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    Clinical Trial Results:
    A Phase III, Open-Label, Multicenter, Two Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma

    Summary
    EudraCT number
    		 2016-004387-18
    Trial protocol
    		 DE   NL   BE   HU   PL   GB   ES   GR   FR   IT  
    Global end of trial date
    19 Feb 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Mar 2022
    First version publication date
    01 May 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CO39722
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03273153
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    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
    19 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab compared with pembrolizumab in treatment-naive participants with advanced BRAFV600 wild-type melanoma.
    Protection of trial subjects
    All participants were required to sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    France: 59
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Greece: 25
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Italy: 64
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    446
    EEA total number of subjects
    285
    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)
    202
    From 65 to 84 years
    237
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Treatment-naive adult participants with advanced BRAFV600 wild-type melanoma.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 200 mg of IV pembrolizumab once every 3 weeks.

    Arm title
    		 Cobimetinib and Atezolizumab
    Arm description
    		 Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 60 mg of oral cobimetinib once daily on a 21 days on, 7 days off schedule.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 840 mg of IV atezolizumab once every 2 weeks.

    Number of subjects in period 1
    		Pembrolizumab Cobimetinib and Atezolizumab
    Started
    224
    222
    Completed
    0
    0
    Not completed
    224
    222
         Consent withdrawn by subject
    26
    25
         Physician decision
    1
    3
         Symptomatic deterioration
    -
    1
         Death
    66
    69
         Protocol deviation
    3
    -
         Adverse event
    1
    2
         Study terminated by sponsor
    112
    102
         Unspecified
    3
    2
         Lost to follow-up
    6
    11
         Progressive disease
    6
    5
         Missing
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.

    Reporting group title
    Cobimetinib and Atezolizumab
    Reporting group description
    		 Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.

    Reporting group values
    		 Pembrolizumab Cobimetinib and Atezolizumab Total
    Number of subjects
    		 224 222 446
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 100 102 202
        From 65-84 years
    		 122 115 237
        85 years and over
    		 2 5 7
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.5 ( 12.9 ) 63.6 ( 13.1 ) -
    Sex: Female, Male
    Units:
        Female
    		 83 93 176
        Male
    		 141 129 270
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 6 12
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 6 7
        White
    		 198 188 386
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 19 22 41
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 15 22
        Not Hispanic or Latino
    		 190 180 370
        Unknown or Not Reported
    		 27 27 54

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.

    Reporting group title
    Cobimetinib and Atezolizumab
    Reporting group description
    		 Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.

    Primary: Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)

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    End point title
    		 Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)
    End point 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. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions. Tumor assessments, including contrast-enhanced CT or MRI scans, will be performed every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter, until confirmed disease progression or loss of clinical benefit, withdrawal of consent, study termination by the Sponsor or death, whichever occurs first.
    End point type
    Primary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    224
    222
    Units: Months
        median (confidence interval 95%)
    5.7 (3.7 to 9.6)
    5.5 (3.8 to 7.2)
    Statistical analysis title
    		 PFS
    Comparison groups
    Pembrolizumab v Cobimetinib and Atezolizumab
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2954
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.5

    Secondary: PFS as Determined by the Investigator

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    End point title
    		 PFS as Determined by the Investigator
    End point 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. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    224
    222
    Units: Months
        median (confidence interval 95%)
    7.2 (3.8 to 10.1)
    5.6 (3.9 to 6.6)
    No statistical analyses for this end point

    Secondary: Objective Response as Determined by the Investigator

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    End point title
    		 Objective Response as Determined by the Investigator
    End point description
    Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions >/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis).
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    221
    222
    Units: Percentage of Participants
        number (confidence interval 95%)
    36.7 (30.29 to 43.38)
    27.9 (22.13 to 34.32)
    No statistical analyses for this end point

