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    Clinical Trial Results:
    A phase II, multicenter, open-label, randomized-controlled trial evaluating the efficacy and safety of a sequencing schedule of cobimetinib plus vemurafenib followed by immunotherapy with an anti- PD-L1 antibody atezolizumab for the treatment in patients with unresectable or metastatic BRAF V600 mutant melanoma

    Summary
    EudraCT number
    		 2015-005097-37
    Trial protocol
    		 DE   FR   GR  
    Global end of trial date
    18 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions
    Summary report(s)
    		 ImmunoCobiVem_Synopsis_Final_v1.0_2025-03-18_all_redacted

    Trial information

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    Trial identification
    Sponsor protocol code
    ImmunoCobiVem_2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02902029
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Essen
    Sponsor organisation address
    Hufelandstraße 55, Essen, Germany, 45122
    Public contact
    Departement of Dermatology, University Hospital Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    Scientific contact
    Departement of Dermatology, University Hospital Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jul 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to assess if an early switch (i.e. switch at 3 months) from targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition to immunologic checkpoint inhibition with an anti-PD-L1 antibody leads to prolongation of progressionfree and overall survival outcomes in patients with unresectable or metastatic BRAFV600 mutant melanoma. Furthermore, the safety of the study treatment will be assessed. The following endpoints will help to address the study objectives: Primary endpoint: PFS1 defined as time from start of run-in phase (date of first intake of study drug) to first documented tumor progression date according to RECIST v. 1.1 (PD1) or death by any cause, whichever occurs first (Figure 2). PFS1 will be based on the disease assessment or date of death provided by the local investigator. For patients who remain alive and whose disease has not progressed, PFS1 will be censored on the date of last visit/contact when a disease assessment was performed.
    Protection of trial subjects
    The treatment was conducted as described in the protocol. The regulatory basis of the conduct of this study consisted of the Declaration of Helsinki (in its current version), the AMG [German Medicinal Products Act] / Regulation EU No 536/2014 (Clinical Trials Regulation), Regulation (EU) 2016/679 (General Data Protection Regulation), and the principles of the proper conduct of clinical trials (ICH GCP). Any protocol deviations were reported. Throughout the study, participants were under close observation.
    Background therapy
    		 All treatments that the investigator considered necessary for a subject’s welfare and that did not interfere with the trial drugs could be administered at the discretion of the investigator in keeping with the community standards of medical care.
    Evidence for comparator
    		 After the 3 month run-in phase during which patients received vemurafenib and cobimetinib, patients who did not show disease progression or treatment interruption for more than 28 days during run-in phase were randomized in a 1:1 ratio either to proceed vemurafenib and cobimetinib until disease progression and subsequently cross over to atezolizumab treatment until disease progression (Arm A) or to receive atezolizumab treatment until disease progression and subsequently cross back to vemurafenib and cobimetinib until disease progression (Arm B).
    Actual start date of recruitment
    23 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 117
    Country: Number of subjects enrolled
    Greece: 30
    Country: Number of subjects enrolled
    Serbia: 21
    Worldwide total number of subjects
    185
    EEA total number of subjects
    164
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    112
    From 65 to 84 years
    67
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were selected by the investigator. After obtaining signed informed consent, patients were screened to ensure that they meet the inclusion and exclusion criteria. Between November 23, 2016 and December 27, 2019, 244 patients were assessed for eligibility, including 59 screening failures. Thus, 185 patients could be enrolled.

    Pre-assignment
    Screening details
    		 Patients withBRAF V600 melanoma stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c that fullfilled the inclusion / excluison criteria were included in the run-in-phase and were treated with a combination of vemurafenib and cobimetinib. Screening evaluations had to be performed within 28 days before administration of first study treatment.

    Period 1
    Period 1 title
    Run-in period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding; Study treatmetn was administered in an open-label manner.

