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
Phase: PHASE3
Conditions: Advanced BRAFV600 Wild-type Melanoma
Sponsor: Hoffmann-La Roche

Official Title: 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 Brafv600 Wild-Type Melanoma 
NCT Number: 
NCT03273153 
Document Date: 
Protocol Version 6: 05 February 2021 

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol CO39722, Version 6
PROTOCOL
TITLE:
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 
BRAFV600 WILD-TYPE MELANOMA
PROTOCOL NUMBER: CO39722
VERSION NUMBER:
6
EUDRACT NUMBER:
2016-004387-18
IND NUMBER:
135,717
NCT NUMBER:
NCT03273153
TEST PRODUCTS:
Cobimetinib (RO5514041)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 8 May 2017
DATES AMENDED:
Version 2 (VHP): 8 August 2017
Version 3: 8 August 2017
Version 4: 12 March 2018
Version 5:  19 September 2018
Version 6:  See electronic date stamp below.
 
05-Feb-2021 16:47:30
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol CO39722, Version 6
PROTOCOL AMENDMENT, CO39722 VERSION 6:
RATIONALE
Protocol CO39722 has been amended primarily to update atezolizumab safety 
information.  Changes to the protocol, along with a rationale for each change, are 
summarized below:

The list of approved indications for atezolizumab has been updated to include 
small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, and 
melanoma (Section 1.2.2).

Lists of identified risks for atezolizumab have been revised to include myositis and
severe cutaneous adverse reactions for consistency with the list of identified risks in 
the Atezolizumab Investigator's Brochure (Section 5.1.2).

Language has been added to clarify that hemophagocytic lymphohistiocytosis (HLH) 
and macrophage activation syndrome (MAS) are considered potential risks for 
atezolizumab (Sections 5.1.2 and Appendix 11).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), systemic immune activation has been replaced by 
HLH and MAS in the list of potential risks for atezolizumab (Section 5.1.2) and the 
management guidelines for systemic immune activation have been replaced with 
management guidelines for hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (Appendix 11).  In addition, systemic immune activation has 
been removed from the list of adverse events of special interest (Section 5.2.3).

To align with the Atezolizumab Investigator's Brochure, "immune-related" has been 
changed to "immune-mediated" when describing events associated with 
atezolizumab (Sections 5.1.2 and 5.1.5.3; Appendices 10 and 11).

To address a request by the French ANSM, HLH and MAS have replaced systemic 
inflammatory response syndrome on the list of atezolizumab-associated adverse 
events of special interest (Section 5.2.3).

To address a request by the French ANSM, the management guidelines for 
infusion-related reactions associated with atezolizumab have been updated to 
include guidelines for CRS to align with the definition, grading, and management of 
CRS reflected in a recent publication (Lee et al. 2019) (Section 5.3.5.1; 
Appendices 10 and 11).

Appendix 6 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a severe or 
life-threatening skin adverse reaction while receiving another immunostimulatory 
anti-cancer agent.

Anaphylaxis Precautions (Appendix 7) has been modified to remove the 
requirement for use of a tourniquet.  The application of a tourniquet is no longer 
recommended due to the limited therapeutic benefit and risk of losing time for more 
important measures (Ring J, Beyer K, Biedermann T, et al. Allergo J Int. 
2014;23:96112).

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
Guidelines for management of atezolizumab-associated dermatologic adverse 
events have been revised to provide guidance on severe cutaneous adverse 
reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis 
(Appendices 10 and 11).

Guidelines for managing patients who experience atezolizumab-associated adverse 
events have been revised to include myositis (Appendix 11).

To address a request by the French ANSM, the atezolizumab adverse event 
management guidelines have been revised to add laboratory (e.g., B-type natriuretic 
peptide) and cardiac imaging abnormalities as signs or symptoms that are 
suggestive of myocarditis (Appendix 11).

To address a request by the French ANSM, the management guidelines for HLH 
and MAS have been modified to indicate that HLH should be considered when 
cytokine-release syndrome (CRS) presentation is atypical or prolonged, to add 
anti-cytokine therapy as an option for treating HLH or MAS, and to suggest that 
published guidelines should be followed for HLH or MAS events that do not respond 
to treatment within 24 hours (Appendix 11).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Melanoma..................................................... 29
1.2
Background on Study Treatments ......................................... 31
1.2.1
Cobimetinib............................................................................ 31
1.2.2
Atezolizumab......................................................................... 31
1.3
Study Rationale and BenefitRisk Assessment..................... 32
1.3.1
Rationale for Combining Cobimetinib and 
Atezolizumab in Advanced BRAFV600 Wild-Type 
Melanoma in Treatment-Naive Patients ................................ 32
1.3.2
Effect on MAPK Inhibition on Tumor Immune 
Contexture............................................................................. 32
1.3.2.1
Nonclinical Data..................................................................... 32
1.3.2.2
Clinical Data .......................................................................... 33
1.3.3
Activity of Cobimetinib and Other MEK Inhibitors 
in BRAFV600 Wild-Type Melanoma...................................... 33
1.3.4
Activity of Atezolizumab in Advanced Melanoma .................. 34
1.3.4.1
Study PCD4989g:  Atezolizumab Monotherapy..................... 34
1.3.5
Clinical Data for Combination Treatment with 
Cobimetinib and Atezolizumab in 
Advanced Melanoma............................................................. 34
1.3.5.1
Study GP28363 ..................................................................... 34
1.3.6
BenefitRisk Assessment...................................................... 38
2.
OBJECTIVES AND ENDPOINTS ............................................................... 39
3.
STUDY DESIGN......................................................................................... 42
3.1
Description of the Study......................................................... 42
3.1.1
Overview of Study Design ..................................................... 42
3.1.2
Dosing of Study Treatment beyond 
Disease Progression ............................................................. 45
3.1.3
Safety Data Review ............................................................... 46
3.2
End of Study and Length of Study......................................... 46

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3.3
Rationale for Study Design.................................................... 47
3.3.1
Rationale for Cobimetinib and Atezolizumab 
Dose and Schedule (Arm A).................................................. 47
3.3.2
Rationale for Pembrolizumab Dose and 
Schedule (Arm B, Control)..................................................... 47
3.3.3
Rationale for Patient Population and Cohorts........................ 47
3.3.4
Rationale for Control Arm ...................................................... 48
3.3.5
Rationale for Confirmation of Progressive 
Disease per RECIST v1.1...................................................... 49
3.3.6
Rationale for Pharmacokinetic Sample Collection................. 50
3.3.7
Rationale for Biomarker Assessments................................... 50
3.3.7.1
Rationale for Biomarker Assessments in Tumor 
Tissue.................................................................................... 50
3.3.7.2
Rationale for Biomarker Assessments in Blood..................... 51
3.3.8
Rationale for Open-Label Design .......................................... 51
3.3.9
Rationale for Selection of Primary Endpoint:  
Progression-Free Survival, as Assessed by the 
Independent Review Committee............................................ 52
3.3.10
Rationale for Choice of Stratification Factors......................... 52
3.3.11
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 53
4.
MATERIALS AND METHODS .................................................................... 53
4.1
Patients.................................................................................. 53
4.1.1
Inclusion Criteria.................................................................... 54
4.1.1.1
Disease-Specific Inclusion Criteria ........................................ 54
4.1.1.2
General Inclusion Criteria ...................................................... 54
4.1.2
Exclusion Criteria................................................................... 56
4.1.2.1
General Exclusion Criteria..................................................... 56
4.1.2.2
Cancer-Related Exclusion Criteria......................................... 56
4.1.2.3
Exclusion Criteria based on Organ Function or 
Medical History...................................................................... 57
4.1.2.4
Autoimmune Conditions and Immunomodulatory 
Drugs..................................................................................... 59
4.1.2.5
Exclusions Related to Other Medical Conditions 
or Medications ....................................................................... 60
4.2
Method of Treatment Assignment.......................................... 60

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4.3
Study Treatment.................................................................... 60
4.3.1
Formulation, Packaging, and Handling.................................. 61
4.3.1.1
Cobimetinib............................................................................ 61
4.3.1.2
Atezolizumab......................................................................... 61
4.3.1.3
Pembrolizumab...................................................................... 61
4.3.2
Dosage, Administration, and Compliance.............................. 61
4.3.2.1
Cobimetinib............................................................................ 61
4.3.2.2
Atezolizumab......................................................................... 62
4.3.2.3
Pembrolizumab...................................................................... 63
4.3.3
Assessment of Compliance ................................................... 63
4.3.4
Investigational Medicinal Product Accountability ................... 63
4.3.5
Continued Access to Cobimetinib and 
Atezolizumab......................................................................... 64
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 65
4.4.1
Permitted Therapy................................................................. 65
4.4.2
Prohibited Therapy ................................................................ 66
4.4.3
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 67
4.4.3.1
Corticosteroids and Tumor Necrosis Factor-
Inhibitors................................................................................ 67
4.5
Study Assessments ............................................................... 67
4.5.1
Informed Consent Forms and Screening Log........................ 67
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 68
4.5.3
Physical Examinations........................................................... 68
4.5.4
Vital Signs.............................................................................. 69
4.5.5
Tumor and Response Evaluations......................................... 69
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 70
4.5.6.1
Local Laboratory Assessments.............................................. 70
4.5.6.2
Central Laboratory Assessments........................................... 72
4.5.7
Tumor Tissue Samples.......................................................... 74
4.5.8
Electrocardiograms................................................................ 74
4.5.9
Left Ventricular Ejection Fraction........................................... 75

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4.5.10
Ophthalmologic Examination................................................. 76
4.5.11
Patient-Reported Outcomes .................................................. 76
4.5.11.1
EORTC QLQ-C30.................................................................. 77
4.5.11.2
EQ-5D-5L .............................................................................. 77
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 78
4.6.1
Patient Discontinuation from Study........................................ 78
4.6.2
Study Treatment Discontinuation........................................... 78
4.6.3
Study Discontinuation............................................................ 79
4.6.4
Site Discontinuation............................................................... 79
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Plan ............................................................................ 79
5.1.1
Risks Associated with Cobimetinib........................................ 80
5.1.1.1
Important Identified Risks Associated with 
Cobimetinib............................................................................ 80
5.1.1.2
Potential Risks Associated with Cobimetinib ......................... 82
5.1.1.3
Other Risks with Cobimetinib................................................. 83
5.1.2
Risks Associated with Atezolizumab ..................................... 84
5.1.3
Anticipated Overlapping Adverse Events for 
Cobimetinib and Atezolizumab .............................................. 84
5.1.4
Risks Associated with Pembrolizumab .................................. 85
5.1.5
Management of Patients Who Experience 
Specific Adverse Events........................................................ 85
5.1.5.1
Cobimetinib Dose Modifications ............................................ 85
5.1.5.2
Atezolizumab and Pembrolizumab Dose 
Modifications.......................................................................... 86
5.1.5.3
Management of Cobimetinib- and 
Atezolizumab-Specific Adverse Events (Arm A).................... 86
5.2
Safety Parameters and Definitions ........................................ 86
5.2.1
Adverse Events ..................................................................... 87
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 87
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 88

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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 89
5.3.1
Adverse Event Reporting Period ........................................... 89
5.3.2
Eliciting Adverse Event Information....................................... 90
5.3.3
Assessment of Severity of Adverse Events ........................... 90
5.3.4
Assessment of Causality of Adverse Events ......................... 91
5.3.5
Procedures for Recording Adverse Events............................ 92
5.3.5.1
Infusion-Related Reactions and Cytokine-
Release Syndrome................................................................ 92
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 93
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 93
5.3.5.4
Persistent or Recurrent Adverse Events................................ 94
5.3.5.5
Abnormal Laboratory Values ................................................. 94
5.3.5.6
Abnormal Vital Sign Values ................................................... 95
5.3.5.7
Abnormal Liver Function Tests.............................................. 95
5.3.5.8
Deaths ................................................................................... 96
5.3.5.9
Preexisting Medical Conditions.............................................. 96
5.3.5.10
Lack of Efficacy or Worsening of Melanoma.......................... 97
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 97
5.3.5.12
Patient-Reported Outcome Data ........................................... 97
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 98
5.4.1
Emergency Medical Contacts................................................ 98
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 99
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 99
5.4.2.2
Events That Occur after Study Drug Initiation........................ 99
5.4.3
Reporting Requirements for Pregnancies.............................. 99
5.4.3.1
Pregnancies in Female Patients............................................ 99
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 100
5.4.3.3
Abortions ............................................................................. 100
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 101
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ................... 101

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5.5
Follow-Up of Patients after Adverse Events ........................ 103
5.5.1
Investigator Follow-Up......................................................... 103
5.5.2
Sponsor Follow-Up .............................................................. 103
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ......................................... 103
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 104
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 104
6.1
Determination of Sample Size ............................................. 104
6.2
Summaries of Conduct of Study.......................................... 105
6.3
Summaries of Treatment Group Comparability ................... 105
6.4
Efficacy Analyses ................................................................ 105
6.4.1
Primary Efficacy Endpoint.................................................... 105
6.4.2
Secondary Efficacy Endpoints............................................. 106
6.4.3
Exploratory Efficacy Endpoints............................................ 107
6.5
Safety Analyses................................................................... 108
6.6
Pharmacokinetic Analyses................................................... 109
6.7
Immunogenicity Analyses.................................................... 109
6.8
Biomarker Analyses............................................................. 109
6.9
Interim Analyses .................................................................. 110
6.9.1
Planned Interim Analysis of the 
Primary Efficacy Endpoint.................................................... 110
6.9.2
Interim Efficacy Analyses of the 
Secondary Efficacy Endpoint............................................... 110
7.
DATA COLLECTION AND MANAGEMENT ............................................. 111
7.1
Data Quality Assurance....................................................... 111
7.2
Electronic Case Report Forms............................................. 112
7.3
Electronic Patient-Reported Outcome Data......................... 112
7.4
Source Data Documentation................................................ 113
7.5
Use of Computerized Systems ............................................ 113
7.6
Retention of Records........................................................... 113
8.
ETHICAL CONSIDERATIONS.................................................................. 114
8.1
Compliance with Laws and Regulations .............................. 114

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8.2
Informed Consent................................................................ 114
8.3
Institutional Review Board or Ethics Committee.................. 115
8.4
Confidentiality...................................................................... 116
8.5
Financial Disclosure ............................................................ 116
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 116
9.1
Study Documentation .......................................................... 116
9.2
Protocol Deviations.............................................................. 117
9.3
Site Inspections ................................................................... 117
9.4
Administrative Structure....................................................... 117
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 117
9.6
Protocol Amendments ......................................................... 118
10. REFERENCES ......................................................................................... 119
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 40
Table 2
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 62
Table 3
Recommended Cobimetinib Dose Modifications......................... 86
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 91
Table 5
Causal Attribution Guidance ....................................................... 92
Table 6
Assumptions and Characteristics for the Interim and 
Final Analyses of Overall Survival............................................. 111
LIST OF FIGURES
Figure 1
Tumor Burden over Time by Investigator-Confirmed 
Response per RECIST v1.1 in All Melanoma Patients:  
Study GP28363........................................................................... 35
Figure 2
Tumor Burden over Time by Investigator-Confirmed 
Response per RECIST v1.1 in Patients with BRAFV600 
Wild-Type Melanoma:  Study GP28363...................................... 36
Figure 3
Study Schema............................................................................. 43
Figure 4
Treatment and Schedule............................................................. 45

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LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 126
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples................................................................... 137
Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1...... 138
Appendix 4
Immune-Modified Response Evaluation Criteria in Solid 
Tumors (Immune-Modified RECIST)......................................... 147
Appendix 5
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 157
Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies .. 158
Appendix 7
Anaphylaxis Precautions........................................................... 159
Appendix 8
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-
C30).......................................................................................... 160
Appendix 9
EuroQol 5-Dimension, 5-Level Questionnaire........................... 162
Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) ........................................................... 164
Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 180

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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
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 
BRAFV600 WILD-TYPE MELANOMA
PROTOCOL NUMBER:
CO39722
VERSION NUMBER:
6
EUDRACT NUMBER:
2016-004387-18
IND NUMBER:
135,717
NCT NUMBER:
NCT03273153
TEST PRODUCTS:
Cobimetinib (RO5514041)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to the Sponsor or its designee.  Please retain a 
copy of the signed copy for your study files.

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This study will be conducted globally and approximately 450 patients will be randomized in a 
1:1 ratio to one of two treatment arms:

Arm A:  Patients will receive 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days 
off (21/7) schedule (dosing on Days 1–21, followed by no dosing on Days 22–28) plus 
840 mg of atezolizumab by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle 
(n 225).

Arm B:  Patients will receive 200 mg of pembrolizumab administered by IV infusion every 
3 weeks (Q3W) (n 225).
Stratification factors are PD-L1 status (IC0 vs. IC1, 2, 3), baseline serum LDH level (less than or 
equal to the upper limit of normal [ULN] vs. greater than the ULN), and geographic region (North 
America vs. Europe vs. Australia, New Zealand, and others).
A permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization and stratification will be managed through an interactive 
Web-based response system (IWRS).
The Sponsor will monitor enrollment in each region (North America, Europe, Australia, New 
Zealand, and others).  To ensure balanced global enrollment, the Sponsor may institute 
temporary limitations on enrollment in certain regions in the event of disproportionate accrual of 
patients.
Assessments and Monitoring
After signing informed consent, all patients will undergo screening procedures that include 
testing for BRAFV600 wild-type melanoma and PD-L1 status; laboratory tests (e.g., hematology, 
chemistries, liver function tests); left ventricular function evaluation (on echocardiogram [ECHO] 
or multiple-gated acquisition [MUGA] scan); ECG, contrast-enhanced computed tomography 
(CT) or magnetic resonance imaging (MRI) scans of the brain, chest, abdomen, and pelvis; and 
ophthalmologic assessments.
All eligible patients will be randomized to treatment in a 1:1 ratio to either Arm A (cobimetinib 
plus atezolizumab) or Arm B (pembrolizumab).
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at the 
treatment discontinuation visit, and during the follow-up period.  The National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) will be used 
to characterize the toxicity profile of study treatments for all patients.  Patients will be assessed 
for adverse events according to the schedule of activities and as necessary throughout the 
study.
Tumor response will be evaluated according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1).  Any evaluable and measurable disease must be documented at 
screening and re-assessed at each subsequent tumor evaluation.  Investigators will assess 
tumor response at 8-week intervals, regardless of any dose delays or treatment cycle.
Study treatment will continue for all patients until investigator-determined disease progression 
according to RECIST v1.1 that is confirmed by repeat scans 48 weeks later, unacceptable 
toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first.  
Patients who experience disease progression must have scans repeated 48 weeks after initial 
documentation of progression to confirm disease progression.  These results will be used as 
part of the exploratory analyses for assessing efficacy based on immune-modified RECIST.  
Tumor assessments are to continue according to schedule for patients who discontinue 
treatment for reasons other than confirmed disease progression.  Clinically stable patients who 
have disease progression may continue, as described below.
Clinically stable patients who have a favorable benefitrisk ratio may continue study treatment 
following radiographic progression per RECIST v1.1 but approval will need to be provided by 
the Medical Monitor on a case-by-case basis.  Patients who continue treatment beyond 
radiographic disease progression will be closely monitored.  Treatment will be discontinued if 
clinical deterioration because of disease progression occurs at any time or if persistent disease 
growth is confirmed on follow-up scans performed 48 weeks later.
Patients who discontinue one study drug in Arm A may be able to continue the other study drug, 
per guidelines for management of specific adverse events.  After treatment discontinuation, 

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patients will be followed for disease progression if applicable, and followed for survival until 
death, withdrawal of consent, or loss to follow-up, whichever occurs first.  If a patient withdraws 
from the study, study staff may use a public information source (e.g., county records) to obtain 
information about survival status only.
This study will not allow crossover to other study drug(s) at the time of progression.
All patients who discontinue from study treatment because of radiographic disease progression 
or any other reasons will be asked to complete the European Quality of Life 5-Dimension, 
5-Level questionnaire (EQ-5D-5L) and the European Organisation for Research and Treatment 
of Cancer Quality of Life QuestionnaireCore 30 (EORTC QLQ-C30), approximately every 
28 days for 6 months after the last dose of study treatment. 
Dosing of Study Treatment beyond Disease Progression
Dosing of study treatment beyond RECIST v1.1defined disease progression is allowed for 
patients in all treatment arms.  
Dosing of study treatment will continue until unacceptable toxicity or loss of clinical benefit, as 
determined by the investigator, after an integrated assessment of radiographic and biochemical 
data, local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease).  Because of the possibility of an initial increase in tumor burden 
caused by IC infiltration in the setting of a T-cell response (termed pseudoprogression) with 
anti-PD-1 or anti-PD-L1 treatment, radiographic progression per RECIST v1.1 may not be 
indicative of true disease progression.  In the absence of unacceptable toxicity, patients who 
meet criteria for disease progression per RECIST v1.1 while receiving study treatment will be 
permitted to continue study treatment if they meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of all 
available data

Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status that can 
be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions

Approval by the Medical Monitor
Safety Data Review
The Sponsor’s study team will review data on adverse events, serious adverse events, the 
frequency of deaths from all causes, and any other safety data (for both treatment arms 
combined) in the study on an ongoing basis.
It is the responsibility of the study team to review accumulating safety data, to assess and 
monitor ongoing safety in patients, to evaluate potential changes to the clinical study protocol, 
and ultimately, to safeguard patient safety.
An independent Data Monitoring Committee (iDMC) will be employed to conduct periodic 
evaluations of safety data.  All analyses for the iDMC’s review will be prepared by an 
independent data coordinating center.  Specific details, including responsibilities and structure 
of the iDMC, will be specified in an iDMC charter.
Number of Patients
The planned enrollment specifies a total of approximately 450 patients.  
Target Population
Approximately 450 patients with advanced, unresectable, or metastatic BRAFV600 wild-type 
melanoma who are naive to treatment will be enrolled in this study. 

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Inclusion Criteria
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific inclusion criteria for study entry:

Histologically confirmed locally advanced and unresectable or metastatic melanoma

Naive to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal 
therapy, targeted therapy, immunotherapy, or other biologic therapies), with the following 
exceptions:
–
Adjuvant treatment with interferon-(IFN-), interleukin-2 (IL-2), or vaccine therapies, if 
discontinued at least 28 days prior to initiation of study treatment
–
Adjuvant treatment with ipilimumab, if discontinued at least 90 days prior to initiation of 
study treatment
–
Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation 
of study treatment

Documentation of BRAFV600 wild-type status in melanoma tumor tissue (archival or newly 
obtained) through use of a clinical mutation test approved by the local health authority 
(e.g., U.S. Food and Drug Administration [FDA]-approved test, College of American 
Pathologists [CAP], external quality assurance by European Molecular and Genetics Quality 
Network [EQMN], and EMQN for clinical diagnosis, CE-marked [European conformity] in 
vitro diagnostic in EU countries, or equivalent)

A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin 
block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study entry.  If 20 slides are not 
available or the tissue block is not of sufficient size, the patient may still be eligible for the 
study, after discussion with and approval by the Medical Monitor.
If archival tissue is unavailable or is determined to be inadequate, tumor tissue must be 
obtained from a biopsy performed at screening. 

Measurable disease according to RECIST v1.1
General Inclusion Criteria
Patients must meet the following general inclusion criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Histologically or cytologically confirmed BRAFV600 wild-type melanoma

ECOG Performance Status of 0 or 1

Life expectancy 3 months

Adequate hematologic and end-organ function, defined using the following laboratory 
results obtained within 14 days prior to first dose of study drug treatment:
–
ANC 1.5109/L (1500/L)
–
Lymphocyte count 0.5109/L (500/L)
–
Platelet count 100109/L (100,000/L) without transfusion 
–
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
–
Creatinine clearance 40 mL/min
–
Serum albumin 25 g/L (2.5 g/dL)
–
Serum bilirubin 1.5ULN, with the following exception:
Patients with known Gilbert disease:  serum bilirubin level 3 ULN
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN

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–
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 28 days immediately preceding initiation of study treatment
–
AST, ALT, and ALP 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use at least two forms of effective contraceptive with a failure 
rate of 1% per year during the treatment period and for at least 3 months after the last 
dose of cobimetinib and at least 5 months after the last dose of atezolizumab or 
pembrolizumab.   Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for 
at least 3 months after the last dose of cobimetinib
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 3 months 
after the last dose of cobimetinib to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.

Willingness and ability of patients to report selected study outcomes (e.g., global health 
status [GHS] and health-related quality of life [HRQoL]) using an electronic device or paper 
backup questionnaire.
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered medications

Pregnancy, breastfeeding, or intention of becoming pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, 
or pembrolizumab formulations

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation of need for such a vaccine during the study

Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 2 weeks prior 
to initiation of study treatment

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
Treatment with systemic immunostimulatory agents (including, but not limited to, IFNs, IL-2) 
within 28 days or 5 half-lives of the drug, whichever is shorter, prior to Day 1 of Cycle 1

Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis agents) within 2 weeks prior to Day 1 of Cycle 1
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of 
the study
Cancer-Related Exclusion Criteria
Patients who meet any of the following cancer-related exclusion criteria will be excluded from 
study entry:

Ocular melanoma 

Any anti-cancer therapy for advanced melanoma 

Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of 
needing such procedure while receiving study treatment

Uncontrolled tumor-related pain  
–
Patients requiring narcotic pain medication must be on a stable regimen at study entry.
–
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.  Patients 
should be recovered from the effects of radiation.  There is no required minimum 
recovery period.
–
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage 
more than once every 28 days 
Indwelling drainage catheters (e.g., PleurX®) are allowed.

