Clinical trial NCT03625141
Conditions: Metastatic Melanoma
Sponsor: Hoffmann-La Roche
Start date: 2018-12-13; Completion date: 2023-04-13
Enrollment: 80 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.

Detailed description:

Arms: arm 1: Participants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1-21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle. arm 2: Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.
Interventions: intervention 1: Cobimetinib intervention 2: Atezolizumab intervention 3: Vemurafenib
Intervention descriptions: intervention 1: 60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle. intervention 2: Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1). intervention 3: Participants will receive vemurafenib 960 mg (four 240 mg tablets) orally (PO) twice daily (BID) on days 1-21 of the run-in period (cycle 1); thereafter, they will receive vemurafenib 720 mg dose (three 240 mg tablets) PO BID on days 22-28 of cycle 1 and on days 1-28 of all subsequent cycles.

Protocol documents:
Prot_000.pdf: 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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, atezolizumab vemurafenib — F. Hoffmann-La Roche Ltd
Protocol MO39136, Version 5.0
PROTOCOL
TITLE:
A PHASE II TWO COHORT STUDY EVALUATING 
THE SAFETY AND EFFICACY OF COBIMETINIB 
PLUS ATEZOLIZUMAB IN BRAFV600 WILD-TYPE 
MELANOMA WITH CENTRAL NERVOUS SYSTEM 
METASTASES AND COBIMETINIB PLUS 
ATEZOLIZUMAB AND VEMURAFENIB IN BRAFV600
MUTATION-POSITIVE MELANOMA WITH 
CENTRAL NERVOUS SYSTEM METASTASES
PROTOCOL NUMBER:
MO39136
VERSION NUMBER:
5.0
EUDRACT NUMBER:
2018-000759-41
IND NUMBER:
117296, 135717, and 111271
NCT NUMBER:
NCT03625141
TEST PRODUCTS:
Cobimetinib (RO5514041)
Atezolizumab (RO5541267)
Vemurafenib (RO5185426)
MEDICAL MONITOR:
Dr 
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
(
)
Company Signatory
Approver's Name
Title
Date and Time (UTC)
04-Mar-2022 17:21:18


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PROTOCOL HISTORY
Protocol
Version
Date Final
5
See electronic date stamp on title page
4
26 February 2020
3
12 August 2019
2
10 October 2018
1
5 April 2018


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PROTOCOL AMENDMENT, VERSION 5.0:
RATIONALE
The protocol for study MO39136 has been amended to include the following updates 
and clarifications:

The list of approved indications for atezolizumab has been updated to include 
hepatocellular carcinoma and melanoma (Section 1.2.2).

Provisions related to performing the study in the setting of the coronavirus disease 
2019 (COVID-19) pandemic have been added (Sections 1.3, 4.1, and 5.1;
Appendix 14).

Benefit-risk assessment and guidance on concomitant administration of COVID-19
vaccines with atezolizumab have been added (Sections 1.3 and 4.4).

The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 18 (Appendices 10, 12, 13, and 14).

The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility and during study conduct have been clarified 
(Sections 3.1, 4.1, 4.3, 4.4, 4.5, and 5.1; Appendices 10, 12, 13, and 14).

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product (IMP) transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.3).

Immunosuppressive medications have been removed from the prohibited therapy 
section (4.4.5) and added to the cautionary therapy section (4.4.2.2) to align with 
atezolizumab management guidelines in Appendix 14 that permit use of 
immunosuppressive medications for the treatment of corticosteroid-refractory 
immune-mediated adverse events.

Updates related to the risks associated with atezolizumab: 
–
The list of identified risks for atezolizumab has been revised to include severe 
cutaneous adverse reactions (SCARs, previously a potential risk;
Section 5.1.2). This update aligns with a Dear Investigator Letter (DIL) issued 
on 12 October 2020.
–
Language has been added to clarify that hemophagocytic lymphohistiocytosis 
and macrophage activation syndrome are considered potential risks for 
atezolizumab (Section 5.1.2 and Appendix 14).
–
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 12, 13, and 14).
–
Appendix 10 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. 


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
To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), hemophagocytic lymphohistiocytosis (HLH) and 
macrophage activation syndrome (MAS) have replaced systemic inflammatory 
response syndrome on the list of atezolizumab-associated adverse events of 
special interest (Section 5.2.3).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12).

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

Language regarding investigator reporting of pregnancies has been clarified 
(Section 5.4.3.2).

The name of a Roche policy on data sharing has been corrected (Section 9.6).

The management guidelines for Grade 4 myositis have been removed because 
Version 4.0 of the Common Terminology Criteria for Adverse Events does not have 
a Grade 4 category for myositis. Instructions regarding recurrent Grade 3 events 
have been modified accordingly (Appendix 14).

To align with the Atezolizumab Investigator's Brochure, Version 17, the 
management guidelines for HLH and MAS have been modified to indicate that HLH 
should be considered when CRS presentation is atypical or prolonged, to add 
anticytokine 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 14).

Minor updates to the management guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome (Appendix 14).