    Secondary: Objective Response as Determined by IRC

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    End point title
    		 Objective Response as Determined by IRC
    End point description
    Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    206
    204
    Units: Percentage of Participants
        number (confidence interval 95%)
    31.6 (25.27 to 38.38)
    26.0 (20.11 to 32.57)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    221
    222
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator-assessed
    49.8 (43.00 to 56.56)
    46.8 (40.14 to 53.64)
        IRC-assessed (n= 206, 204)
    44.2 (37.28 to 51.24)
    45.6 (38.62 to 52.69)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    224 [1]
    222 [2]
    Units: Months
        median (confidence interval 95%)
    29.3 (21.5 to 9999)
    9999 (24.1 to 9999)
    Notes
    [1] - 9999 = value not available due to insufficient number of participants with event
    [2] - 9999 = value not available due to insufficient number of participants with event
    No statistical analyses for this end point

    Secondary: Duration of objective response determined by the IRC

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    End point title
    		 Duration of objective response determined by the IRC
    End point description
    Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    65 [3]
    53 [4]
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9.2 to 9999)
    Notes
    [3] - 9999 = Values are not estimable due to an insufficient number of participants with the event.
    [4] - 9999 = Values are not estimable due to an insufficient number of participants with the event.
    No statistical analyses for this end point

    Secondary: Duration of Objective Response determined by the Investigator

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    End point title
    		 Duration of Objective Response determined by the Investigator
    End point description
    Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through 80 wks and then every 12 wks thereafter
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    81 [5]
    62 [6]
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9.2 to 9999)
    Notes
    [5] - 9999 = value not available due to insufficient number of participants with event
    [6] - 9999 = value not available due to insufficient number of participants with event
    No statistical analyses for this end point

    Secondary: Two-year Landmark Survival

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    End point title
    		 Two-year Landmark Survival
    End point description
    Two-year landmark survival is defined as survival at 2 years.
    End point type
    Secondary
    End point timeframe
    At 2 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    224
    222
    Units: Months
        median (confidence interval 95%)
    57.88 (48.25 to 67.52)
    60.19 (51.58 to 68.79)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-related Quality of Life (HRQoL) Scores

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    End point title
    		 Change From Baseline in Health-related Quality of Life (HRQoL) Scores
    End point description
    HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    174 [7]
    160 [8]
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline value
    73.27 ( 20.41 )
    73.85 ( 19.73 )
        Week 4
    -2.99 ( 17.05 )
    -9.14 ( 20.83 )
        Week 8
    -3.15 ( 18.67 )
    -5.21 ( 18.18 )
        Week 12
    -1.77 ( 19.93 )
    -7.65 ( 21.20 )
        Week 16
    1.16 ( 15.02 )
    -6.44 ( 20.58 )
        Week 20
    1.69 ( 17.50 )
    -6.31 ( 19.17 )
        Week 24
    -1.84 ( 19.82 )
    -2.49 ( 15.98 )
        Week 28
    2.46 ( 19.07 )
    -3.86 ( 19.10 )
        Week 32
    -0.88 ( 22.41 )
    -4.66 ( 20.94 )
        Week 36
    4.17 ( 20.56 )
    -6.00 ( 18.24 )
        Week 40
    7.22 ( 19.38 )
    -4.63 ( 21.62 )
        Week 44
    0.46 ( 19.27 )
    1.67 ( 12.91 )
        Week 48
    7.64 ( 13.04 )
    0.00 ( 15.96 )
        Week 52
    1.67 ( 12.36 )
    8.33 ( 15.21 )
        Week 56
    -11.11 ( 17.21 )
    -2.08 ( 4.17 )
        Week 60
    -8.33 ( 11.79 )
    -4.17 ( 5.89 )
        Week 64
    33.33 ( 9999 )
    9999 ( 9999 )
        Treatment Discontinuation
    -6.05 ( 22.53 )
    -14.42 ( 25.68 )
        Follow-up 4
    -7.64 ( 14.85 )
    -2.27 ( 18.67 )
        Follow-up 8
    -14.25 ( 21.96 )
    -14.10 ( 24.15 )
        Follow-up 12
    -21.38 ( 24.34 )
    -24.31 ( 28.08 )
        Follow-up 16
    -13.73 ( 19.53 )
    -23.61 ( 23.26 )
        Follow-up 20
    -20.83 ( 26.53 )
    -8.33 ( 12.91 )
        Follow-up 24
    -17.71 ( 29.36 )
    -10.00 ( 14.91 )
        Follow-up 28
    -27.78 ( 22.15 )
    -16.67 ( 23.57 )
    Notes
    [7] - 9999 = value is NA due to an insufficient number of participants with the event at this timepoint.
    [8] - 9999 = value is NA due to an insufficient number of participants with the event at this timepoint.
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    216
    220
    Units: Number of Participants
    195
    218
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Vital Signs