Active or untreated CNS metastases 
Patients with treated and asymptomatic CNS metastases are eligible, if they meet all of 
the following:
–
Evaluable or measurable disease outside the CNS
–
No metastases to midbrain, pons, medulla or within 10 mm of the optic nerves and 
chiasm
–
No history or evidence of intracranial hemorrhage or spinal cord hemorrhage
–
No evidence of clinically significant vasogenic edema
–
No corticosteroids for 2 weeks; anti-convulsant medications at a stable dose are 
allowed
–
No evidence of clinical and radiographic disease progression in the CNS for 
3 weeks after radiotherapy or surgery

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Exclusion Criteria based on Organ Function or Medical History
Exclusions Related to Cardiovascular Disease
Patients who meet any of the following exclusion criteria related to cardiovascular disease will 
be excluded from study entry:

Unstable angina, new-onset angina within last 3 months, myocardial infarction within the 
last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as 
New York Heart Association Class II or higher

Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or 50%, 
whichever is lower

Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline 
hypertension consistently above 159/99 mmHg despite optimal medical management

History or presence of an abnormal ECG that is clinically significant in the investigator’s 
opinion, including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction
Exclusions Related to Infections
Patients who meet any of the following exclusion criteria related to infections will be excluded 
from study entry:

HIV infection

Active tuberculosis infection

Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1

Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or 
COPD) are eligible.

Active or chronic viral hepatitis B or C infection
Patients with a past or resolved hepatitis B virus (HBV) infection, defined as having a 
negative hepatitis B surface antigen (HBsAg) test and a positive total hepatitis B core 
antibody (HBcAb) test at screening, are eligible for the study if HBV DNA are negative.
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain reaction 
test for HCV RNA is negative.
Exclusions Related to Ocular Disease
Patients who meet any of the following exclusion criteria related to ocular disease will be 
excluded from study entry:

Known risk factors for ocular toxicity, consisting of any of the following: 
–
History of serous retinopathy
–
History of retinal vein occlusion (RVO)
–
Evidence of ongoing serous retinopathy or RVO at screening
Autoimmune Conditions and Immunomodulatory Drugs
Patients who meet any of the following exclusion criteria related to autoimmune conditions and 
immunomodulatory drugs will be excluded from study entry:

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 
with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.

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Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met:
–
Rash covering 10% of body surface area
–
Well-controlled disease at baseline, requiring only low-potency topical 
corticosteroids
–
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF 
agents) within 2 weeks prior to Day 1, Cycle 1
Exclusions Related to Other Medical Conditions or Medications
Patients who meet any of the following exclusion criteria related to other medical conditions or 
medications will be excluded from study entry:

Active malignancy (other than melanoma) or a prior malignancy within the past 3 years 
Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma, cervical carcinoma in situ, breast carcinoma in situ, and patients with isolated 
elevation in prostate-specific antigen in the absence of radiographic evidence of 
metastatic prostate cancer are eligible for the study.

Any Grade 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1

History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 
6 months prior to Day 1

Proteinuria 3.5 g/24 hr

Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme 
inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment
These include St. John’s wort or hyperforin (strong CYP3A4 enzyme inducer) and 
grapefruit juice (strong cytochrome P450 CYP3A4 enzyme inhibitor)
End of Study
The study will end when all patients enrolled have been followed until death, withdrawal of 
consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs first.  
Patients may continue on study treatment until the development of progressive disease, 
unacceptable toxicity, and/or withdrawal of consent.  After treatment discontinuation, information 
on disease progression, survival, and new anti-cancer therapy will be collected via telephone 
calls, patient medical records, and/or clinical visits approximately every 3 months.  Patients who 
start a subsequent anti-cancer treatment after study treatment discontinuation will be followed 
for survival and safety per protocol.
Length of Study
The total length of the study, from screening of the first patient to last patient, last visit (LPLV) is 
expected to be approximately 7 years. 

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Investigational Medicinal Products
The investigational medicinal products (IMP) for this study are cobimetinib and atezolizumab. 
Pembrolizumab is an approved treatment for melanoma and can be considered standard of 
care in some countries.  Pembrolizumab is a non-investigational medicinal product in this study, 
unless local regulations require it to be an IMP.
Test Products
Cobimetinib
Patients randomized to Arm A will receive cobimetinib 60 mg (three tablets of 20 mg each) PO 
QD on Days 121 of each 28-day cycle.  This 4-week period is considered a treatment cycle.
Cobimetinib should be taken at the same time every day.  It can be taken with or without food.  
If a daily dose of cobimetinib is missed or if vomiting occurs when the dose is taken, resume 
dosing with the next scheduled dose.
Atezolizumab
Patients randomized to Arm A will receive atezolizumab 840 mg Q2W (twice in one cycle).  
A 4-week period is considered a treatment cycle.
Pembrolizumab
Patients randomized to Arm B will receive 200 mg of pembrolizumab by IV infusion Q3W as 
monotherapy.  A 3-week period is considered a treatment cycle.
Statistical Methods
Unless otherwise noted, all efficacy analyses will include all randomized patients (i.e., the 
intent-to-treat population), and patients will be grouped according to the treatment assigned at 
randomization.
Primary Analysis
Unless otherwise noted, all efficacy analyses will include all randomized patients (i.e., the 
intent-to-treat population), and patients will be grouped according to the treatment assigned at 
randomization.
The primary efficacy analysis will be the comparison of PFS, as determined by the IRC, 
between the two treatment arms using the stratified log-rank test at an overall 0.01 significance 
level (two-sided).  
PFS is defined as the time from randomization to the first occurrence of disease progression, as 
determined by the IRC according to RECIST v1.1, or death from any cause, whichever occurs 
first.  Data for patients who have not experienced disease progression or death will be censored 
at the last tumor assessment date.  Data for patients with no post-baseline tumor assessment 
will be censored at randomization.  
The HR for PFS will be estimated using a stratified Cox model, and two-sided 95% confidence 
intervals (CIs) for the hazard ratio (HR) will be provided.  The stratification factors used for 
analysis will be the same as the randomization stratification factors:  PD-L1 status (IC0 vs. IC1, 
2, 3), baseline LDH (less than or equal to the ULN vs. greater than the ULN), and geographic 
region (North America vs. Europe vs. Australia, New Zealand, and others).  Results from an 
unstratified analysis will also be provided.  Kaplan-Meier methodology will be used to estimate 
the median PFS for each treatment arm, and Kaplan-Meier curves will be produced.  The 95% 
CI of the median PFS for each treatment arm will be constructed using the Brookmeyer and 
Crowley method.  Sensitivity analyses will be conducted to determine the impact of missed 
scheduled tumor assessments on PFS, depending on the number of patients with missed 
assessments. 
Determination of Sample Size  
Approximately 450 patients will be randomized into the study.
The overall type I error () for this study is 0.05 (two-sided). 

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The type I error () for the analysis of the primary endpoint of IRC-assessed PFS is 0.01 
(two-sided).  The analysis of the primary endpoint of IRC-assessed PFS will take place when 
approximately 240 PFS events have occurred.  Statistical considerations are based on the 
following assumptions: 

Stratified log-rank test at 0.01 significance level (two-sided) 

Median PFS of 5.5 months for the pembrolizumab arm 

Median PFS of 10.0 months for the cobimetinib plus atezolizumab arm 

Enrollment period of approximately 12 months

Annual dropout rate of 5%

No interim analysis for PFS
A total of 240 PFS events provides approximately 98% power to detect an improvement in 
median PFS from 5.5 months in the pembrolizumab arm to 10.0 months in the cobimetinib plus 
atezolizumab arm.  This corresponds to a HR of 0.55, with a minimal detectable difference of 
0.72.  The PFS analysis will be conducted approximately 17 months after FPI. 
The final analysis of the secondary endpoint of OS will be performed after the occurrence of 
approximately 295 deaths.  A total of 295 deaths provides approximately 60% power to detect 
an improvement in median OS from 28 months in the pembrolizumab arm to 37.5 months in the 
cobimetinib plus atezolizumab arm, corresponding to an HR of 0.75, or 80% power to detect an 
HR of 0.70.  Two interim analyses of OS will be conducted.  The final OS analysis will be 
conducted approximately 68 months after FPI.
Interim Analyses
No interim analyses of the primary endpoint of PFS will be performed.
Interim Efficacy Analyses of the Secondary Efficacy Endpoint
The study will incorporate three OS analyses (two interim analyses and one final analysis).  The 
first overall survival (OS) interim analysis will be performed at the time of the primary PFS 
analysis when a projected number of 80 deaths are expected to have occurred.  The second 
OS interim analysis will be performed after the occurrence of approximately 153 deaths and is 
projected to occur at approximately 28 months after the first patient is randomized.  The final 
OS analysis will be performed after the occurrence of approximately 295 deaths and is 
projected to occur approximately 68 months after the first patient is randomized.  Generalized 
Haybittle-Peto boundaries with unequal p-values will be used to control the overall type I error of 
the OS comparison at a two-sided 0.05 significance level. 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody; also known as anti-therapeutic 
antibody (ATA)
APC
antigen-presenting cell
CI
confidence interval
CPK
creatine phosphokinase
CRC
colorectal cancer
CRS
cytokine-release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating-tumor DNA
CTLA-4
cytotoxic T lymphocyteassociated protein-4 
DCR
disease control rate
DOR
duration of response
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
European Quality of Life 5-Dimension, 5-Level 
questionnaire
EDC
electronic data capture
EORTC QLQ-C30
European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire Core 30
EU
European Union
FDA
(U.S.) Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FPI
first patient in
GHS
global health status
HBcAb
hepatitis B core antibody
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HLH
hemophagocytic lymphohistiocytosis
HR
hazard ratio
HRQoL
health-related quality of life

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Abbreviation
Term
IC
immune cell
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IFN-
interferon-
IL-2
interleukin-2
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRC
independent review committee
IRR
infusion-related reaction
ITT
intent to treat
IWRS
interactive Web-based response system
LVEF
left ventricular ejection fraction
LLN
lower limit of normal
LPLV
last patient, last visit
LS
least square (means)
MAPK
mitogen-activated protein kinase
MAS
macrophage activation syndrome
MDSC
myeloid-derived suppressor cell
MEK
mitogen-activated protein/extracellular signal-
regulated kinase
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NCI CTCAE v4.0
National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0
NCCN
National Comprehensive Cancer Network
NGS
next-generation sequencing
ORR
overall response rate
OS
overall survival
PD-1
programmed death1
PD-L1
programmed deathligand 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PO
by mouth (orally)
PRO
patient-reported outcome

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Abbreviation
Term
QD
once a day
Q3W
every 3 weeks
Q2W
every 2 weeks
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
RVO
retinal vein occlusion
TCR
T-cell receptor
TNF-
tumor necrosis factor
T3
triiodothyronine
T4
Thyroxine
ULN
upper limit of normal

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1.
BACKGROUND
1.1
BACKGROUND ON MELANOMA
Melanoma is a potentially deadly form of skin cancer originating from melanocytes.  
The clinical outcome of patients with melanoma is highly dependent on the stage at 
presentation. The outcome for promptly diagnosed superficial tumors is good.  In the 
metastatic setting, high rates of mortality and disease-related morbidity have improved 
significantly with recent therapeutic advances.  The 5-year overall survival (OS) rates 
were at 15.7% based on Surveillance, Epidemiology, and End Results data from 2012 
(Siegel et al. 2016).  In the KEYNOTE-006 study (pembrolizumab vs. ipilimumab) in 
advanced melanoma, the 1-year OS rates ranged from 58% to 74% (Robert et al. 
2015b).
In 2012, there were approximately 232,000 new cases and 55,000 deaths from 
melanoma worldwide, with more than 100,000 new cases and 22,000 deaths in Europe 
(Ferlay et al. 2013). In the United States in 2016, an estimated 76,380 new diagnoses of 
melanoma were projected and approximately 10,130 patients are expected to die of the 
disease (American Cancer Society 2016).  The incidence of melanoma is particularly 
high among Caucasian populations in Australia (42.4 per 100,000) and Western Europe 
(10.6 per 100,000) (American Cancer Society 2016). Moreover, the number of 
melanoma cases worldwide is increasing faster than any other cancer. The annual 
increase in incidence rate varies between populations, but in general, the rate has 
been in the order of 3%7% per year for fair-skinned Caucasian populations (Diepgen 
and Mahler 2002). Estimates suggest a doubling of the incidence of melanoma every 
1020 years (Garbe and Leiter 2009).
Until recently, treatment options for metastatic melanoma were limited.  Dacarbazine 
was considered to be the standard first-line treatment; however, outcomes were poor,
with response rates of 5%–12%, median progression-free survival (PFS) of less than 
2 months, and median OS of 6.4 to 9.1 months (Middleton et al. 2000; Bedikian et al. 
2006; Chapman et al. 2011; Robert et al. 2011).  Combination chemotherapy and 
chemotherapy combined with interferon-(IFN-) or interleukin-2 (IL-2), although
showing improved response rates, have not resulted in improved OS 
(Chapman et al. 1999; Ives et al. 2007).
The mitogen-activated protein kinase (MAPK) signaling cascade is a key intracellular 
signaling network that transduces multiple proliferative and differentiating signals from 
the extracellular environment to the nucleus of cells to activate cellular growth and 
differentiation (Johnson and Lapadat 2002; Roberts and Der 2007).  This pathway is 
highly implicated in pathogenesis of melanoma.  Approximately 40%50% of all 
melanomas harbor an activating mutation in BRAF, a major driver of RAS, RAF, MEK, 
ERK, and MAPK signaling (Davies et al. 2002; Curtin et al. 2005; Jakob et al. 2012), and 
an additional 15%30% harbor an activating mutation of neuroblastoma RAS (NRAS) 
(Lee et al. 2011; Cancer Genome Atlas Network 2015).  Approximately 14% harbor 

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mutations of NF1, an inhibitory protein of the MAPK pathway (Cancer Genome Atlas 
Network 2015).  Thus, the MAPK pathway is an important driver of pathogenesis in 
BRAFV600 wild-type melanoma, as well as in BRAFV600-mutated melanoma.  In recent 
years, targeting of the MAPK pathway has emerged as an effective treatment strategy in 
BRAFV600-mutated melanoma and several targeted therapies are now approved globally 
for treatment of this indication specifically (Richman et al. 2015). 
Treatment options for BRAFV600 wild-type melanoma have also improved dramatically 
with approvals of several immunotherapeutic agents. Melanoma cells are highly 
immunogenic and thus an appropriate target for these agents (Zhu et al. 2016). Several 
immunotherapeutic agents, which interrupt T-cell suppression and render melanoma 
cells susceptible to immune attack, are currently available or are in development for the 
treatment of melanoma (Zhu et al. 2016). The two-signal model of activation to 
overcome T-cell suppression, involves interaction of the T-cell receptor (TCR) with its 
antigen (signal one), followed by signal two, which is a co-stimulatory interaction 
between CD28 on the T-cell surface and its ligand B7-1 on antigen-presenting cells 
(Chen and Flies 2013). Expression of co-inhibitory receptors, also known as “immune 
checkpoints” by tumor cells, including cytotoxic T lymphocyteassociated protein-4 
(CTLA-4) and programmed death1 (PD-1) receptor, can prevent TCR ligand interaction
and downregulate the immune system, thus rendering cancer cells immune to cytotoxic 
T cells (Freeman et al. 2000). Targeting of these checkpoint inhibitors disables this 
mechanism and allows T cells to recognize and attack the cancer cells.
Immunotherapeutic agents currently approved for advanced BRAF wild-type melanoma 
include the following:

The antiCTLA-4 antibody, ipilimumab

Two antiPD-1 antibodies, nivolumab and pembrolizumab

Combination therapy with nivolumab and ipilimumab
Both single-agent and combination immunotherapy with pembrolizumab, ipilimumab,
and/or nivolumab have demonstrated an increased overall response rate (ORR) and 
improved PFS for the treatment of BRAF wild-type unresectable or metastatic melanoma
with prolonged duration of responses (DORs). Across multiple clinical trials responses 
to antiPD-1 agents are limited to 30%–40% of patients, with median PFS of 
56 months (Robert et al. 2015a, 2015b; Weber et al. 2015) and OS of approximately 
2024 months (Hodi et al. 2016; Robert et al. 2016). For ipilimumab monotherapy, 
reported response rates are 10%15% and OS is 1011 months (Hodi et al. 2010; 
Robert et al. 2011). Of note, these response rates and PFS outcomes both in patients 
with BRAF-mutant melanoma and BRAF wild-type melanoma are still lower than the
rates achieved with combined BRAF and MEK inhibition. Combination immunotherapy,
in particular, results in challenging toxicity. In Phase III testing in previously untreated 
patients with advanced melanoma, the combination of ipilimumab and nivolumab 
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monotherapy but resulted in challenging toxicity, with more than 50% of patients 
experiencing Grade 3 adverse events. The OS benefit for this combination is not yet 
known (Larkin et al. 2015).
Despite the therapeutic advances achieved by development of these agents, high unmet 
need still exists for patients with advanced BRAFV600 wild-type melanoma.
1.2
BACKGROUND ON STUDY TREATMENTS
1.2.1
Cobimetinib
Cobimetinib is a potent and highly selective inhibitor of MEK, a central component of the 
MAPK pathway.  Activated MEK triggers downstream signaling through ERK to promote 
growth.  Cancer cells transformed by BRAFV600 are exceptionally sensitive to MEK 
inhibition in vitro.  Allosteric MEK inhibitors can result in G1 phase growth arrest in 
melanoma cells (Solit et al. 2006; Haass et al. 2008).  In vitro, MEK inhibitors reduce cell 
proliferation, soft agar colony formation, and matrigel invasion of BRAFV600
mutationpositive melanoma cells, and are also effective against BRAFV600
mutationpositive melanoma xenografts, which is suggestive of a potentially important 
role for MEK inhibitors in melanoma and other tumors that harbor the BRAFV600 mutation 
(Solit et al. 2006).  
Cobimetinib (Cotellic®), in combination with vemurafenib, is approved in the 
United States, European Union, and multiple other countries across the world for use 
with vemurafenib for the treatment of advanced BRAF-mutated melanoma.
Cobimetinib shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies 
and in combination with chemotherapy, other targeted therapies, and cancer 
immunotherapy.
Refer to the Cobimetinib Investigator’s Brochure for details on nonclinical and 
clinical studies.
1.2.2
Atezolizumab
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed 
deathligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, 
PD-1 and B7-1 (also known as CD80), both of which function as inhibitory receptors 
expressed on T cells.  Therapeutic blockade of PD-L1 binding by atezolizumab has been 
shown to enhance the magnitude and quality of tumor-specific T-cell responses, 
resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 
2016).  Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable 
Fc-effector function and associated antibody-mediated clearance of activated effector 
T cells.

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Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.  
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
1.3.1
Rationale for Combining Cobimetinib and Atezolizumab in 
Advanced BRAFV600 Wild-Type Melanoma in 
Treatment-Naive Patients
The rationale for combining cobimetinib, a MEK inhibitor, with atezolizumab, an 
antiPD-L1 antibody, in the treatment of patients with advanced BRAFV600 wild-type 
melanoma is based on the complementary mechanisms of action of these agents.  The 
effects of MAPK pathway inhibition on tumor microenvironment may enhance anti-tumor 
T cellmediated immunity and is supported by preclinical and clinical data as 
summarized in this section.  The nonclinical data elucidating the effect of MAPK 
inhibition on tumor immune contexture are presented in Section 1.3.2.  The effects of 
MAPK inhibitors on tumor immune contexture in patients treated with BRAF and MEK 
inhibitors in clinical trials are summarized in Section 1.3.3.
1.3.2
Effect on MAPK Inhibition on Tumor Immune Contexture
1.3.2.1
Nonclinical Data
The MAPK pathway has been implicated in the regulation of the immune 
microenvironment of tumors.  In in vitro cell lines, blocking the MAPK pathway was 
shown to increase antigen expression and enhance reactivity to antigen-specific 
T lymphocytes (Boni et al. 2010). MEK inhibition has also been shown to increase tumor 
major histocompatibility complex (MHC) expression and PD-L1 expression in 
triple-negative breast cancer cells in vivo and in vitro (Loi et al. 2016).
Additional MAPK inhibition effects may further modulate the tumor microenvironment in 
ways that could enable an improved immune reaction against the tumor.  These effects 
include increased recruitment and activation status of CD8-positive and CD4-positive 
T cells and reduced secretion of granulocyte-colony stimulating factor, which reduces 
mobilization and activity of CD11-positive GRL-positive myeloid-derived suppressor cells 
(Phan et al. 2013; Ebert et al. 2016) as well as reduces expression of angiogenesis 
factors with altered tumor vascular support (Ciuffreda et al. 2009; Chang et al. 2013; 
Mohan et al. 2015).

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The MEK inhibitor G-38963, which is mechanistically similar to cobimetinib, promotes 
the effector phenotype and longevity of tumor-infiltrating T cells in a CT26 colon cancer 
mouse model and combines synergistically with antiPD-L1 in inhibiting growth of CT26 
tumors (Ebert et al. 2016).  
1.3.2.2
Clinical Data
This section describes the tumor biopsy data from patients treated with MAPK inhibitors 
in clinical trials.  Clinical data from cobimetinib and atezolizumab monotherapy trials are 
presented in Sections 1.3.3 and 1.3.4, respectively.  Clinical efficacy, safety, and 
biomarker data from patients treated with the combination in Study GP28363 are 
provided in Section 1.3.5.
In tumor biopsies from patients with melanoma, BRAF and MEK inhibitors, alone or in 
combination, have been shown to increase melanoma antigen expression, MHC Class I 
expression, T-cell infiltration, and PD-L1 expression (Wilmott et al. 2012; 
Frederick et al. 2013; Hu-Lieskovan et al. 2015; Kavakand et al. 2015; Liu et al. 2015). 
Furthermore, pretreatment biopsies in which there were increased tumor-infiltrating 
lymphocytes demonstrated a larger increase in tumor-infiltrating lymphocytes and PD-L1 
expression after treatment with a BRAF inhibitor and MEK inhibitor (Kakavand et al. 
2015; Liu et al. 2015).  
Collectively, and as presented in Section 1.3.4, the data demonstrate that inhibition of 
the MAPK pathway leads to an increase in immune effector cells in the tumor, thus 
priming the microenvironment to enable the immune system to attack the tumor.
1.3.3
Activity of Cobimetinib and Other MEK Inhibitors in 
BRAFV600 Wild-Type Melanoma
In the Phase Ia study MEK4592g, activity of cobimetinib given as a single agent was 
limited to BRAF-mutated melanoma.
Clinical evidence for modest anti-tumor activity of MEK inhibition in a subset of patients 
with BRAFV600 wild-type melanoma has recently been provided by the NEMO Phase III 
study, which demonstrated improved PFS for single-agent binimetinib, a small molecule 
MEK inhibitor, in patients with BRAFV600 wild-type NRAS-mutated advanced melanoma 
relative to dacarbazine (hazard ratio [HR]0.62).  Even binimetinib has limited efficacy 
in the NRAS-mutated population for which a MEK inhibitor would be expected to have 
optimal efficacy (Dummer et al. 2016).
As described in Section 1.1, the MAPK pathway is also highly implicated in BRAF
wild-type melanoma.  

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1.3.4
Activity of Atezolizumab in Advanced Melanoma
1.3.4.1
Study PCD4989g:  Atezolizumab Monotherapy
In the Phase Ia setting (Study PCD4989g), atezolizumab monotherapy has 
demonstrated anti-tumor efficacy in melanoma with a response rate comparable to that 
of two PD-1 inhibitors that are currently approved for the treatment of melanoma 
(pembrolizumab and nivolumab) (Hodi et al. 2014).  Among patients with metastatic 
non-ocular melanoma (n37) enrolled in this study, as of the updated data cutoff date of 
December 2015, the ORR according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) was 32% and median PFS was 5.5 months.  In addition, 
atezolizumab monotherapy was well tolerated by patients with metastatic melanoma. 
1.3.5
Clinical Data for Combination Treatment with Cobimetinib and 
Atezolizumab in Advanced Melanoma
1.3.5.1
Study GP28363 
Study GP28363 is an ongoing Phase Ib, open-label, multicenter study designed to 
assess the safety, tolerability, and pharmacokinetics of cobimetinib plus atezolizumab in 
patients with advanced solid tumors who are naive to antiPD-1 therapy and for whom 
no standard therapy is available.
The study has two stages:  Stage 1 (dose escalation) and Stage 2 (expansion).  
Stage 1 is designed to establish the combination maximum tolerated dose or maximum 
administered dose for cobimetinib plus atezolizumab.  In Stage 2, the recommended 
Phase II dose and schedule were investigated in tumor-specific expansion cohorts:  
metastatic melanoma, KRAS-mutant and wild-type metastatic colorectal cancer (CRC), 
and nonsmall cell lung cancer.  
In a separate mandatory biopsy cohort, patients with diverse solid tumors (n16), 
including CRC, received 60 mg of cobimetinib once a day (QD) as monotherapy before 
initiation of atezolizumab treatment and underwent mandatory fresh biopsy collection 
before initiation of cobimetinib dosing and at the end of the 14-day period of cobimetinib 
monotherapy.
In a separate mandatory biopsy cohort, patients with diverse solid tumors (n16), 
including CRC, received 60 mg of cobimetinib once daily (QD) as monotherapy before 
initiation of atezolizumab treatment and underwent mandatory fresh biopsy collection 
before initiation of cobimetinib dosing and at the end of the 14-day period of cobimetinib 
monotherapy.
During the Stage 1 dose-escalation phase, there were no dose-limiting toxicities, and 
60 mg of cobimetinib on a 21 days on/7 days off schedule with 800 mg of atezolizumab 
every 2 weeks (Q2W) was determined to be the recommended Phase II dose.