The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in MedDRA 
(Appendix 10).
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...................................14
PROTOCOL SYNOPSIS ............................................................................15
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.....................28
1.
BACKGROUND.....................................................................31
1.1
Background on Melanoma and Melanoma with Central 
Nervous System Metastases ...........................................31
1.2
Background on Study Medications...................................33
1.2.1
Background on Cobimetinib.............................................33
1.2.2
Background on Atezolizumab ..........................................33
1.2.3
Background on Vemurafenib............................................34
1.3
Study Rationale and Benefit-Risk Assessment................34
1.3.1
Immunomodulation and the MAPK Pathway in Melanoma: 
Preclinical Data................................................................35
1.3.2
Clinical Experience with Cobimetinib, Atezolizumab and 
Vemurafenib in Melanoma ...............................................36
1.3.2.1
Study PCD4989g: Atezolizumab Monotherapy................36
1.3.2.2
Study GP28363:  Cobimetinib plus Atezolizumab............36
1.3.2.3
Study GP28384:  Cobimetinib plus Atezolizumab and 
Vemurafenib in BRAFV600 Mutation-Positive Melanoma...37
1.3.2.4
Ongoing Phase III Studies CO39722 and CO39262........39
1.3.3
Benefit-Risk Assessment .................................................40
2.
OBJECTIVES AND ENDPOINTS..........................................42
3.
STUDY DESIGN ...................................................................45
3.1
Description of the Study...................................................45
3.1.1
Independent Review Committee......................................48
3.1.2
Internal Monitoring Committee.........................................48
3.2
End of Study and Length of Study ...................................49
3.3
Rationale for Study Design ..............................................49
3.3.1
Rationale for Cobimetinib and Atezolizumab Dosing in 
Cohort 1 ...........................................................................49


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3.3.2
Rationale for Cobimetinib, Atezolizumab and Vemurafenib 
Dosing in Cohort 2 ...........................................................50
3.3.3
Rationale for Patient Populations.....................................51
3.3.4
Rationale for Intracranial Objective Response Rate as 
Primary Endpoint .............................................................51
3.3.5
Rationale for Treatment beyond Disease Progression per 
RECIST v1.1....................................................................52
3.3.6
Rationale for Patient-Reported Outcome Assessments...52
3.3.7
Rationale for Biomarker Assessments .............................53
4.
MATERIALS AND METHODS...............................................54
4.1
Patients............................................................................54
4.1.1
Inclusion Criteria ..............................................................54
4.1.2
Exclusion Criteria .............................................................56
4.2
Method of Treatment Assignment....................................60
4.3
Study Treatment ..............................................................60
4.3.1
Study Treatment Formulation, Packaging and Handling..60
4.3.1.1
Cobimetinib......................................................................60
4.3.1.2
Atezolizumab ...................................................................60
4.3.1.3
Vemurafenib.....................................................................61
4.3.2
Study Treatment Dosage, Administration and 
Compliance......................................................................61
4.3.2.1
Study Treatment Dosage – Cohort 1 ...............................61
4.3.2.2
Study Treatment Dosage – Cohort 2 ...............................62
4.3.2.3
Dosing of Study Treatment Beyond Disease 
Progression......................................................................63
4.3.2.4
Cobimetinib Administration ..............................................64
4.3.2.5
Atezolizumab Administration............................................64
4.3.2.6
Vemurafenib Administration.............................................65
4.3.2.7
Assessment of Compliance..............................................66
4.3.3
Investigational Medicinal Product Accountability..............66
4.3.4
Continued Access to Cobimetinib, Atezolizumab and 
Vemurafenib.....................................................................66
4.4
Concomitant Therapy.......................................................67
4.4.1
Permitted Therapy ...........................................................67


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4.4.2
Cautionary Therapy..........................................................68
4.4.2.1
Antiplatelet Agents ...........................................................68
4.4.2.2
Systemic Corticosteroids, Immunosuppressive 
Medications, and TNF-Inhibitors...................................68
4.4.2.3
Bisphosphonates .............................................................69
4.4.2.4
Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes.........................................69
4.4.2.5
Herbal Therapies .............................................................70
4.4.2.6
Medications Affecting the QT Interval – Cohort 2 Only ....70
4.4.3
Stereotactic Radiation in Cohort 2 ...................................71
4.4.4
Cautionary Food ..............................................................71
4.4.5
Prohibited Therapy...........................................................71
4.4.6
Prohibited Food................................................................72
4.5
Study Assessments..........................................................72
4.5.1
Informed Consent Forms and Screening Log ..................73
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data ...........................................................73
4.5.3
Physical Examinations .....................................................74
4.5.4
Vital Signs........................................................................74
4.5.5
ECOG Performance Status..............................................74
4.5.6
Tumour and Response Evaluations .................................74
4.5.7
Study-Specific Safety Monitoring Assessments (Cohorts 1 
and 2)...............................................................................76
4.5.7.1
Ophthalmologic Examinations..........................................76
4.5.7.2
Cardiac Monitoring...........................................................76
4.5.8
Study-Specific Safety Monitoring Assessments in Cohort 2 
Only..................................................................................77
4.5.8.1
Monitoring for New Primary Neoplasms...........................77
4.5.9
Laboratory, Biomarker and Other Biological Samples......79
4.5.10
Patient-Reported Outcomes.............................................80
4.5.10.1
EORTC QLQ-C30 ............................................................81
4.5.10.2
QLQ-BN20 .......................................................................81
4.5.11
Post-treatment Survival....................................................81
4.5.12
Optional Samples for Research Biosample Repository ...82