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    End point title
    		 Number of Participants With Abnormal Vital Signs
    End point description
    Vital signs will include temperature pulse rate, respiratory rate, and systolic and diastolic blood pressure.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    216
    220
    Units: Number of Participants
    number (not applicable)
        Sitting diastolic blood pressure - low
    41
    42
        Sitting diastolic blood pressure - high
    77
    85
        Sitting systolic blood pressure - low
    4
    7
        Sitting systolic blood pressure - high
    53
    47
        Pulse rate - low
    58
    67
        Pulse rate - high
    13
    27
        Respiratory rate - low
    8
    11
        Respiratory rate - high
    55
    52
        Temperature - low
    91
    93
        Temperature - high
    20
    47
    No statistical analyses for this end point

    Secondary: Number of Participants With Laboratory Abnormalities

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    End point title
    		 Number of Participants With Laboratory Abnormalities
    End point description
    Participants with laboratory abnormalities (values outside of a defined range) are reported.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Number of subjects analysed
    216
    220
    Units: Number of Participants
        SGPT/ALT
    1
    1
        Amylase (n= 201, 204)
    4
    5
        SGOT/AST (n= 215, 220)
    0
    2
        Calcium
    0
    1
        Creatine Kinase (n= 215, 220)
    1
    17
        Creatinine
    1
    4
        Glucose (n= 210, 218)
    8
    13
        Triacylglycerol Lipase (n= 197, 200)
    8
    10
        Magnesium (n= 215, 217)
    3
    2
        Phosphorus (n= 216, 217)
    6
    10
        Potassium
    1
    6
        Sodium
    2
    4
        Uric Acid (n= 179, 188)
    36
    30
        Hemoglobin
    2
    2
        Lymphocytes Abs (n= 173, 178)
    6
    15
        Neutrophils, Total, Abs (n= 174, 179)
    0
    1
        Total Leukocyte Count
    3
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Cobimetinib

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    End point title
    		 Plasma Concentration of Cobimetinib [9]
    End point description
    Plasma concentration of cobimetinib at specified time points will be reported.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycle 1
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to the reported arm. Participants in the other arm did not receive cobimetinib.
    End point values
    		 Cobimetinib and Atezolizumab
    Number of subjects analysed
    202
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    49.2 ( 614.7 )
        Cycle 1 Day 15 pre-dose
    126 ( 284.1 )
        Cycle 1 Day 15 post-dose
    231 ( 213.3 )
    No statistical analyses for this end point

    Secondary: Serum Concentration of Atezolizumab

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    End point title
    		 Serum Concentration of Atezolizumab [10]
    End point description
    Serum concentration of atezolizumab at specified time points will be reported.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to the reported arm. Participants in the other arm did not receive atezolizumab.
    End point values
    		 Cobimetinib and Atezolizumab
    Number of subjects analysed
    196 [11]
    Units: micrograms/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    256 ( 35.3 )
        Cycle 2 Day 1
    72.2 ( 177.1 )
        Cycle 3 Day 1
    126 ( 104.3 )
    Notes
    [11] - PK parameters will be reported with final results.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-drug Antibodies (ADAs)

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    End point title
    		 Percentage of Participants with Anti-drug Antibodies (ADAs) [12]
    End point description
    Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to the reported arm. Participants in the other arm did not receive cobimetinib.
    End point values
    		 Cobimetinib and Atezolizumab
    Number of subjects analysed
    210
    Units: Percentage of participants
        number (not applicable)
    23.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For up to 135 days after the last dose of study drug, or until a new systemic anti-cancer therapy was initiated, whichever occurred first.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received 200 mg of IV pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.