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1.3.5.1.1
Efficacy in Non-Ocular Melanoma
As of the data cutoff (17 January 2017), 20 patients with non-ocular melanoma, including 
10 patients with BRAFV600-mutated disease and 10 patients with BRAFV600 wild-type 
disease who had received no prior antiPD-1 or antiPD-L1 therapy, were evaluable for 
efficacy (Miller et al. 2017).  The data were comparable in both BRAFV600-mutant and 
BRAFV600 wild-type melanoma. Of note, 3 of the patients with BRAFV600-mutated 
melanoma who progressed without any tumor shrinkage had received prior trametinib, a 
MEK inhibitor.  Figure 1 and Figure 2 show the RECIST v1.1 responses for all patients 
with melanoma and all patients with BRAFV600 wild-type melanoma, respectively.
Among these patients (n20), the ORR was 45% (confirmed response per RECIST 
v1.1), disease control rate (DCR; defined as a complete response, a partial response, or 
stable disease) was 75%, and median PFS was 12 months (95% CI: 2.8 months, not 
evaluable).  Patients with metastatic melanoma had durability of response, as shown 
over time in Figure 1.
Figure 1
Tumor Burden over Time by Investigator-Confirmed Response 
per RECIST v1.1 in All Melanoma Patients:  Study GP28363
CRcomplete response; PDprogressive disease; PRpartial response;
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SDstable disease.
Note:  n10.

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For patients with BRAFV600 wild-type melanoma, the ORR was 50% (confirmed response 
per RECIST v1.1), the DCR was 80%, and median PFS was 15.7 months (95% CI: 
2.8 months, not evaluable).  Patients with BRAFV600 wild-type metastatic melanoma had 
durability of response (confirmed response per RECIST v1.1), as shown in Figure 2. 
Figure 2
Tumor Burden over Time by Investigator-Confirmed Response 
per RECIST v1.1 in Patients with BRAFV600 Wild-Type Melanoma:
Study GP28363
CRcomplete response; PDprogressive disease; PRpartial response; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SDstable disease.
Note:  n10.

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Biomarker Data
Biomarker evaluation from the serial tumor biopsy cohort showed a 4-fold increase in 
CD8-positive T-cell infiltration in 75% of tumors, as well as increases in PD-L1 and 
MHC-I expression (Bendell et al. 2016).  The data support the hypothesis that 
cobimetinib has beneficial immunomodulatory effects at the tumor site that allow for 
immune anti-tumor activity.
Safety in Patients with Melanoma 
In the 17 January 2017 data cut for melanoma, the safety data were generally similar for 
the 22 patients with melanoma and the overall treated population (N=150).  The mean 
duration of safety follow-up was 14 months (range: 226 months).  For treatment-related 
adverse events, 100% of patients experienced at least one adverse event; 59.0% of 
patients experienced a Grade 3 adverse event; and 14.0% of patients experienced a 
serious adverse event, which included pulmonary embolism, bacterial infection, and pain 
management.  There were no Grade 5 (fatal) adverse events in the melanoma cohort.
The most common treatment-related adverse events (occurring in 20% of melanoma 
patients) as of 17 January 2017 were diarrhea (86.0%), rash (68.0%), fatigue (45.0%), 
nausea (45.0%), pruritus (45.0%), blood creatine phosphokinase increased (32.0%), 
vomiting (32.0%), abdominal pain (23.0%), decreased appetite (23.0%), and dermatitis 
acneiform (23.0%).  In this cohort, the most common Grade3 events (occurring in 5% 
of patients) were diarrhea (14.0%), anemia (9.0%), dermatitis acneiform (9.0%), amylase 
increased (5.0%), asthenia (5.0%), bacterial infection (5.0%), edema peripheral (5%), 
lipase increased (5.0%), maculopapular rash (5.0%), musculoskeletal pain (5.0%), 
myalgia (5.0%), rash (5.0%), pain management (5.0%), pulmonary embolism (5.0%), 
pruritus (5.0%), seizure (5.0%), and vomiting (5.0%).
Safety in All Patients
As of 12 July 2016, a total of 150 patients were enrolled in the study and evaluable for 
safety.  Fourteen patients had been accrued in the dose-escalation phase (Stage 1, 
Cohorts 13), and 136 patients had been accrued in the expansion phase (Stage 2). 
To be considered evaluable for safety, patients must have received at least one dose of 
cobimetinib or atezolizumab.  All patients who received atezolizumab also received 
cobimetinib.  The mean duration of safety follow-up was 6.59 months (range: 
0.7–26.4 months).  Safety follow-up is defined as the number of days from the date of 
the first dose to the minimum date of the last dose plus 30 days, discontinuation date, 
initiation date of another anti-cancer therapy, cutoff date, or the date of death.  
Overall, 96.7% of patients experienced at least one adverse event regardless of 
attribution; 65.3% of patients experienced a Grade 3 adverse event; and 44.0% of 
patients experienced a serious adverse event.  There were five Grade 5 (fatal) adverse 
events (3.3%) in the study, of which four were assessed as unrelated to study drug.  The 
patient whose death was considered to be related to atezolizumab was being treated 

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with chronic steroids for preexisting hypopituitarism and succumbed to sepsis; 
cobimetinib was discontinued prior to the event and was considered not related.  
The most common adverse events (occurring in 20% of patients) were diarrhea 
(69.3%), fatigue (52.7%), rash (46.0%), vomiting (38.7%), nausea (34.0%), pruritus 
(32.7%), decreased appetite (30.0%), constipation (28.0%), peripheral edema (26.0%), 
pyrexia (23.3%), acneiform dermatitis (23.3%), increased CPK (22.7%), dyspnea 
(20.0%), and anemia (20.0%).  The most common Grade3 events (occurring in 5% of 
patients) were fatigue (9.3%), anemia (8.7%), and diarrhea (8.0%). 
1.3.5.1.2
Summary
The improved ORR and DCR suggest that the combination of cobimetinib and 
atezolizumab may lead to longer PFS than either agent given as monotherapy in 
patients with metastatic melanoma.  Together with the biomarker data from the 
mandatory biopsy cohort, the data suggest that cobimetinib may alter tumor immune 
contexture, thereby enhancing atezolizumab activity.  The safety profile was consistent 
with other cobimetinib studies, and no new safety concerns were reported.
1.3.6
BenefitRisk Assessment
This Phase III protocol is based on a strong scientific rationale for combining cobimetinib 
and atezolizumab for the treatment of patients with advanced BRAFV600 wild-type 
melanoma (see Section 1.3.1) and is supported by compelling clinical data from 
melanoma patients treated with the combination in Study GP28363 (see Section 1.3.5.1).  
The protocol includes eligibility criteria, baseline measurements, and recommendations 
for management of adverse events, including guidelines for dose modifications, delays, 
and discontinuation of one or more of the study drugs that are designed to enhance the 
safety of patients in this trial. Oversight of this study will be provided by the Sponsor’s 
Medical Monitor (see Section 3.1.3). Additionally, an independent data monitoring 
committee (iDMC) will be employed to monitor and evaluate patient safety throughout 
the study.
Treatment options are limited for patients with advanced BRAFV600 wild-type melanoma 
whose disease is unresectable or metastatic. Given the unmet need in this indication, 
the efficacy and safety data for cobimetinib and atezolizumab given as single agents and 
in combination (Study GP28363) in advanced melanoma, the biomarker data from 
Study GP28363 that suggest that the effects of cobimetinib on tumor immune contexture 
may sensitize tumors to antiPD-1 and antiPD-L1 agents, together with a potentially 
much improved tolerated safety profile and the extent of safety monitoring proposed, the 
potential benefits for patients with this indication outweigh the potential risks.
Given the unmet need that still exists in advanced BRAFV600 wild-type melanoma, these 
data support development of cobimetinib plus atezolizumab in this indication.

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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus 
atezolizumab compared with pembrolizumab in treatment-naive patients with advanced
or unresectable BRAFV600 wild-type melanoma.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 1.

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This study will be conducted globally and approximately 450 patients will be randomized 
in a 1:1 ratio to one of two treatment arms:

Arm A: Patients will receive 60 mg of cobimetinib by mouth (PO) on a 21 days on, 
7 days off (21/7) schedule (dosing on Days 1–21, followed by no dosing on 
Days 22–28) plus 840 mg of atezolizumab by intravenous (IV) infusion on Days 1 
and 15 of each 28-day cycle (n225).

Arm B: Patients will receive 200 mg of pembrolizumab administered by IV infusion
every 3 weeks (Q3W) (n225).
The study schema is presented in Figure 3.
Figure 3
Study Schema
PDprogressive disease; PD-L1programmed deathligand 1; Q3W every 3 weeks; 
Q2W every 2 weeks, Rrandomization; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors, Version 1.1; 21/721 days on/7 days off (schedule).
Stratification factors are PD-L1 status (IC0 vs. IC1, 2, 3), baseline serum LDH level (less
than or equal to the upper limit of normal [ULN] vs. greater than the ULN), and 
geographic region (North America vs. Europe vs. Australia, New Zealand, and others).
A permuted-block randomization will be applied to ensure a balanced assignment to 
each treatment arm.  Randomization and stratification will be managed through an 
interactive Web-based response system (IWRS).
The Sponsor will monitor enrollment in each region (North America, Europe, Australia, 
New Zealand, and others).  To ensure balanced global enrollment, the Sponsor may 
institute temporary limitations on enrollment in certain regions in the event of 
disproportionate accrual of patients.
Assessments and Monitoring
After signing informed consent, all patients will undergo screening procedures that 
include testing for BRAFV600 wild-type melanoma and PD-L1 status; laboratory tests 
(e.g., hematology, chemistries, liver function tests); left ventricular function evaluation 
(on echocardiogram [ECHO] or multiple-gated acquisition [MUGA] scan); ECG, 

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contrast-enhanced computed tomography (CT), or magnetic resonance imaging (MRI) 
scans of the brain, chest, abdomen, and pelvis; and ophthalmologic assessments.
All eligible patients will be randomized to treatment in a 1:1 ratio to either Arm A 
(cobimetinib plus atezolizumab) or Arm B (pembrolizumab).
All patients will be closely monitored for safety and tolerability during all cycles of therapy, 
at the treatment discontinuation visit, and during the follow-up period.  The National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
(NCI CTCAE v4.0) will be used to characterize the toxicity profile of study treatments for
all patients.  Patients will be assessed for adverse events according to the schedule of 
activities (see Appendix 1) and as necessary throughout the study.
Tumor response will be evaluated according to RECIST v1.1 (see Appendix 3).  Any 
evaluable and measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Investigators will assess tumor response at 
8-week intervals, regardless of any dose delays or treatment cycle.
Study treatment will continue for all patients until investigator-determined disease 
progression according to RECIST v1.1 that is confirmed by repeat scans 4-8 weeks later, 
unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, 
whichever occurs first. Patients who experience disease progression must have scans 
repeated 48 weeks after initial documentation of progression to confirm disease 
progression.  These results will be used as part of the exploratory analyses for 
assessing efficacy based on immune-modified RECIST.  Tumor assessments are to 
continue according to schedule for patients who discontinue treatment for reasons other 
than confirmed disease progression. Clinically stable patients who have disease 
progression may continue, as described below.
Clinically stable patients who have a favorable benefitrisk ratio may continue study 
treatment following radiographic progression per RECIST v1.1, but approval will need to 
be provided by the Medical Monitor on a case-by-case basis.  Patients who continue 
treatment beyond radiographic disease progression will be closely monitored.  
Treatment will be discontinued if clinical deterioration because of disease progression 
occurs at any time or if persistent disease growth is confirmed on follow-up scans 
performed 4-8 weeks later.
Patients who discontinue one study drug in Arm A may be able to continue the other 
study drug, per guidelines for management of specific adverse events provided in 
Section 5.1.5 and Appendix 10.  After treatment discontinuation, patients will be followed 
for disease progression if applicable and followed for survival until death, withdrawal of 
consent, or loss to follow-up, whichever occurs first.  If a patient withdraws from the 
study, study staff may use a public information source (e.g., county records) to obtain 
information about survival status only.

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This study will not allow for crossover to other study drug(s) at the time of progression.
All patients who discontinue from study treatment because of radiographic disease 
progression or any other reasons will be asked to complete the European Quality of Life 
5-Dimension, 5-Level (EQ-5D-5L) questionnaire and the European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC 
QLQ-C30), approximately every 28 days for 6 months after the last dose of 
study treatment. 
A schedule of activities is provided in Appendix 1 (see Table 1 for the cobimetinib and 
atezolizumab arm and Table 2 for the pembrolizumab arm).  The treatment and 
schedule for cobimetinib and atezolizumab combination treatment and pembrolizumab 
are shown in Figure 4.
Figure 4
Treatment and Schedule
DDay; POby mouth.
3.1.2
Dosing of Study Treatment beyond Disease Progression
Dosing of study treatment beyond RECIST v1.1defined disease progression is allowed 
for patients in all treatment arms.  Treatment will be discontinued if clinical deterioration 
due to disease progression occurs at any time or if persistent disease growth is 
confirmed on follow-up scans performed 48 weeks later.
Dosing of study treatment will continue until unacceptable toxicity or loss of clinical 
benefit, as determined by the investigator, after an integrated assessment of 
radiographic and biochemical data, local biopsy results (if available), and clinical status 
D1 
D28 
D15 
D21 
Atezolizumab
840 mg IV 
Cobimetinib
60 mg PO
D28 
D15 
D21 
D1 
7 days 
off 
Cycle 1 
Cycle 2 
Cobimetinib and Atezolizumab Combination
7 days 
off 

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(e.g., symptomatic deterioration, such as pain secondary to disease).  Because of the 
possibility of an initial increase in tumor burden caused by IC infiltration in the setting of 
a T-cell response (termed "pseudoprogression") with anti-PD-1 or anti-PD-L1 treatment, 
radiographic progression per RECIST v1.1 may not be indicative of true disease 
progression.  In the absence of unacceptable toxicity, patients who meet criteria for 
disease progression per RECIST v1.1 while receiving study treatment will be permitted 
to continue study treatment if they meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of 
all available data

Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal disease progression

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Approval by the Medical Monitor
3.1.3
Safety Data Review
The Sponsor’s study team will review data on adverse events, serious adverse events, 
the frequency of deaths from all causes, and any other safety data (for both treatment 
arms combined) in the study on an ongoing basis.
It is the responsibility of the study team to review accumulating safety data, to assess 
and monitor ongoing safety in patients, to evaluate potential changes to the clinical study 
protocol, and ultimately, to safeguard patient safety.
An iDMC will be employed to conduct periodic evaluations of safety data.  All analyses 
for the iDMC’s review will be prepared by an independent data coordinating center.  
Specific details, including responsibilities and structure of the iDMC, will be specified in 
an iDMC charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The study will end when all patients enrolled have been followed until death, withdrawal 
of consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs 
first. Patients may continue on study treatment until the development of progressive 
disease, unacceptable toxicity, and/or withdrawal of consent.  After treatment 
discontinuation, information on disease progression, survival, and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinical 
visits approximately every 3 months. Patients who start a subsequent anti-cancer 
treatment after study treatment discontinuation will be followed for survival and safety 
per protocol.

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The total length of the study, from screening of the first patient to last patient, last visit is 
expected to be approximately 7 years. 
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Cobimetinib and Atezolizumab Dose 
and Schedule (Arm A)
Concomitant administration of atezolizumab and cobimetinib was studied in 
Study GP28363. Cobimetinib and atezolizumab in combination were found to be safe 
and tolerable with cobimetinib on the approved dose and schedule of 60 mg QD 21/7, 
and atezolizumab 800 mg IV Q2W, which is equivalent to the approved dose and 
schedule for treatment of bladder cancer of 1200 mg IV Q3W.
Cobimetinib will be administered at the approved dose and schedule of 60 mg QD 21/7 
for each 28-day cycle.  The 800-mg Q2W dose of atezolizumab was evaluated in 
Study GP28363, which is the pharmacokinetic (PK) equivalent of the dose of 1200 mg 
Q3W in bladder cancer.  To simplify dosing, the dose was rounded up to 840 mg (1 mL 
of drug), which is further supported by the nonclinical dosing data and is not expected to 
be different from the 800-mg dose. 
3.3.2
Rationale for Pembrolizumab Dose and Schedule 
(Arm B, Control)
Pembrolizumab will be administered at the approved dose and schedule of 200 mg IV 
Q3W.  Pembrolizumab is considered standard of care and is approved for the treatment 
of unresectable or metastatic melanoma.  Please refer to pembrolizumab (Keytruda®) 
local prescribing information for a list of approved indications and a complete summary 
of safety information.
Based on the KEYNOTE-006 Phase III trial of pembrolizumab versus ipilimumab in 
advanced melanoma, the estimated 6-month PFS rate was 46.4% and 26.5% for 
pembrolizumab Q3W and ipilimumab, respectively (HR0.58).  The median estimates of 
PFS were 5.5 months versus 2.8 months.  The estimated 12-month OS rates were 68.4% 
and 58.2% for pembrolizumab and ipilimumab, respectively (HR0.69).  The ORR with 
pembrolizumab was 32.9% relative to 11.9% with ipilimumab (Robert et al. 2015b).
In KEYNOTE-001, a Phase Ib trial of pembrolizumab in patients with ipilimumab-naive 
and ipilimumab-treated advanced melanoma, the median OS for all patients (n655) 
was 24.4 months. Of note, the median OS for patients who had not received any prior 
systemic treatment (n152) was 32.2 months.  Three-year OS rates were 40% and 45%,
respectively (Robert et al. 2016). Refer to the prescribing information for more details.
3.3.3
Rationale for Patient Population and Cohorts
Arm A and Arm B of Study CO39722 will enroll patients with advanced BRAF V600
wild-type melanoma without a history of systemic therapy for locally advanced or 
metastatic disease. Despite the recent advances in treatment options provided by 

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immunotherapies, this patient population continues to have high unmet need. The 
known effects of MAPK inhibitors, including cobimetinib, on the tumor microenvironment 
(see Section 1.3.2) include effects that may enable conversion to an immunoresponsive 
phenotype, sensitize refractory tumors to antiPD-1 and antiPD-L1 agents, and 
suggest that combination therapy with cobimetinib and atezolizumab may be efficacious 
in this population.  This hypothesis is supported by clinical data from Study GP28363 
(see Section 1.3.5), indicating that combination therapy with cobimetinib and 
atezolizumab in advanced melanoma results in improved ORR and PFS relative to 
antiPD-1, antiPD-L1, or MEK inhibitor monotherapy.
In order to ensure BRAFV600 wild-type status, the inclusion criteria require that BRAF 
status be confirmed using an approved clinical test before randomization.
In order to ensure that the primary endpoint of PFS by independent review, and the 
secondary endpoints of ORR and DOR can be adequately assessed, patients must have
measurable disease (per RECIST v1.1) and locally advanced and unresectable or 
metastatic melanoma.
Additional eligibility criteria have been incorporated that are pertinent to the safety 
profiles of cobimetinib and atezolizumab (and antiPD-L1 targeted therapies as a 
therapeutic class). These have been informed by the known safety profiles of each drug 
and supplemented by experience in Study GP28363, which evaluated the combination 
of atezolizumab and cobimetinib in patients with diverse solid tumors, including 
advanced melanoma. 
3.3.4
Rationale for Control Arm
The control arm will receive 200 mg of pembrolizumab administered by IV infusion Q3W.
The intent of this study is to evaluate the magnitude of benefit achievable with the 
combination of cobimetinib plus atezolizumab, relative to current standard of care, in 
treatment-naive patients with advanced BRAFV600 wild-type melanoma.
Several therapies are currently available for this indication (refer to Section 1.1). The 
current guidelines from the National Comprehensive Cancer Network (NCCN) and the 
European Society of Medical Oncology clinical practice guidelines (Dummer et al. 2015; 
NCCN 2016) are the antiPD-1 monotherapies pembrolizumab and nivolumab and the 
combination of nivolumab with ipilimumab.  The choice of treatment is based on 
evaluation of the individual patient by the treating physician.
The antiPD-1 monotherapies pembrolizumab and nivolumab have demonstrated 
comparable efficacy in patients with advanced melanoma across multiple clinical trials. 
Efficacy has been established for survival endpoints, as well as for the correlated 
surrogate endpoints of PFS and ORR (median PFS for these agents in advanced 
melanoma is 5–6 months, with an ORR of approximately 30% [Hodi et al. 2014; Robert

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et al. 2015a, 2015b; Weber et al. 2015] and OS of approximately 2024 months [Hodi 
et al. 2016; Robert et al. 2016]).
Both pembrolizumab and nivolumab are used for the treatment of BRAFV600 wild-type 
advanced melanoma in clinical practice.  Recently, a Phase III trial (KEYNOTE-006; 
Schachter et al. 2016) demonstrated improved PFS and survival rates for 
pembrolizumab relative to ipilimumab in patients with advanced melanoma.  In this trial, 
patients were randomized in a 1:1:1 ratio to receive pembrolizumab at a dose of 
10 mg/kg either Q2W or Q3W or four cycles of ipilimumab at a dose of 3 mg/kg Q3W.  
The final OS analysis at 24 months demonstrated survival rates of 55%, 55%, and 43%, 
respectively (HR for pembrolizumab Q2W 0.68; 95% CI: 0.53, 0.87; p0.00085; HR for 
pembrolizumab Q3W 0.68; 95% CI: 0.53, 0.86; p0.00083) (Schachter et al. 2016).  
Pembrolizumab is preferred over nivolumab for this open-label study because the dosing 
frequency is reduced relative to that of nivolumab (Q3W vs. Q2W [Keytruda® and 
Opdivo® U.S. Package Inserts and EU Summary of Product Characteristics]), which 
reduces the visit burden for patients enrolled in the control arm.
On the basis of antiPD-1 monotherapy being a currently approved, widely used 
standard of care, which affords the longest established survival benefit of currently 
available therapies and is recommended by advisory bodies for treatment of patients 
with BRAFV600 wild-type melanoma, pembrolizumab is considered an appropriate 
comparator arm for Study CO39722.  Pembrolizumab is the preferred treatment option 
compared with nivolumab because of the reduced dosing frequency.
3.3.5
Rationale for Confirmation of Progressive Disease 
per RECIST v1.1
In this study, all patients will have confirmatory scans performed 48 weeks after initial 
documentation of progression per RECIST v1.1.  Studies with immunotherapeutic 
agents indicate that conventional response criteria may not adequately assess the
activity of immunotherapeutic agents because progressive disease (by initial 
radiographic evaluation) does not necessarily reflect therapeutic failure.  Initial increase 
in tumor size caused by IC infiltration in the setting of a T-cell response can occur with 
immunotherapy and has been termed pseudoprogression (Hales et al. 2010).  However, 
the implications of atypical anti-tumor responses in the setting of immunotherapy 
combined with targeted therapy are currently unknown. 
Clinically stable patients who have a favorable benefitrisk ratio will continue on study 
treatment following radiographic progression according to RECIST v1.1.  Patients who 
continue treatment beyond radiographic disease progression will be closely monitored.  
Treatment will be discontinued if clinical deterioration because of disease progression 
at any time or if persistent disease growth is confirmed by follow-up scans performed 
48 weeks later.