    Arms
    Arm title
    		 Run-in
    Arm description
    		 All enrolled patients were treated with vemurafenib and cobimetinib. Vemurafenib and cobimetinib were administered in 28-days cycles. During the run-in phase, vemurafenib and cobimetinib were given for three cycles.
    Arm type
    		 Run-in Phase

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of vemurafenib was 960 mg (4 tablets of 240 mg) taken orally twice daily (equivalent to a total daily dose of 1,920 mg). The first dose of vemurafenib was taken in the morning, and the second dose was taken in the evening, at least 8 hours after the first dose (the ideal interval between the doses was 12 hours). Vemurafenib was taken continuously during each 28-day cycle.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Cotellic
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was taken orally in a 28-day cycle. Each dose consisted of three 20 mg tablets (60 mg in total). Cobimetinib was taken once daily for 21 consecutive days (days 1 to 21-treatment period), followed by a 7-day break (days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle was started after the 7-day treatment break was elapsed. Cobimetinib was taken once daily at approximately the same time each day with the morning vemurafenib dose, and not later than 4 hours after the scheduled time.

    Number of subjects in period 1
    		Run-in
    Started
    185
    Completed
    135
    Not completed
    50
         Physician decision
    2
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    28
         Patient's wish
    4
         Death
    3
         Progression of primary disease
    11
    Period 2
    Period 2 title
    Randomized phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding; study medication was administered open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (CobiVem, switch to Atezolizumab)
    Arm description
    		 Patients who terminated the three cycles of the Run-in phase without progressive disease were randomized. Patients randomized to Arm A proceeded vemurafenib and cobimetinib. If a patient required a dose reduction of vemurafenib and / or cobimetinib during the Run-in phase due to toxicity, vemurafenib and cobimetinib were administered for this patient with the reduced dose during the randomized phase. Treatment was continued until unacceptable toxicities, patient's wish, withdrawal of informed consent, investigator's decision or progression ot the disease. Patients wiht disease progression (except of brain metastases) were subsequently crossed-over to atezolizumab treatment (1,200 mg / q3w).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of vemurafenib was 960 mg (4 tablets of 240 mg) taken orally twice daily (equivalent to a total daily dose of 1,920 mg). The first dose of vemurafenib was taken in the morning, and the second dose was taken in the evening, at least 8 hours after the first dose (the ideal interval between the doses was 12 hours). Vemurafenib was taken continuously during each 28-day cycle.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Cotellic
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was taken orally in a 28-day cycle. Each dose consisted of three 20 mg tablets (60 mg in total). Cobimetinib was taken once daily for 21 consecutive days (days 1 to 21-treatment period), followed by a 7-day break (days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle was started after the 7-day treatment break was elapsed. Cobimetinib was taken once daily at approximately the same time each day with the morning vemurafenib dose, and not later than 4 hours after the scheduled time.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose level of atezolizumab tested in this study was 1,200 mg (equivalent to an average body weight based dose of 15 mg/kg) administered by IV infusion q3w (21 [± 3] days) according to the FDA-approved prescribing information for atezolizumab. The initial dose of atezolizumab was delivered over 60 (± 15) minutes. If the first infusion was tolerated without infusion-associated adverse events and cytokine release syndrome, the second infusion was delivered over 30 (± 10) minutes. If the 30-minute infusion was well tolerated, all subsequent infusions were delivered over 30 (± 10) minutes. At all infusions, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) were determined within 60 minutes before and 30 (± 10) minutes after the infusion. Vital signs were also collected during the first infusion (every 15 [± 5] minutes). During subsequent infusions, vital signs were collected if clinically indicated.

    Arm title
    		 Arm B (Atezolizumab, switch to CobiVem)
    Arm description
    		 Patients who terminated the three cycles of the Run-in phase without progressive disease were randomized. Patients who were randomized to Arm B received 1,200 mg atezolizumab administered by IV infusion q3w (21 [± 3] days). Treatment was continued until unacceptable toxicities, patient's wish, withdrawal of informed consent, investigator's decision or progression of the disease. Patients with disease progression (except of brain metastases) were subsequently crossed over to treatment with vemurafenib (960 mg) and cobimetinib (60 mg QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose level of atezolizumab tested in this study was 1,200 mg (equivalent to an average body weight based dose of 15 mg/kg) administered by IV infusion q3w (21 [± 3] days) according to the FDA-approved prescribing information for atezolizumab. The initial dose of atezolizumab was delivered over 60 (± 15) minutes. If the first infusion was tolerated without infusion-associated adverse events and cytokine release syndrome, the second infusion was delivered over 30 (± 10) minutes. If the 30-minute infusion was well tolerated, all subsequent infusions were delivered over 30 (± 10) minutes. At all infusions, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) were determined within 60 minutes before and 30 (± 10) minutes after the infusion. Vital signs were also collected during the first infusion (every 15 [± 5] minutes). During subsequent infusions, vital signs were collected if clinically indicated.