    Reporting group title
    Cobimetinib and Atezolizumab
    Reporting group description
    		 Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.

    Serious adverse events
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 216 (25.93%)
    105 / 220 (47.73%)
         number of deaths (all causes)
    68
    70
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotensive crisis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 216 (0.93%)
    12 / 220 (5.45%)
         occurrences causally related to treatment / all
    0 / 2
    7 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 216 (1.39%)
    4 / 220 (1.82%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 216 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    5 / 216 (2.31%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 216 (0.93%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 216 (0.93%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Transaminases increased
         subjects affected / exposed
    2 / 216 (0.93%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increase
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 216 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 216 (0.46%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    2 / 216 (0.93%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune encephalopathy
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis autoimmune
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated neuropathy
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 216 (0.93%)
    9 / 220 (4.09%)
         occurrences causally related to treatment / all
    2 / 2
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 216 (0.00%)
    5 / 220 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 216 (1.39%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 216 (1.39%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis mesenteric vessel
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    2 / 216 (0.93%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 216 (0.46%)
    4 / 220 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 216 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 216 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute kidney injury
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 216 (0.93%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 216 (0.00%)
    4 / 220 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 216 (0.00%)
    6 / 220 (2.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Erysipelas
         subjects affected / exposed
    1 / 216 (0.46%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 216 (0.46%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 216 (0.46%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 216 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryocystitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spleen tuberculosis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection viral
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device-related infection
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab Cobimetinib and Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    173 / 216 (80.09%)
    209 / 220 (95.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 216 (8.33%)
    30 / 220 (13.64%)
         occurrences all number
    19
    42
    Amylase increased
         subjects affected / exposed
    9 / 216 (4.17%)
    19 / 220 (8.64%)
         occurrences all number
    10
    29
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 216 (8.33%)
    42 / 220 (19.09%)
         occurrences all number
    20
    57
    Blood creatine phosphokinase increased
         subjects affected / exposed
    13 / 216 (6.02%)
    81 / 220 (36.82%)
         occurrences all number
    16
    127
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 216 (2.31%)
    15 / 220 (6.82%)
         occurrences all number
    5
    19
    Lipase increased
         subjects affected / exposed
    15 / 216 (6.94%)
    28 / 220 (12.73%)
         occurrences all number
    18
    51
    Weight decreased
         subjects affected / exposed
    12 / 216 (5.56%)
    11 / 220 (5.00%)
         occurrences all number
    13
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 216 (6.94%)
    24 / 220 (10.91%)
         occurrences all number
    21
    29
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 216 (3.70%)
    18 / 220 (8.18%)
         occurrences all number
    11
    23
    Headache
         subjects affected / exposed
    17 / 216 (7.87%)
    30 / 220 (13.64%)
         occurrences all number
    19
    36
    Paraesthesia
         subjects affected / exposed
    6 / 216 (2.78%)
    11 / 220 (5.00%)
         occurrences all number
    6
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 216 (7.87%)
    32 / 220 (14.55%)
         occurrences all number
    18
    50
