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

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ClinicalTrials.gov Identifier: NCT02908672

Recruitment Status : Active, not recruiting

First Posted : September 21, 2016

Results First Posted : November 19, 2020

Last Update Posted : March 22, 2024

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Sponsor:

Information provided by (Responsible Party):

Hoffmann-La Roche

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Melanoma
Interventions	Drug: Atezolizumab Drug: Atezolizumab Placebo Drug: Cobimetinib Drug: Vemurafenib Drug: Vemurafenib Placebo
Enrollment	514

Participant Flow

Recruitment Details
Pre-assignment Details	22 participants in the experimetal arm stopped treatment during the run-in period and received no atezo. 4 more in the experimental arm completed the run-in period but did not receive atezolizumab and were included in the safety population. 3 participants from the control arm were not treated with either cobimetinib or vemurafenib.


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Period Title: Overall Study
Started	258	256
Completed	0	0
Not Completed	258	256
Reason Not Completed
Death	112	93
Lost to Follow-up	3	3
Other	2	0
Protocol Violation	1	1
Withdrawal by Subject	13	18
Study is ongoing	124	141
Discontinued the study during run-in	3	0

Baseline Characteristics

Arm/Group Title		Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo	Total
Arm/Group Description		Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...	Total of all reporting groups
Arm/Group Description		Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Total of all reporting groups
Overall Number of Baseline Participants		258	256	514
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	258 participants	256 participants	514 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	199 77.1%	195 76.2%	394 76.7%
	>=65 years	59 22.9%	61 23.8%	120 23.3%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	258 participants	256 participants	514 participants
		53.2 (14.1)	54.0 (14.2)	53.6 (14.1)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	258 participants	256 participants	514 participants
	Female	109 42.2%	106 41.4%	215 41.8%
	Male	149 57.8%	150 58.6%	299 58.2%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	258 participants	256 participants	514 participants
	Hispanic or Latino	20 7.8%	27 10.5%	47 9.1%
	Not Hispanic or Latino	225 87.2%	223 87.1%	448 87.2%
	Unknown or Not Reported	13 5.0%	6 2.3%	19 3.7%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	258 participants	256 participants	514 participants
	American Indian or Alaska Native	1 0.4%	1 0.4%	2 0.4%
	Asian	4 1.6%	7 2.7%	11 2.1%
	Native Hawaiian or Other Pacific Islander	1 0.4%	0 0.0%	1 0.2%
	Black or African American	0 0.0%	1 0.4%	1 0.2%
	White	246 95.3%	243 94.9%	489 95.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	6 2.3%	4 1.6%	10 1.9%

Outcome Measures

1.Primary Outcome


Title	Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Description	PFS is defined as the time from randomization to the first occurrence ...
Description	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Median (95% Confidence Interval) Unit of Measure: Months
	10.6 (9.3 to 12.7)	15.1 (11.4 to 18.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atezolizumab Placebo + Cobimetinib + Vemurafenib, Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0249
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	95% 0.63 to 0.97
	Estimation Comments	Stratified Hazard Ratio

2.Secondary Outcome


Title	Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1
Description	PFS is defined as the time from randomization to the first occurrence ...
Description	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Median (95% Confidence Interval) Unit of Measure: Months
	12.3 (10.8 to 14.7)	16.1 (11.3 to 18.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atezolizumab Placebo + Cobimetinib + Vemurafenib, Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1607
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.67 to 1.06
	Estimation Comments	Stratified Hazard Ratio

3.Secondary Outcome


Title	Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1
Description	Objective response is defined as a CR or PR on two consecutive occasio...
Description	Objective response is defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

ITT Population with measurable disease at baseline


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	246	255
Measure Type: Number Unit of Measure: Percentage
Responders	65.0	66.3
Non-Responders	35.0	33.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atezolizumab Placebo + Cobimetinib + Vemurafenib, Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7701
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95% -7.30 to 9.77
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Duration of Response, as Determined by Investigator Using RECIST v1.1
Description	DOR, defined as the time from the first occurrence of a documented obj...
Description	DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

ITT Population with measurable disease at baseline


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	246	255
Median (95% Confidence Interval) Unit of Measure: Months
	12.6 (10.5 to 16.6)	21.0 ^[1] (15.1 to NA)

[1]

Insufficient number of participants with event.