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of vemurafenib was 960 mg (4 tablets of 240 mg) taken orally twice daily (equivalent to a total daily dose of 1,920 mg). The first dose of vemurafenib was taken in the morning, and the second dose was taken in the evening, at least 8 hours after the first dose (the ideal interval between the doses was 12 hours). Vemurafenib was taken continuously during each 28-day cycle.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Cotellic
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was taken orally in a 28-day cycle. Each dose consisted of three 20 mg tablets (60 mg in total). Cobimetinib was taken once daily for 21 consecutive days (days 1 to 21-treatment period), followed by a 7-day break (days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle was started after the 7-day treatment break was elapsed. Cobimetinib was taken once daily at approximately the same time each day with the morning vemurafenib dose, and not later than 4 hours after the scheduled time.

    Number of subjects in period 2
    		Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Started
    69
    66
    Switch to treatment of other arm
    21
    35
    Completed
    7
    6
    Not completed
    62
    60
         Physician decision
    3
    2
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    12
    4
         Patient's wish
    7
    3
         Death
    3
    4
         Other reason
    3
    10
         Progression of primary disease
    27
    29
         Brain metastasis
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in period
    Reporting group description
    		 -

    Reporting group values
    		 Run-in period Total
    Number of subjects
    		 185 185
    Age categorical
    Age per patient was calculated as 'age at enrollment' minus 'date of birth'.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 112 112
        From 65-84 years
    		 67 67
        85 years and over
    		 6 6
    Age continuous
    Age per patient was calculated as 'age at date of enrollment' minus 'date of birth'.
    Units: years
        median (full range (min-max))
    		 58 (19 to 91) -
    Gender categorical
    Men and women could be enrolled, as no sex specific differences were expected concerning the efficacy and safety of the used trial medication.
    Units: Subjects
        Female
    		 68 68
        Male
    		 117 117

    End points

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    End points reporting groups
    Reporting group title
    Run-in
    Reporting group description
    		 All enrolled patients were treated with vemurafenib and cobimetinib. Vemurafenib and cobimetinib were administered in 28-days cycles. During the run-in phase, vemurafenib and cobimetinib were given for three cycles.
    Reporting group title
    Arm A (CobiVem, switch to Atezolizumab)
    Reporting group description
    		 Patients who terminated the three cycles of the Run-in phase without progressive disease were randomized. Patients randomized to Arm A proceeded vemurafenib and cobimetinib. If a patient required a dose reduction of vemurafenib and / or cobimetinib during the Run-in phase due to toxicity, vemurafenib and cobimetinib were administered for this patient with the reduced dose during the randomized phase. Treatment was continued until unacceptable toxicities, patient's wish, withdrawal of informed consent, investigator's decision or progression ot the disease. Patients wiht disease progression (except of brain metastases) were subsequently crossed-over to atezolizumab treatment (1,200 mg / q3w).

    Reporting group title
    Arm B (Atezolizumab, switch to CobiVem)
    Reporting group description
    		 Patients who terminated the three cycles of the Run-in phase without progressive disease were randomized. Patients who were randomized to Arm B received 1,200 mg atezolizumab administered by IV infusion q3w (21 [± 3] days). Treatment was continued until unacceptable toxicities, patient's wish, withdrawal of informed consent, investigator's decision or progression of the disease. Patients with disease progression (except of brain metastases) were subsequently crossed over to treatment with vemurafenib (960 mg) and cobimetinib (60 mg QD).