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4.5.12.1
Overview of the Research Biosample Repository............82
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee........................................................................82
4.5.12.3
Sample Collection ............................................................82
4.5.12.4
Confidentiality ..................................................................83
4.5.12.5
Consent to Participate in the Research Biosample 
Repository........................................................................83
4.5.12.6
Withdrawal from the Research Biosample Repository .....84
4.5.12.7
Monitoring and Oversight.................................................84
4.6
Treatment, Patient, Study and Site Discontinuation.........84
4.6.1
Study Treatment Discontinuation.....................................84
4.6.2
Patient Discontinuation from Study ..................................85
4.6.3
Study Discontinuation ......................................................86
4.6.4
Site Discontinuation .........................................................86
5.
ASSESSMENT OF SAFETY.................................................86
5.1
Safety Plan.......................................................................86
5.1.1
Risks Associated with Cobimetinib ..................................87
5.1.1.1
Serous Retinopathy..........................................................88
5.1.1.2
Left Ventricular Dysfunction .............................................88
5.1.1.3
Photosensitivity (When Administered with Vemurafenib).88
5.1.1.4
Pneumonitis .....................................................................88
5.1.1.5
Rhabdomyolysis...............................................................88
5.1.1.6
Haemorrhage...................................................................88
5.1.1.7
Severe Hepatotoxicity (Grade ≥ 3)...................................89
5.1.1.8
Impaired Female Fertility..................................................89
5.1.1.9
Teratogenicity and Developmental Toxicity......................89
5.1.2
Risks Associated with Atezolizumab................................89
5.1.3
Risks Associated with Vemurafenib .................................90
5.1.3.1
Cutaneous Squamous Cell Carcinoma and New Primary 
Melanoma ........................................................................90
5.1.3.2
Non-Cutaneous Squamous Cell Carcinoma ....................90
5.1.3.3
RAS-Mutant Malignancies................................................91
5.1.3.4
Photosensitivity and Sunburn...........................................91
5.1.3.5
Liver Injury .......................................................................91


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5.1.3.6
QT Prolongation...............................................................91
5.1.3.7
Hypersensitivity and Severe Cutaneous Reactions .........91
5.1.3.8
Uveitis and Retinal Vein Occlusion ..................................92
5.1.3.9
VIIth Nerve Paralysis.........................................................92
5.1.3.10
Radiation Recall and Radiation Sensitization...................92
5.1.3.11
Acute Kidney Injury and Renal Function Alterations ........92
5.1.3.12
Drug-Drug Interaction.......................................................93
5.1.3.13
Gastrointestinal Polyps ....................................................93
5.1.3.14
Neutropenia .....................................................................93
5.1.3.15
Pancreatitis ......................................................................93
5.1.3.16
Dupuytren’s Contracture and Plantar Fascial 
Fibromatosis ....................................................................93
5.1.4
Risks Associated with Combination Use of Cobimetinib 
and Atezolizumab ............................................................93
5.1.4.1
Dermatologic Toxicity.......................................................94
5.1.4.2
Ocular Toxicity .................................................................94
5.1.4.3
Hepatic Toxicity................................................................94
5.1.4.4
Pulmonary Toxicity...........................................................94
5.1.4.5
Gastrointestinal Toxicity...................................................95
5.1.5
Risks Associated with Combination Use of Cobimetinib, 
Atezolizumab and Vemurafenib .......................................95
5.1.5.1
Gastrointestinal Toxicity...................................................95
5.1.5.2
Hepatic Toxicity................................................................96
5.1.5.3
Dermatologic Toxicity.......................................................96
5.1.5.4
Pancreatic Events ............................................................96
5.1.5.5
Renal Events....................................................................97
5.1.5.6
Hyperglycaemia ...............................................................97
5.1.5.7
Ocular Toxicity .................................................................97
5.1.5.8
Pulmonary Toxicity...........................................................97
5.1.6
Management of Patients Who Experience Specific 
Adverse Events................................................................97
5.1.6.1
Dose Modifications – Cohort 1.........................................97
5.1.6.2
Dose Modifications – Cohort 2.........................................98
5.1.6.3
Treatment Interruption or Discontinuation........................99


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5.1.6.4
Management Guidelines – Cohort 1...............................100
5.1.6.5
Management Guidelines – Cohort 2...............................100
5.2
Safety Parameters and Definitions.................................101
5.2.1
Adverse Events..............................................................101
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ........................................................................101
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)............................................102
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters .........................................................104
5.3.1
Adverse Event Reporting Period....................................104
5.3.2
Eliciting Adverse Event Information ...............................105
5.3.3
Assessment of Severity of Adverse Events....................105
5.3.4
Assessment of Causality of Adverse Events..................106
5.3.5
Procedures for Recording Adverse Events ....................106
5.3.5.1
Infusion-Related Reactions............................................107
5.3.5.2
Diagnosis versus Signs and Symptoms.........................107
5.3.5.3
Adverse Events That Are Secondary to Other Events ...107
5.3.5.4
Persistent or Recurrent Adverse Events ........................108
5.3.5.5
Abnormal Laboratory Values..........................................108
5.3.5.6
Abnormal Vital Sign Values............................................109
5.3.5.7
Abnormal Liver Function Tests ......................................109
5.3.5.8
Deaths............................................................................110
5.3.5.9
Pre-existing Medical Conditions.....................................110
5.3.5.10
Lack of Efficacy or Worsening of Melanoma..................110
5.3.5.11
Hospitalization or Prolonged Hospitalization..................111
5.3.5.12
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse...................................................................111
5.3.5.13
Patient-Reported Outcome Data....................................113
5.4
Immediate Reporting Requirements from Investigator to 
Sponsor..........................................................................113
5.4.1
Emergency Medical Contacts ........................................114
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ................................114
5.4.2.1
Events That Occur prior to Study Treatment Initiation ...114