5.Secondary Outcome


Title	Overall Survival
Description	OS is defined as the time from randomization to death from any cause
Description	OS is defined as the time from randomization to death from any cause
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Median (95% Confidence Interval) Unit of Measure: Months
	25.1 ^[1] (22.3 to NA)	28.8 ^[1] (27.4 to NA)

[1]

Insufficient number of participants with event.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atezolizumab Placebo + Cobimetinib + Vemurafenib, Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2310
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.64 to 1.11
	Estimation Comments	Stratified Hazard Ratio

6.Secondary Outcome


Title	Percentage of Participants Who Have Survived at 2 Years
Description	2-year landmark survival, defined as survival at 2 years
Description	2-year landmark survival, defined as survival at 2 years
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage
	53.07 (46.20 to 59.93)	60.44 (53.77 to 67.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atezolizumab Placebo + Cobimetinib + Vemurafenib, Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1312
	Comments	[Not Specified]
	Method	z test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in event free rate
	Estimated Value	-7.37
	Confidence Interval	95% -16.95 to 2.20
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Scale Score
Description	Time to deterioration in global health status/healthrelated quality of...
Description	Time to deterioration in global health status/healthrelated quality of life (GHS/HRQoL), 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. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (15.0 to NA)	14.4 ^[1] (9.2 to NA)

[1]

Insufficient number of participants with event.

8.Secondary Outcome


Title	Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score
Description	Time to deterioration in physical functioning, defined as the time fro...
Description	Time to deterioration in physical functioning, defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	258	256
Median (95% Confidence Interval) Unit of Measure: Months
	22.4 ^[1] (15.7 to NA)	17.5 ^[1] (11.7 to NA)

[1]

Insufficient number of participants with event.

9.Secondary Outcome


Title	Percentage of Participants With Adverse Events and Serious Adverse Events
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Baseline up to 6 months after the last dose of study treatment (approximately 33 months)

Outcome Measure Data

Analysis Population Description

Safety-evaluable population,


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	281	230
Measure Type: Number Unit of Measure: Percentage
	99.6	100

10.Secondary Outcome


Title	Serum Concentration of Atezolizumab
Description	[Not Specified]
Description	[Not Specified]
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)

Outcome Measure Data

Analysis Population Description

PK Evaluable Population


Arm/Group Title		Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:		Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:		Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed		0	223
Mean (Standard Deviation) Unit of Measure: ug/mL
Cycle 1 Day 1/30 Min Postdose	Number Analyzed	0 participants	187 participants
Cycle 1 Day 1/30 Min Postdose			281 (111)
Cycle 2 Day 1/Predose	Number Analyzed	0 participants	186 participants
Cycle 2 Day 1/Predose			102 (47.4)
Cycle 3 Day 1/Predose	Number Analyzed	0 participants	171 participants
Cycle 3 Day 1/Predose			149 (61.9)
Cycle 4 Day 1/Predose	Number Analyzed	0 participants	159 participants
Cycle 4 Day 1/Predose			181 (75.5)
Cycle 4 Day 1/30 Min Postdose	Number Analyzed	0 participants	144 participants
Cycle 4 Day 1/30 Min Postdose			431 (158)
Study Drugs Discontinuation Visit	Number Analyzed	0 participants	101 participants
Study Drugs Discontinuation Visit			122 (97.7)

11.Secondary Outcome


Title	Plasma Concentration of Cobimetinib Dose: 20/40 mg
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population is defined as all participants who have received any dose of Cobimetinib 20/40 mg and for whom at least one evaluable PK sample is collected.