    Primary: Progression-free survival 1 (PFS1)

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    End point title
    		 Progression-free survival 1 (PFS1)
    End point description
    PFS 1 was defined as time from start of run-in phase (date of first intake of study drug) to first documented tumor progression date according to RECIST v. 1.1 (PD1) or death by any cause, whichever occurred first. PFS1 was based on the disease assessment or date of death provided by the local investigator. For patients who remained alive and whose disease had not progressed, PFS1 was censored on the date of last visit/contact when a disease assessment was performed The analysis of the primary endpoint was based on the 'primary endpoint population' (PEP), which included all randomized patients who had at least one dose of the scheduled treatment in the randomized phase and who did not have had major disqualifying protocol violations. One patient in each arm was excluded from the PEP due to protocol violation (= Patients were randomized despite having a progress during the Run-in phase).
    End point type
    Primary
    End point timeframe
    Time from start of run-in phase (date of first intake of study drug) to first documented tumor progression date according to RECIST v. 1.1 (= PD1) or death by any cause, whichever occurred first.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    68
    65
    Units: months
        median (confidence interval 95%)
    12.96 (9.87 to 15.59)
    5.94 (5.46 to 8.29)
    Statistical analysis title
    		 PFS1_primary endpoint population
    Statistical analysis description
    Comparison of the progression-free survival of the 2 randomized arms.
    Comparison groups
    Arm B (Atezolizumab, switch to CobiVem) v Arm A (CobiVem, switch to Atezolizumab)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0141
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.91

    Secondary: Progression-free survival 2 (PFS2)

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    End point title
    		 Progression-free survival 2 (PFS2)
    End point description
    PFS2 was defined as time from start of run-in phase (date of first intake of study drug) to second documented disease progression according to RECIST v. 1.1 (PD2, progression after therapy switch) following randomization or death by any cause. PFS2 was based on the disease assessment or date of death provided by the local investigator. For patients who remained alive and whose disease had not progressed, PFS2 was censored on the date of last visit/contact when a disease assessment was performed. Analysis was based on the randomized patients, who switched therapy after the 1st progression.
    End point type
    Secondary
    End point timeframe
    Time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1 (PD2) following randomization or death by any cause.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    21 [1]
    35 [2]
    Units: month
        median (confidence interval 95%)
    12.57 (8.32 to 17.01)
    14.61 (8.55 to 25.56)
    Notes
    [1] - Patients in Arm A with switch
    [2] - Patients in Arm B with switch
    Statistical analysis title
    		 PFS2_switch patients
    Comparison groups
    Arm A (CobiVem, switch to Atezolizumab) v Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4069
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.38

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall Survival (OS) of patients was defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death, for any cause. Patients still alive were censored at the time of last visit/contact. Analysis was based on the randomized patients of the run-in phase (Intention-to Treat population (ITT)).
    End point type
    Secondary
    End point timeframe
    Time from start of run-in phase (date of first intake of study drug) until documented date of death, for any cause.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: months
        median (confidence interval 95%)
    40.23 (18.88 to 1000)
    49.64 (26.05 to 1000)
    Statistical analysis title
    		 OS_ITT
    Comparison groups
    Arm A (CobiVem, switch to Atezolizumab) v Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5339
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.91

    Secondary: Overall survival rate at 12 months

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    End point title
    		 Overall survival rate at 12 months
    End point description
    Overall survival rate at 12 months was defined as the rate of patients alive 12 months after start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to-Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    12 months after start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    55
    53
    No statistical analyses for this end point

    Secondary: Overall survival rate at 24 months

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    End point title
    		 Overall survival rate at 24 months
    End point description
    Overall survival rate at 24 months was defined as the rate of patients alive 24 months after start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to-Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    24 months after start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    43
    47
    No statistical analyses for this end point

    Secondary: Overall survival rate at 36 months

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    End point title
    		 Overall survival rate at 36 months
    End point description
    Overall survival rate at 36 months was defined as the rate of patients alive 36 months after start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to-Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    36 months after start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    41
    41
    No statistical analyses for this end point

    Secondary: Overall survival rate at 48 months

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    End point title
    		 Overall survival rate at 48 months
    End point description
    Overall survival rate at 24 months was defined as the rate of patients alive 24 months after start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to-Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    48 months after start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    35
    40
    No statistical analyses for this end point

    Secondary: 12-months DCR

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    End point title
    		 12-months DCR
    End point description
    Disease control rate (DCR) was defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months after the start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    12 months after the start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    31
    16
    No statistical analyses for this end point

    Secondary: 24-months DCR

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    End point title
    		 24-months DCR
    End point description
    DCR was defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months after the start of run-in phase (date of first intake of study drug). Analysis was based on the Intention-to Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    24 months after the start of run-in phase (date of first intake of study drug).
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    13
    9
    No statistical analyses for this end point