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3.3.6
Rationale for Pharmacokinetic Sample Collection
The proposed PK sampling scheme for assessment of cobimetinib and atezolizumab 
concentration, together with available data from other clinical studies, will be used to 
investigate any drug interaction between the two molecules by comparing the PK data
from this study with single-agent data from previous studies.  PK samples will not be 
obtained from patients in the control arm (pembrolizumab) since it is an established 
product.
Atezolizumab is primarily eliminated by catabolism to inactive metabolites and therefore 
has a low potential for drug interactions.  Cobimetinib is metabolized primarily by CYP3A, 
and to a lesser extent by UGT2B7, based on in vitro studies.  Strong and moderate 
inhibitors and inducers of CYP3A can alter cobimetinib exposure, and no other clinically 
relevant drugdrug interactions have been observed.  There is an approximate 7-fold 
increase in the area under the concentrationtime curve with potent CYP3A inhibitors
(see Section 4.4.2).  Because of the differences in metabolism, no drugdrug interaction 
is anticipated between cobimetinib and atezolizumab.  PK samples of cobimetinib and 
atezolizumab will be obtained as indicated in Appendix 2 to evaluate the 
pharmacokinetics of each molecule when administered in combination. 
3.3.7
Rationale for Biomarker Assessments
3.3.7.1
Rationale for Biomarker Assessments in Tumor Tissue
To characterize the heterogeneity of tumors among patients and its relationship to 
clinical response, tumor tissue will be collected at screening (archival tissues of sample 
collection date 5 years or pretreatment biopsies), on Day 15 of Cycle 1 (optional 
biopsy), and at disease progression (fresh biopsy to be obtained either at first evidence 
of progression or confirmation of progression, whichever is closest to the last date of 
study treatment administration). 
Tumor tissue will be evaluated for tumor immunity contextures, such as CD8-positive 
T-cell infiltrate, PD-L1, and MHC expression, and other components of tumor immunity. 
In addition, DNA and/or RNA will be extracted from these tumor samples to enable 
next-generation sequencing (NGS) of DNA and RNA to identify tumor-specific somatic 
mutations, immune and stromal signatures, and the clonalities of TCRs to aid the 
understanding of disease pathobiology.  These molecular characterizations of tumors 
will be analyzed in relation to clinical response to identify patients who will likely benefit 
more from the treatment.  Because these biomarkers may also have prognostic value, 
their potential association with disease progression will also be explored.  Comparison of 
biomarkers between tissue acquired before treatment and tissue acquired at the time of 
progression will further elucidate the potential mechanism of acquired resistance to this 
combination.  Detailed mutation and immune profiles from biopsies obtained from 
patients at disease progression may also provide data for consideration of subsequent 
therapeutic options.

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3.3.7.2
Rationale for Biomarker Assessments in Blood 
An exploratory objective of this study is to evaluate biomarkers in available blood 
samples. Factors in blood samples may hold important clues regarding the disease 
pathobiology of cancer patients. Potential blood biomarkers may include, but are not 
limited to, mutations in circulating-tumor DNA (ctDNA) such as, NRAS or NF-1 mutations, 
total mutation load, or protein factors such as S100. Analysis of the characteristics of 
biomarkers from each patient before treatment, during treatment, and at disease 
progression, along with clinical data collected in this study, may increase the opportunity 
for developing new approaches for monitoring disease dynamics or that would be 
predictive of clinical benefit for this treatment combination.
3.3.8
Rationale for Open-Label Design
Study CO39722 is intended to evaluate the efficacy of cobimetinib in combination with 
atezolizumab in patients with BRAFV600 wild-type unresectable, locally advanced, or 
metastatic melanoma compared with pembrolizumab, a widely used standard-of-care 
treatment in this indication.  Study CO39722 is designed as an open-label study for the 
following reasons:

Patients receiving cobimetinib are required to undergo safety monitoring tests for 
MEK inhibitorassociated adverse events, including extensive ophthalmologic tests 
(requiring a time commitment of approximately 1 hour) and left ventricular ejection 
fraction (LVEF) monitoring by ECHO or MUGA scan.  Both of these investigations 
will be performed at baseline, after 1 month, and every 3 months thereafter, with 
additional testing if an abnormality is detected.  These assessments are not 
indicated for patients receiving pembrolizumab monotherapy and would therefore 
present an excessive and unnecessary burden to patients in the control arm in a 
blinded study. 

Several adverse events observed with cobimetinib, including serous retinopathy, 
elevated CPK, and decreased LVEF, are recognized class effects of MEK inhibitors.  
In the Phase III study GO28141, at the time of the primary analysis, for patients in
the cobimetinib plus vemurafenib arm relative to the vemurafenib plus placebo arm, 
the incidence of these adverse events was as follows:  serous retinopathy, 24% 
versus 2.1%; Grade 3 elevated CPK, 10.6% versus 0.4%; and Grade 2 LVEF 
reductions, 8.5% versus 3.7%.  Although the majority of these events have been 
asymptomatic or mild in nature, they are prospectively monitored in cobimetinib 
trials and will be monitored in this trial.  Because patients in the pembrolizumab 
control arm will not receive a MEK inhibitor, occurrence of these adverse events 
would likely alert investigators and patients to the treatment assignment of patients 
receiving cobimetinib and atezolizumab in the experimental arm, compromising 
blinding in many cases.
Study CO39722 has been designed to prevent compromise of study outcomes by the 
absence of blinding.  The primary endpoint is independent review committee 
(IRC)-assessed PFS, and IRC members will be blinded to patient treatment assignment.  
IRC-assessed PFS will be supported by a secondary endpoint of investigator-assessed 

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PFS.  Furthermore, the secondary endpoints of OS, 2-year landmark OS, and 
IRC-assessed ORR and DOR will provide additional information for patients and 
physicians that is unaffected by knowledge of treatment assignment.
3.3.9
Rationale for Selection of Primary Endpoint:  Progression-Free 
Survival, as Assessed by the Independent Review Committee
PFS is established as a clinically relevant measure of treatment benefit and a correlate 
of OS in advanced melanoma, which in recent years has been an approvable endpoint 
in the setting of metastatic or unresectable melanoma for both targeted and 
immunotherapies (European Medicines Agency 2012).  In a meta-analysis of 
4416 metastatic melanoma patients, PFS was found to be a robust surrogate for OS in 
dacarbazine-controlled randomized trials of metastatic melanoma. Furthermore, PFS 
has also been demonstrated to be predictive of landmark OS for pembrolizumab 
(Robert et al. 2015a). In addition, owing to the increased number of active treatment 
options available and under investigation, resulting in patients receiving more lines of 
therapy than have previously been available, OS would likely be confounded by the use 
of effective subsequent-line therapies or by mortality unrelated to cancer (Flaherty et al. 
2012). 
Finally, full powering for OS requires large numbers of patients, and for this study, it 
would result in a significantly longer timeline, such that analysis of clinical benefit would 
not be available to patients with remaining unmet need and their physicians in a 
reasonable timeframe.  As progression events provide reliable information on the 
treatment effect observed and generally are not confounded by subsequent lines of 
therapy, PFS provides a meaningful efficacy endpoint with earlier time to evaluation 
(Di Leo et al. 2003).  In addition, 2-year landmark survival may provide a meaningful 
measure of benefit to patients and physicians.
In summary, multiple drugs, including both targeted therapy and immunotherapies, have 
been approved in metastatic melanoma in recent years on the basis of PFS, and 
extensive clinical experience validates PFS as a consistent strong correlate of survival 
across different treatment modalities.
3.3.10
Rationale for Choice of Stratification Factors
In Study CO39722, randomization will be stratified by three factors:  PD-L1 status (IC0
vs. IC1/2/3), baseline LDH (less than or equal to the ULN vs.greater than theULN), and 
geographic region (North America vs. Europe vs. Australia, New Zealand, and others). 

PD-L1 expression has recently been recognized as a strong favorable prognostic 
factor in melanoma and is associated with improved outcome for 
antiPD-1/PD-L1directed therapy (Carbognin et al. 2015; Hauschild et al. 2016;
Wang et al. 2016).

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
Baseline LDH level is recognized as a strong prognostic factor in melanoma for 
long-term OS.  Elevated LDH level is associated with poorer outcomes across 
multiple therapies and is reflective of other factors associated with aggressive 
disease, such as tumor stage and burden (Balch et al. 2009; Chapman et al. 2011;
Hauschild et al. 2012, 2015, 2016; Ascierto 2013; Kelderman et al. 2014;
Long et al. 2014, 2015; McArthur et al. 2014; Diem et al. 2015; Robert et al. 2015b).

Different regions employ different treatment paradigms based on regulatory 
approvals and economic considerations.  These factors can influence the population 
of patients enrolled in clinical trials.  It is therefore appropriate to include geographic 
region as a stratification factor.
3.3.11
Rationale for Patient-Reported Outcome Assessments
Metastatic melanoma is a deadly cancer that impacts patients’ health-related quality of 
life (HRQoL) (Cornish et al. 2009).  Current treatment goals include improving survival, 
managing disease or treatment-related symptoms (insomnia, pain, and fatigue), and 
preserving HRQoL outcomes as feasible (NCCN 2016).  Studies have shown that 
patients with advanced melanoma tend to experience a decrease in global health status 
(GHS) and physical functioning while undergoing treatment, which can vary by therapy 
and presence of disease progression (Schadendorf et al. 2015; Long et al. 2016).  
Results from the KEYNOTE-002 study (pembrolizumab vs. chemotherapy) indicate that 
newer treatments such as pembrolizumab are more tolerable than chemotherapy and 
that by extending PFS, maintenance of patients’ HRQoL is prolonged as well 
(Schadendorf et al. 2015).
In this study (CO39722), the EORTC QLQ-C30, a generic cancer questionnaire that 
assesses commonly reported symptoms, functioning, and GHS/HRQoL, will be used to 
obtain patient-relevant information and therefore address a measurement needed to 
understand patients’ experience with treatment of melanoma (see Section 4.5.11.1).  
The EQ-5D-5L (see Section 4.5.11.2) will be used to derive utility scores for use in 
economic models. 
Assessment of the effects of combination treatment with atezolizumab and cobimetinib 
in relation to disease and treatment burden is important and will allow oncologists to 
appropriately educate patients on the benefits and risks of treatment with this doublet 
combination therapy.  The measurement hypothesis is whether the combination of 
atezolizumab with cobimetinib will result in maintained HRQoL until progression 
compared with pembrolizumab.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 450 patients with advanced, unresectable, or metastatic BRAFV600
wild-type melanoma who are naive to treatment will be enrolled in this study. 

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4.1.1
Inclusion Criteria
4.1.1.1
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific inclusion criteria for study entry:

Histologically confirmed locally advanced and unresectable or metastatic melanoma 

Naive to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, 
hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies), 
with the following exceptions:
Adjuvant treatment with IFN-, IL-2, or vaccine therapies, if discontinued at least 
28 days prior to initiation of study treatment
Adjuvant treatment with ipilimumab, if discontinued at least 90 days prior to 
initiation of study treatment
Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to 
initiation of study treatment

Documentation of BRAFV600 wild-type status in melanoma tumor tissue (archival or 
newly obtained) through use of a clinical mutation test approved by the local health 
authority (e.g., U.S. Food and Drug Administration [FDA]-approved test, College of 
American Pathologists [CAP], external quality assurance by European Molecular 
and Genetics Quality Network [EMQN], and EMQN for clinical diagnosis, 
CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent)

A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a 
paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial 
sections must be submitted along with an associated pathology report prior to 
study entry.  If 20 slides are not available or the tissue block is not of sufficient size, 
the patient may still be eligible for the study, after discussion with and approval by 
the Medical Monitor.
If archival tissue is unavailable or is determined to be inadequate, tumor tissue 
must be obtained from a biopsy performed at screening. 

Measurable disease according to RECIST v1.1 (see Appendix 3)
4.1.1.2
General Inclusion Criteria
Patients must meet the following general inclusion criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Histologically or cytologically confirmed BRAFV600 wild-type melanoma

ECOG Performance Status of 0 or 1 (see Appendix 5)

Life expectancy 3 months

Adequate hematologic and end-organ function, defined using the following 
laboratory results obtained within 14 days prior to first dose of study drug treatment:
ANC 1.5 109/L (1500/L)

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Lymphocyte count 0.5 109/L (500/L)
Platelet count 100 109/L (100,000/L) without transfusion 
Hemoglobin 90 g/L (9 g/dL)
– Patients may be transfused to meet this criterion.
Creatinine clearance 40 mL/min
Serum albumin 25 g/L (2.5 g/dL)
Serum bilirubin 1.5ULN, with the following exception:
– Patients with known Gilbert disease:  serum bilirubin level 3ULN
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
and stable INR during the 28 days immediately preceding initiation of study 
treatment
AST, ALT, and ALP 2.5ULN, with the following exceptions:
– Patients with documented liver metastases:  AST and ALT 5ULN
– Patients with documented liver or bone metastases:  ALP 5ULN

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use at least two forms of effective contraceptive with a 
failure rate of 1% per year during the treatment period and for at least 3 months
after the last dose of cobimetinib and at least 5 months after the last dose of
atezolizumab or pembrolizumab.  Women must refrain from donating eggs during 
this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures (e.g., condom), and agreement to refrain from donating 
sperm, for at least 3 months after the last dose of cobimetinib
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 3 months after the last dose of cobimetinib, to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period.

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The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.

Willingness and ability of patients to report selected study outcomes (e.g., GHS and 
HRQoL) using an electronic device or paper backup questionnaires.
4.1.2
Exclusion Criteria
4.1.2.1
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered 
medications

Pregnancy, breastfeeding, or intention of becoming pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

History of severe hypersensitivity reactions to components of the cobimetinib, 
atezolizumab, or pembrolizumab formulations

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation of need for such a vaccine during the study

Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 
2 weeks prior to initiation of study treatment

Treatment with systemic immunostimulatory agents (including, but not limited to,
IFNs, IL-2) within 28 days or 5 half-lives of the drug, whichever is shorter, prior to 
Day 1 of Cycle 1

Treatment with systemic immunosuppressive medications (including, but not limited 
to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF] agents) within 2 weeks prior to Day 1 of Cycle 1
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study
4.1.2.2
Cancer-Related Exclusion Criteria
Patients who meet any of the following cancer-related exclusion criteria will be excluded 
from study entry:

Ocular melanoma 

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
Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation 
of needing such procedure while receiving study treatment

Uncontrolled tumor-related pain  
Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases 
or metastases causing nerve impingement) should be treated prior to enrollment. 
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated 
drainage more than once every 28 days
Indwelling drainage catheters (e.g., PleurX®) are allowed.

Active or untreated CNS metastases 
Patients with treated and asymptomatic CNS metastases are eligible, if they 
meet all of the following:
– Evaluable or measurable disease outside the CNS
– No metastases to midbrain, pons, medulla or within 10 mm of the optic nerves 
and chiasm
– No history or evidence of intracranial hemorrhage or spinal cord hemorrhage
– No evidence of clinically significant vasogenic edema
– No corticosteroids for2 weeks; anti-convulsant medications at a stable dose 
are allowed
– No evidence of clinical and radiographic disease progression in the CNS for 
3 weeks after radiotherapy or surgery
4.1.2.3
Exclusion Criteria based on Organ Function or Medical History
4.1.2.3.1
Exclusions Related to Cardiovascular Disease
Patients who meet any of the following exclusion criteria related to cardiovascular 
disease will be excluded from study entry:

Unstable angina, new-onset angina within the last 3 months, myocardial infarction 
within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure 
classified as New York Heart Association Class II or higher

LVEF below institutional lower limit of normal or 50%, whichever is lower

Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic 
baseline hypertension consistently above 159/99 mmHg despite optimal medical 
management

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
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction
4.1.2.3.2
Exclusions Related to Infections
Patients who meet any of the following exclusion criteria related to infections will be 
excluded from study entry:

HIV infection

Active tuberculosis infection

Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited 
to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of 
Cycle 1

Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract 
infection or COPD) are eligible.

Active or chronic viral hepatitis B or C infection
Patients with a past or resolved hepatitis B virus (HBV) infection, defined as 
having a negative hepatitis B surface antigen (HBsAg) test at screening, are 
eligible for the study if HBV DNA is negative.
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain 
reaction test for HCV RNA is negative.
4.1.2.3.3
Exclusions Related to Ocular Disease
Patients who meet any of the following exclusion criteria related to ocular disease will be 
excluded from study entry:

Known risk factors for ocular toxicity, consisting of any of the following: 
– History of serous retinopathy
– History of retinal vein occlusion (RVO)
– Evidence of ongoing serous retinopathy or RVO at screening

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4.1.2.4
Autoimmune Conditions and Immunomodulatory Drugs
Patients who meet any of the following exclusion criteria related to autoimmune 
conditions and immunomodulatory drugs will be excluded from study entry:

Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 6 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
–
Rash covering 10% of body surface area
–
Well-controlled disease at baseline requiring only low-potency topical 
corticosteroids
–
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Treatment with systemic immunosuppressive medications (including, but not limited 
to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-TNF agents) within 2 weeks prior to Day 1, Cycle 1

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4.1.2.5
Exclusions Related to Other Medical Conditions or Medications
Patients who meet any of the following exclusion criteria related to other medical 
conditions or medications will be excluded from study entry:

Active malignancy (other than melanoma) or a prior malignancy within the past 
3 years 
Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma, cervical carcinoma in situ, breast carcinoma in situ, and patients with 
isolated elevation in prostate-specific antigen in the absence of radiographic 
evidence of metastatic prostate cancer are eligible for the study
No previous cancer immunotherapy including anti-PD-1 or anti-PD-L1

Any Grade 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1

History of stroke, reversible ischemic neurological defect, or transient ischemic 
attack within 6 months prior to Day 1

Proteinuria 3.5 g/24 hr

Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 
enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during 
study treatment
These include St. John’s wort or hyperforin (strong CYP3A4 enzyme inducer) 
and grapefruit juice (strong cytochrome P450 CYP3A4 enzyme inhibitor)
4.2
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label trial.  After written informed consent has been obtained and 
eligibility has been established, each patient will be assigned an identification number 
and be randomized to one of the two treatment arms through use of an IWRS.
Randomization will be stratified by PD-L1 status (IC0 vs. IC1, 2, 3), baseline LDH (less 
than or equal to the ULN vs. greater than the ULN), and geographic region (North 
America vs. Europe vs. Australia, New Zealand, and others). A stratified, permuted 
block randomization scheme will be used to obtain approximately a 1:1 ratio between the 
two treatment arms.
Patients should receive their first dose of study treatment as soon as possible and within 
3 days of randomization, unless approved by Medical Monitor.
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are cobimetinib and
atezolizumab. Pembrolizumab is an approved treatment for melanoma and can be 
considered standard of care in some countries.  Pembrolizumab is a non-investigational 
medicinal product (NIMP) in this study, unless local regulations require it to be an IMP.

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4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Cobimetinib
Cobimetinib will be supplied as 20-mg, film-coated tablets packaged in blister packs 
(21 tablets per pack; 3 packs per box) for oral administration. 
For information on the formulation and handling of cobimetinib, see the Cobimetinib 
Investigator's Brochure and pharmacy manual. 
4.3.1.2
Atezolizumab
Atezolizumab will be supplied as sterile liquid in 20-mL glass vials.  The vial is designed 
to deliver 20 mL (1200 mg) of atezolizumab solution, but it may contain more than the 
stated volume to enable delivery of the entire 20-mL volume. Extraction of 14 mL of 
atezolizumab solution from a 1200 mg per vial contains an 840-mg dose.
For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Investigator's Brochure and pharmacy manual.
4.3.1.3
Pembrolizumab 
Patients in the control arm (Arm B) will receive pembrolizumab. In the countries where 
pembrolizumab is considered a NIMP, by local regulations, the commercial formulation 
of pembrolizumab will be provided by the local institution as part of standard of care 
treatment.  It will be provided by the Sponsor where it is considered an IMP or not 
commercially available.
For information on the formulation, packaging, and handling of pembrolizumab, see the 
local prescribing information for pembrolizumab.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Cobimetinib
Patients randomized to Arm A will receive cobimetinib 60 mg (three tablets of 20 mg 
each) by mouth QD on Days 121 of each 28-day cycle.  This 4-week period is 
considered a treatment cycle.
Cobimetinib should be taken at the same time every day.  It can be taken with or without
food.  If a daily dose of cobimetinib is missed or if vomiting occurs when the dose is 
taken, resume dosing with the next scheduled dose.
Guidelines for dosage modification and treatment interruption or discontinuation of 
cobimetinib are provided in Section 5.1.5.1.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF (see Section 5.4.4).

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4.3.2.2
Atezolizumab
Patients randomized to Arm A will receive atezolizumab 840 mg by IV infusion on Day 1 
and Day 15 of each 28-day cycle.  This 4-week period is considered a treatment cycle.
Atezolizumab will be administered in a monitored setting where there is immediate 
access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  
For more detailed information on drug preparation, storage, and administration, refer to 
the Atezolizumab Investigator’s Brochure and pharmacy manual.
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
Table 2
Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate,
blood pressure, and temperature) should be 
recorded within 60 minutes prior to the 
infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, 
and 60 minutes (5 minutes for all 
timepoints) during the infusion and at 
30 (10) minutes after the infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (10) minutes after the infusion.
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Section 5.1.5, Appendix 10 (cobimetinib plus atezolizumab-associated 
AE management), Appendix 11 (atezolizumab-associated AE management).
For anaphylaxis precautions, see Appendix 7. 
See the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration or guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.5.2, Appendix 10, and Appendix 11.

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Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF
(see Section 5.4.4).
4.3.2.3
Pembrolizumab
Patients randomized to Arm B will receive 200 mg of pembrolizumab by IV infusion Q3W
as monotherapy.  A 3-week period is considered a treatment cycle.
Pembrolizumab will be supplied in the commercially available formulation.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5.  For information on the formulation and handling of 
pembrolizumab, refer to the pembrolizumab prescribing information.
Any overdose or incorrect administration of pembrolizumab should be noted on the 
Pembrolizumab Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of pembrolizumab should be recorded on the Adverse Event 
eCRF (see Section 5.4.4).
4.3.3
Assessment of Compliance
To assess patient compliance with self-administration of cobimetinib, patients will be 
required to record the time and date they took each dose in a medication diary; missed 
doses will also be recorded.  Patients will be instructed to bring all unused study 
medication and their medication diaries at specified study visits (see Appendix 1) for 
assessments of compliance.
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (cobimetinib and atezolizumab) will be 
provided by the Sponsor where required by local health authority regulations;
pembrolizumab is an approved treatment for melanoma and can be considered standard 
of care in some countries.  Pembrolizumab will be provided by the Sponsor where 
required by local health authority regulations.  The study site will acknowledge receipt of 
cobimetinib and atezolizumab, using the IWRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  Where pembrolizumab is supplied 
by the Sponsor, shipment receipt will be documented using the IWRS; otherwise, it will 
be documented per local practice.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.

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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.5
Continued Access to Cobimetinib and Atezolizumab
The Sponsor will offer post-trial access to Sponsor study drugs (atezolizumab and 
cobimetinib) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Sponsor study drugs after completing the study if all
of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Sponsor study drugs after completing the study if 
any of the following conditions are met:

The study drugs are commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
would not otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drugs or data suggest that 
the study drug is not effective for melanoma

The Sponsor has reasonable safety concerns regarding the study drugs as 
treatment for melanoma

Provision of study drugs is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
The following therapies are permitted in the study:

Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low-molecular-weight 
heparin or warfarin at a stable dose level)
Although allowable, caution should be used when using concomitant medications 
that increase the risk of bleeding, including antiplatelet or anticoagulant therapy, 
because of the risk of hemorrhage with cobimetinib.

Palliative radiotherapy (e.g., treatment of known bone metastases), provided it does 
not interfere with assessment of tumor target lesions
It is not required to withhold atezolizumab during palliative radiotherapy.  

Inactive influenza vaccinations during influenza season only

Megestrol administered as an appetite stimulant

Inhaled corticosteroids for COPD

Mineralocorticoids (e.g., fludrocortisone)
Anti-emetic and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drugs.  At the discretion of the investigator, 
prophylactic anti-emetic and anti-diarrheal medication(s) may be used per standard 
clinical practice before subsequent doses of study drugs.  Hematopoietic growth factors 
should not be administered prophylactically before initial treatment with study drugs. 
Hematopoietic growth factors may be administered according to local guidelines if 
indicated during the study. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 

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hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists).
All medications must be recorded on the Concomitant Medications eCRF.
4.4.2
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the anti-cancer agent (see Section 4.1.2.5), and 
during study treatment until disease progression is documented and patient has 
discontinued study treatment.  This includes, but is not limited to, chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy.
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2.2), and during study treatment until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and local therapy under certain circumstances (see 
Section 4.4.1 for details). 

Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days or 5 half-lives prior to initiation of study treatment and during study 
treatment.

Immunomodulatory agents, including, but not limited to, ipilimumab, IFNs or IL-2, are 
prohibited during the entire study; these agents could potentially increase the risk for 
autoimmune conditions when received in combination with atezolizumab and 
pembrolizumab.

Immunosuppressive medications, including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, and thalidomide are prohibited during study treatment; 
these agents could potentially alter the activity and the safety of atezolizumab and 
pembrolizumab.
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab and pembrolizumab.  
Therefore, in situations where systemic corticosteroids or TNF-inhibitors would 
be routinely administered, alternatives, including antihistamines, should be 
considered first by the treating physician.  If the alternatives are not feasible, 

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systemic corticosteroids and TNF-inhibitors may be administered at the 
discretion of the treating physician (see Section 4.4.3).