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	218	208
Mean (Standard Deviation) Unit of Measure: mg
Cycle 1 Day 15/Predose	79.9 (72.2)	144 (101)
Cycle 1 Day 15/3-6 Hr Postdose	167 (116)	216 (145)
Cycle 4 Day 15/Predose	108 (97.5)	92.3 (79.5)
Cycle 4 Day 15/3-6 Hr Postdose	167 (126)	171 (140)

12.Secondary Outcome


Title	Plasma Concentration of Cobimetinib Dose: 60 mg
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population is defined as all participants who have received any dose of Cobimetinib 60 mg and for whom at least one evaluable PK sample is collected.


Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:	Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed	218	208
Mean (Standard Deviation) Unit of Measure: mg
Cycle 1 Day 15/Predose	169 (171)	216 (188)
Cycle 1 Day 15/3-6 Hr Postdose	278 (206)	375 (243)
Cycle 4 Day 15/Predose	150 (113)	151 (120)
Cycle 4 Day 15/3-6 Hr Postdose	240 (195)	256 (197)

13.Secondary Outcome


Title	Plasma Concentration of Vemurafenib
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)

Outcome Measure Data

Analysis Population Description

Vemurafenib PK was characterized in the PK-evaluable population, of 218 out of 255 treated in the placebo+cobi+vem arm and 209 out of 256 treated in the atezo+cobi+vem arm.


Arm/Group Title		Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:		Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:		Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed		218	209
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: μg/mL
Cycle 1 Day 15/ predose	Number Analyzed	199 participants	179 participants
Cycle 1 Day 15/ predose		38.9 (100%)	27.0 (102%)
Cycle 1 Day 15/ 3-6 hr	Number Analyzed	205 participants	168 participants
Cycle 1 Day 15/ 3-6 hr		41.3 (57.7%)	28.0 (88.6%)
Cycle 4 Day 15/ predose	Number Analyzed	168 participants	158 participants
Cycle 4 Day 15/ predose		39.2 (105%)	24.7 (202%)
Cycle 4 Day 15/ 3-6 hr postdose	Number Analyzed	168 participants	154 participants
Cycle 4 Day 15/ 3-6 hr postdose		42.3 (59.4%)	26.5 (135%)

14.Secondary Outcome


Title	Percentage of Participants Positive for Anti-Drug Antibodies (ADA) to Atezolizumab
Description	Presence of ADAs against atezolizumab during the study relative to the...
Description	Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline
Time Frame	Pre-infusion Day 1 of Cycles 1-4; at Atezolizumab discontinuation (up to approximately 90 months)(1 Cycle=28 days) (approximately up to 33 months)

Outcome Measure Data

Analysis Population Description

The ADA-evaluable population was defined as participants who received at least one dose of Atezolizumab and had ≥ 1 post-baseline ADA result.


Arm/Group Title		Atezolizumab Placebo + Cobimetinib + Vemurafenib	Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description:		Run-In Period (Cycle1=28 days): Par...	Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description:		Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.	Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
Overall Number of Participants Analyzed		0	218
Measure Type: Number Unit of Measure: Percentage
Baseline evaluable participants	Number Analyzed	0 participants	208 participants
Baseline evaluable participants			1.4
Post-baseline evaluable participants	Number Analyzed	0 participants	218 participants
Post-baseline evaluable participants			13.3

Adverse Events

Time Frame	From baseline to primary data cut-off (up to 2 years 9 months).
Adverse Event Reporting Description	22 participants in the atezo+cobi+vem arm stopped treatment during the run-in period and received no atezo and 4 more in the atezo+cobi+vem arm completed the run-in period but did not receive atezolizumab. These 26 participants were included in the placebo+cobi+vem arm for safety evaluation. 3 participants from the placebo+cobi+vem arm were not treated with either cobimetinib or vemurafenib.

