dacarbazine Refuse Treatment	9	6
Vemurafenib and Dacarbazine Protocol Violation	2	3
Vemurafenib and Dacarbazine Reason Not Specified	26	43
Crossover: Dacarbazine to Vemurafenib Adverse Event	0	4
Crossover: Dacarbazine to Vemurafenib Death	0	4
Crossover: Dacarbazine to Vemurafenib Progression	0	65
Crossover: Dacarbazine to Vemurafenib Withdrawal of Consent	0	1
Crossover: Dacarbazine to Vemurafenib Reason Not Specified	0	10

Baseline Characteristics

A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vemurafenib n=337 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=338 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).	Total n=675 Participants Total of all reporting groups
Age, Customized < 65 years	244 participants n=5 Participants	270 participants n=7 Participants	514 participants n=5 Participants
Age, Customized >=65 years	93 participants n=5 Participants	68 participants n=7 Participants	161 participants n=5 Participants
Sex: Female, Male Female	137 Participants n=5 Participants	157 Participants n=7 Participants	294 Participants n=5 Participants
Sex: Female, Male Male	200 Participants n=5 Participants	181 Participants n=7 Participants	381 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization (initiated January 2010) to December 30 2010. Median follow-up time in the vemurafenib group was 3.75 months (range 0.3 to 10.8) and in the dacarbazine group was 2.33 months (range <0.1 to 10.3).

Population: The intent-to-treat (ITT) population was defined as all randomized participants, whether or not study treatment was received. The ITT population was analyzed according to the treatment assigned at randomization. Overall survival was assessed on participants randomized at least 15 days prior to the clinical cutoff date of December 30, 2010.

An Overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported.

Outcome measures

Outcome measures
Measure	Vemurafenib n=336 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=336 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Overall Survival Participants with events	43 participants	75 participants
Overall Survival Participants without events	293 participants	261 participants

PRIMARY outcome

Timeframe: From randomization (initiated January 2010) to December 30 2010.

Population: The analysis population for PFS consisted of all ITT participants randomized by October 27, 2010 (at least 9 weeks prior to the clinical cutoff date of December 30, 2010). The 9-week interval was chosen to allow time for participants to have had their first scheduled post baseline tumor assessment CT scan.

Outcome measures

Outcome measures
Measure	Vemurafenib n=275 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=274 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Progression-free Survival Participants with events	104 participants	182 participants
Progression-free Survival Participants without events	171 participants	92 participants

SECONDARY outcome

Timeframe: From randomization (initiated January 2010) until December 30, 2010

Population: The analysis population consisted of all ITT participants randomized by September 22, 2010 (at least 14 weeks prior to the clinical cutoff date of December 30, 2010). The 14-week interval was chosen as it was the minimum time needed to observe a confirmed overall response according to protocol-specified schedule for the first two tumor assessments.

BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Participants who never received study treatment and treated participants without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion and no new lesion.

Outcome measures

Outcome measures
Measure	Vemurafenib n=219 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=220 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Participants With a Best Overall Response (BOR) of Complete Response or Partial Response Responders	106 participants	12 participants
Participants With a Best Overall Response (BOR) of Complete Response or Partial Response Non-responders	113 participants	208 participants

SECONDARY outcome

Timeframe: From randomization (initiated in January 2010) until December 30, 2010.

Population: The analysis population included all participants randomized by September 22, 2010 and with a best overall confirmed response of complete response or partial response.

Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause. Duration of response was calculated only for participants who had a best overall response of Complete Response or Partial Response and was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Vemurafenib n=106 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=12 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Duration of Response	5.49 months Interval 3.98 to 5.72	NA months Interval 4.6 to Median duration of response was not reached as only 2 of the 12 participants with a qualifying response had subsequent disease progression or death due to any cause at the time of the analysis.

SECONDARY outcome

Timeframe: From randomization (initiated January 2010) until December 30, 2010.

Population: The analysis population included all participants randomized by September 22, 2010 and with a best overall confirmed response of complete response or partial response.

Time to response was defined as the time from randomization to confirmed response (complete response or partial response).