For patients randomized to receive cobimetinib and atezolizumab:
Concomitant use of strong and moderate inhibitors of CYP3A 
(e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, 
telithromycin, and voriconazole) should be avoided as cobimetinib is a sensitive 
substrate of CYP3A and exposures will be increased in presence of these agents 
(approximately 7-fold increase in presence of itraconazole in healthy subjects).
Avoidance of strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, and St. John’s wort) as they increase the 
metabolism of cobimetinib.  Strong inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product, with no or minimal 
potential to induce CYP3A4, should be considered.
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication is metabolized by or strongly inhibits or 
induces CYP3A.  In addition, the investigator should contact the Medical Monitor if 
questions arise regarding any medications not listed above.
4.4.3
Cautionary Therapy for Atezolizumab-Treated Patients
4.4.3.1
Corticosteroids and Tumor Necrosis Factor-Inhibitors
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered.  If the alternatives are not feasible, 
systemic corticosteroids and TNF-inhibitors may be administered at the discretion of 
the investigator (see Section 4.4.2).
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to the Appendix 11 for details).
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study.  Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment 
and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 

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Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
BRAF status will be prescreened prior to beginning the remaining screening evaluations.
Standard-of-care screening assessments may be performed concurrently with BRAFV600
mutation testing.  Locally or centrally tested BRAFV600 status must be known prior to 
performing subsequent study-specific screening assessments.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Screening Window Extension
The screening window may be extended for an agreed upon and acceptable period to 
allow re-evaluation of assessments after discussion and agreement with the 
Medical Monitor.
Rescreening
Rescreening may be allowed in certain cases (e.g., such as an aberrant laboratory value, 
washout of a prior medication, unavailability of study drug, or inability to complete 
screening within the screening window) in which patients have not previously been 
randomized into the study and have not received study treatment, after discussion and 
agreement with the Medical Monitor.  For these patients, one rescreening will be allowed.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, prior surgeries within 5 years 
prior to initiation of study treatment, and use of alcohol, will be recorded at baseline.  In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to initiation of study drug will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.  Baseline 
disease characteristics data will include melanoma disease status (metastatic or locally 
advanced and unresectable) at enrollment, ECOG Performance Status, date of 
diagnosis of first metastatic disease, site of primary disease, RAS status, history of 
melanoma cancer surgery, and location of metastasis at enrollment.
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  

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Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF (see Section 5.3.5).
Height will be recorded at screening only. Weight will be recorded at screening and at 
various timepoints indicated in Appendix 1.
In addition, patients randomized to receive cobimetinib plus atezolizumab will be asked 
specifically about vision-related changes as part of each physical examination in addition 
to interval medical history.  Note:  If physical examinations are performed within 7 days 
of Day 1, Cycle 1, they do not have to be repeated on Day 1 of Cycle 1.
4.5.4
Vital Signs 
Vital signs will include temperature (measured in degrees Centigrade), pulse rate, 
respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position. Blood pressure and pulse rate measurements will be recorded after a 5-minute 
rest while the patient is in a seated position.  Resting oxygen saturation will be measured 
during screening and at subsequent visits.
Vital signs will be measured and recorded at the following timepoints:

Within 60 minutes prior to infusion

During infusion or after infusion per schedule of assessments
For patients who experienced an infusion-related reaction (IRR) during the previous 
atezolizumab infusion, refer to Section 4.3.2.2.  For patients who experienced an IRR 
during the previous pembrolizumab infusion, refer to the prescribing information for 
pembrolizumab. 
4.5.5
Tumor and Response Evaluations
All measurable and non-measurable lesions must be documented at screening (within 
35 days prior to initiation of study treatment). Evaluation of tumor response conforming 
to RECIST v1.1 must then be documented every 8 weeks (1 week) from the date of 
first study drug administration (Day 1) through 18 months (80 weeks) and then every 
12 weeks (1 week) thereafter, until investigator-determined disease progression 
(according to RECIST v1.1 that is confirmed 48 weeks after initial documentation of 
progression), withdrawal of consent, study termination by the Sponsor, or death, 
whichever occurs first.  Thus, tumor assessments are to continue according to schedule 
for patients who discontinue treatment for reasons other than disease progression. At 
the investigator’s discretion, tumor assessments may be repeated at any time if disease 
progression is suspected. 

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Tumor assessments must be performed independently of changes to the study 
treatment administration schedule (i.e., when treatment is withheld). If a tumor 
assessment has to be performed early or late, subsequent assessments should be 
conducted according to the original schedule based on the date of first study treatment 
administration on Day 1 of Cycle 1. The tumor assessment schedule is identical in both 
arms to avoid potential bias.
Tumor assessments will include contrast-enhanced CT or MRI scans of the chest, 
abdomen, and pelvis. Imaging of the neck should be included if clinically indicated.
In the event a positron emission tomography (PET)/CT scanner is used for tumor 
assessments, the CT portion of the PET/CT must meet criteria for diagnostic quality. 
A CT or MRI scan of the head must be performed at screening to assess CNS 
metastasis. An MRI scan of the brain is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal scan. Patients with untreated 
or actively progressing CNS metastases are not eligible for the study (see Section 4.1.2). 
Stable brain metastases (as defined in Section 4.1.2) must be evaluated at each tumor 
assessment using the same radiographic procedure as the baseline study. Patients 
without brain metastases do not need brain scans for tumor assessment unless clinically 
warranted. Clinical disease assessments by physical examination should be performed 
for patients with palpable or superficial lesions. Tumor measurements for each patient 
should be made by the same investigator or radiologist, if feasible, using the same 
assessment technique or procedure throughout the study. 
Tumor response and progression will be evaluated according to RECIST v1.1 (see 
Appendix 3) and immune-modified RECIST (see Appendix 4). Objective response (a 
complete response or partial response) must be confirmed by repeat assessments 
4-8 weeks after initial documentation. In the case of stable disease, tumor 
measurements must meet criteria for stable disease 6 weeks after initiation of study 
treatment. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
4.5.6.1
Local Laboratory Assessments
Study Inclusion Assessment
A sample for the following laboratory test for study inclusion will be sent to the study 
site's local laboratory for analysis:

BRAFV600 status 

If local analysis is not available, the sample is to be sent for central assessment.

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Screening Assessments
Samples for the following laboratory tests during screening will be sent to the study site's 
local laboratory for analysis:

Hematology:  RBC, reticulocytes, hemoglobin, hematocrit, WBC count with 
differential count (neutrophils, bands, eosinophils, basophils, monocytes, and 
lymphocytes), and platelet count

Serum chemistry panel:  BUN or urea, creatinine, sodium, potassium, chloride, 
bicarbonate or total CO2 (HCO3 and CO2 not mandatory if unavailable at site),
magnesium, calcium, phosphorus, total bilirubin, direct bilirubin, ALT, AST, ALP, 
CPK, uric acid, total protein, LDH, and albumin

Fasting blood glucose (after a minimum 8-hour fast), at screening only

Fasting lipids:  total cholesterol, LDL cholesterol, and triglycerides (after a minimum 
8-hour fast), at screening only

Coagulation:  INR and aPTT

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and 
blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, and bacteria).

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (defined as 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone permanent surgical sterilization (removal of bilateral ovaries and/or 
uterus).

Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4)

HBV serology:  HBsAg, antibodies against HBsAg, anti-HBcAb
HBV DNA should be obtained prior to randomization if patient has a negative 
serology for HBsAg and a positive serology for anti-HBcAb.

HCV serology:  HCV antibody (anti-HCV)
HCV RNA should be obtained prior to randomization if patient tests positive for 
anti-HCV.

HIV testing
All patients will be tested for HIV prior to the inclusion into the study, and 
HIV-positive patients will be excluded from the study.

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Treatment
Samples for the following laboratory tests during study treatment will be sent to the study 
site's local laboratory for analysis:

Hematology:   RBC, reticulocytes, hemoglobin, hematocrit, WBC count with 
differential count (neutrophils, bands, eosinophils, basophils, monophils, 
lymphocytes, and platelet count)

Serum chemistry panel:  glucose, BUN or urea, creatinine, sodium, potassium, 
chloride, bicarbonate or total CO2 (HCO3 and CO2 not mandatory if unavailable at 
site), magnesium, calcium, phosphorus, total bilirubin, direct bilirubin, ALT, AST, 
ALP, CPK, uric acid, LDH, albumin

Thyroid-function testing:  thyroid-stimulating hormone, T3 (or total T3 for sites where 
free T3 is not performed), and free T4
4.5.6.2
Central Laboratory Assessments
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories.  Instruction manuals and supply kits will 
be provided for all central laboratory assessments.  Samples for the following laboratory 
tests will be sent to one or several central laboratories for analysis:

BRAFV600 testing 

LDH

PD-L1

Anti-drug antibody (ADA) assays for patients in Arm A only, provided that it does not 
cause undue hardship to the patient (e.g., the patient is in hospice care and not able 
to come in for a visit)
Serum samples also may be assayed for other anti-atezolizumab antibodies with 
use of validated immunoassays.

PK assay, provided that it does not cause undue hardship to the patient (e.g., the 
patient is in hospice care and not able to come in for a visit)
Serum samples will be assayed for atezolizumab concentrations with use of a 
validated immunoassay.  
Plasma samples for cobimetinib concentrations will be measured using validated 
liquid chromatography combined with tandem mass spectrometry method.

Plasma samples for exploratory research on biomarkers 

Archival (the most recently obtained and sample collection date 5 years) or fresh 
tumor tissue sample consistent with the patient's diagnosis, collected at screening 
for determination of extended BRAFV600 mutation status and for exploratory research 
on biomarkers 
A representative FFPE tumor specimen in a paraffin block (preferred) or 
20 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study randomization. 

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Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method. 
Tumor tissue should be of good quality based on total and viable tumor content. 
Acceptable samples include those from resections, core-needle biopsies (at 
least three cores, embedded in a single paraffin block), or excisional, incisional, 
or forceps biopsies. Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), brushing, 
cell pellets from pleural effusion, and lavage samples are not acceptable. 
Tumor tissue from bone metastases that have been decalcified is not 
acceptable. 
If 20 slides are not available or the tissue block is not of sufficient size, the 
patient may still be eligible for the study, after discussion with and approval by 
the Medical Monitor. If archival tissue is unavailable or unacceptable, a 
pretreatment tumor biopsy is required. 
For archival samples, remaining tumor tissue blocks from randomized patients 
will be returned to the site upon request, after biomarker testing has been 
completed. Remaining tumor tissue blocks from patients who are not 
randomized into the study will be returned to the site no later than 3 months 
after eligibility determination.  Slides will not be returned.

An optional biopsy during treatment is requested on Day 15 (5 days) of Cycle 1, 
provided the patient’s disease is easily accessible and tumor biopsies can be 
performed with minimal risk and discomfort.

Tumor tissue sample collected at the time of progression, if deemed clinically 
feasible by the investigator, for exploratory research on biomarkers
Biopsies should be performed at the time of confirmed disease progression, 
preferably within 3 days after the last dose of study treatment.  Acceptable 
samples include those from resections, core-needle biopsies (three cores 
preferred), excisional, incisional, or forceps biopsies.

Exploratory biomarker research may include, but will not be limited to, analysis of 
S100, ctDNA, genes or gene signatures associated with tumor immunobiology, 
tumor immune profiles (e.g., CD8, MHC, and PD-L1), lymphocytes, TCR repertoire, 
or cytokines associated with T-cell activation and may involve DNA or RNA 
extraction, analysis of somatic mutations, and use of NGS.
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from these analyses in the form of an NGS report, 
which is available upon request directly from Foundation Medicine.  If allowed by local 
laws, the investigator may share and discuss the results with the patient, unless the 
patient chooses otherwise.  The Foundation Medicine NGS assay has not been cleared 
or approved by health authorities.  The NGS report is generated for research purposes 
and is not provided for the purpose of guiding future treatment decisions.  Results may 
not be available for samples that do not meet testing criteria.

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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biologic samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 

Plasma and serum samples collected for PK analysis or immunogenicity analysis 
may be needed for additional immunogenicity characterization and PK and 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed. 

Blood samples collected for whole genome sequencing will be stored until they are 
no longer needed or until they are exhausted.

Blood and tissue samples collected for biomarker analyses will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed, or earlier 
depending on local regulations. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine). The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.7
Tumor Tissue Samples
A central laboratory will coordinate the sample collection of tissue samples for 
research-related testing at central laboratories or at the Sponsor.  Instruction manuals 
and supply kits will be provided for all central laboratory assessments.
See the laboratory manual for additional details on tissue sample handling.
4.5.8
Electrocardiograms
A 12-lead ECG will be performed at screening for all patients, as outlined in the schedule 
of activities (see Appendix 1), and may be obtained at unscheduled timepoints as 
indicated. 

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All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at the same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.
4.5.9
Left Ventricular Ejection Fraction
All patients will require evaluation of LVEF at screening, and only patients receiving 
cobimetinib (Arm A) will require subsequent evaluations of LVEF.
Evaluation of LVEF by ECHO or MUGA must be performed at the following timepoints: 

Screening 

Day 1 of Cycle 2 (1 week)

Day 1 of every three treatment cycles and starting at Cycle 5 and thereafter
(2 weeks)

The treatment discontinuation visit evaluation of LVEF does not need to be 
performed at the treatment discontinuation visit if an evaluation has been performed 
within the last 12 weeks and there are no clinically significant findings and/or 
changes from baseline. 

All patients restarting treatment with a dose reduction of cobimetinib because of a 
decrease in LVEF should have LVEF measurements taken after approximately 
2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then resume monitoring of LVEF 
every three treatment cycles.
Any patient who develops clinical signs or symptoms suspicious of cardiac failure should 
undergo an LVEF assessment.  Evaluation of LVEF must be performed using the same 
method (ECHO or MUGA) for each patient.  It is strongly encouraged that the same 
laboratory and operator perform ECHO or MUGA scans for each individual patient.  
Investigators must be aware of local institution regulations regarding repeat MUGA 
scans.  The repeat administration of radioisotopes is limited in some nuclear medicine 
laboratories, and some patients in this study could require monitoring on four or more 
occasions.

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4.5.10
Ophthalmologic Examination
All patients will require an ophthalmologic examination at screening, and only patients 
receiving cobimetinib (Arm A) will require subsequent ophthalmologic examinations.
Ophthalmologic examination must be performed at the following timepoints:

Screening

Day 1 of Cycle 2 (1 week)

Day 1 of Cycles 5, 8, and 11 (every three treatment cycles; 2 weeks)

Day 1 of Cycles 15, 19, and 23 (every four treatment cycles; 2 weeks)

Day 1 of Cycles 29, 35, 41, 47, etc. (every six treatment cycles; 2 weeks)

Treatment discontinuation visit: The treatment discontinuation visit evaluation does 
not need to be performed if an evaluation has been performed within the last 
12 weeks and there are no clinically significant findings and/or changes from 
baseline.
The objective of baseline ophthalmologic examination is to evaluate for evidence of 
retinal pathology that may be a risk factor for central serous retinopathy or RVO.  
Ophthalmologic examination must be performed by a qualified ophthalmologist.  Risk 
factors for RVO include uncontrolled serum cholesterol, hypertriglyceridemia, 
hyperglycemia, hypertension, and glaucoma. See Sections 4.1.2.1 and 4.1.2.3.3 for 
inclusion and exclusion criteria.
Baseline and serial surveillance ophthalmologic examination will include visual acuity 
testing, intraocular pressure measurements by tonometry, slitlamp ophthalmoscopy, 
indirect ophthalmoscopy, and spectraldomain optical coherence tomography.  
Spectral-domain optical coherence tomography, if not available, may be substituted with 
time-domain optical coherence tomography.
4.5.11
Patient-Reported Outcomes
To more fully characterize disease burden and clinical benefit of atezolizumab and 
cobimetinib in patients with advanced melanoma, patient-reported outcome (PRO) data 
will be obtained through use of the following instruments:  EORTC QLQ-C30 and the 
EQ-5D-5L.  The questionnaires will be translated as appropriate into the local language. 
Reminders will be provided in order to maximize compliance. It is critical to rigorously 
collect the PRO data as they support the secondary and exploratory efficacy endpoints. 
The EORTC QLQ-C30 and EQ-5D-5L will be completed on Day 1 of Cycle 1 and every 
4 weeks thereafter, including prior to tumor assessments visits every 8 weeks. In 
addition, the questionnaires will be completed at the site for the treatment 
discontinuation visit and at unscheduled visits.  All PRO questionnaires must be 
completed prior to any study assessment(s) that could bias a patient’s responses. 

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Also, the PROs will be collected every 4 weeks for 6 months after the treatment 
discontinuation visit.  PRO data collected post-study treatment will be used as a unique 
opportunity to quantify patients’ post-treatment experience in terms of humanistic 
outcomes. 
Patients will use an electronic device to capture all PRO data. Instructions to use the 
device and to complete the PRO questionnaires will be provided by site staff once the 
patient is randomized and before initiation of study treatment. The data will be 
transmitted to a centralized database maintained by the vendor and will be made 
available for access by appropriate study personnel at the site. In the event that the 
device or the Web-based system is not readily available, paper questionnaires formatted 
for use as backup data collection forms should be used to minimize missing data.  
Compliance with data collection will be documented throughout the study.
4.5.11.1
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-reported measure (Aaronson et al. 
1993; Fitzsimmons et al. 1999) that is commonly used in clinical trials involving patients 
with metastatic melanoma (Revicki et al. 2012; Schadendorf et al. 2015).  It consists of 
30 questions that assess five aspects of patient functioning (physical, emotional, role, 
cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), 
GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties) with a recall period of the previous week.  Scale scores can be 
obtained for the multi-item scales.  The EORTC QLQ-C30 module takes approximately 
10 minutes to complete.  A 10-point change is defined as a clinically meaningful 
difference for the EORTC QLQ-C30 (Osoba et al. 1998) and has been used in other 
melanoma studies (Long et al. 2016; Shadendorf et al. 2015).
4.5.11.2
EQ-5D-5L
The EQ-5D-5L is a validated, self-reported health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). There are two 
components to the EQ-5D-5L:  a five-item health state profile that assesses mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a visual 
analog scale that measures health state.  Published weighting systems allow for creation 
of a single composite score of a patient’s health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete. It will be utilized in this study for informing 
pharmacoeconomic evaluations.

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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Study termination or site closure

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.2
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Confirmed disease progression or loss of clinical benefit (see Section 3.1.2 for 
dosing beyond progression)

Symptomatic deterioration attributed to disease progression, as determined by the 
investigator, after integrated assessment of radiographic data, biopsy results, and 
clinical status

Intolerable toxicity related to any study drug

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.2)

Pregnancy

Withdrawal of consent

Investigator of Sponsor determines it is in the best interest of the patient (e.g., 
unwillingness to comply with study assessments that compromise their safety)

Any adverse event that requires study treatment discontinuation per the guidelines 
in Section 5.1, Appendix 10, and Appendix 11.

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
In cases where discontinuation of one study drug is required for toxicity, patients 
may continue on the remaining drug (Arm A only) per the guidelines in Section 5.1
and Appendix 10.
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with cobimetinib 
and atezolizumab in completed and ongoing studies, and published data from similar 
molecules.  The anticipated important safety risks for cobimetinib and atezolizumab are 
outlined below.  Refer to the Cobimetinib Investigator's Brochure and Atezolizumab 
Investigator’s Brochure for a complete summary of safety information. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study. Eligibility criteria have been designed to exclude patients at 
higher risk for toxicities.   Administration of atezolizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  

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Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification, and treatment interruption or 
discontinuation, are provided below.  There are separate guidelines for the two different 
arms as the toxicities and management guidelines are distinct.  Refer to the specific 
guidelines for each arm individually.
The risks associated with cobimetinib, atezolizumab, and pembrolizumab are detailed in 
Sections 5.1.1, 5.1.2, and 5.1.4, respectively.
Adverse events will be reported as described in Sections 5.25.6.  In addition to the 
oversight provided by the Medical Monitor and drug safety personnel for this trial, an 
iDMC will monitor and evaluate patient safety throughout the study.
5.1.1
Risks Associated with Cobimetinib
The information related to the risks attributed to cobimetinib is based on safety data from 
Studies GO28141, NO25395, and MEK4592g.  Additional clinical experience has been 
obtained through postmarketing experience and clinical studies with cobimetinib in 
combination with other agents.  The safety data is also based on postmarketing 
experience.  For further information regarding clinical safety, refer to the current 
Cobimetinib Investigator’s Brochure.
5.1.1.1
Important Identified Risks Associated with Cobimetinib
5.1.1.1.1
Hemorrhage
Hemorrhage, including major hemorrhages, defined as symptomatic bleeding in a critical 
area or organ, can occur with cobimetinib.  In clinical studies with cobimetinib, events of 
cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract hemorrhage, 
and hematuria have been reported.
In Study GO28141, Grade 14 hemorrhagic events were reported in 13.0% of patients 
treated with cobimetinib plus vemurafenib and in 7.3% of patients treated with placebo 
plus vemurafenib.  The majority of hemorrhagic events were Grade 1 or 2 and 
non-serious.  Grade 3 and 4 hemorrhage events were reported in 1.2% of patients 
receiving cobimetinib plus vemurafenib and in 0.8% of patients receiving placebo plus 
vemurafenib.
Caution should be used in patients with additional risk factors for bleeding, such as brain 
metastases, and/or in patients that use concomitant medications that increase the risk of 
bleeding (including antiplatelet or anticoagulant therapy).
Instructions for dose modification for hemorrhagic events are included in Appendix 10.

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5.1.1.1.2
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK-inhibitors, including cobimetinib (Flaherty et al. 2012).  
Manifestations of serous retinopathy include visual disturbances, findings of retinal 
detachment, and retinopathy.  Serous retinopathy events may also be asymptomatic.
Serous retinopathy has been characterized in Study GO28141.  The study incorporated 
prospective serial ophthalmologic examinations for all enrolled patients.  Serous 
retinopathy was reported more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half the events were asymptomatic Grade 1 events.  Few patients treated 
with cobimetinib plus vemurafenib experienced Grade3 ocular events (2.8%); the 
majority of these events were managed with dose modification of both cobimetinib and 
vemurafenib.
To address serous retinopathy with cobimetinib treatment, all patients are required to 
undergo a baseline ophthalmologic examination to assess for history or evidence of 
retinal pathology that is considered to be a risk factor for or indicative of neurosensory 
retinal detachment, central serous chorioretinopathy, neovascular retinopathy, or 
retinopathy of prematurity.  Patients will also undergo ophthalmologic examinations at 
specified timepoints throughout the study (see Appendix 1).  Details regarding baseline 
and subsequent ophthalmologic examinations are provided in Section 4.5.10.
Guidelines for management of patients who develop Grade 2 visual disorders or 
retinopathy are provided in Appendix 10.
5.1.1.1.3
Left Ventricular Dysfunction
Decreases in LVEF from baseline have been reported in patients receiving cobimetinib. 
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF events may be asymptomatic.
Left ventricular dysfunction has been characterized in Study GO28141.  The study 
incorporated prospective serial LVEF evaluations in all patients.  With active surveillance, 
measured Grade 2 or 3 reductions in LVEF were observed more frequently in patients 
treated with cobimetinib plus vemurafenib than placebo plus vemurafenib (8.5% vs. 
3.7%, respectively).  Of the patients treated with cobimetinib plus vemurafenib, 
2 patients (0.8%) had symptomatic reduction in LVEF and the remaining patients were 
asymptomatic.  Most LVEF reduction events in patients treated with cobimetinib plus 
vemurafenib (62%) improved or resolved with management according to dose 
modification guidelines (see Appendix 10). 
5.1.1.1.4
Rhabdomyolysis and CPK Elevations
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 

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elevations reported were asymptomatic, non-serious, and resolved with or without study 
drug interruption.  One event of rhabdomyolysis was reported in the Phase III study 
GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported in the 
postmarketing experience.
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade 3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade 3 events).  
CPK will be monitored at baseline and monthly during treatment or as clinically 
indicated. Instructions for Dose Modification for elevated CPK and rhabdomyolysis are 
included in Appendix 10.
5.1.1.1.5
Pneumonitis
Events of pneumonitis have been reported in cobimetinib clinical studies.  Most reported 
events were considered to be non-serious and of low severity grade.  In Study GO28141, 
pneumonitis events were reported more frequently in patients treated with cobimetinib 
plus vemurafenib than placebo plus vemurafenib (1.6% vs. 0.4%; all grades).  
There were no reported Grade 3 events in either study arm.  Serious events were 
reported for 2 patients (0.8%) treated with cobimetinib plus vemurafenib. Refer to 
Appendix 10 for pneumonitis management guidelines.
5.1.1.2
Potential Risks Associated with Cobimetinib
5.1.1.2.1
Liver Laboratory Abnormalities and Severe Hepatoxicity 
(Grade 3)
Liver laboratory test abnormalities, including increases in ALT, AST, and ALP have been 
reported as adverse events and serious adverse events in patients treated with 
cobimetinib plus vemurafenib.
In the Phase III study GO28141, liver laboratory test abnormalities reported as Grade 3 
adverse events occurred more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (20.5% vs. 15.1%, respectively).
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines. In both study arms, the majority of Grade ≥ 3 liver laboratory test 
abnormalities resolved. Refer to Appendix 10 for hepatotoxicity management guidelines.
5.1.1.2.2
Impaired Female Fertility and Developmental Toxicity
There is a potential for effects on fertility and embryofetal toxicity based on results from 
nonclinical studies. 
Although no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased 
apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal 

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epithelial cells in rats, and epididymal epithelial cells in dogs.  These changes were 
reversible upon discontinuation of cobimetinib administration.
5.1.1.2.3
Teratogenicity and Developmental Toxicity
In a dedicated embryofetal toxicity study, cobimetinib produced fetal toxicity 
(resorptions and reductions in fetal weight) and teratogenicity (malformations of the great 
vessels and skull) at similar systemic exposures to those observed in patients 
administered the 60-mg dose.
5.1.1.3
Other Risks with Cobimetinib
5.1.1.3.1
Rash
In Study GO28141, combined rash events of all types and grades were reported more 
frequently in patients treated with cobimetinib plus vemurafenib than placebo plus 
vemurafenib (71.7% vs. 66.7%, respectively), although Grade 3 events (approximately 
16% of patients) and types of rash reported were similar between study arms.  Specific 
events in patients treated with cobimetinib plus vemurafenib included rash (39% all 
grades, 5.9% Grade3, and 1.6% serious adverse events) and maculopapular rash 
(14.6% all grades, 6.3% Grade3, and 1.2% serious adverse events).
Generally, Grade3 rash events were effectively managed with dose modification 
guidelines.  In Study GO28141, approximately 90% of Grade 3 rash events resolved in 
both arms. Refer to Appendix 10 for rash management guidelines.
5.1.1.3.2
Gastrointestinal Toxicity
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, 
have been reported in all cobimetinib studies in adult patients with cancer.
In Study GO28141, diarrhea was the most common adverse event reported. Diarrhea 
events of all severity grades were reported in 59.9% of patients and Grade 3 or 4 events 
were reported in 6.5% of patients treated with cobimetinib plus vemurafenib versus 30.9% 
(Grade 3) and 0.8% (Grade 4) in the patients treated with placebo plus vemurafenib. No 
Grade 5 events of diarrhea have been reported. Serious adverse events of diarrhea 
were reported for 1.2% of patients treated with cobimetinib plus vemurafenib.
Nausea and vomiting have been reported in association with cobimetinib. Most nausea 
and vomiting events were considered to be non-serious and of low severity grade.  In 
Study GO28141, nausea and vomiting events were reported more frequently in the 
active cobimetinib arm than the control arm (nausea, 41.3% vs. 25.2%; vomiting, 24.3% 
vs. 12.6%).  However, of patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea, 0.8%; vomiting, 1.2%).
In the Phase I, single-agent study (MEK4592g), all grades of nausea and vomiting were 
both reported as 33.9%, with 0.9% reported for Grade 3 nausea and none reported for 
vomiting.