Arm/Group Title	Atezolizumab Placebo + Cobimetinib + Vemurafenib		Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
Arm/Group Description	Run-In Period (Cycle1=28 days): Par...		Run-In Period (Cycle 1=28 days): Pa...
Arm/Group Description	Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.		Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
All-Cause Mortality
	Atezolizumab Placebo + Cobimetinib + Vemurafenib		Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	120/281 (42.70%)		85/230 (36.96%)
Serious Adverse Events Serious Adverse Events
	Atezolizumab Placebo + Cobimetinib + Vemurafenib		Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/281 (39.86%)		103/230 (44.78%)
Blood and lymphatic system disorders
AGRANULOCYTOSIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
LEUKOPENIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
NEUTROPENIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
THROMBOCYTOPENIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Cardiac disorders
ACUTE CORONARY SYNDROME ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
ACUTE MYOCARDIAL INFARCTION ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
ARRHYTHMIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
ATRIAL FIBRILLATION ^† 1	1/281 (0.36%)	2	2/230 (0.87%)	2
BRADYCARDIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
CARDIAC ARREST ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
CARDIAC FAILURE ^† 1	1/281 (0.36%)	1	3/230 (1.30%)	3
LEFT VENTRICULAR FAILURE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
MYOCARDIAL INFARCTION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
MYOCARDIAL ISCHAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PALPITATIONS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PERICARDITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
STRESS CARDIOMYOPATHY ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
TACHYCARDIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
VENTRICULAR ARRHYTHMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Ear and labyrinth disorders
VERTIGO ^† 1	2/281 (0.71%)	2	1/230 (0.43%)	1
Endocrine disorders
HYPERTHYROIDISM ^† 1	2/281 (0.71%)	2	3/230 (1.30%)	3
HYPOPHYSITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Eye disorders
CHORIORETINOPATHY ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
DETACHMENT OF RETINAL PIGMENT EPITHELIUM ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
EYE PAIN ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
MACULOPATHY ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
UVEITIS ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
Gastrointestinal disorders
AUTOIMMUNE COLITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
AUTOIMMUNE PANCREATITIS ^† 1	1/281 (0.36%)	2	0/230 (0.00%)	0
COLITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
DIARRHOEA ^† 1	4/281 (1.42%)	4	2/230 (0.87%)	2
FAECALOMA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
GASTRITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
GASTRITIS EROSIVE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
GASTROINTESTINAL HAEMORRHAGE ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
ILEUS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
INTUSSUSCEPTION ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
OESOPHAGITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
OESOPHAGITIS HAEMORRHAGIC ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PANCREATITIS ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
PANCREATITIS ACUTE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PANCREATITIS NECROTISING ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
RECTAL HAEMORRHAGE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
SMALL INTESTINAL OBSTRUCTION ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
VOLVULUS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
VOMITING ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
General disorders
ASTHENIA ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