Outcome measures

Outcome measures
Measure	Vemurafenib n=106 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=12 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Time to Confirmed Response	1.45 months Interval 1.0 to 5.5	2.72 months Interval 1.6 to 5.8

SECONDARY outcome

Timeframe: approximately 3 years

Treatment failure was defined as a secondary endpoint in the protocol, defined as death, disease progression or premature withdrawal of study treatment. This endpoint was not included in the Statistical analysis plan; therefore no analyses of time to treatment failure were performed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From randomization (initiated January 2010) until December 30, 2010.

Population: The safety population was defined as all treated participants who had at least one on-study assessment. The safety population was analyzed according to the treatment received.

The intensity of AEs was graded according to the NCI Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a five-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening and Death). A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution, for example is life-threatening, requires hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or requires intervention to prevent one or other of the outcomes listed above.

Outcome measures

Outcome measures
Measure	Vemurafenib n=336 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=282 Participants Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Number of Participants With Adverse Events (AEs) Any adverse event	326 participants	253 participants
Number of Participants With Adverse Events (AEs) Serious adverse event	110 participants	45 participants

SECONDARY outcome

Timeframe: Plasma samples were collected before the morning dose (troughs) and 2-4 hours after the morning dose at the beginning of each cycle (Days 1, 22, 43, 64, 106, 148 and 190).

Population: The pharmacokinetic (PK) analysis population included all participants who received vemurafenib and provided valid PK assessments. The PK population at specific time points varied depending on the availability of confirmed dosing and PK assessment times. "n" indicates the number of participants with available PK data at each time point.

The pharmacokinetics of vemurafenib were assessed at the beginning of each 21-day cycle using pre-dose and 2-4 hours post-dose sampling.

Outcome measures

Outcome measures
Measure	Vemurafenib n=260 Participants Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 1 (n = 260)	0 μg/mL Standard Deviation 0	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 1 (n = 255)	4.3 μg/mL Standard Deviation 4.35	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 22 (n = 204)	53.0 μg/mL Standard Deviation 26.66	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 22 (n = 221)	54.0 μg/mL Standard Deviation 25.67	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 43 (n = 166)	54.4 μg/mL Standard Deviation 24.13	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 43 (n = 170)	54.4 μg/mL Standard Deviation 23.28	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 64 (n = 141)	57.4 μg/mL Standard Deviation 23.79	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 64 (n = 138)	57.7 μg/mL Standard Deviation 22.29	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 106 (n = 77)	55.0 μg/mL Standard Deviation 17.62	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 106 (n = 75)	56.3 μg/mL Standard Deviation 20.36	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 148 (n = 38)	51.8 μg/mL Standard Deviation 24.13	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 148 (n = 39)	53.3 μg/mL Standard Deviation 21.55	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Pre-Dose Day 190 (n = 9)	53.6 μg/mL Standard Deviation 12.6	—
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day Post-Dose Day 190 (n = 9)	50.5 μg/mL Standard Deviation 20.16	—

Adverse Events

Vemurafenib

Serious events: 165 serious events

Other events: 333 other events

Deaths: 0 deaths

Dacarbazine

Serious events: 52 serious events

Other events: 247 other events

Deaths: 0 deaths

Vemurafenib After Crossover

Serious events: 44 serious events

Other events: 83 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Vemurafenib n=336 participants at risk Adverse events reported for this group include those occurring in participants receiving vemurafenib starting at their baseline visit. Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=293 participants at risk Adverse events reported for this group include those occurring in participants receiving dacarbazine starting at their baseline visit until study discontinuation or treatment switch. Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).	Vemurafenib After Crossover n=84 participants at risk Adverse events reported for this group include those occurring following switch to vemurafenib in those participants who switched from dacarbazine to vemurafenib during the study.
General disorders Device occlusion	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Fatigue	0.60% 2/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Gait disturbance	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders General physical health deterioration	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Malaise	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Oedema peripheral	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Pyrexia	1.5% 5/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.4% 4/293 • Baseline through the end of study (maximum exposure: 57.07 months)	3.6% 3/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Hepatobiliary disorders Cholecystitis	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Hepatobiliary disorders Hepatitis acute	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Immune system disorders Hypersensitivity	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Anaemia	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Bone marrow failure	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Neutropenia	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Acute myocardial infarction	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Atrial fibrillation	0.89% 3/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Atrial tachycardia	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Cardiac arrest	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Cardiac failure	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Cardiac failure congestive	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Cardiac tamponade	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Cardiopulmonary failure	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Coronary artery disease	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Myocardial infarction	0.60% 2/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Pericardial effusion	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Cardiac disorders Pericarditis	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Eye disorders Diplopia	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Eye disorders Orbital oedema	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Eye disorders Uveitis	0.89% 3/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal pain	0.60% 2/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal pain lower	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal pain upper	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Constipation	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Diarrhoea haemorrhagic	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Gastric ulcer	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.60% 2/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Gastrointestinal ulcer	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Gastrooesophageal reflux disease	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Intussusception	0.00% 0/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)