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The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake. In the majority of cases, diarrhea has been effectively 
managed with anti-diarrheal agents and supportive care. Routine anti-emetic 
prophylaxis is not recommended. Refer to Appendix 10 for gastrointestinal toxicity 
management guidelines.
5.1.1.3.3
Hypersensitivity
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib monotherapy or cobimetinib when used 
with other agents.  These have appeared to be isolated reports, and in some cases, 
occurred in patients with history of drug allergies.  Thus, the relationship of cobimetinib 
to these events is unclear.
In Study GO28141, Grade 3 hypersensitivity events were reported for 3 patients in the 
cobimetinib plus vemurafenib arm compared with no such events in the placebo plus 
vemurafenib arm.  All events required hospitalization and treatment with steroids. 
Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction.
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as IRRs and immune-mediated
hepatitis, pneumonitis, myocarditis, colitis, pancreatitis, diabetes mellitus, hypophysitis, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, nephritis, myositis, 
and severe cutaneous adverse reactions.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH) and 
macrophage activation syndrome (MAS), which are considered to be potential risks for 
atezolizumab.  Refer to Section 6 of the Atezolizumab Investigator's Brochure and 
Appendix 11 of the protocol for a detailed description of anticipated safety risks for 
atezolizumab.
5.1.3
Anticipated Overlapping Adverse Events for Cobimetinib and 
Atezolizumab
Special consideration is given to areas of potential overlapping toxicity based on data 
from previous clinical experience with each compound individually or with other 
molecules.  Potential overlapping toxicities of cobimetinib and atezolizumab include 
dermatologic reactions, ocular toxicity, hepatic toxicity, liver laboratory abnormalities, 
pneumonitis, and gastrointestinal toxicity.  Refer to the Atezolizumab Investigator’s 
Brochure, Cobimetinib Investigator’s Brochure, and Appendix 10 for details regarding 
these adverse events.  Patients treated with cobimetinib and atezolizumab should be 
closely monitored for evidence of overlapping and/or potentiation of these and any other 
acute toxicities.  If any evidence of overlapping and/or potentiation of the below toxicities 

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is observed, patients should receive maximal supportive care as clinically indicated.  
Management guidelines for these potential overlapping toxicities are included in
Appendix 10.
5.1.4
Risks Associated with Pembrolizumab
The overall safety profile for pembrolizumab is based on data from more than 
2300 patients in clinical trials, including Phase III data for 1500 patients with metastatic 
melanoma. Some of the most serious adverse drug reactions in patients who received 
pembrolizumab are immune-mediated pneumonitis, immune-mediated colitis, 
immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated 
nephritis, immune-mediated skin reactions, other immune-mediated adverse reactions,
infusion-related reactions (IRRs), complications of allogeneic hematopoietic stem cell
transplantation (HSCT), and embryofetal toxicity.  The most frequently observed 
adverse drug reactions (20%) in patients who received pembrolizumab are fatigue, 
musculoskeletal pain, pyrexia, decreased appetite, dyspnea, pruritus, rash, constipation, 
diarrhea, and nausea.
Of note, this is not an exhaustive list of risks associated with pembrolizumab.  Please 
refer to the pembrolizumab prescribing information for complete information regarding 
clinical safety.
5.1.5
Management of Patients Who Experience Specific 
Adverse Events
5.1.5.1
Cobimetinib Dose Modifications
General dose modification for cobimetinib is provided in Table 3. Dose modification for 
specific adverse events is provided in Appendix 10. After dose reduction, consideration 
may be given to allow for dose escalation of cobimetinib by a maximum of one dose 
level (20 mg) increments following resolution of the adverse event that resulted in dose 
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Table 3
Recommended Cobimetinib Dose Modifications
Grade 
(NCI CTCAE) a
Recommended 
Cobimetinib Dose
Grade 1 or Grade 2 
(tolerable)
No dose reduction. Maintain cobimetinib at the 
same dose of 60 mg QD (3 tablets).
Grade 2 (intolerable) or 
Grade 3 or 4 (any)
First appearance
Interrupt treatment until Grade 1: restart 
treatment at 40 mg QD (2 tablets).
Second appearance
Interrupt treatment until Grade 1: restart 
treatment at 20 mg QD (1 tablet).
Third appearance
Consider permanent discontinuation.
NCI CTCAENational Cancer Institute Common Terminology Criteria for 
Adverse Events; QDonce a day.
5.1.5.2
Atezolizumab and Pembrolizumab Dose Modifications
There will be no dose reduction for atezolizumab or pembrolizumab in this study.
5.1.5.3
Management of Cobimetinib- and Atezolizumab-Specific 
Adverse Events (Arm A)
Toxicities associated or possibly associated with cobimetinib plus atezolizumab 
treatment should be managed according to standard medical practice.  
For management of cobimetinib- and atezolizumab-specific toxicities, including IRRs,
gastrointestinal toxicity, dermatologic toxicity, hepatotoxicity, pulmonary toxicity, potential 
eye toxicity, reductions in LVEF from baseline, rhabdomyolysis, elevated CPK, and 
hemorrhage, see Appendix 10.
Guidelines for management of patients who experience atezolizumab-associated or 
possibly associated adverse events, including infusion-related reactions and 
immune-mediated reactions (e.g., pulmonary, hepatic, gastrointestinal, endocrine, ocular, 
myocarditis, pancreatic, dermatologic, neurologic, meningoencephalitis, and renal
events) are provided in Appendix 11.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.

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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)

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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) and based on the following observations:
Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)
Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice
Hepatitis, including AST or ALT 10ULN
Significant liver toxicity

Suspected transmission of an infectious agent by the study treatment, as 
defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Systemic lupus erythematosus

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
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome (CRS), 
influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities
Uveitis or retinitis
RVO
Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment, and central serous 
chorioretinopathy 

Myositis

Cardiac disorders for the following events
Grade 2 cardiac disorders, including atrial fibrillation, myocarditis, 
and pericarditis
Symptomatic heart failure or Grade 3 reduction in LVEF 

Vasculitis

Myopathies, including rhabdomyolysis or Grade 3 CPK elevation

Grade 3 hemorrhage or any-grade cerebral hemorrhage 

Grade3 rash

Grade3 diarrhea 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 

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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, serious adverse events, and adverse 
events of special interest will be reported until 135 days after the last dose of study drug, 
or until a new systemic anti-cancer therapy is initiated, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  Examples of 
non-directive questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.

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Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event

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Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Infusion-Related Reactions and Cytokine-Release Syndrome
There may be significant overlap in signs and symptoms of IRRs and CRS.  While IRRs 
occur during or within 24 hours after treatment administration, time to onset of CRS 
may vary.  Differential diagnosis should be applied, particularly for late-onset CRS 
(occurring more than 24 hours after treatment administration), to rule out other 
etiologies such as delayed hypersensitivity reactions, sepsis or infections, HLH, tumor 
lysis syndrome, early disease progression, or other manifestations of systemic 
inflammation.
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured on the Adverse Event 
eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine-release syndrome").  
Avoid ambiguous terms such as "systemic reaction."  Cases of late-onset CRS should be 
reported as "cytokine-release syndrome" on the Adverse Event eCRF.  Associated signs 
and symptoms of an IRR should be recorded on the dedicated Infusion-Related 
Reaction eCRF. 

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If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an IRR also recorded separately on the 
dedicated Infusion-Related Reaction eCRF.
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 11.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.

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5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."

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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with 
total bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).

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5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of melanoma should be recorded on the Death 
during Adverse Event Reporting Period Attributed to Progressive Disease eCRF.  All 
other deaths that occur during the adverse event reporting period, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").

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5.3.5.10
Lack of Efficacy or Worsening of Melanoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data (i.e., EORTC QLQ-C30 and 
EQ-5D-5L) by the Sponsor, and safety analyses will not be performed using PRO data.  
Although sites are not expected to review the PRO data, it is possible that an 
investigator could become aware of PRO data that may be indicative of an adverse 
event.  Under these circumstances, the investigator will determine whether the criteria 
for an adverse event have been met and, if so, will report the event on the Adverse 
Event eCRF.

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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4
for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board or Ethics Committee 
(IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
Email:
24-HOUR MEDICAL COVERAGE (Roche Emergency Medical Call Center Help 
Desk):  To reach the Roche Emergency Medical Call Center Help Desk, please refer to 
your Regulatory binder for country-specific access numbers.
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
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medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators (see 
"Protocol Administrative and Contact Information and List of Investigators").
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, all adverse events, serious adverse events, and adverse 
events of special interest will be reported until 135 days after the last dose of study drug, 
or until a new systemic anti-cancer therapy is initiated, whichever occurs first.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab or pembrolizumab or within 3 months after the last dose of 
cobimetinib.  A Clinical Trial Pregnancy Reporting Form should be completed and 

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submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of cobimetinib.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to cobimetinib.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.

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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.}
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with cobimetinib and atezolizumab regardless 
of whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
For cobimetinib, atezolizumab, and pembrolizumab, each adverse event associated with 
a special situation should be recorded separately on the Adverse Event eCRF.  If the 
associated adverse event fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  For cobimetinib and atezolizumab, adverse events associated with 
special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

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
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 135 days for all adverse 
events, serious adverse events, and adverse events of special interest after the last 
dose of study drug, or until a new systemic anti-cancer therapy is initiated, whichever
occurs first), all deaths, regardless of cause, should be reported through use of the 
Long-Term Survival Follow-Up eCRF or Post-Study Reporting of Death by Public 
Records eCRF, as appropriate.  If the patient withdraws from the study, the study staff 
may use a public information source (e.g., county records) to obtain information about 
survival status only.  In addition, if the investigator becomes aware of a serious adverse 
event that is believed to be related to prior study drug treatment, the event should be 
reported through use of the Adverse Event eCRF.  However, if the EDC system is not 
available, the investigator should report these events directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the paper Clinical Trial Serious 

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Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Cobimetinib Investigator's Brochure

Atezolizumab Investigator's Brochure 

Local prescribing information for pembrolizumab
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a Phase III, randomized, open-label study designed to evaluate the efficacy and 
safety of cobimetinib plus atezolizumab compared with pembrolizumab in patients with 
previously untreated BRAFV600 wild-type melanoma. Please refer to the Statistical 
Analysis Plan for additional details.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 450 patients will be randomized into the study.
The overall type I error () for this study is 0.05 (two-sided).
The type I error () for the analysis of the primary endpoint of IRC-assessed PFS is 0.01 
(two-sided).  The analysis of the primary endpoint of IRC-assessed PFS will take place 
when approximately 240 PFS events have occurred.  Statistical considerations are 
based on the following assumptions: 

Stratified log-rank test at 0.01 significance level (two-sided) 

Median PFS of 5.5 months for the pembrolizumab arm 

Median PFS of 10.0 months for the cobimetinib plus atezolizumab arm 

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
Enrollment period of approximately 12 months

Annual dropout rate of 5%

No interim analysis for PFS
A total of 240 PFS events provides approximately 98% power to detect an improvement 
in median PFS from 5.5 months in the pembrolizumab arm to 10.0 months in the 
cobimetinib plus atezolizumab arm.  This corresponds to a HR of 0.55, with a minimal 
detectable difference of 0.72.  The PFS analysis will be conducted approximately 
17 months after FPI.
The final analysis of the secondary endpoint of OS will be performed after the 
occurrence of approximately 295 deaths. A total of 295 deaths provides approximately 
60% power to detect an improvement in median OS from 28 months in the 
pembrolizumab arm to 37.5 months in the cobimetinib plus atezolizumab arm, 
corresponding to an HR of 0.75, or 80% power to detect an HR of 0.70.  Two interim 
analyses of OS will be conducted.  The final OS analysis will be conducted 
approximately 68 months after FPI.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, eligibility violations, and patient disposition will be summarized for 
randomized patients by treatment arm. Study treatment administration will be 
summarized by treatment arm for all treated patients. 
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables, stratification factors, and other baseline and disease 
characteristics will be summarized by treatment group using descriptive statistics.
6.4
EFFICACY ANALYSES
Unless otherwise noted, all efficacy analyses will include all randomized patients 
(i.e., the intent-to-treat population), and patients will be grouped according to the 
treatment assigned at randomization.
6.4.1
Primary Efficacy Endpoint
The primary efficacy analysis will be the comparison of PFS, as determined by the IRC, 
between the two treatment arms using the stratified log-rank test at an overall 0.01 
significance level (two-sided).  
PFS is defined as the time from randomization to the first occurrence of disease 
progression, as determined by the IRC according to RECIST v1.1, or death from any 
cause, whichever occurs first.  Data for patients who have not experienced disease 
progression or death will be censored at the last tumor assessment date.  Data for 
patients with no post-baseline tumor assessment will be censored at randomization.  

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The HR for PFS will be estimated using a stratified Cox model, and two-sided 95% CIs 
for the HR will be provided.  The stratification factors used for analysis will be the same 
as the randomization stratification factors:  PD-L1 status (IC0 vs. IC1, 2, 3), baseline 
LDH (less than or equal to the ULN vs. greater than the ULN), and geographic region 
(North America vs. Europe vs. Australia, New Zealand, and others).  Results from an 
unstratified analysis will also be provided.  Kaplan-Meier methodology will be used to 
estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be 
produced.  The 95% CI of the median PFS for each treatment arm will be constructed 
using the Brookmeyer and Crowley method (Brookmeyer and Crowley 1982).  Sensitivity 
analyses will be conducted to determine the impact of missed scheduled tumor 
assessments on PFS, depending on the number of patients with missed assessments. 
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are listed in Section 2 (see Table 1).
OS is defined as the time from randomization to death from any cause.  For patients who 
are alive at the time of analysis data cutoff, OS time will be censored at the date the 
patient was last known to be alive.  Survival time for patients with no post-baseline 
survival information will be censored at randomization.  The HR for OS will be estimated 
using a stratified Cox model, and a two-sided 95% CI for the HR will be provided.  The 
stratification factors used for analysis will be the same as the randomization stratification 
factors.  Results from an unstratified analysis will also be provided.  The Kaplan-Meier 
approach will be used to estimate median OS and 2-year landmark survival rate.  The 95% 
CI of the median OS will be estimated using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982).  The 95% CI of landmark survival rate will be 
calculated using the standard error derived from Greenwood’s formula (Greenwood 
1926).
Objective response will be presented as ORR, defined as the total number of patients 
whose objective response is a complete response or a partial response, divided by the 
number of patients in the intent-to-treat population with measurable disease at baseline.  
Objective response is defined as a complete response or partial response on two
consecutive occasions 4 weeks apart, as determined by the IRC and investigator using 
RECIST v1.1. A 95% Clopper-Pearson CI will be calculated for the ORR.  The 
difference in ORR between treatment arms will be tested using the stratified 
Cochrane-Mantel-Haenszel test.
PFS, as determined by the investigator according to RECIST v1.1, will be analyzed 
using the same methods as described for PFS in Section 6.4.1.
DCR is defined as the proportion of patients with a complete response, a partial 
response, or stable disease at 16 weeks after the baseline tumor assessment, as 
determined by the IRC and investigator using RECIST v1.1.  A 95% Clopper-Pearson CI 
will be calculated for the DCR.

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For patients who achieve an objective response, DOR is defined as the time from the 
first occurrence of a documented objective response to disease progression, as 
determined by the IRC and investigator according to RECIST v1.1, or death from any 
cause, whichever occurs first.  The censoring method for DOR will be the same as that 
for PFS. The Kaplan-Meier approach will be used to estimate median DOR.  The 95% CI 
of the median DOR will be estimated using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982).  Comparisons of DOR between treatment arms will be 
for descriptive purposes only.
The GHS/HRQoL will be scored according to the EORTC scoring manual as listed in 
Section 6.4.3.  The change from baseline in GHS/HRQoL scores at each timepoint by 
treatment arm during treatment, as measured by the EORTC QLQ-C30 GHS/HRQoL 
scale, will be analyzed for all randomized patients who had a baseline and one or more 
post-baseline assessments.
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are listed in Section 2 (see Table 1).
Objective response, DOR, and PFS according to immune-modified RECIST, will be 
analyzed using the methods as described above.
Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and 
range) and the mean change from baseline of linear-transformed scores will be 
calculated for all subscales of the EORTC QLQ-C30 according to the EORTC scoring 
manual guideline at each assessment timepoint for each arm, including progression, 
treatment discontinuation, and post-study treatment.  The mean (and 95% CI) and 
median of the absolute scores and the change from baseline will be reported for interval 
and continuous variables.  Completion and compliance rates will be summarized at each 
timepoint by treatment arm.  Compliance with PRO assessments will be calculated as 
the number of forms received divided by the number expected at every assessment. 
Only patients with a non-missing baseline assessment and at least one non-missing 
post-baseline assessment will be included in the analyses.
All of the scales and single-item measures range in score from 0 to 100. A high score 
for a functional scale represents a high, healthy level of functioning, a high score for the 
GHS/QoL represents a high QoL, but a high score for a symptom scale or item 
represents a high level of symptomatology and problems. 
A longitudinal analysis will be conducted to estimate the effect difference on PRO 
repeated responses over the time on study treatment and between the treatment arms, 
and mixed models on a set of covariates (baseline domain score, patient demographics, 
and clinical variables) will be conducted.  The change from baseline at subsequent 
cycles will be presented by treatment arm and will include LS mean, the difference in LS 

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mean between two treatment arms, and 95% CIs for the differences.  The standard error 
will also be calculated for each LS mean.
Patients’ post-baseline PRO scores will be classified as being “improved,” “stable,” or 
“worsened” according to a 10-point change in the GHS/QoL, functional, and symptom 
scores of the EORTC QLQ-C30. The number and proportion of patients who improve, 
remain stable, or worsen from baseline will be summarized by treatment group and 
study visit, at each timepoint, including progression, treatment discontinuation, and 
post-study treatment. 
The EQ-5D-5L will be scored according to its manual, and results will be reported 
separately from the Clinical Study Report.
Relevant subgroup and sensitivity analyses will be performed and will be detailed in the 
Statistical Analysis Plan.
6.5
SAFETY ANALYSES
The safety analyses will include all randomized patients who received at least one dose 
of study drug, with patients grouped according to treatment received. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and study treatment exposure, presented by 
treatment arm. 
Verbatim description of adverse events will be summarized by mapped terms and 
appropriate thesaurus levels and graded according to NCI CTCAE v4.0. All adverse 
events that occur during or after the first study drug dose will be summarized by 
treatment arm and NCI CTCAE grade. In addition, serious adverse events, severe 
adverse events (Grade 3), adverse events of special interest, and adverse events 
leading to study drug discontinuation or interruption will be summarized accordingly. 
Multiple occurrences of the same event will be counted once at the maximum severity. 
The proportion of patients who experience at least one adverse event will be reported by 
toxicity term and treatment arm. 
Study drug exposure, including treatment duration, number of doses, and dose intensity, 
will be summarized for each treatment arm using descriptive statistics. 
All deaths and causes of death will be summarized by treatment arm. 
Laboratory data with values outside the normal ranges will be identified. In addition, 
relevant laboratory data and vital signs will be summarized by treatment arm.

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6.6
PHARMACOKINETIC ANALYSES
The PK analyses will include patients who have received at least one dose of study drug
and for whom at least one evaluable PK sample is collected (actual dose and actual 
sampling time recorded for each sample).  Because only a few samples will be collected 
from patients, data will be analyzed using existing population PK models for post-hoc 
estimates of apparent clearance or systemic clearance for cobimetinib and atezolizumab,
respectively. The maximum or minimum concentration (Cmax or Cmin) will be reported for 
individual patients and summarized by study day, as the data permit.  In addition, 
atezolizumab and cobimetinib PK samples will be used to conduct exposureresponse 
analyses for efficacy and safety.
Additional PK analyses will be conducted as appropriate based on the available data.
6.7
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses for atezolizumab will include patients from Arm A with any
ADA assessment, with patients grouped by disease status (metastatic or locally 
advanced and unresectable) and arm.
The numbers and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by disease status (metastatic or locally advanced and unresectable) and
arm.  When determining the post-baseline incidence, patients are considered to be ADA 
positive if they are ADA negative or have missing data at baseline but develop an ADA 
response following study drug exposure (treatment-induced ADA response), or if they
are ADA positive at baseline and the titer of one or more post-baseline samples is at 
least 0.60-titer unit greater than the titer of the baseline sample (treatment-enhanced 
ADA response).  Patients are considered to be ADA negative if they are ADA negative or 
have missing data at baseline and all post-baseline samples are negative, or if they are 
ADA positive at baseline but do not have any post-baseline samples with a titer that is at 
least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported using descriptive statistics.
6.8
BIOMARKER ANALYSES
Efficacy will be explored in biomarker subgroups defined by PD-L1 expression, CD8 
T-cell density, and other significant biomarkers at the conclusion of this study. 
NGS data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researchers’ understanding of disease pathobiology 
and guide the development of new therapeutic approaches. 

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6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analysis of the Primary Efficacy Endpoint
No interim analyses of the primary endpoint of PFS will be performed.
6.9.2
Interim Efficacy Analyses of the Secondary Efficacy Endpoint
The study will incorporate three OS analyses (two interim analyses and one final 
analysis).  The first OS interim analysis will be performed at the time of the primary PFS 
analysis when a projected number of 80 deaths are expected to have occurred.  The 
second OS interim analysis will be performed after the occurrence of approximately 
153 deaths and is projected to occur at approximately 28 months after the first patient is 
randomized.  The final OS analysis will be performed after the occurrence of 
approximately 295 deaths and is projected to occur approximately 68 months after the 
first patient is randomized.  The actual number of observed OS events at each interim 
analysis may differ from the estimates presented.  The stopping boundaries are 
computed using Generalized Haybittle-Peto boundaries with unequal p-values of 0.001, 
0.040, and 0.018 at the three OS analyses to control the overall type I error of the OS 
comparison at a two-sided 0.05 significance level.  Table 6 summarizes the assumptions 
and characteristics of the interim and final analyses for OS.