FATIGUE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
GENERAL PHYSICAL HEALTH DETERIORATION ^† 1	4/281 (1.42%)	4	2/230 (0.87%)	2
INFLUENZA LIKE ILLNESS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PYREXIA ^† 1	12/281 (4.27%)	14	13/230 (5.65%)	19
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Hepatobiliary disorders
AUTOIMMUNE HEPATITIS ^† 1	3/281 (1.07%)	4	0/230 (0.00%)	0
CHOLANGITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
CHOLECYSTITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
CHOLECYSTITIS ACUTE ^† 1	0/281 (0.00%)	0	3/230 (1.30%)	3
HEPATIC FAILURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HEPATITIS ^† 1	0/281 (0.00%)	0	4/230 (1.74%)	4
HEPATITIS FULMINANT ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HEPATOTOXICITY ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
HYPERTRANSAMINASAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Immune system disorders
HYPERSENSITIVITY ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
SARCOIDOSIS ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
Infections and infestations
ARTHRITIS BACTERIAL ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
ATYPICAL PNEUMONIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
BACTERAEMIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
BACTERIAL INFECTION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	2
BACTERIAL PROSTATITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
BARTHOLIN'S ABSCESS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
CELLULITIS ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
ENCEPHALITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
ERYSIPELAS ^† 1	2/281 (0.71%)	3	2/230 (0.87%)	2
GASTROENTERITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
INFECTION ^† 1	2/281 (0.71%)	2	2/230 (0.87%)	2
INFLUENZA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
LARGE INTESTINE INFECTION ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
LOWER RESPIRATORY TRACT INFECTION ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
MENINGITIS ASEPTIC ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
ORAL HERPES ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PERITONITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PHARYNGOTONSILLITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PNEUMONIA ^† 1	5/281 (1.78%)	5	7/230 (3.04%)	9
POSTOPERATIVE WOUND INFECTION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
SEPSIS ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
SEPTIC SHOCK ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
SERRATIA BACTERAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
SOFT TISSUE INFECTION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
UPPER RESPIRATORY TRACT INFECTION ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	3
URINARY TRACT INFECTION ^† 1	2/281 (0.71%)	2	4/230 (1.74%)	4
UROSEPSIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
VASCULAR DEVICE INFECTION ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
VIRAL INFECTION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Injury, poisoning and procedural complications
HUMERUS FRACTURE ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
INFUSION RELATED REACTION ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
LIGAMENT RUPTURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	2
LOWER LIMB FRACTURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
STERNAL FRACTURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED ^† 1	2/281 (0.71%)	2	5/230 (2.17%)	5
ASPARTATE AMINOTRANSFERASE INCREASED ^† 1	1/281 (0.36%)	1	4/230 (1.74%)	4
BLOOD CREATINE PHOSPHOKINASE INCREASED ^† 1	6/281 (2.14%)	7	1/230 (0.43%)	1
BODY TEMPERATURE INCREASED ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
EJECTION FRACTION DECREASED ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
ELECTROCARDIOGRAM QT PROLONGED ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	4
HEPATIC ENZYME INCREASED ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