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5.4.2.2
Events That Occur after Study Treatment Initiation .......114
5.4.3
Reporting Requirements for Pregnancies ......................115
5.4.3.1
Pregnancies in Female Patients ....................................115
5.4.3.2
Pregnancies in Female Partners of Male Patients .........115
5.4.3.3
Abortions........................................................................116
5.4.3.4
Congenital Anomalies/Birth Defects...............................116
5.5
Follow-Up of Patients after Adverse Events...................116
5.5.1
Investigator Follow-Up ...................................................116
5.5.2
Sponsor Follow-Up.........................................................117
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period ............................................................117
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards and Ethics Committees......117
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN...................................................................................118
6.1
Determination of Sample Size........................................118
6.2
Summaries of Conduct of Study ....................................119
6.3
Summaries of Demographic and Baseline 
Characteristics ...............................................................119
6.4
Efficacy Analyses...........................................................119
6.4.1
Primary Efficacy Endpoint..............................................119
6.4.2
Secondary Efficacy Endpoints .......................................120
6.4.2.1
Patient-reported Secondary Efficacy Endpoints.............121
6.4.3
Exploratory Efficacy Endpoints ......................................121
6.5
Safety Analyses .............................................................122
6.6
Biomarker Analyses .......................................................123
6.7
Interim Analysis..............................................................123
7.
DATA COLLECTION AND MANAGEMENT........................123
7.1
Data Quality Assurance .................................................123
7.2
Electronic Case Report Forms.......................................124
7.3
Source Data Documentation..........................................124
7.4
Use of Computerized Systems.......................................125
7.5
Retention of Records .....................................................125


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8.
ETHICAL CONSIDERATIONS............................................125
8.1
Compliance with Laws and Regulations.........................125
8.2
Informed Consent ..........................................................125
8.3
Institutional Review Board or Ethics Committee ............126
8.4
Confidentiality ................................................................127
8.5
Financial Disclosure.......................................................127
9.
STUDY DOCUMENTATION, MONITORING AND 
ADMINISTRATION..............................................................128
9.1
Study Documentation.....................................................128
9.2
Protocol Deviations ........................................................128
9.3
management of study quality .........................................128
9.4
Site Inspections..............................................................128
9.5
Administrative Structure.................................................128
9.6
Publication of Data and Protection of Trade Secrets .....129
9.7
Protocol Amendments....................................................130
10.
REFERENCES....................................................................130
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints ...........................43
Table 2
Cohort 1 Treatment Regimen..............................................61
Table 3
Cohort 2 Treatment Regimen..............................................62
Table 4
Administration of First and Subsequent Atezolizumab 
Infusions..............................................................................65
Table 5
Recommended Cobimetinib Dose Modifications.................98
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE......................................105
Table 7
Causal Attribution Guidance..............................................106
Table 8
Objective Response Rate Estimates and Confidence 
Intervals with 50 Evaluable Patients per Treatment 
Cohort ...............................................................................119
LIST OF FIGURES
Figure 1
Study Schema.....................................................................20
Figure 2
Study Schema.....................................................................48


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LIST OF APPENDICES
Appendix 1
Schedule of Activities for Cohort 1 ....................................137
Appendix 2
Schedule of Activities for Cohort 2 ....................................142
Appendix 3
Schedule of Biomarker Samples.......................................150
Appendix 4
ECOG Performance Status Scale .....................................151
Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)...................................................................152
Appendix 6
Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)..........................................................161
Appendix 7
Immunotherapy Response Assessment for Neuro-Oncology 
(iRANO) Criteria ................................................................170
Appendix 8
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 173
Appendix 9
EORTC QLQ-BN20 Questionnaire....................................175
Appendix 10
Pre-existing Autoimmune Diseases and Immune 
Deficiencies.......................................................................176
Appendix 11
Anaphylaxis Precautions...................................................177
Appendix 12
Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1 .................................178
Appendix 13
Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2 .................................193
Appendix 14
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab.....................................................................217


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II TWO COHORT STUDY EVALUATING 
THE SAFETY AND EFFICACY OF COBIMETINIB 
PLUS ATEZOLIZUMAB IN BRAFV600 WILD-TYPE 
MELANOMA WITH CENTRAL NERVOUS SYSTEM 
METASTASES AND COBIMETINIB PLUS 
ATEZOLIZUMAB AND VEMURAFENIB IN BRAFV600
MUTATION-POSITIVE MELANOMA WITH 
CENTRAL NERVOUS SYSTEM METASTASES
PROTOCOL NUMBER:
MO39136
VERSION NUMBER:
5.0
EUDRACT NUMBER:
2018-000759-41
IND NUMBER:
117296, 135717, and 111271
NCT NUMBER:
NCT03625141
TEST PRODUCT:
Cobimetinib (RO5514041)
Atezolizumab (RO5541267)
Vemurafenib (RO5185426)
MEDICAL MONITOR:
Dr 
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 retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 








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CR complete response; DCR disease control rate; DOR duration of response; EORTC QLQ-
C30 and QLQ-BN20 European Organization for Research and Treatment of Cancer Quality of 
Life questionnaire core questionnaire and brain cancer specific module; GHS Global Health
Status; HRQoL health-related quality of life; MRI magnetic resonance imaging; 
iRANO immunotherapy Response Assessment for Neuro-Oncology; IRC Independent Review 
Committee; NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events; ORR objective response rate; OS overall survival; PFS progression-free survival; 
PR partial response; PRO patient-reported outcome; RECIST v1.1 Response Evaluation 
Criteria in Solid Tumors version 1.1; SD stable disease; SRT stereotactic radiotherapy.
Study Design
Description of Study
Study MO39136 is a Phase II, two cohort, efficacy and safety study of BRAFV600 status-specific 
combination treatment with cobimetinib, atezolizumab and vemurafenib for melanoma with CNS 
metastases. Study patients will be assigned to a study treatment cohort based on locally 
determined BRAFV600 disease status. Patients with BRAFV600 wild-type disease will be assigned 
to treatment with cobimetinib plus atezolizumab in Cohort 1. Patients with BRAFV600
mutation-positive disease will be assigned to treatment with cobimetinib plus atezolizumab and 
vemurafenib in Cohort 2. The study includes assessment of patient reported quality of life 
outcomes as well as exploratory biomarker evaluations.  
Based on the results of the primary analysis for Study CO39722 (IMspire170) of cobimetinib 
plus atezolizumab combination in previously untreated advanced BRAFV600 wild-type melanoma 
patients (see Section 1.3.2.4), enrollment in the BRAFV600 wild-type cohort has been 
discontinued. Ongoing patients in this cohort may continue study treatment as per protocol, 
according to investigator’s medical judgement.
Following provision of informed consent, potential patients will be screened for study eligibility 
over a 28-day period. Eligible patients will be assigned to a treatment cohort at enrollment. 
Study treatment in Cohort 1 will consist of orally administered cobimetinib and intravenously (IV) 
administered atezolizumab. Study treatment in Cohort 2 will consist of orally administered 
cobimetinib and vemurafenib for an initial 28-day treatment run-in period, followed by 
cobimetinib, vemurafenib and IV atezolizumab for subsequent 28-day cycles. Disease status for 
the purposes of treatment decisions will be determined by the investigator. Study treatment for 
all patients in both cohorts will be continued until investigator-determined disease progression 
according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (with two 
exceptions as described below), death, unacceptable toxicity, withdrawal of consent, or 
pregnancy, whichever occurs first. 
Study treatment may be continued beyond progression per RECIST v1.1 if pseudoprogression 
due to the effects of immunotherapy is suspected to have occurred or if disease progression is 
limited to ≤3 intracranial lesions that can be controlled with stereotactic radiotherapy (SRT). 
Clinically stable patients who have a favourable benefit-risk ratio may continue study treatment 
beyond progression per RECIST v1.1 for either reason if all of the following criteria are met:

Clinically stable patient with evidence of clinical benefit and favourable benefit−risk ratio as 
determined by the investigator 

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 tumour progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions

Documented investigator/patient discussion of treatment options alternative to continuing 
study treatment at the time of RECIST v1.1-defined disease progression

Consultation with the Medical Monitor is advised
Study treatment will be discontinued in any patient who continues treatment beyond disease 
progression per RECIST v1.1 if clinical deterioration because of disease progression occurs at 


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any time or if persistent disease growth is confirmed on follow-up disease assessments
performed approximately four weeks later. Post-progression assessments may be conducted 
sooner if necessary e.g., due to clinical progression. The disease status of patients who 
continued study treatment and underwent intracranial SRT will be determined by the 
investigator according to RECIST v1.1 modified by excluding any treated lesions from the sum 
of largest diameters from baseline onwards. 
Patients will attend a Study Treatment Discontinuation Visit after 28 ± 7 days of their last study 
treatment dose. All adverse events will be reported until 30 days after the last study treatment 
dose. After the Study Treatment Discontinuation Visit, patients who have not yet progressed will 
be followed every 8 or 12 weeks for disease status until disease progression has been 
confirmed, and all patients will be followed every three months for survival and new anti-cancer 
treatments. 
Figure 1 presents an overview of the study design.  
Efficacy will be assessed in intracranial disease alone (primary efficacy endpoint) as well as in 
extracranial and overall (both intracranial and extracranial) disease (secondary and exploratory 
efficacy endpoints). Disease status will be determined according to RECIST v1.1 with a 
modified measurability definition for intracranial lesions (≥0.5 cm by magnetic resonance 
imaging [MRI]) and allowing up to five intracranial target lesions (in addition to any extracranial 
target lesions). Exploratory analyses of disease status will include evaluations by 
immune-modified RECIST, RECIST v1.1 modified by excluding any SRT-treated lesions from 
the sum of largest diameters from baseline onwards (if applicable), and immunotherapy 
Response Assessment for Neuro-Oncology (iRANO) criteria. Disease status for the primary 
endpoint will be determined by an Independent Review Committee (IRC). IRC membership and 
procedures will be described in the IRC Charter. All other efficacy endpoints will be analysed
according to investigator disease status determinations. Disease responses for all endpoints will 
be confirmed by two consecutive assessments at least four weeks apart. Regardless of whether 
patients continue treatment beyond disease progression per RECIST v1.1, tumour 
assessments must be repeated approximately four weeks later (or sooner if necessary e.g., due 
to clinical progression).
Efficacy will also be evaluated according to patient-reported outcomes (PROs) measured at 
baseline and during study treatment. Patients will complete the European Organisation for 
Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) 
and brain cancer module (QLQ-BN20) to assess disease and/or treatment-related symptoms 
(e.g., headache, seizure, diarrhoea, functioning, and health-related quality of life). After study 
treatment discontinuation, a subset of the EORTC QLQ-C30 only will be administered. 
Safety will be assessed by regular evaluation of adverse events and conduct of physical 
examinations, vital signs, clinical laboratory tests (haematology, blood chemistry) and 
electrocardiograms. Adverse events will be reported and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. An 
Internal Monitoring Committee (IMC) will monitor patient safety throughout the study and will 
provide safety-related recommendations. Details of the IMC including its responsibilities, 
composition, and operating procedures will be provided in the IMC charter. 
To evaluate molecular biomarkers associated with disease outcomes including response to 
study treatment, tumour tissue obtained prior to treatment initiation will be collected (if available) 
and plasma will be collected at baseline and at the time of disease progression.
Schedules of activities are provided Appendix 1 and Appendix 2
. The schedule of biomarker 
sampling is provided in Appendix 3
.
The study will be conducted at approximately 23 sites worldwide. Approximately 60 patients will 
be enrolled into the BRAFV600 mutation-positive cohort, and 15 patients have been enrolled into 
the BRAFV600 wild-type cohort, for a total of approximately 75 patients enrolled. With an 
estimated study drop-out rate of 15%, approximately 50 patients in the BRAFV600 mutation-
positive cohort are expected to be evaluable for the primary efficacy endpoint. Patients in the 
BRAFV600 wild-type cohort will be analysed descriptively. Patients who do not meet the criteria 
for participation in this study (screen failure) may qualify for re-screening once at the 
investigator's discretion. 