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    42 / 216 (19.44%)
    59 / 220 (26.82%)
         occurrences all number
    49
    89
    Fatigue
         subjects affected / exposed
    42 / 216 (19.44%)
    43 / 220 (19.55%)
         occurrences all number
    54
    64
    Oedema peripheral
         subjects affected / exposed
    17 / 216 (7.87%)
    50 / 220 (22.73%)
         occurrences all number
    20
    76
    Pyrexia
         subjects affected / exposed
    17 / 216 (7.87%)
    65 / 220 (29.55%)
         occurrences all number
    19
    87
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 216 (8.33%)
    24 / 220 (10.91%)
         occurrences all number
    22
    29
    Constipation
         subjects affected / exposed
    20 / 216 (9.26%)
    32 / 220 (14.55%)
         occurrences all number
    26
    36
    Diarrhoea
         subjects affected / exposed
    42 / 216 (19.44%)
    120 / 220 (54.55%)
         occurrences all number
    58
    293
    Dry mouth
         subjects affected / exposed
    9 / 216 (4.17%)
    18 / 220 (8.18%)
         occurrences all number
    9
    19
    Nausea
         subjects affected / exposed
    28 / 216 (12.96%)
    54 / 220 (24.55%)
         occurrences all number
    32
    61
    Stomatitis
         subjects affected / exposed
    3 / 216 (1.39%)
    14 / 220 (6.36%)
         occurrences all number
    4
    19
    Vomiting
         subjects affected / exposed
    15 / 216 (6.94%)
    41 / 220 (18.64%)
         occurrences all number
    16
    53
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 216 (10.65%)
    21 / 220 (9.55%)
         occurrences all number
    27
    26
    Dyspnoea
         subjects affected / exposed
    19 / 216 (8.80%)
    18 / 220 (8.18%)
         occurrences all number
    20
    24
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    3 / 216 (1.39%)
    50 / 220 (22.73%)
         occurrences all number
    3
    68
    Dry skin
         subjects affected / exposed
    14 / 216 (6.48%)
    15 / 220 (6.82%)
         occurrences all number
    15
    21
    Erythema
         subjects affected / exposed
    9 / 216 (4.17%)
    16 / 220 (7.27%)
         occurrences all number
    12
    20
    Pruritis
         subjects affected / exposed
    35 / 216 (16.20%)
    44 / 220 (20.00%)
         occurrences all number
    42
    64
    Rash
         subjects affected / exposed
    27 / 216 (12.50%)
    90 / 220 (40.91%)
         occurrences all number
    37
    154
    Rash maculo-papular
         subjects affected / exposed
    5 / 216 (2.31%)
    26 / 220 (11.82%)
         occurrences all number
    7
    39
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    21 / 216 (9.72%)
    10 / 220 (4.55%)
         occurrences all number
    22
    10
    Hypothyroidism
         subjects affected / exposed
    17 / 216 (7.87%)
    15 / 220 (6.82%)
         occurrences all number
    17
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    37 / 216 (17.13%)
    21 / 220 (9.55%)
         occurrences all number
    48
    23
    Back pain
         subjects affected / exposed
    19 / 216 (8.80%)
    12 / 220 (5.45%)
         occurrences all number
    20
    17
    Myalgia
         subjects affected / exposed
    12 / 216 (5.56%)
    18 / 220 (8.18%)
         occurrences all number
    12
    20
    Pain in extremity
         subjects affected / exposed
    8 / 216 (3.70%)
    11 / 220 (5.00%)
         occurrences all number
    9
    12
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    2 / 216 (0.93%)
    15 / 220 (6.82%)
         occurrences all number
    2
    24
    Rash pustular
         subjects affected / exposed
    2 / 216 (0.93%)
    11 / 220 (5.00%)
         occurrences all number
    2
    12
    Urinary tract infection
         subjects affected / exposed
    4 / 216 (1.85%)
    13 / 220 (5.91%)
         occurrences all number
    4
    18
    Nasopharyngitis
         subjects affected / exposed
    10 / 216 (4.63%)
    12 / 220 (5.45%)
         occurrences all number
    15
    13
    Paronychia
         subjects affected / exposed
    1 / 216 (0.46%)
    13 / 220 (5.91%)
         occurrences all number
    1
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 216 (7.41%)
    30 / 220 (13.64%)
         occurrences all number
    18
    35
    Hyperglycaemia
         subjects affected / exposed
    11 / 216 (5.09%)
    19 / 220 (8.64%)
         occurrences all number
    13
    23

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2017
    Updated eligibility criteria; changed pembrolizumab dosing per United Surgical Partners International (USPI)
    12 Mar 2018
    Added IRB assessment for secondary endpoints ORR and DOR; updated eligibility criteria
    19 Sep 2018
    Updated eligibility criteria

    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
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