Other adverse events
Measure	Vemurafenib n=336 participants at risk Adverse events reported for this group include those occurring in participants receiving vemurafenib starting at their baseline visit. Participants received continuous oral doses of vemurafenib (RO5185426) 960 mg twice a day. Participants took four 240 mg tablets in the morning and four 240 mg tablets in the evening (960 mg twice a day for a total daily dose of 1920 mg).	Dacarbazine n=293 participants at risk Adverse events reported for this group include those occurring in participants receiving dacarbazine starting at their baseline visit until study discontinuation or treatment switch. Dacarbazine was administered intravenously 1000 mg/m˄2 up to 60 minutes on Day 1 of every 3 weeks (3 weeks was one cycle length).	Vemurafenib After Crossover n=84 participants at risk Adverse events reported for this group include those occurring following switch to vemurafenib in those participants who switched from dacarbazine to vemurafenib during the study.
Skin and subcutaneous tissue disorders Rash Maculo-Papular	10.1% 34/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	11.9% 10/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Anaemia	9.5% 32/336 • Baseline through the end of study (maximum exposure: 57.07 months)	7.5% 22/293 • Baseline through the end of study (maximum exposure: 57.07 months)	15.5% 13/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Neutropenia	0.30% 1/336 • Baseline through the end of study (maximum exposure: 57.07 months)	11.6% 34/293 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Blood and lymphatic system disorders Thrombocytopenia	1.5% 5/336 • Baseline through the end of study (maximum exposure: 57.07 months)	6.8% 20/293 • Baseline through the end of study (maximum exposure: 57.07 months)	1.2% 1/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal Distension	5.4% 18/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.7% 5/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal Pain	10.4% 35/336 • Baseline through the end of study (maximum exposure: 57.07 months)	4.1% 12/293 • Baseline through the end of study (maximum exposure: 57.07 months)	3.6% 3/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Abdominal Pain Upper	11.0% 37/336 • Baseline through the end of study (maximum exposure: 57.07 months)	2.7% 8/293 • Baseline through the end of study (maximum exposure: 57.07 months)	6.0% 5/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Constipation	15.5% 52/336 • Baseline through the end of study (maximum exposure: 57.07 months)	24.6% 72/293 • Baseline through the end of study (maximum exposure: 57.07 months)	9.5% 8/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Diarrhoea	36.9% 124/336 • Baseline through the end of study (maximum exposure: 57.07 months)	12.3% 36/293 • Baseline through the end of study (maximum exposure: 57.07 months)	28.6% 24/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Dyspepsia	6.0% 20/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.68% 2/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Nausea	39.3% 132/336 • Baseline through the end of study (maximum exposure: 57.07 months)	43.7% 128/293 • Baseline through the end of study (maximum exposure: 57.07 months)	39.3% 33/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Gastrointestinal disorders Vomiting	21.7% 73/336 • Baseline through the end of study (maximum exposure: 57.07 months)	26.3% 77/293 • Baseline through the end of study (maximum exposure: 57.07 months)	23.8% 20/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Asthenia	14.9% 50/336 • Baseline through the end of study (maximum exposure: 57.07 months)	9.9% 29/293 • Baseline through the end of study (maximum exposure: 57.07 months)	8.3% 7/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Chest Pain	7.7% 26/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.7% 5/293 • Baseline through the end of study (maximum exposure: 57.07 months)	4.8% 4/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Chills	6.8% 23/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.0% 3/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Fatigue	47.0% 158/336 • Baseline through the end of study (maximum exposure: 57.07 months)	34.5% 101/293 • Baseline through the end of study (maximum exposure: 57.07 months)	38.1% 32/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Influenza Like Illness	8.6% 29/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.7% 5/293 • Baseline through the end of study (maximum exposure: 57.07 months)	3.6% 3/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Oedema Peripheral	14.6% 49/336 • Baseline through the end of study (maximum exposure: 57.07 months)	5.1% 15/293 • Baseline through the end of study (maximum exposure: 57.07 months)	9.5% 8/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Pain	8.9% 30/336 • Baseline through the end of study (maximum exposure: 57.07 months)	4.8% 14/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Peripheral Swelling	7.7% 26/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	6.0% 5/84 • Baseline through the end of study (maximum exposure: 57.07 months)