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A Steering Committee (SC) will provide scientific oversight of the trial. Details of the composition 
and mandate of the SC will be provided in the SC Charter. 
Figure 1 Study Schema
Number of Patients
Approximately 60 patients will be enrolled in the BRAFV600 mutation-positive cohort and 
15 patients in the BRAFV600 wild-type cohort for a total of approximately 75 patients enrolled. 
Based on an estimated 15% study drop-out rate, 50 patients will be evaluable in the BRAFV600
mutation-positive cohort for the primary study endpoint.
Target Population
Patients must meet the following criteria for study entry.
Inclusion Criteria
Disease-specific criteria

Histologically confirmed melanoma with radiologically confirmed brain metastases

Documented BRAFV600 mutation status of melanoma tumour tissue using a validated 
genetic test.

Measurable brain metastases defined as any lesion that can be accurately measured in at 
least one dimension as ≥0.5 cm. Patients who have received prior SRT or surgery for brain 
metastases must have untreated brain lesions that can be accurately measured in at least 
one dimension as ≥0.5 cm by MRI. 

Prior anti-cancer therapy for metastatic melanoma is allowed, with the following exceptions:
–
Prior BRAF or MEK inhibitors are not allowed in either the metastatic or adjuvant 
settings
–
Prior immunotherapy is not allowed. As an exception, for patients in Cohort 1 
(BRAFv600 wild-type) prior immunotherapy is allowed in the adjuvant setting if 
completed ≥90 days prior to study treatment initiation. Examples of immunotherapy 
include, but are not limited to, nivolumab, pembrolizumab and ipilimumab.
–
Any anti-cancer therapy, including chemotherapy, hormonal therapy and radiotherapy, 
is prohibited within two weeks prior to initiation of study treatment.

Prior SRT or surgical therapy of ≤10 brain metastases is allowed but prior whole brain 
radiation therapy (WBRT) is not allowed. 

Adverse effects of all prior systemic or local treatment must have either returned to baseline 
or become stable and manageable prior to initiation of study treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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General criteria

Willing and able to provide informed consent and have signed the study Informed Consent 
Form

Age 18 years at time of signing Informed Consent Form

Able to comply with the study protocol, in the investigator’s judgment

ECOG Performance Status ≤2

Life expectancy of > 3 months

Willing and able to complete health and quality of life questionnaires required by the 
protocol

Adequate hematologic and end-organ function, defined using the following laboratory 
results obtained within 14 days prior to first dose of study treatment with the exception of 
amylase and lipase which may be obtained within 28 days prior to study treatment initiation:
–
Absolute neutrophil count ≥1.5 × 109/L without granulocyte colony-stimulating factor 
support
–
White blood cell count ≥2.5 x 109/L
–
Lymphocyte count ≥0.5 × 109/L
–
Platelet count ≥100 × 109/L without transfusion
–
Haemoglobin ≥90 g/L without transfusion
–
Serum albumin ≥25 g/L 
–
Total bilirubin ≤1.5 × upper limit of normal (ULN)
–
Aspartate transaminase and alanine aminotransferase ≤2.0 × ULN, or for patients with 
documented liver metastases, ≤5.0 ULN 
–
For patients assigned to Cohort 2 only: Amylase and lipase ≤1.5 × ULN
–
Alkaline phosphatase (ALP) ≤2.5 × ULN or, for patients with documented liver or bone 
metastases ALP ≤5 × ULN 
–
Serum creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥40 mL/min on the basis 
of measured CrCl from a 24-hour urine collection or Cockcroft-Gault glomerular 
filtration rate estimation as follows:
CrCl =
(140 − age) × (weight in kg) (× 0.85 if female)
72 × (serum creatinine in mg/dL)
–
For patients not receiving therapeutic anticoagulation: international normalised ratio 
(INR) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN within 28 days prior 
to initiation of study treatment
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen that 
does not include coumarin anticoagulants, stable INR, and stable aPTT during the 28 
days immediately preceding initiation of study treatment

Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to always use two effective forms of contraception including at least 
one method with a failure rate of 1% per year during the course of this study and for at 
least six months after completion of study therapy.
–
Females of childbearing potential are defined as sexually mature women without prior 
oophorectomy or hysterectomy who have had menses within the last 12 months.
–
Females are not considered to be of childbearing potential if amenorrhoeic
for > 12 months and follicle-stimulating hormone (FSH) level ≥ 40 IU/L. For females 
who have been amenorrhoeic for ≥ 2 years, the requirement for FSH measurement at 
screening will be waived.


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–
Examples of effective contraception methods with a failure rate of < 1% per year
include bilateral tubal ligation and male surgical sterilization; hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices; and copper intrauterine 
devices. A reliable barrier method may be used as the second contraceptive method. 
Hormonal contraceptive methods must be supplemented by a barrier method.  Please 
note that potential interactions between vemurafenib and hormonal contraceptives may 
decrease the effectiveness of hormonal contraceptives.
–
Male patients who are surgically sterilized are required to use barrier methods of 
contraception.

Female patients of childbearing potential must agree to refrain from donating eggs during 
the course of the study and for at least 5 months after their final dose of atezolizumab 

Male patients must agree to refrain from donating sperm during the course of the study and 
for at least six months after the last dose of cobimetinib
Exclusion Criteria
Patients who meet any of the following cancer-related or general criteria will be excluded from 
study entry:
Cancer-related criteria

Ocular melanoma

Leptomeningeal involvement

Uncontrolled tumour-related pain
Patients requiring narcotic pain medication must be on a stable regimen at start of study 
treatment.
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. Note: indwelling drainage catheters (e.g., PleurX®) are 
allowed.