    Secondary: Best overall objective response rate (OORR)

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    End point title
    		 Best overall objective response rate (OORR)
    End point description
    OORR was defined as the rate of patients showing complete response (CR) or partial response (PR) according to RECIST v1.1 Criteria. Analysis was based on the Intention-to Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    From the start of run-in phase (date of first intake of study drug) until the end of the study.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    69
    66
    Units: patients
    56
    55
    No statistical analyses for this end point

    Secondary: Rate of patients with PD and without change to subsequent therapy line

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    End point title
    		 Rate of patients with PD and without change to subsequent therapy line
    End point description
    Rate of patients with progressive disease (PD) who could not change to subsequent line of therapy due to deterioration of ECOG status or multiple and/or symptomatic brain metastasis and/or leptomeningeal disease o from vemurafenib + cobimetinib to atezolizumab (Arm A) o from atezolizumab to vemurafenib + cobimetinib (Arm B) Analysis was based on the Intention-to Treat population (ITT).
    End point type
    Secondary
    End point timeframe
    From the start of run-in phase (date of first intake of study drug) until first documented PD (PD1) after randomization.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    37 [3]
    50 [4]
    Units: patients
    16
    15
    Notes
    [3] - Patients with progressive disease during treatment with vemurafenib and cobimetinib
    [4] - Patients with progressive disease during atezolizumab treatment
    No statistical analyses for this end point

    Secondary: Progression-free survival 3 (PFS3)

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    End point title
    		 Progression-free survival 3 (PFS3)
    End point description
    PFS3 was based on the disease assessment or date of death provided by the local investigator. For patients who remained alive and whose disease had not progressed, PFS3 was censored on the date of last visit/contact when a disease assessment was performed. Analysis was based on the patients of the Intention-to Treat population (ITT), who switched therapy after the 1st progression.
    End point type
    Secondary
    End point timeframe
    Time from the first documented tumor progression date (PD1) after randomization until the second documented tumor progression date (PD2) or death by any cause, whichever occurred first.
    End point values
    		 Arm A (CobiVem, switch to Atezolizumab) Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects analysed
    21 [5]
    35 [6]
    Units: months
        median (confidence interval 95%)
    2.83 (2.14 to 3.32)
    6.02 (2.14 to 8.75)
    Notes
    [5] - Patients in Arm A with switch
    [6] - Patients in Arm B with switch
    Statistical analysis title
    		 PFS3_switch patients
    Comparison groups
    Arm A (CobiVem, switch to Atezolizumab) v Arm B (Atezolizumab, switch to CobiVem)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0801
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 3.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of written consent until 90 days of discontinuation of dosing of the investigational product.
    Adverse event reporting additional description
    All patients who received at least one dose of study treatment with vemurafenib and cobimetinib during the run-in phase of the study were considered evaluable for safety parameters. Safety was evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 The safety population (SP) comprised a total of 182 enrolled patients, who received at least one dose of the investigational agent(s).

