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

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

Time frame: 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.

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).

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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

Time frame: 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.

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

Time frame: 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.

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.

Time frame: approximately 3 years