General disorders Pyrexia	21.1% 71/336 • Baseline through the end of study (maximum exposure: 57.07 months)	8.9% 26/293 • Baseline through the end of study (maximum exposure: 57.07 months)	21.4% 18/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Infections and infestations Conjunctivitis	6.0% 20/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Infections and infestations Folliculitis	8.3% 28/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.0% 3/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Infections and infestations Influenza	5.4% 18/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.4% 4/293 • Baseline through the end of study (maximum exposure: 57.07 months)	3.6% 3/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Infections and infestations Nasopharyngitis	10.7% 36/336 • Baseline through the end of study (maximum exposure: 57.07 months)	3.4% 10/293 • Baseline through the end of study (maximum exposure: 57.07 months)	4.8% 4/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Infections and infestations Upper Respiratory Tract Infection	5.7% 19/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.7% 5/293 • Baseline through the end of study (maximum exposure: 57.07 months)	4.8% 4/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Injury, poisoning and procedural complications Sunburn	17.0% 57/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	17.9% 15/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Alanine Aminotransferase Increased	8.3% 28/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.4% 4/293 • Baseline through the end of study (maximum exposure: 57.07 months)	7.1% 6/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Aspartate Aminotransferase Increased	7.4% 25/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.0% 3/293 • Baseline through the end of study (maximum exposure: 57.07 months)	9.5% 8/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Blood Alkaline Phosphatase Increased	9.8% 33/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.00% 0/293 • Baseline through the end of study (maximum exposure: 57.07 months)	10.7% 9/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Blood Bilirubin Increased	9.2% 31/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	2.4% 2/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Blood Creatinine Increased	8.3% 28/336 • Baseline through the end of study (maximum exposure: 57.07 months)	0.34% 1/293 • Baseline through the end of study (maximum exposure: 57.07 months)	8.3% 7/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Gamma-Glutamyltransferase Increased	7.1% 24/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.4% 4/293 • Baseline through the end of study (maximum exposure: 57.07 months)	8.3% 7/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Investigations Weight Decreased	9.5% 32/336 • Baseline through the end of study (maximum exposure: 57.07 months)	2.7% 8/293 • Baseline through the end of study (maximum exposure: 57.07 months)	4.8% 4/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Metabolism and nutrition disorders Decreased Appetite	22.6% 76/336 • Baseline through the end of study (maximum exposure: 57.07 months)	8.2% 24/293 • Baseline through the end of study (maximum exposure: 57.07 months)	23.8% 20/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Musculoskeletal and connective tissue disorders Arthralgia	56.2% 189/336 • Baseline through the end of study (maximum exposure: 57.07 months)	3.1% 9/293 • Baseline through the end of study (maximum exposure: 57.07 months)	57.1% 48/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Musculoskeletal and connective tissue disorders Back Pain	15.8% 53/336 • Baseline through the end of study (maximum exposure: 57.07 months)	6.8% 20/293 • Baseline through the end of study (maximum exposure: 57.07 months)	13.1% 11/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	13.1% 44/336 • Baseline through the end of study (maximum exposure: 57.07 months)	3.8% 11/293 • Baseline through the end of study (maximum exposure: 57.07 months)	14.3% 12/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Musculoskeletal and connective tissue disorders Myalgia	14.9% 50/336 • Baseline through the end of study (maximum exposure: 57.07 months)	1.7% 5/293 • Baseline through the end of study (maximum exposure: 57.07 months)	17.9% 15/84 • Baseline through the end of study (maximum exposure: 57.07 months)
Musculoskeletal and connective tissue disorders Pain In Extremity	22.6% 76/336 • Baseline through the end of study (maximum exposure: 57.07 months)	6.1% 18/293 • Baseline through the end of study (maximum exposure: 57.07 months)	16.7% 14/84 • Baseline through the end of study (maximum exposure: 57.07 months)