A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma

PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference smallest sum on study, including baseline. In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of at least 5 millimeters (mm).

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 33 months)

Population: ITT population included all randomized participants, whether or not study treatment was received.

DOR was defined as the time from the first occurrence of a documented OR to PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study, including baseline. In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of at least 5 mm. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 56 months)

Population: ITT population included all randomized participants, whether or not study treatment was received. Only participants with measurable disease at baseline were analyzed for this outcome measure.

OS was defined as the time from randomization to death from any cause.

Time frame: Baseline up to death due to any cause (up to approximately 85 months)

Population: ITT population included all randomized participants, whether or not study treatment was received.

Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline. The percentage of ADA-positive participants after drug administration were determined for participants exposed to atezolizumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result.

Time frame: Pre-infusion Day 1 of Cycles 1-4 (1 Cycle=28 days); at Atezolizumab discontinuation (approximately up to 33 months)

Population: The ADA-evaluable population included participants who received at least one dose of atezolizumab and had ≥ 1 post-baseline ADA result. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Percentage of participants with OS which was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate 2-year landmark survival rate. The 95% CI of landmark survival rate was calculated using the standard error derived from Greenwood's formula.

Time frame: 2 years

Population: ITT population included all randomized participants, whether or not study treatment was received.

An AE is any untoward medical occurrence in a participant when administered a pharmaceutical product regardless of the causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. All AEs were reported until 30 days and SAEs until 90 days after the final dose of study treatment or until initiation of subsequent anti-cancer therapy, whichever occurred first.

Time frame: Up to approximately 85 months

Population: Safety population included all participants who received any amount of any atezolizumab, cobimetinib, or vemurafenib. 26 were included in the placebo+cobi+vem arm for safety evaluation (22 participants in atezo+cobi+vem arm stopped run-in treatment \& didn't received atezo \& 4 in atezo+cobi+vem arm completed the run-in treatment but did not receive atezo). During the study, 2 participants in placebo+cobi+vem arm received atezo \& were considered in the atezo+cobi+vem arm for safety analysis.

OR rate was defined as percentage of participants with partial response (PR) or complete response (CR) on 2 consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 56 months)

Population: ITT population included all randomized participants, whether or not study treatment was received. Only participants with measurable disease at baseline were analyzed for this outcome measure.

PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by the IRC according to RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study, including baseline. In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of at least 5 mm.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 33 months)

Population: ITT population included all randomized participants, whether or not study treatment was received.

Time frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cycles 1 and 4 (1 Cycle = 28 days)

Population: The Cobi PK-evaluable population included all participants who received any dose of cobimetinib 20/40 mg and for whom at least one evaluable PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Time frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cycles 1 and 4 (1 Cycle = 28 days)

Population: The Cobi PK-evaluable population included all participants who received any dose of Cobimetinib 60 mg and for whom at least one evaluable PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Time frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cycles 1 and 4 (1 Cycle = 28 days)

Population: The Vem PK-evaluable population included all participants who received any dose of vemurafenib and for whom at least one evaluable PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Time frame: Pre-infusion Day 1 of Cycles 1-4; 30 minutes post-infusion Day 1 of Cycles 1 and 4; at Atezolizumab discontinuation (up to approximately 33 months) (1 Cycle = 28 days)

Population: Pharmacokinetic (PK)-evaluable population included all participants who have received any dose of atezolizumab and for whom at least one evaluable PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Time to deterioration in GHS/health related quality of life (HRQoL) was defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. EORTC QLQ-C30 consists of 30 questions that assess five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The GHS/QoL are scored on a 7-point scale (1=Very Poor to 7=Excellent). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level and better QoL.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 33 months)

Population: ITT population included all randomized participants, whether or not study treatment was received.

Time to deterioration in PF = time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed PF scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). PF scale has 5 questions about participant's PF and daily activities (strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves, or using the toilet). PF are scored on a 4-point scale (1=Not at All to 4=Very Much). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level, functioning/support.

Time frame: Baseline up to PD or death due to any cause, whichever occurred first (up to approximately 33 months)

Population: ITT population included all randomized participants, whether or not study treatment was received.