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    96 / 182 (52.75%)
         number of deaths (all causes)
    88
         number of deaths resulting from adverse events
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain radiation necrosis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medication error
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Product administration error
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splinter
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Demyelination
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    Monoparesis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pterygium
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 182 (3.85%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermo-hypodermitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    8 / 182 (4.40%)
         occurrences causally related to treatment / all
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences causally related to treatment / all
    7 / 11
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 182 (3.85%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    181 / 182 (99.45%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 182 (14.29%)
         occurrences all number
    33
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    19 / 182 (10.44%)
         occurrences all number
    22
    Fatigue
         subjects affected / exposed
    71 / 182 (39.01%)
         occurrences all number
    103
    Influenza like illness
         subjects affected / exposed
    22 / 182 (12.09%)
         occurrences all number
    30
    Oedema peripheral
         subjects affected / exposed
    15 / 182 (8.24%)
         occurrences all number
    18
    Pain
         subjects affected / exposed
    15 / 182 (8.24%)
         occurrences all number
    18
    Pyrexia
         subjects affected / exposed
    56 / 182 (30.77%)
         occurrences all number
    93
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 182 (6.59%)
         occurrences all number
    12
    Dyspnoea
         subjects affected / exposed
    20 / 182 (10.99%)
         occurrences all number
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences all number
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    45 / 182 (24.73%)
         occurrences all number
    65
    Amylase increased
         subjects affected / exposed
    20 / 182 (10.99%)
         occurrences all number
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    43 / 182 (23.63%)
         occurrences all number
    60
    Blood alkaline phosphatase increased
         subjects affected / exposed
    33 / 182 (18.13%)
         occurrences all number
    54
    Blood bilirubin increased
         subjects affected / exposed
    19 / 182 (10.44%)
         occurrences all number
    33
    Blood creatine phosphokinase increased
         subjects affected / exposed
    51 / 182 (28.02%)
         occurrences all number
    104
    Blood creatinine increased
         subjects affected / exposed
    42 / 182 (23.08%)
         occurrences all number
    58
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    44 / 182 (24.18%)
         occurrences all number
    68
    Lipase increased
         subjects affected / exposed
    40 / 182 (21.98%)
         occurrences all number
    83
    Lymphocyte count decreased
         subjects affected / exposed
    27 / 182 (14.84%)
         occurrences all number
    59
    Electrocardiogram QT prolonged
         subjects affected / exposed
    15 / 182 (8.24%)
         occurrences all number
    17
    Platelet count decreased
         subjects affected / exposed
    12 / 182 (6.59%)
         occurrences all number
    18
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    28 / 182 (15.38%)
         occurrences all number
    48
    Fall
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    12
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    11
    Headache
         subjects affected / exposed
    21 / 182 (11.54%)
         occurrences all number
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    37 / 182 (20.33%)
         occurrences all number
    55
    Eye disorders
    Vision blurred
         subjects affected / exposed
    13 / 182 (7.14%)
         occurrences all number
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    104 / 182 (57.14%)
         occurrences all number
    360
    Nausea
         subjects affected / exposed
    51 / 182 (28.02%)
         occurrences all number
    83
    Vomiting
         subjects affected / exposed
    38 / 182 (20.88%)
         occurrences all number
    55
    Abdominal pain lower
         subjects affected / exposed
    16 / 182 (8.79%)
         occurrences all number
    18
    Abdominal pain upper
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences all number
    12
    Constipation
         subjects affected / exposed
    14 / 182 (7.69%)
         occurrences all number
    15
    Dry mouth
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    12
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 182 (9.89%)
         occurrences all number
    18
    Dermatitis acneiform
         subjects affected / exposed
    32 / 182 (17.58%)
         occurrences all number
    40
    Dry skin
         subjects affected / exposed
    16 / 182 (8.79%)
         occurrences all number
    18
    Eczema
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences all number
    11
    Erythema multiforme
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences all number
    10
    Photosensitivity reaction
         subjects affected / exposed
    57 / 182 (31.32%)
         occurrences all number
    84
    Pruritus
         subjects affected / exposed
    23 / 182 (12.64%)
         occurrences all number
    29
    Rash
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    19
    Rash maculo-papular
         subjects affected / exposed
    69 / 182 (37.91%)
         occurrences all number
    93
    Solar dermatitis
         subjects affected / exposed
    12 / 182 (6.59%)
         occurrences all number
    19
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    22 / 182 (12.09%)
         occurrences all number
    31
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    31 / 182 (17.03%)