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Table 6
Assumptions and Characteristics for the Interim
and Final Analyses of Overall Survival
Assumptions
Findings
HR targeted
0.75
Targeted median (pembrolizumab)
28.0 months
Targeted median (cobimetinibatezolizumab)
37.5 months
Projected enrollment period
12 months
First interim analysis (performed at the time
of the PFS analysis)
Estimated cutoff date a
17 months
Projected number of events (% of final events)
80 (27%)
Projected MDD b (p-value)
0.42 (0.001)
Second interim analysis
Estimated cutoff date a
28 months
Projected number of events (% of final events)
153 (52%)
Projected MDD b (p-value)
0.72 (0.040)
Final analysis
Estimated cutoff date a
Projected number of events (% of final events)
68 months
295 (100%)
Projected MDD b (p-value)
0.76 (0.018) 
Power
60%
level (two-sided)
0.05
HRhazard ratio; MDDminimally detectable difference; 
PFSprogression-free survival; 
a Estimated data cutoff time from first randomization.  Analysis results 
will be available after data cleaning.
b The largest observed HR that is projected to be statistically significant.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC through use of 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study specification document that describes the 
quality checking to be performed on the data. Non-eCRF data and IWRS data will be 
sent directly to the Sponsor, using the Sponsor’s standard procedures to handle and 
process the electronic transfer of these data.

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eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details). 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Upon randomization, patients will use an electronic device to capture PRO data. The 
device is designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. FDA regulations for electronic records (21 CFR, Part 11).  The 
data will be transmitted to a centralized database maintained by the electronic device 
vendor. 
The electronic data will be available for view access only, via a secure method.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data. 
Acknowledgement of receipt of the compact disc is required. In addition, the Sponsor will 
receive all data in a machine-readable format.
In case of electronic device failure or patient refusal to use the electronic device, a paper 
backup solution will be implemented.

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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, including PRO backup 
forms, evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies of transcriptions that are certified after verification as 
being accurate and complete, microfiche, photographic negatives, microfilm or magnetic 
media, X-rays, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 

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the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.

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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 

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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last 
visit).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.

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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  Approximately 160 study centers 
will participate in this study globally and enroll a total of approximately 450 patients.  
The Sponsor will provide clinical operations oversight, data management support, and 
medical monitoring. 
An IWRS will be used to manage site drug supply and to randomize patients to study 
drug.  For patients not previously tested for tumor mutational status, testing will be 
performed at screening.  Plasma and serum will be sent to a central laboratory for 
analysis and sample storage.  Routine sample analysis will be performed by an 
accredited external vendor or the center’s local laboratory; central and local laboratory 
ranges will be collected.
An iDMC will be employed to monitor and evaluate patient safety throughout the study. 
Tumor response will be evaluated by an IRC as the primary efficacy endpoint in this 
study.
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf

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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
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Appendix 1
Schedule of Activities
Table 1
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycles)
Assessment/Procedure
(Visit Window in Days)
Screen a
Cycle 1
Cycle 2
Cycles 3
Tx
Discon b
Unscheduled
Visit e
Survival 
FU c
Days
–35 to 
–1
Day 1 
(3) d
Day 15
(3)
Day 1 
(3)
Day 15
(3)
Day 1 
(3)
Day 15
(3)
30 Days 
after Last 
Dose
(7)
Every 
3 Months
Informed consent f
x
Demographic data
x
Medical and cancer history
x
x
Vital signs g, h
x
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
Weight
x
x
x
x
x
Height
x
Complete physical examination
x
x
Limited physical examination
x i
x
x
Hematology j
x
x
x
x
x
Coagulation (INR and aPTT)
x
PK sample for cobimetinib
See Appendix 2
PK sample and ADA sample for 
atezolizumab
See Appendix 2
Chemistry panel k
x
x
x
x
x

Appendix 1
Schedule of Activities (cont.)
Table 1
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycles)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol CO39722, Version 6
ADAanti-drug antibody; Discondiscontinuation; ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; eCRF electronic 
Case Report Form; EORTC QLQ-C30European Organisation for Research and Treatment of Cancer Quality of Life Core 30 Questionnaire; 
EQ-5D-5LEuropean Quality of Life 5-Dimension, 5-Level questionnaire; FUfollow-up; HBcAbhepatitis B core antibody; HBsAghepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; IRRinfusion-related reaction; LVEFleft ventricular ejection fraction; 
MUGAmultiple-gated acquisition; PKpharmacokinetic; PO by mouth; PROpatient-reported outcome; RECIST v1.1Response Evaluation 
Criteria in Solid Tumors, Version 1.1; T3triiodothyronine; T4thyroxine; Tx treatment; WGSwhole genome sequencing.
Notes:  All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified.  On treatment days, pre-infusion laboratory samples should be 
drawn 0–4 hours before the start of infusion, and post-infusion laboratory samples should be drawn 030 minutes after the end of infusion, unless 
otherwise specified.  Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the 
eCRF (except in the case of an adverse event). 
a Perform screening tests within 35 days prior to treatment initiation (Day 1) unless the patient meets criteria specified in Section 4.5.1.  
Standard-of-care screening assessments may be performed concurrently with BRAFV600 mutation and PD-L1 testing.  BRAFV600 status must be 
known prior to performing study-specific screening assessments.  The 35-day window begins at the time of the first standard-of-care screening 
assessment or the first study-specific screening assessment after the BRAFV600 mutation test result is available, whichever is earlier.  Results 
of standard-of-care tests or examinations performed prior to obtaining informed consent and within 35 days prior to treatment initiation (Day 1) 
may be used; such tests do not need to be repeated for screening.  For a list of laboratory tests for which results must be obtained within 
14 days prior to the first dose of study drug, see Section 4.1.1.2.  Test results should be reviewed prior to administration of study drug. PD-L1 
will be assessed by central laboratory and the result will be used for stratification and randomization only.
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within 30 (+7) days.  The visit at which response 
assessment shows progressive disease may be used as the study discontinuation visit.
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or study 
termination by the Sponsor.
d Day 1 of Cycle 1 can occur up to 3 days after randomization.
e Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated.
f
Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment.
g Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature.  Resting oxygen saturation will be measured during screening and subsequent visits.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
h At the first atezolizumab infusion, vital signs will be recorded within 60 minutes prior to the infusion, every 15 (5) minutes during the 
atezolizumab infusion, and 30 (10) minutes after the infusion if clinically indicated.  For subsequent infusions, vital signs will be collected 
within 60 minutes prior to the infusion and, if the patient experienced an infusion-related reaction with the previous infusion or if clinically 
indicated, vital signs should be collected during the infusion and 30 (10) minutes after the infusion.

Appendix 1
Schedule of Activities (cont.)
Table 1
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycles)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol CO39722, Version 6
i
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.  If physical examinations are assessed within 7 days of the Day 1, Cycle 1 visit, they do 
not have to be repeated on Day 1.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, reticulocyte count, platelet count, and differential count (neutrophils, 
bands, eosinophils, basophils, monocytes, and lymphocytes)
k Chemistry panel (serum) includes sodium, potassium, chloride, bicarbonate or total CO2 (HCO3 and CO2 not mandatory if unavailable at site), 
glucose, BUN or urea, creatinine, albumin, magnesium, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, CPK, uric acid, LDH, 
and total protein.  Fasting triglycerides, fasting cholesterol, fasting LDL cholesterol, and fasting glucose will be assessed after a minimum 8-
hour fast for screening only.  Non-fasting laboratory values will be accepted for subsequent visits after screening.  If fasting laboratory values 
are clinically warranted in a subject, then it will be at the discretion of the investigator. LDH will be assessed by both local and central 
laboratory, and the central laboratory result will be used for stratification and randomization only.
l
All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA, at screening.  Evaluation of LVEF by ECHO or 
MUGA scan must be performed at the following timepoints only for patients randomized to receive cobimetinib:

Day 1 of Cycle 2 (1 week).

Day 1 of Cycles 5, 8, 11, 14, 17, etc. (every three treatment cycles; 2 weeks).

Treatment discontinuation visit evaluation of LVEF does not need to be performed at treatment discontinuation visit if an evaluation has 
been performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline.
m Tumor assessments will be performed every 8 weeks (1 week) from the date of first study drug administration (Day 1) through 18 months
(80 weeks) and then every 12 weeks (1 week) thereafter.  Refer to Section 4.5.5.
n Tumor assessments will continue until disease progression per RECIST v1.1, loss of clinical benefit (for patients who continue treatment after 
disease progression according to RECIST v1.1) (see Section 3.1.2), withdrawal of consent, study termination by the Sponsor, or death, 
whichever occurs first.  Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled 
tumor assessments until disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  A 
confirmatory scan will be needed 48 weeks after progression of disease to confirm progression and exclude pseudoprogression.  Refer to 
Section 4.5.5 for details.
o All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study.  HBV serology 
will include HBsAg, antibodies against HBsAg, total anti-HBcAb.  HBV DNA should be obtained prior to randomization if patient has a negative 
serology for HBsAg and a positive serology for anti-HBcAb.  HCV serology will include HCV antibody (anti-HCV).  HCV RNA should be 
obtained prior to randomization if patient tests positive for anti-HCV. 
p Thyroid-function testing (thyroid-stimulating hormone, free T3 [or total T3 for sites where free T3 is not performed], and free T4) collected on 
Day 1 of Cycles 15, and every second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.

Appendix 1
Schedule of Activities (cont.)
Table 1
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycles)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol CO39722, Version 6
q All patients will undergo ophthalmologic examination (see Section 4.5.10 for exam requirements) at screening.  Ophthalmologic examination 
must be performed at the following timepoints only for patients randomized to receive cobimetinib:

Day 1 of Cycle 2 (1 week).

Day 1 of Cycles 5, 8, and 11 (every three treatment cycles; 2 weeks).

Day 1 of Cycles 15, 19, and 23 (every four treatment cycles; 2 weeks).

Day 1 of Cycles 29, 35, 41, 47, etc. (every six treatment cycles; 2 weeks).

Treatment discontinuation visit.
r
All women of childbearing potential will have a serum pregnancy test at screening within 7 days prior to Day 1 of Cycle 1.  Urine pregnancy 
tests will be performed on Day 1 of every cycle, at the treatment discontinuation visit, and 3 months after cobimetinib discontinuation and
5 months after atezolizumab discontinuation.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
s Includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood), and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria).
t
Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug until 30 days after the last dose of study drug.
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 135 days after the last dose of study drug 
or initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported (per 
Section 5.3.5.8).  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events or adverse events of special interest considered to be related to 
study drug or trial-related procedures until a final outcome can be reported.
v Archival tumor tissue with sample collection date 5 years or fresh baseline tumor tissue will be collected during screening.  An optional on-
treatment biopsy will be obtained at Cycle 1, Day 15 (5 days), and a mandatory biopsy will be obtained at progression if clinically feasible.
w PRO instruments, the EORTC QLQ-C30 and EQ-5D-5L, will be completed in this order using an electronic device on Day 1 of Cycle 1 and 
every 4 weeks (3 days) thereafter, prior to tumor assessments visits every 8 weeks, at the treatment discontinuation visit, and at unscheduled 
visits, as clinically indicated.  Patients will also complete the questionnaires every 4 weeks for 6 months after treatment discontinuation.  All 
PRO questionnaires are required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) 
that could bias a patient’s responses.
x The initial dose will be delivered over 60 (15) minutes.  If the first infusion is well tolerated all subsequent infusions will be delivered over 
30 (10) minutes until loss of clinical benefit.  Study drug administration may be 3 days after the first cycle.
y Medication diaries should be collected and reviewed and unused medications should be collected for assessment of compliance.

Appendix 1
Schedule of Activities (cont.)
Table 1
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycles)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol CO39722, Version 6
z Cobimetinib 60 mg/day PO will be given on a 21 days on/7 days off dosing schedule.  Study drug administration may be 3 days after the first 
cycle, commensurate with atezolizumab administration. 
aa After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (unless the patient withdraws 
consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the 
source documents and signed by the investigator.  If the patient withdraws from study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only.

Appendix 1
Schedule of Activities (cont.)
Table 2Arm B:  Pembrolizumab Schedule of Activities (21-Day Cycles) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol CO39722, Version 6
a Perform screening tests within 35 days prior to treatment initiation (Day 1) unless a patient meets criteria specified in Section 4.5.1.  
Standard-of-care screening assessments may be performed concurrently with BRAFV600 mutation and PD-L1 testing.  BRAFV600 status 
must be known prior to performing study-specific screening assessments.  The 35-day window begins at the time of the first standard-
of-care screening assessment or the first study-specific screening assessment after the BRAFV600 mutation test result is available, 
whichever is earlier.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 35 
days prior to treatment initiation (Day 1) may be used; such tests do not need to be repeated for screening.  For a list of laboratory tests 
for which results must be obtained within 14 days prior to the first dose of study drug, see Section 4.1.1.2.  Test results should be 
reviewed prior to administration of study drug.  PD-L1 will be assessed by central laboratory and the result will be used for stratification 
and randomization only.
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within 30 (+7) days.  The visit at which 
response assessment shows progressive disease may be used as the study discontinuation visit.
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or 
study termination by the Sponsor.
d Day 1 of Cycle 1 can occur 3 days after randomization.
e Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated.
f
Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 35 days 
before initiation of study treatment.
g Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature.  Resting oxygen saturation will be measured during screening and subsequent visits.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
h Vital signs at the first pembrolizumab infusion will be recorded within 60 minutes prior to the infusion, every 15 (5) minutes during the 
pembrolizumab infusion and 30 (10) minutes after the infusion.  For subsequent infusions, vital signs will be collected within 60 
minutes prior to the infusion and, if the patient experienced an infusion-related reaction with the previous infusion or if clinically 
indicated, vital signs should be collected during the infusion, and 30 (10) minutes after the infusion.
i
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.  At the baseline visit only, any abnormality should be recorded on the General 
Medical History and Baseline Conditions eCRF.  If physical examinations are assessed within 7 days of the Cycle 1, Day 1 visit, they 
do not have to be repeated on Day 1.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, reticulocyte count, platelet count, and differential count 
(neutrophils, bands, eosinophils, basophils, monocytes, and lymphocytes).

Appendix 1
Schedule of Activities (cont.)
Table 2Arm B:  Pembrolizumab Schedule of Activities (21-Day Cycles) (cont.)
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135/Protocol CO39722, Version 6
k Chemistry panel (serum) includes sodium, potassium, chloride, bicarbonate or total CO2 (HCO3 and CO2 not mandatory if unavailable 
at site), glucose, BUN or urea, creatinine, albumin, magnesium, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, CPK, 
uric acid, LDH, and total protein.  Fasting triglycerides, fasting cholesterol, fasting LDL cholesterol, and fasting glucose will be obtained 
after a minimum 8-hour fast for screening only.  Non-fasting laboratory values will be accepted for subsequent visits after screening.  If 
fasting laboratory values are clinically warranted in a subject, then it will be at the discretion of the investigator.  LDH will be assessed 
by both local and central laboratory, and the central laboratory result will be used for stratification and randomization only.
l
Tumor assessments will be performed every 8 weeks (1 week) from the date of first study drug administration (Day 1) through 
18 months (80 weeks) and then every 12 weeks (1 week) thereafter.  Refer to Section 4.5.5.
m Tumor assessments will continue until disease progression per RECIST v1.1, loss of clinical benefit for patients who continue 
treatment after disease progression according to RECIST v1.1 (see Section 3.1.2), consent withdrawal, study termination by the 
Sponsor, or death, whichever occurs first.  Patients who discontinue treatment for reasons other than disease progression (e.g. 
toxicity) will continue scheduled tumor assessments until disease progression, withdrawal of consent, study termination by Sponsor, or 
death, whichever occurs first. A confirmatory scan will be needed 48 weeks after progression of disease to confirm progression and 
exclude pseudoprogression.  Refer to Section 4.5.5 for details.
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.  
HBV serology will include HBsAg, antibodies against HBsAg, total anti-HBcAb.  HBV DNA should be obtained prior to randomization if 
patient has a negative serology for HBsAg and a positive serology for anti-HBcAb.  HCV serology will include HCV antibody (anti-
HCV).  HCV RNA should be obtained prior to randomization if patient tests positive for anti-HCV.   
o Thyroid-function testing (thyroid-stimulating hormone, free T3 [or total T3 for sites where free T3 is not performed], and free T4) 
collected on Day 1 of Cycles 15, and every second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.
p All patients will undergo ophthalmologic examination (see Section 4.5.10 for exam requirements) at screening.  
q All women of childbearing potential will have a serum pregnancy test at screening within 14 days prior to Day 1 of Cycle 1.  Urine 
pregnancy tests will be performed on Day 1 of every cycle, at the treatment discontinuation visit, and 5 months after pembrolizumab 
discontinuation.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
r
Includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, and bacteria).
s Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from 7 days prior to initiation of study drug until 30 days after the last dose of study drug.

Appendix 1
Schedule of Activities (cont.)
Table 2Arm B:  Pembrolizumab Schedule of Activities (21-Day Cycles) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol CO39722, Version 6
t
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-
mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 135 days after the last 
dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, 
should be reported (see Section 5.3.5.8).  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  The investigator should follow 
each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the 
patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events or 
adverse events of special interest considered to be related to study drug or trial-related procedures until a final outcome can be 
reported.
u Archival tumor tissue with sample collection date 5 years or fresh baseline tumor tissue will be collected during screening.  An 
optional on-treatment biopsy will be obtained at Cycle 1, Day 15 (5 days), and a mandatory biopsy will be obtained at progression if 
clinically feasible.
v PRO instruments, the EORTC QLQ-C30 and EQ-5D-5L, will be completed in this order using an electronic device on Day 1 of Cycle 1 
and every 4 weeks (3 days) thereafter, prior to tumor assessments visits every 8 weeks, at the end-of-treatment visit, and at 
unscheduled visits, as clinically indicated.  Patients will also complete the questionnaires every 4 weeks for 6 months after treatment 
discontinuation.  All PRO questionnaires are required to be completed prior to the administration of study treatment and/or prior to any 
other study assessment(s) that could bias patient’s responses.
w Pembrolizumab will be delivered over 30 (± 10) minutes.  Study drug administration may occur3 days after the first cycle. 
x After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (unless 
the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request 
must be documented in the source documents and signed by the investigator.  If the patient withdraws from study, the study staff may 
use a public information source (e.g., county records) to obtain information about survival status only.

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples
Visit
Timepoint
Sample Type(s)
Cycle 1, Day 1
Prior to the first infusion
Atezolizumab PK and ADA 
(serum)
30 (10) minutes following the 
end of atezolizumab infusion
Atezolizumab PK (serum)
24 hours post-cobimetinib 
dose
Cobimetinib PK (plasma)
Cycle 1, Day 15
Prior to cobimetinib dose
24 hours post-cobimetinib 
dose
Cobimetinib PK (plasma)
Cobimetinib PK (plasma)
Cycles 2 and 3, Day 1
Prior to the first infusion
Atezolizumab PK and ADA 
(serum)
Day 1 of Cycles 1 and 2, and at 
time of subsequent radiologic 
tumor assessments a
Prior to the first infusion
Biomarkers (plasma)
Treatment discontinuation visit b
At visit
Atezolizumab PK and ADA 
(serum)
Biomarkers (plasma) c
ADAanti-drug antibody; PKpharmacokinetic; RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1.
a Biomarker assessments on Day 1 of Cycles 1 and 2 must be done on the day of study drug 
administration, prior to infusion.  A 7-day window for biomarker sampling will be allowed at the 
time of subsequent radiologic tumor assessments.
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit 
30 (7) days after the last dose of study drug.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.
c At confirmed disease progression, lack of clinical benefit, or at treatment discontinuation.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within 7 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009), are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol CO39722, Version 6
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol CO39722, Version 6
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol CO39722, Version 6
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol CO39722, Version 6
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol CO39722, Version 6
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the eCRF as part of the assessment of 
non-target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (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

Progressive disease (PD):  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.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol CO39722, Version 6
CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  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).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF 
NON-TARGET LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol CO39722, Version 6
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 

Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol CO39722, Version 6
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCE
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol CO39722, Version 6
Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST)
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiographic progression, including 
the appearance of new lesions.  Therefore, immune-modified response criteria have 
been developed to incorporate new lesions into the assessment of total tumor burden 
and allow radiographic progression to be confirmed at a subsequent assessment.  
Immune-modified Response Evaluation Criteria in Solid Tumors (RECIST), as described 
within this appendix, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer et al.
2009), in the same manner that immune-related response criteria were adapted from 
WHO criteria (Wolchok et al. 2009) and RECIST v1.0 (Nishino et al. 2014). When not 
otherwise specified, RECIST v1.1 conventions will apply.  Differences between 
immune-modified RECIST and RECIST v1.1 are summarized in Table 1.
Table 1
Comparison of RECIST v1.1 and Immune-Modified RECIST
RECIST v1.1
Immune-Modified RECIST
Measurable new lesions
Always represent progression
Incorporated into the total tumor 
burden a and followed
Non-measurable new 
lesions
Always represent progression
Do not represent progression, but 
preclude CR
Non-target lesions
Contribute to defining CR, PR, 
SD, and PD
Contribute to defining CR only
CR
Disappearance of all lesions
Disappearance of all lesions
PR
30% decrease in sum of 
diameters of target lesions, in 
the absence of CR, new 
lesions, and unequivocal 
progression in non-target 
lesions
30% decrease in tumor burden, a
in the absence of CR
PD
20% increase in sum of 
diameters of target lesions,
unequivocal progression in 
non-target lesions, and/or 
appearance of new lesions
20% increase in tumor burden a
SD
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for 
PD
Neither sufficient shrinkage to 
qualify for CR or PR nor sufficient 
increase to qualify for PD
CRcomplete response; PDprogressive disease; PRpartial response; RECIST Response
Evaluation Criteria in Solid Tumors; SDstable disease.
a Tumor burden is the sum of diameters of target lesions and measurable new lesions.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol CO39722, Version 6
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.  
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions," "New Lesions," and 
"Calculation of Sum of Diameters").
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol CO39722, Version 6
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol CO39722, Version 6
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol CO39722, Version 6
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol CO39722, Version 6
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST (e.g., 
nonlymph node lesions must be 10 mm on the longest diameter; new lymph nodes 
must be 15 mm on the short axis [see note below]).  All new lesions (measurable or 
non-measurable) must be assessed and recorded at the time of identification and at all 
subsequent tumor assessment timepoints. 
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden that is performed as part of 
the tumor response evaluation.  New lesion types that would not qualify as target lesions 
per RECIST cannot be included in the calculation of tumor burden and thus will not 
affect overall tumor response evaluation.  New lesions that are not measurable at first 
appearance but meet measurability criteria at a subsequent timepoint can be included in 
the tumor response evaluation from that point on, if the maximum number of measurable 
new lesions has not been reached.
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is 10 mm and 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 
axis of a lymph node is 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is 15 mm.
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline as a measure of 
tumor burden.  At each subsequent tumor assessment, a sum of the diameters (longest 
diameter for non-lymph node lesions, short axis for lymph node lesions) will be 
calculated for all target lesions plus measurable new lesions (up to five new lesions, with 
a maximum of two new lesions per organ) that have emerged after baseline.  Hence, 
each net percentage change in tumor burden per assessment accounts for the size and 
growth kinetics of both old lesions and new lesions as they appear.
Measuring Lymph Nodes
If at first appearance the short axis of a new lymph node lesion is 15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters.  
If the new lymph node lesion is included in the sum of diameters, it will continue to be 

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol CO39722, Version 6
measured and included in the sum of diameters at subsequent timepoints, even if the 
short axis decreases to 15 mm (or even 10 mm).  However, if it subsequently 
decreases to 10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of 10 mm (if lymph nodes), a response assessment of 
complete response may be assigned.
Lymph nodes should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the node 
regresses to 10 mm during the study.  Thus, when lymph nodes are included in the 
sum of diameters, the sum may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions and up to five measurable new lesions (lymph node 
and nonlymph node) should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions or lymph nodes become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol CO39722, Version 6
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE 
NEW LESIONS
Measurements are not required for non-target lesions or non-measurable new lesions.  
Non-target lesions should be noted at baseline, and non-measurable new lesions should 
be noted at the time of identification.  At subsequent evaluations, non-target lesions and 
non-measurable new lesions will be categorized as "present" or "absent."
After baseline, changes in non-target lesions or non-measurable new lesions (or 
measurable new lesions in excess of five total or two per organ) will contribute only in 
the assessment of complete response (i.e., a complete response is attained only with 
the complete disappearance of all tumor lesions, including non-target lesions and non-
measurable new lesions) and will not be used to assess progressive disease.
RESPONSE CRITERIA
Definitions of the criteria used to determine objective tumor response are provided below:

Complete response (CR):  Disappearance of all lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of all 
target lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), 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.
New lesions alone do not qualify as progressive disease.  However, their 
contribution to total tumor burden is factored into the sum of the diameters, 
which is used to determine the overall immune-modified RECIST tumor 
response.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 2 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol CO39722, Version 6
Table 2
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions and 
Measurable New Lesions a
Non-Target Lesions and 
Non-Measurable New Lesions b
Overall Response
CR
Absent
CR
CR
Present or not all evaluated
PR
PR
Any
PR
SD
Any
SD
Not all evaluated
Any
NE
PD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
a Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden, in addition to the target 
lesions identified at baseline.
b Also includes measurable new lesions in excess of five total or two per organ.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target or 
measurable new lesions at a timepoint, usually the case is also considered not evaluable 
at that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions, as well as new lesions, as shown in Table 2.

Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol CO39722, Version 6
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Can 2014;2:17.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 
2009;15:741220.