Prior WBRT treatment for CNS disease

Increasing corticosteroid dose during the seven days prior to initiation of study treatment or 
current dexamethasone or equivalent dose of > 8 mg/day

Prior treatment with a BRAF or MEK inhibitor

Major surgical procedure other than for diagnosis within four weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the course of 
the study

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary 
cells or to any formulation component of cobimetinib or atezolizumab or, for patients 
assigned to Cohort 2 only, vemurafenib.

Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants other than 
gabapentin, vigabatrin and levetiracetam

Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days prior to 
initiation of study treatment unless the patient has an absolute contraindication to the use of 
non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin (i.e., severe allergy or reactive 
airway disease sensitive to NSAIDs or aspirin).

Active malignancy (other than melanoma) or a prior malignancy within the past three years


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Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma, cervical carcinoma in situ, breast carcinoma in situ, prostate cancer in situ or 
limited stage bladder cancer, and patients with isolated elevation in prostate-specific 
antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible 
for the study.
General criteria

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 baseline

History of clinically significant cardiac dysfunction, including the following:
–
Unstable angina or new-onset angina within three months prior to initiation of study 
treatment
–
Current symptomatic congestive heart failure, defined as New York Heart Association 
Class II or higher
–
Myocardial infarction within three months prior to initiation of study treatment
–
Unstable arrhythmia
–
Left ventricular ejection fraction below the institutional lower limit of normal or below 
50%, whichever is lower
–
Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic 
baseline hypertension consistently above 159/99 mmHg despite optimal medical 
management
–
For patients assigned to Cohort 2 only: History of congenital long QT syndrome
–
For patients assigned to Cohort 2 only: Mean (average of triplicate measurements) 
QTc interval corrected using Fridericia’s method (QTcF) ≥480 ms at screening, or 
uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, 
magnesium and phosphorus)

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered medications

Traumatic injury within two weeks prior to initiation of study treatment

Prior allogeneic stem cell or solid organ transplantation

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 complete list in Appendix 10 ), 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 from the study) 
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 12 months of 
study treatment initiation


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
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Uncontrolled diabetes or symptomatic hyperglycaemia

Any Grade ≥3 haemorrhage or bleeding event within 28 days of study treatment initiation

History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 
six months prior to study treatment initiation

Positive human immunodeficiency virus test at screening

Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B 
surface antigen (HBsAg) test at screening or a positive quantitative HBV DNA test.
If a patient has a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) 
test at screening, a quantitative HBV DNA test must be performed.  If positive, the patient is 
not eligible.
Patients receiving anti-viral therapy for HBV are not eligible for study enrollment.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and 
a positive HCV RNA test at screening

Active tuberculosis

History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Severe infection within four weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteraemia, or severe pneumonia, 
or any active infection that, in the opinion of the investigator, could impact patient safety

Signs or symptoms of infection within two weeks prior to initiation of study treatment

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

Any psychological, familial, sociological, or geographical condition that may hamper 
compliance with the protocol and follow-up after treatment discontinuation

Pregnancy, breastfeeding, or intention of becoming pregnant during the study. Women of 
childbearing potential must have a negative serum pregnancy test result within seven days
prior to initiation of study treatment.

Treatment with therapeutic oral or IV antibiotics within two weeks prior to initiation of study 
treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic 
obstructive pulmonary disease exacerbation) are eligible for the study.

Administration of a live, attenuated vaccine within four weeks prior to initiation 
of study treatment or anticipation of need for such a vaccine during the study

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons, interleukin-2) within 28 days or 5 half-lives of the drug, whichever is shorter, 
prior to study treatment initiation

Treatment with systemic immunosuppressive medications (including, but not limited to 
cyclophosphamide, azathioprine, methotrexate and thalidomide) within two weeks prior to 
study treatment initiation.
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.

Treatment with investigational drug within 28 days or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment


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
For patients to be assigned to Cohort 2 only: anticipated use of any concomitant medication 
during or within seven days prior to initiation of study treatment that is known to cause QT 
prolongation

Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme 
inducers or inhibitors at least seven days prior to initiation of 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 either been followed for at least 24 months, 
died, withdrawn consent, or been lost to follow-up; or the Sponsor decides to end the trial; 
whichever occurs first.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
Investigational Medicinal Products
Test Product (Investigational Drugs)
Cobimetinib and atezolizumab are investigational drugs in Cohort 1 and cobimetinib,
atezolizumab and vemurafenib are investigational drugs in Cohort 2. 
Cohort 1 – BRAFV600 wild-type melanoma patients
Patients with BRAFV600 wild-type disease treated in Cohort 1 will receive the following test drugs 
in 28-day treatment cycles:
Cobimetinib:
60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1−21 
of each 28-day cycle. 
Atezolizumab:
840 mg IV on Days 1 and 15 of each treatment cycle
Cohort 2 – BRAFV600 mutation-positive melanoma patients
Patients with BRAFV600 mutation-positive disease treated in Cohort 2 will receive cobimetinib, 
atezolizumab and vemurafenib in 28-day treatment cycles. Treatment in the cohort will include a
28-day run-in period wherein patients will receive cobimetinib and vemurafenib only. Upon 
completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen. 
Test drug administration in Cohort 2 will be as follows:
Cobimetinib
Run-in Period (Cycle 1)
Days 1−21 
60 mg (three tablets of 20 mg each) PO QD
≥Cycle 2
Days 1-21 
60 mg (three tablets of 20 mg each) PO QD
Vemurafenib
Run-in Period (Cycle 1)
Days 1-21 
960 mg (four 240-mg tablets) PO twice daily (BID)
Days 22−28 
720 mg dose (three 240-mg tablets) PO BID
≥Cycle 2
Days 1-28 
720 mg dose (three 240-mg tablets) PO BID