LIPASE INCREASED ^† 1	2/281 (0.71%)	2	2/230 (0.87%)	2
NEUTROPHIL COUNT DECREASED ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
WHITE BLOOD CELL COUNT DECREASED ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Metabolism and nutrition disorders
DEHYDRATION ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
HYPERGLYCAEMIA ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
HYPERKALAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HYPOGLYCAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HYPOKALAEMIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
HYPONATRAEMIA ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
METABOLIC ACIDOSIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
TYPE 2 DIABETES MELLITUS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
BACK PAIN ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
FRACTURE PAIN ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HYPERCREATINAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
MUSCULAR WEAKNESS ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
MYOSITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
OSTEOARTHRITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PATHOLOGICAL FRACTURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
RHABDOMYOLYSIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
LIP NEOPLASM ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
LIPOSARCOMA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
MALIGNANT MELANOMA ^† 1	2/281 (0.71%)	2	1/230 (0.43%)	1
MALIGNANT MELANOMA IN SITU ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
NON-HODGKIN'S LYMPHOMA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PAPILLARY THYROID CANCER ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PROSTATE CANCER ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
SQUAMOUS CELL CARCINOMA ^† 1	1/281 (0.36%)	1	1/230 (0.43%)	1
SQUAMOUS CELL CARCINOMA OF SKIN ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
TUMOUR PAIN ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Nervous system disorders
APHASIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
CEREBRAL ISCHAEMIA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
CEREBROVASCULAR ACCIDENT ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
DIZZINESS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
ENCEPHALITIS AUTOIMMUNE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
EPILEPSY ^† 1	1/281 (0.36%)	1	4/230 (1.74%)	4
FACIAL PARALYSIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
GUILLAIN-BARRE SYNDROME ^† 1	0/281 (0.00%)	0	2/230 (0.87%)	2
HAEMORRHAGIC STROKE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HEADACHE ^† 1	1/281 (0.36%)	3	0/230 (0.00%)	0
HYDROCEPHALUS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
HYPERTONIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
IMMUNE-MEDIATED ENCEPHALITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
LETHARGY ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
LIMBIC ENCEPHALITIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
LOSS OF CONSCIOUSNESS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PERIPHERAL SENSORIMOTOR NEUROPATHY ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
SEIZURE ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
SYNCOPE ^† 1	0/281 (0.00%)	0	3/230 (1.30%)	3
TRANSIENT ISCHAEMIC ATTACK ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Psychiatric disorders
ALCOHOL ABUSE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
DELIRIUM ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
MENTAL STATUS CHANGES ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY ^† 1	1/281 (0.36%)	1	5/230 (2.17%)	5
NEPHRITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PRERENAL FAILURE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
RENAL COLIC ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
RENAL FAILURE ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
URETEROLITHIASIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PELVIC PAIN ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PROSTATITIS ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
DYSPNOEA ^† 1	1/281 (0.36%)	1	2/230 (0.87%)	2
HAEMOPTYSIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
INTERSTITIAL LUNG DISEASE ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
LUNG DISORDER ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PLEURAL EFFUSION ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
PNEUMONITIS ^† 1	3/281 (1.07%)	3	3/230 (1.30%)	3
PULMONARY EMBOLISM ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
PULMONARY HAEMORRHAGE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
RESPIRATORY FAILURE ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
VOCAL CORD LEUKOPLAKIA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Skin and subcutaneous tissue disorders
ANGIOEDEMA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
ERYTHEMA MULTIFORME ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
NEUTROPHILIC DERMATOSIS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
PHOTOSENSITIVITY REACTION ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
PURPURA ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
RASH ^† 1	5/281 (1.78%)	5	1/230 (0.43%)	1
RASH ERYTHEMATOUS ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
RASH MACULO-PAPULAR ^† 1	4/281 (1.42%)	4	2/230 (0.87%)	2
RASH PAPULAR ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
STEVENS-JOHNSON SYNDROME ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
TOXIC SKIN ERUPTION ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
Vascular disorders
ATHEROEMBOLISM ^† 1	1/281 (0.36%)	1	0/230 (0.00%)	0
HYPERTENSION ^† 1	0/281 (0.00%)	0	1/230 (0.43%)	1
HYPOTENSION ^† 1	2/281 (0.71%)	2	0/230 (0.00%)	0
1 Term from vocabulary, MedDRA 22.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Atezolizumab Placebo + Cobimetinib + Vemurafenib		Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	278/281 (98.93%)		230/230 (100.00%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	40/281 (14.23%)	64	41/230 (17.83%)	64
LYMPHOPENIA ^† 1	17/281 (6.05%)	22	16/230 (6.96%)	29
Endocrine disorders
HYPERTHYROIDISM ^† 1	21/281 (7.47%)	22	40/230 (17.39%)	46
HYPOTHYROIDISM ^† 1	20/281 (7.12%)	20	43/230 (18.70%)	52
Eye disorders
CHORIORETINOPATHY ^† 1	38/281 (13.52%)	50	33/230 (14.35%)	41
RETINOPATHY ^† 1	7/281 (2.49%)	7	12/230 (5.22%)	14
VISION BLURRED ^† 1	20/281 (7.12%)	24	13/230 (5.65%)	14
Gastrointestinal disorders
ABDOMINAL PAIN ^† 1	25/281 (8.90%)	31	25/230 (10.87%)	32
ABDOMINAL PAIN UPPER ^† 1	29/281 (10.32%)	41	18/230 (7.83%)	20
CONSTIPATION ^† 1	31/281 (11.03%)	37	31/230 (13.48%)	34
DIARRHOEA ^† 1	155/281 (55.16%)	297	115/230 (50.00%)	244
DRY MOUTH ^† 1	12/281 (4.27%)	12	18/230 (7.83%)	19
DYSPEPSIA ^† 1	18/281 (6.41%)	26	19/230 (8.26%)	21
NAUSEA ^† 1	89/281 (31.67%)	134	69/230 (30.00%)	105
STOMATITIS ^† 1	15/281 (5.34%)	21	22/230 (9.57%)	38
VOMITING ^† 1	70/281 (24.91%)	102	48/230 (20.87%)	70
General disorders
ASTHENIA ^† 1	50/281 (17.79%)	72	50/230 (21.74%)	95
CHILLS ^† 1	23/281 (8.19%)	31	21/230 (9.13%)	26
FATIGUE ^† 1	82/281 (29.18%)	116	68/230 (29.57%)	97
INFLUENZA LIKE ILLNESS ^† 1	15/281 (5.34%)	17	13/230 (5.65%)	17
MUCOSAL INFLAMMATION ^† 1	17/281 (6.05%)	22	15/230 (6.52%)	27
OEDEMA PERIPHERAL ^† 1	38/281 (13.52%)	47	47/230 (20.43%)	62
PYREXIA ^† 1	91/281 (32.38%)	150	105/230 (45.65%)	230
Infections and infestations
CONJUNCTIVITIS ^† 1	16/281 (5.69%)	17	16/230 (6.96%)	16
INFLUENZA ^† 1	10/281 (3.56%)	11	14/230 (6.09%)	18
NASOPHARYNGITIS ^† 1	28/281 (9.96%)	34	21/230 (9.13%)	36
UPPER RESPIRATORY TRACT INFECTION ^† 1	21/281 (7.47%)	23	18/230 (7.83%)	22
URINARY TRACT INFECTION ^† 1	12/281 (4.27%)	14	16/230 (6.96%)	26
Injury, poisoning and procedural complications
INFUSION RELATED REACTION ^† 1	18/281 (6.41%)	25	23/230 (10.00%)	29
SUNBURN ^† 1	32/281 (11.39%)	52	27/230 (11.74%)	46
Investigations
ALANINE AMINOTRANSFERASE INCREASED ^† 1	66/281 (23.49%)	90	77/230 (33.48%)	121