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol CO39722, Version 6
Appendix 5
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care; confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead

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Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias for whom the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty about autoimmune exclusions.  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus, Type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis

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Appendix 7
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
Continue to observe the patient and document observations.

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Appendix 8
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 

Appendix 8
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol CO39722, Version 6

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol CO39722, Version 6
Appendix 9
EuroQol 5-Dimension, 5-Level Questionnaire

Appendix 9
EuroQol 5-Dimension, 5-Level Questionnaire (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol CO39722, Version 6

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol CO39722, Version 6
Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated
Adverse Events (Arm A)
Note: For information regarding management of atezolizumab-associated adverse 
events, please refer to Appendix 11.
Guidelines for Management of Cobimetinib plus Atezolizumab Adverse 
Events
Event
Action to Be Taken
General guidance for dose 
modifications and treatment 
delays and discontinuation
There will be no dose modifications for atezolizumab.  
If atezolizumab is withheld and corticosteroids are initiated for 
an atezolizumab-related toxicity, corticosteroids must be 
tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. a, b, c
The dose of cobimetinib can be reduced by 20 mg (one dose 
level) up to two times (i.e., from 60 mg to 40 mg and then from 
40 mg to 20 mg).  If further dose reduction is indicated after 
two dose reductions, the patient must discontinue cobimetinib 
but may continue treatment with atezolizumab at the 
investigator’s discretion.
If cobimetinib is withheld for 28 days because of toxicity, the 
patient should be discontinued from cobimetinib, unless 
resumption of treatment is approved by the Medical Monitor 
after discussion with the investigator. 
After dose reduction, consideration may be given to allow for 
dose escalation of cobimetinib by a maximum of one dose 
level following resolution of the adverse event that resulted in 
dose modification, provided there are no safety concerns.
If atezolizumab is withheld for 12 weeks because of toxicity, 
the patient should be discontinued from atezolizumab, unless 
resumption of treatment is approved by the Medical Monitor 
after discussion with the investigator.
IRRs, CRS, anaphylaxis, 
and hypersensitivity 
reaction
Guidelines for management of IRRs and CRS are provided in 
the Atezolizumab Investigator's Brochure and. Appendix 11
For anaphylaxis precautions, see Appendix 7.
For severe hypersensitivity reactions, permanently discontinue 
all study treatment.
CRS cytokine-release syndrome; IRRinfusion-related reaction.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for 
corticosteroids to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol CO39722, Version 6
GASTROINTESTINAL TOXICITY
Diarrhea and colitis have been associated with the administration of cobimetinib plus 
atezolizumab (see Section 5.1.1.3.2).
See Table 1 for guidelines on how to manage gastrointestinal toxicity in patients treated 
with cobimetinib plus atezolizumab.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol CO39722, Version 6
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity
Event
Action to Be Taken
Gastrointestinal toxicity
Gastrointestinal events:  
general guidance
All events of diarrhea or colitis should be thoroughly evaluated for
more common etiologies other than drug-induced effects.
For events of significant duration or severity or associated with 
signs of systemic inflammation or acute-phase reactants, check for 
immune-mediated colitis. 
Administer anti-diarrheal agents and other maximal supportive care 
per institutional guidelines, such as at the first report of watery 
diarrhea or loose stool, initiate maximal anti-diarrheal supportive 
care (Lomotil ® and loperamide).
Suggested regimen: 
–
Loperamide: Initiate dose with 4 mg, then 4 mg/6 hr around the 
clock, alternating with Lomotil. ®
–
Lomotil ® (diphenoxylate and atropine):  Dispense 2 tablets 
(diphenoxylate 5 mg, atropine 0.05 mg) every 6 hours around 
the clock. 
–
Continue Lomotil® and loperamide until no loose stools for 
24 hours. 
–
If Grade 2 diarrhea persists after 48 hours of total treatment 
with Lomotil® and loperamide, consider second-line agents 
(e.g., octreotide, budesonide, tincture of opium). 

Oral supplementation: 
–
Initiate oral supplementation of potassium and/or magnesium if
serum levels are LLN. 
–
Consider oral rehydration therapy (e.g., Pedialyte®) for 
Grade 1 diarrhea or vomiting. 
Dietary modifications: 
–
Stop all lactose-containing products and instruct patient to eat 
small meals. 
–
Suggest the BRAT diet (banana, rice, apples, toast) diet, 
without fiber (other vegetables and fruits). 
–
Encourage adequate hydration with salt-containing liquids, such 
as broth or Gatorade®.
Diarrhea, Grade 1 or 
Grade 2 (tolerable)
Continue atezolizumab and cobimetinib. 
Investigate etiology, referring patient to GI specialist for evaluation 
of possible colitis if appropriate.
Initiate supportive care and monitor patient closely. 

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol CO39722, Version 6
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity (cont.)
Event
Action to Be Taken
Diarrhea, Grade 2 
(intolerable) or Grade 3
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) 
while investigating etiology.
Investigate etiology and refer patient to GI specialist for evaluation 
of possible colitis, including biopsy if appropriate.
If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and cobimetinib. a, b, c
If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with the dose reduced by one level.  If not, permanently
discontinue cobimetinib.
Diarrhea, Grade 4
Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. c
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) 
while investigating etiology.
Rule out bowel perforation.
Investigate etiology, referring patient to GI specialist for evaluation 
of possible colitis, including biopsy if appropriate.
Colitis, Grade 1
Continue atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely. 
Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy 
if symptoms persist for 7 days.
Colitis, Grade 2
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory 
biopsy.
For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and cobimetinib. a, b, c
If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with the dose reduced by one level.  If not, permanently
discontinue cobimetinib.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol CO39722, Version 6
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity (cont.)
Event
Action to Be Taken
Colitis, Grade 3
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory 
biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and cobimetinib. a, b, c 
If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, permanently
discontinue cobimetinib.
Colitis, Grade 4
Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. c
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory 
biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug. 
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids 
to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol CO39722, Version 6
HEPATOTOXICITY
Hepatoxicity has been associated with the administration of atezolizumab and 
cobimetinib (see Section 5.1.1.2.1)
Patients with LFT abnormalities should be managed according to the guidelines in 
Table 2.
Table 2
Guidelines for Managing Atezolizumab and 
CobimetinibAssociated Hepatotoxicity
Event
Action to Be Taken
Elevations in ALT, AST, 
and/or bilirubin
AST/ALT ULN to 3 ULN 
with total bilirubin 2 ULN
Continue atezolizumab and cobimetinib.
Continue with the standard monitoring plan (i.e., LFTs Q4W 
before dosing).
AST/ALT 3 ULN
to 5 ULN with total 
bilirubin 2 ULN
Continue all study treatment.
Monitor LFTs at least weekly.  
Consider referral to a hepatologist and liver biopsy.
For suspected immune-mediated events of 5 days duration
–
Consider withholding atezolizumab c
–
Consider administering 12 mg/kg/day oral prednisone or 
equivalent followed by 1 month taper 
–
Restart atezolizumab if event resolves to Grade 1 or better 
within 12 weeks a, b
–
Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 
12 weeks a, b, c
AST/ALT 5 ULN 
to 10 ULN with total 
bilirubin 2 ULN
Continue all study treatment.
Monitor LFTs at least weekly.  
Consider referral to a hepatologist and liver biopsy.
For suspected immune-mediated events:
– Withhold atezolizumab 
– Consider administering 12 mg/kg/day oral prednisone or 
equivalent followed by 1 month taper 
– If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
– Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 
12 weeks a, b, c

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol CO39722, Version 6
Table 2
Guidelines for Managing Atezolizumab and 
CobimetinibAssociated Hepatotoxicity (cont.)
Event
Action to Be Taken
AST/ALT 3 ULN with 
bilirubin 2 ULN
Withhold atezolizumab and cobimetinib.
Consult hepatologist and consider liver biopsy.
Consider administering 12 mg/kg/day oral prednisone or 
equivalent followed by 1 month taper (for possible 
autoimmune hepatitis).
If LFTs do not decrease within 48 hours after initiation of 
systemic steroids, consider adding an immunosuppressive 
agent (e.g., mycophenolate mofetil or TNF-antagonist).
Monitor LFTs every 4872 hours until decreasing and then 
follow weekly.
Restart atezolizumab at fixed dose and cobimetinib at 1 dose 
reduction after discussion with medical monitor if 
AST/ALT 3 ULN with bilirubin 2 ULN and steroid 
dose 10 mg oral prednisone equivalent per day. a, b, c
Permanently discontinue atezolizumab and cobimetinib for 
life-threatening hepatic events, and contact the Medical Monitor.
AST/ALT 10 ULN
Permanently discontinue atezolizumab and cobimetinib. c
Consult hepatologist and consider liver biopsy.
Consider administering 12 mg/kg/day oral prednisone or 
equivalent (for possible autoimmune hepatitis).  If event resolves 
to Grade 1 or better, taper corticosteroids over 1 month.
If LFTs do not decrease within 48 hr after initiation of systemic 
steroids, addition of an alternative immunosuppressive agent 
(e.g., mycophenolate mofetil or TNF-antagonist) or dose 
escalation of corticosteroids may be considered.
Monitor LFTs every 4872 hours until decreasing and then 
follow weekly.
LFTliver function test; Q4W every 4 weeks; ULNupper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids 
to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol CO39722, Version 6
DERMATOLOGIC TOXICITY
Dermatologic toxicity and rash is associated with cobimetinib and atezolizumab (see 
Section 5.1.1.3.1) and should be managed according to the guidelines in Table 3.  
Although uncommon, cases of severe cutaneous adverse reactions such as 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with 
atezolizumab.  
Table 3
Guidelines for Managing Atezolizumab and Cobimetinib Rash
Event
Action to Be Taken
Dermatologic toxicity
General guidance
A dermatologist should evaluate persistent and/or severe 
rash or pruritus.  A biopsy should be considered unless 
contraindicated.
Dermatologic event, 
Grade 1 or 2
Continue atezolizumab and cobimetinib.
Initiate supportive care (e.g., antihistamines, topical 
corticosteroids).  If event does not improve, consider 
treatment with higher-potency topical corticosteroids.
For Grade 2 rash, consider referral to dermatologist for 
evaluation and, if indicated, biopsy.
Acneiform rash:
Consider topical corticosteroids (e.g., hydrocortisone 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline, 
or antibiotics covering skin flora) as clinically indicated.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol CO39722, Version 6
Table 3
Guidelines for Managing Atezolizumab and Cobimetinib Rash 
(cont.)
Event
Action to Be Taken
Dermatologic event, 
Grade 3
Withhold atezolizumab and cobimetinib.
Refer patient to dermatologist for evaluation and, if 
indicated, biopsy.
Consider initiating treatment with 10 mg/day oral prednisone 
or equivalent, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours.
If event resolves to Grade 2 or better within 12 weeks, 
resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and cobimetinib. a, b
Permanently discontinue atezolizumab and cobimetinib and 
contact Medical Monitor if event does not resolve to Grade 1 
or better within 12 weeks. a, b, c
If event resolves to Grade 2 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib.
Acneiform rash:
Consider continuation of topical corticosteroids (e.g., 2.5% 
alclometasone) and oral antibiotics (e.g., minocycline, 
doxycycline or antibiotics covering skin flora) when restarting 
cobimetinib.
Dermatologic event, 
Grade 4
Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. c
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
(any grade)
Follow guidelines for atezolizumab in Appendix 11.
Withhold cobimetinib.
If event resolves to Grade 1 or better, resume cobimetinib.
Permanently discontinue cobimetinib if withheld for 4 weeks
or if Stevens-Johnson syndrome or toxic epidermal necrolysis 
is confirmed.
a
If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b
Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be 
reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol CO39722, Version 6
PULMONARY EVENTS
Pneumonitis is associated with atezolizumab and cobimetinib (see Section 
Section 5.1.1.1.5 and should be managed according to the guidelines in Table 4.
Table 4
Guidelines for Managing Atezolizumaband 
CobimetinibAssociated Pulmonary Toxicity
Event
Action to Be Taken
Pulmonary events
General guidance
Mild-to-moderate events of pneumonitis have been reported 
with atezolizumab and cobimetinib.  All pulmonary events 
should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic 
carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease, or pulmonary hypertension.
For events concerning for pneumonitis, consider 
comprehensive infectious evaluation including viral etiologies.
Pneumonitis, Grade 1 
(asymptomatic)
Continue atezolizumab and cobimetinib.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
Pneumonitis, Grade 2
Withhold atezolizumab and cobimetinib.
Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
Resume atezolizumab and cobimetinib if event resolves to 
Grade 1 or better within 12 weeks. a, b
Permanently discontinue atezolizumab and cobimetinib and 
contact Medical Monitor if event does not resolve to Grade 1 or 
better within 12 weeks. a, b, c
For recurrent events, treat as a Grade 3 or 4 event.
Pneumonitis, Grade 3 or 4
Permanently discontinue atezolizumab and cobimetinib. c
Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
If pulmonary event does not improve within 48 hours or 
worsens, consider adding an immunosuppressive agent 
(e.g., infliximab, cyclophosphamide, IVIg, or mycophenolate).
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol CO39722, Version 6
Table 4
Guidelines for Managing Atezolizumaband 
CobimetinibAssociated Pulmonary Toxicity (cont.)
BALbronchoscopic alveolar lavage; IVIgintravenous immunoglobulin.
a
If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
b
Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be reduced to 
10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed 
upon by the investigator and the Medical Monitor.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-mediated event.  Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical Monitor.
OCULAR EVENTS
Serous retinopathy and retinal vein occlusion is associated with cobimetinib (see 
Section 5.1.1.1.2) and should be managed according to the guidelines in Table 5. 

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol CO39722, Version 6
Table 5
Guidelines for Managing Cobimetinib-Associated Serous 
Retinopathy and Retinal Vein Occlusion
Description
Management
General guidance

An ophthalmologist should evaluate visual complaints. 

Uveitis or episcleritis and other immunemediated ocular 
disease may be associated with atezolizumab and may be 
treated with topical corticosteroid eye drops.  Atezolizumab 
should be permanently discontinued for immune-mediated
ocular event that is unresponsive to local immunosuppressive
therapy.

Serous retinopathy is associated with cobimetinib.  In clinical 
trials, most events were Grade 1 (asymptomatic) or 2 
(symptomatic).  Most events in clinical trials resolved or 
improved to asymptomatic Grade 1 following dose interruption 
or reduction.  If serous retinopathy is diagnosed, cobimetinib
should be withheld until visual symptoms improve to Grade1 or 
better.  Serous retinopathy can be managed with treatment 
interruption, dose reduction, or with treatment discontinuation. 

RVO has been reported in patients treated with MEK inhibitors 
other than cobimetinib.
Serous retinopathy
Severity grade 
assessment based on 
NCI CTCAE v4 “Eye 
Disorders – Other” 
scale a-d
Serous retinopathy, Grade 1 a or 2 b (tolerable): 
Continue cobimetinib and atezolizumab without dose change.
Continue ophthalmology follow-up as clinically indicated.
Serous retinopathy, Grade 2 b (intolerable) or 3/4 c/d:
Interrupt cobimetinib until Grade1. 
Continue atezolizumab as clinically indicated.
Consult ophthalmology and undergo complete ophthalmologic 
examination, which includes visual acuity testing, intra-ocular 
pressure measurements, slit lamp ophthalmoscopy, indirect 
ophthalmoscopy, visual field, and OCT.  Consider a fluorescein 
angiogram and/or indocyanine green angiogram, if clinically 
indicated.
Cobimetinib should be dose reduced by 1 dose level when 
restarting.
Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite 2 dose level reductions
Retinal vein occlusion
Any grade
If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines.
Continue atezolizumab.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol CO39722, Version 6
Table 5
Guidelines for Managing Cobimetinib-Associated Serous 
Retinopathy and Retinal Vein Occlusion (cont.)
Description
Management
Potential 
immune-mediated
ocular toxicity 
(e.g., uveitis, iritis, 
episcleritis, or retinal 
events)
For atezolizumab, Follow guidelines provided in the Appendix 11.
Continue cobimetinib as clinically indicated.
ADLactivities of daily living; RVO retinal vein occlusion.
a Grade 1:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
b Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL.
c Grade 3:  Severe or medically significant but not immediately sight threatening; 
hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-
care ADL.
d Grade 4:  Sight-threatening consequences; urgent intervention indicated; blindness (20/200 
or worse) in the affected eye.
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
DECREASED LEFT VENTRICULAR EJECTION FRACTION  
Decreased left ventricular ejection fraction (LVEF) has been seen with cobimetinib (see
Section 5.1.1.1.3) and should be managed according to the guidelines in Table 6.  

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol CO39722, Version 6
Table 6
Recommended Dose Modifications for Cobimetinib in Patients 
with Left Ventricular Ejection Fraction Decrease from Baseline
Left Ventricular Ejection Fraction (LVEF) Decrease from Baseline
Patient
LVEF
Value
Recommended
Action with Cobimetinib 
and Atezolizumab
LVEF Value
following 
Treatment Break
Recommended
Cobimetinib 
Daily Dose
Asymptomatic
50%
(or 
40%49% 
and10% 
absolute 
decrease 
from 
baseline)
Continue atezolizumab 
and cobimetinib at current 
dose
NA
NA
40% (or 
40%49% 
and 
10% 
absolute 
decrease 
from 
baseline)
Interrupt cobimetinib 
treatment for 2 weeks
Continue atezolizumab as 
clinically indicated
10% absolute 
decrease from 
baseline
First 
occurrence:
40 mg
Second
occurrence:
20 mg
Third 
occurrence: 
permanent 
discontinuation
40% (or 10% 
absolute decrease 
from baseline)
Permanent 
discontinuation
Symptomatic
NA
Interrupt cobimetinib 
treatment for 4 weeks
Asymptomatic and 
10% absolute 
decrease from 
baseline
First 
occurrence:
40 mg 
Second
occurrence:
20 mg
Third 
occurrence: 
permanent 
discontinuation
Consider withholding 
atezolizumab.
Discuss with Medical 
Monitor regarding 
resumption of 
atezolizumab.
Asymptomatic and 
40% (or 10% 
absolute decrease 
from baseline)
Permanent 
discontinuation
Cardiology consultation is 
strongly recommended.
Symptomatic 
regardless of LVEF
Permanent 
discontinuation
LVEFleft ventricular ejection fraction; NAnot applicable.

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol CO39722, Version 6
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
ELEVATED CPK AND RHABDOMYOLYSIS
Elevated CPK has been reported with cobimetinib (see Section 5.1.1.1.4) and should be 
managed according to the guidelines in Table 7.
Table 7
Recommended Dose Modifications for Cobimetinib and 
Atezolizumab in Patients with CPK Elevations and 
Rhabdomyolysis
Event
Action to Be Taken
Rhabdomyolysis or CPK elevation
General guidance
Rule out cardiac cause (check ECG, serum cardiac 
troponin, and CPK-isoforms M and B fraction) and rule out 
rhabdomyolysis (clinical examination; serum creatinine, 
potassium, calcium, phosphorus, uric acid, and albumin; 
and urine myoglobin). 
Assess patient for any history of strenuous physical activity, 
blunt trauma, or recent intramuscular injections. 
For Grade 3 CPK elevations 
that are asymptomatic and 
deemed not clinically significant
Cobimetinib and atezolizumab dosing does not need to be 
modified or interrupted to manage asymptomatic Grade 3 
CPK elevations.
Recheck CPK at least once a week. 
For Grade 4 CPK elevations that 
are asymptomatic and deemed 
not clinically significant
Interrupt cobimetinib and atezolizumab treatment. 
If improved to Grade 3 within 4 weeks, restart cobimetinib 
at a dose reduced by 20 mg, if clinically indicated.
If CPK elevations do not improve to Grade 3 within 
4 weeks following dose interruption, permanently 
discontinue cobimetinib treatment. 
Resumption of atezolizumab may be considered in patients 
who are deriving benefit.
Rhabdomyolysis or symptomatic 
CPK elevations
Interrupt cobimetinib and atezolizumab treatment.  
If severity is improved by at least one grade and symptoms 
resolve within 4 weeks, restart cobimetinib at a dose 
reduced by 20 mg, if clinically indicated.  
If rhabdomyolysis or symptomatic CPK elevations do not 
improve within 4 weeks, permanently discontinue 
cobimetinib treatment
Resumption of atezolizumab may be considered in patients 
who are deriving benefit after discussion with the Medical 
Monitor. 

Appendix 10
Management of Cobimetinib plus Atezolizumab-Associated 
Adverse Events (Arm A) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol CO39722, Version 6
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
HEMORRHAGE
Hemorrhage has been reported with cobimetinib (see Section 5.1.1.1.1) and should be 
managed according to the guidelines in Table 8.
Table 8
Recommended Dose Modifications in Patients with Hemorrhage
Event
Action to Be Taken
Hemorrhage
Grade 3 hemorrhage
Interrupt cobimetinib treatment.  There are no data on the 
effectiveness of cobimetinib dose modification for hemorrhage 
events.  Clinical judgment should be applied when 
considering restarting cobimetinib treatment.
Continue atezolizumab treatment.
Grade 4 hemorrhage or any 
grade cerebral hemorrhage
Interrupt cobimetinib treatment.  Permanently discontinue 
cobimetinib for hemorrhage events attributed to cobimetinib.
Continue atezolizumab treatment.
Grade 3 or 4 or intolerable 
Grade 2 treatment-related 
toxicities not described 
above and Table 3 (dose 
modifications for
cobimetinib)
Withhold all study treatment.
If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab. a, b, c 
If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib.
a
If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b
Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be 
reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol CO39722, Version 6
Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated.
Although most immune-mediated adverse events observed with atezolizumab have been 
mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered if the patient 
is deriving benefit and has fully recovered from the immune-mediated event.  Patients 
can be re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Medical Monitor.
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the Medical Monitor agrees that the patient is likely to derive
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol CO39722, Version 6
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol CO39722, Version 6
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol CO39722, Version 6
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol CO39722, Version 6
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol CO39722, Version 6
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol CO39722, Version 6
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol CO39722, Version 6
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism.
c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol CO39722, Version 6
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol CO39722, Version 6
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol CO39722, Version 6
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol CO39722, Version 6
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol CO39722, Version 6
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-mediated 
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated 
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol CO39722, Version 6
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE 
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol CO39722, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration.

In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS. 
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia 
requiring low-
flow oxygen d by 
nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion at
half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if
appropriate).  Administer IV fluids as clinically indicated, and manage
constitutional symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).
If no improvement within 24 hours, initiate workup and assess for signs
and symptoms of HLH or MAS as described in this appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Consider hospitalization until complete resolution of symptoms.  If no
improvement within 24 hours, manage as per Grade 3, that is, hospitalize
patient (monitoring in the ICU is recommended), permanently discontinue
atezolizumab, and contact Medical Monitor. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next
dose of atezolizumab may be administered.  For subsequent infusions,
consider administration of oral premedication with antihistamines,
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days,
contact Medical Monitor.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
195/Protocol CO39722, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
196/Protocol CO39722, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive 
airway pressure; CRS cytokine-release syndrome; CTCAE Common Terminology 
Criteria for Adverse Events; eCRF electronic Case Report Form; 
HLH hemophagocytic lymphohistiocytosis; ICU intensive care unit; IRR infusion-
related reaction; MAS macrophage activation syndrome; NCCN National Cancer 
Comprehensive Network; NCI National Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus 
grading for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, 
CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In 
patients who develop CRS and then receive anti-pyretic, anti-cytokine, or 
corticosteroid therapy, fever is no longer required when subsequently determining 
event severity (grade).  In this case, the grade is driven by the presence of 
hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as 
oxygen delivered at 6 L/min.
e
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  For subsequent infusions, administer 
oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the 
infusion time may also be considered after consulting the Medical Monitor and 
considering the benefitrisk ratio.
f
Refer to Riegler et al. (2019).

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
197/Protocol CO39722, Version 6
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol CO39722, Version 6
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated 
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
199/Protocol CO39722, Version 6
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.  A 
biopsy should be considered unless contraindicated.  Management guidelines for 
dermatologic events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist for evaluation and, if indicated, 
biopsy.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol CO39722, Version 6
Table 9
Management Guidelines for Dermatologic Events (cont.)
Event
Management
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) for 
evaluation and, if indicated, biopsy.

Follow the applicable treatment and management guidelines 
above.
If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol CO39722, Version 6
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated 
neuropathy, Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated 
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol CO39722, Version 6
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated 
Meningoencephalitis
Event
Management
Immune-mediated 
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol CO39722, Version 6
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol CO39722, Version 6
the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase 
increase), and imaging (electromyography/MRI) features, and is confirmed with a 
muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol CO39722, Version 6
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab. 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.  

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
206/Protocol CO39722, Version 6
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
– Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
– Platelet count 100 109/L (100,000/L)
– ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
– Platelet count 181 109/L (181,000/L)
– AST 48 U/L
– Triglycerides 1.761 mmol/L (156 mg/dL)
– Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14. 

Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
207/Protocol CO39722, Version 6
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
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Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol CO39722, Version 6
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