         occurrences all number
    34
    Hypothyroidism
         subjects affected / exposed
    29 / 182 (15.93%)
         occurrences all number
    35
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 182 (19.23%)
         occurrences all number
    49
    Back pain
         subjects affected / exposed
    14 / 182 (7.69%)
         occurrences all number
    18
    Myalgia
         subjects affected / exposed
    15 / 182 (8.24%)
         occurrences all number
    20
    Pain in extremity
         subjects affected / exposed
    31 / 182 (17.03%)
         occurrences all number
    36
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 182 (5.49%)
         occurrences all number
    11
    Conjunctivitis
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    13
    Urinary tract infection
         subjects affected / exposed
    11 / 182 (6.04%)
         occurrences all number
    16
    COVID-19
         subjects affected / exposed
    12 / 182 (6.59%)
         occurrences all number
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 182 (6.59%)
         occurrences all number
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2016
    With Amendment No 1 (protocol version 1.3; dated July 12, 2016), questionnaires for patients regarding medication adherence and quality of life became part of the study. New exploratory objectives addressed by patient questionnaires were specified. Furthermore, the amendment included corrections and specification of wording throughout the protocol.
    15 Dec 2016
    Amendment No 2 (protocol version 1.4; dated December 15, 2016) included specification of inclusion and exclusion criteria and an update of risks associated with the study treatment. Moreover, the specification of the BRAF mutation was deleted. A reference for (S)AE documentation and new Adverse Events of Special Interest (AESI) were included and assessment schedules updated.
    18 May 2017
    With Amendment No 3 (protocol version 1.5; dated May 18, 2017) , changes regarding medication adherence questionnaires have been made.
    12 Dec 2017
    With Amendment No 4 (protocol version 1.6, dated December 12, 2017) timelines were updated, and clinical examination schedules were changed. Moreover, based on the updated atezolizumab Investigator Brochure (IB, version 10 from Jul 2017), changes regarding clinical experience and risks associated with atezolizumab were updated.
    29 Apr 2019
    Amendment No 5 (protocol version 1.8; dated April 29, 2019) included update of the study timelines, change of marketing authorization holder, adaptation of schedules of study visits and examinations. Furthermore, clinical experience and risks associated with atezolizumab were updated due to the release of revised IBs for cobimetinib (version 11, dated September 25, 2018), for vemurafenib (version 16, dated December 13, 2018) and for atezolizumab (version 14, dated October 24, 2018), and corresponding addendum 1 (dated December 05, 2018).
    09 Jun 2020
    With Amendment No 6 (protocol version 2.0; dated June 09, 2020) the primary endpoint was changed. The previous secondary endpoint progression-free survival (PFS) 1 is now analyzed as primary endpoint, and the previous primary endpoint PFS2 is now analyzed as secondary endpoint. During regular data review, it was noticed that there were patients not switching therapy after their first progress as planned according to protocol. These patients were previously not included in the primary endpoint population even though they received other therapies. In addition, the follow-up period was extended by two years, to collect further data for overall survival (OS). Moreover, an interim analysis was added in order to gain knowledge on the impact of an early switch from BRAF/MEK inhibition to PD-L1 inhibition on PFS1. This analysis was conducted after 80% of patients have reached PFS1 or prematurely discontinued the study. Furthermore, the protocol was updated according to the release of revised IBs for cobimetinib (version 12, dated September 2019 with new addendum), for vemurafenib (version 17, dated December 2019), and for atezolizumab (version 15, dated December 2019 with corresponding addendum 2). According to the sponsor, these revised documents did not affect the benefit-risk assessment for patients undergoing treatment within the study.
    11 May 2021
    Amendment No 7 (protocol version 3.0; dated May 11, 2021) included changes regarding safety and approved indications of atezolizumab based on the release of revised IBs for cobimetinib (version 13, dated September 2020), for vemurafenib (version 18, dated May 2020), and for atezolizumab (version 17, dated September 2020; version 16 was withdrawn from the marketing authorization holder and did not become effective). According to the sponsor, the revision of these documents did not affect the benefit-risk assessment for patients undergoing treatment within the study.
    04 Apr 2022
    Amendment No 8 (protocol version 4.0; dated April 26, 2022) included changes regarding new risks of vemurafenib and atezolizumab based on the release of revised IBs for vemurafenib (version 19, dated May 2021), and for atezolizumab (version 18 and Addendum 1, dated Jul and Aug 2021, respectively). Furthermore, changes in the management of atezolizumab-specific adverse events were issued. Updates on clinical trials were implemented in chapters 2.2, 2.3, 2.5 and 2.6. According to the sponsor, the revision of these documents did not affect the benefit-risk assessment for patients undergoing treatment within the study.
    24 May 2023
    Amendment No 9 (protocol version 5.0; dated 24 May 2023) included changes regarding safety and approved indications of cobimetinib and vemurafenib based on the release of revised IBs for vemurafenib (versions 20 and 21, dated May 2022 and May 2023, respectively), cobimetinib (version 15, Sep 2022) and for atezolizumab (version 19, dated Aug 2022). Risks associated with atezolizumab and cobimetinib as well as dose modifications and treatment alterations of study treatment were updated. Further, specification for cardiac evaluation was included in the ‘schedule of visits and assessments’.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/40345056
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