AMYLASE INCREASED ^† 1	50/281 (17.79%)	85	49/230 (21.30%)	85
ASPARTATE AMINOTRANSFERASE INCREASED ^† 1	58/281 (20.64%)	82	69/230 (30.00%)	122
BLOOD ALKALINE PHOSPHATASE INCREASED ^† 1	46/281 (16.37%)	63	39/230 (16.96%)	68
BLOOD BILIRUBIN INCREASED ^† 1	18/281 (6.41%)	24	29/230 (12.61%)	53
BLOOD CREATINE PHOSPHOKINASE INCREASED ^† 1	131/281 (46.62%)	332	121/230 (52.61%)	298
BLOOD CREATININE INCREASED ^† 1	43/281 (15.30%)	75	46/230 (20.00%)	93
BLOOD LACTATE DEHYDROGENASE INCREASED ^† 1	15/281 (5.34%)	21	19/230 (8.26%)	27
BLOOD THYROID STIMULATING HORMONE INCREASED ^† 1	8/281 (2.85%)	9	12/230 (5.22%)	13
EJECTION FRACTION DECREASED ^† 1	7/281 (2.49%)	7	12/230 (5.22%)	12
GAMMA-GLUTAMYLTRANSFERASE INCREASED ^† 1	20/281 (7.12%)	25	15/230 (6.52%)	21
LIPASE INCREASED ^† 1	85/281 (30.25%)	195	77/230 (33.48%)	173
Metabolism and nutrition disorders
DECREASED APPETITE ^† 1	42/281 (14.95%)	56	32/230 (13.91%)	35
HYPERGLYCAEMIA ^† 1	14/281 (4.98%)	25	15/230 (6.52%)	26
HYPOKALAEMIA ^† 1	15/281 (5.34%)	20	16/230 (6.96%)	20
HYPOPHOSPHATAEMIA ^† 1	16/281 (5.69%)	28	16/230 (6.96%)	43
Musculoskeletal and connective tissue disorders
ARTHRALGIA ^† 1	89/281 (31.67%)	149	99/230 (43.04%)	179
BACK PAIN ^† 1	19/281 (6.76%)	19	13/230 (5.65%)	14
MUSCLE SPASMS ^† 1	8/281 (2.85%)	8	14/230 (6.09%)	15
MYALGIA ^† 1	44/281 (15.66%)	63	56/230 (24.35%)	88
PAIN IN EXTREMITY ^† 1	27/281 (9.61%)	37	31/230 (13.48%)	43
Nervous system disorders
DIZZINESS ^† 1	15/281 (5.34%)	16	13/230 (5.65%)	13
DYSGEUSIA ^† 1	11/281 (3.91%)	11	20/230 (8.70%)	22
HEADACHE ^† 1	55/281 (19.57%)	78	51/230 (22.17%)	65
Psychiatric disorders
INSOMNIA ^† 1	19/281 (6.76%)	20	12/230 (5.22%)	13
Respiratory, thoracic and mediastinal disorders
COUGH ^† 1	32/281 (11.39%)	40	30/230 (13.04%)	44
DYSPNOEA ^† 1	19/281 (6.76%)	20	18/230 (7.83%)	27
OROPHARYNGEAL PAIN ^† 1	14/281 (4.98%)	17	20/230 (8.70%)	25
PNEUMONITIS ^† 1	13/281 (4.63%)	15	25/230 (10.87%)	31
Skin and subcutaneous tissue disorders
ALOPECIA ^† 1	27/281 (9.61%)	27	22/230 (9.57%)	22
DERMATITIS ACNEIFORM ^† 1	42/281 (14.95%)	61	36/230 (15.65%)	45
DRY SKIN ^† 1	25/281 (8.90%)	29	27/230 (11.74%)	28
ERYTHEMA ^† 1	41/281 (14.59%)	65	37/230 (16.09%)	44
PHOTOSENSITIVITY REACTION ^† 1	69/281 (24.56%)	106	48/230 (20.87%)	64
PRURITUS ^† 1	47/281 (16.73%)	75	60/230 (26.09%)	101
RASH ^† 1	115/281 (40.93%)	193	96/230 (41.74%)	160
RASH MACULO-PAPULAR ^† 1	50/281 (17.79%)	64	45/230 (19.57%)	58
SOLAR DERMATITIS ^† 1	13/281 (4.63%)	20	13/230 (5.65%)	26
Vascular disorders
HYPERTENSION ^† 1	50/281 (17.79%)	63	38/230 (16.52%)	50
1 Term from vocabulary, MedDRA 22.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Communications
Organization:	Hoffmann-La Roche
Phone:	800 821-8590
EMail:	genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Robert C, Lewis KD, Gutzmer R, Stroyakovskiy D, Gogas H, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Caro I, Forbes H, Shah K, Yan Y, Li H, McArthur GA, Ascierto PA. Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma. Ann Oncol. 2022 May;33(5):544-555. doi: 10.1016/j.annonc.2022.01.076. Epub 2022 Feb 4.

de Azevedo SJ, de Melo AC, Roberts L, Caro I, Xue C, Wainstein A. First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. Pigment Cell Melanoma Res. 2021 Sep;34(5):973-977. doi: 10.1111/pcmr.12960. Epub 2021 Feb 15.

Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Manikhas GM, Yan Y, Huang KC, Uyei A, McNally V, McArthur GA, Ascierto PA. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Jun 13;395(10240):1835-1844. doi: 10.1016/S0140-6736(20)30934-X. Erratum In: Lancet. 2020 Aug 15;396(10249):466.

Layout table for additonal information

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT02908672
Other Study ID Numbers:	CO39262 2016-002482-54 ( EudraCT Number )
First Submitted:	September 19, 2016
First Posted:	September 21, 2016
Results First Submitted:	September 15, 2020
Results First Posted:	November 19, 2020
Last Update Posted:	March 22, 2024

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