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Atezolizumab
Run-in Period (Cycle 1)
Not administered during run-in period
≥Cycle 2
Days 1 and 15 
840 mg intravenously (IV)
Statistical Methods
There is no formal statistical study hypothesis. All statistical analyses will be entirely descriptive. 
Primary Analysis
The primary analysis will include analyses of the primary, secondary and exploratory efficacy 
endpoints and safety summaries. It will be conducted six months after the last patient is enrolled
in the study (last patient in [LPI]). The final study analysis including all updated safety and 
efficacy endpoints will be conducted approximately 24 months after LPI. 
The primary efficacy objective is to evaluate the intracranial objective response rate (ORR) in 
each study cohort. Intracranial ORR is defined as the proportion of patients with a complete or 
partial response in their intracranial disease based on two consecutive assessments ≥4 weeks 
apart. Disease status will be determined by an IRC according to RECIST v1.1 with a modified 
measurability definition for intracranial lesions (≥0.5 cm by MRI) and allowing up to five
intracranial target lesions. Data for patients with no post-baseline intracranial tumour
assessment will be excluded from efficacy analyses.
Analysis Populations
The primary efficacy analysis population will be the Evaluable Patient population in each cohort 
consisting of all enrolled patients who received study medication and have at least two post-
baseline tumour assessments for response evaluation.  
The safety analysis population will be the Safety population in each cohort consisting of all 
patients who received at least one dose of study medication. 
Determination of Sample Size
The purpose of this Phase II study is estimation and hypothesis generation regarding the effect 
of cobimetinib plus atezolizumab on CNS metastases from BRAFV600 wild-type melanoma and 
the effect of cobimetinib plus atezolizumab and vemurafenib on CNS metastases from 
BRAFV600 mutation-positive melanoma. The 15 patients enrolled into the BRAFV600 wild-type 
cohort at the time of recruitment stop will be analysed descriptively only. There are no reference 
data available on the use of these combination therapies in these patient populations.
There is no formal statistical hypothesis in this study. The originally planned total sample size of 
approximately 60 patients per cohort was based on an estimated study drop-out rate of 15%,
the primary endpoint and 95% confidence intervals (CIs) for each treatment regimen. No power 
calculation has been performed.
In a Dear Investigator Letter dated 9 July 2019, the Sponsor communicated the decision to 
discontinue enrollment in the BRAFv600 wild-type cohort (Cohort 1).  As of 9 July 2019, 
15 patients were enrolled in Cohort 1.
Point estimates and 95% CIs for a range of possible outcomes produced using nQuery 
(version 7) with 50 evaluable patients in the BRAFV600 mutation-positive cohort are provided 
below.
 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALT
alanine aminotransferase
ALP
alkaline phosphatase
aPTT
activated partial thromboplastin time
AST
aspartate transaminase (aspartate aminotransferase)
AUC
under the concentration-time curve
BID
twice daily
BRAFV600
V600 codon of the BRAF oncogene
CHMP
Committee for Medicinal Products Human Use
CI
confidence interval
CR
complete response
CrCl
creatinine clearance
CRO
contract research organization
CRS
cytokine-release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CTLA-4
cytotoxic T-lymphocyte–associated antigen 4
cuSCC
cutaneous squamous cell carcinoma
DCR
disease control rate
DNA
deoxyribonucleic acid
DOR
duration of response
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
FSH
follicle-stimulating hormone
GHS
Global Health Status
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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Abbreviation
Definition
HEENT
head, eyes, ears, nose, throat
HIV
human immunodeficiency virus
HLH
hemophagocytic lymphohistiocytosis
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
IFN-α
interferon-α
IL-2
interleukin-2
IMC 
Internal Monitoring Committee
IMP
investigational medicinal product
INR
international normalised ratio
iRANO
immunotherapy Response Assessment for Neuro-Oncology
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
IV
intravenous(ly)
LPI
last patient in
LVEF
left ventricular ejection fraction
MAPK 
RAS/RAF/MEK/ERK mitogen-activated protein kinase (cascade)
MAS
macrophage activation syndrome
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next-generation sequencing
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non−small cell lung cancer
OCT
optical coherence tomography
ORR
objective response rate
OS
overall survival
PD-1
programmed death 1
PD-L1
programmed death ligand 1
PET
positron emission tomography
PFS
progression-free survival
PO
orally
PR
partial response
PRO
patient-reported outcome
QD
once-daily (or once a day)
Q2W
every two weeks
Q3W
every three weeks


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Abbreviation
Definition
QLQ-C30
Quality-of-Life Questionnaire Core 30
QLQ-BN20
Quality-of-Life Questionnaire brain cancer module
QTcF
QTc interval corrected using Fridericia’s method
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RVO
retinal vein occlusion
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SCC
squamous cell carcinoma
SD
stable disease
SITC
Society for Immunotherapy of Cancer
SmPC
Summary of Product Characteristics
SRT
stereotactic radiotherapy
ULN
upper limit of normal
WBRT
whole brain radiation
WES
whole exome sequencing 
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON MELANOMA AND MELANOMA WITH 
CENTRAL NERVOUS SYSTEM METASTASES
In 2012, the worldwide incidence of cutaneous melanoma is estimated to have been 
more than 232 000 cases with approximately 55 500 associated deaths. The highest per 
capita incidence and mortality rates were observed in Australia/New Zealand (14 738 
cases, 2019 deaths), Europe (100 442 cases, 22 211 deaths) and North America
(74 515 cases, 11 343 deaths) (Ferlay et al. 2013). The number of melanoma cases 
worldwide is increasing with some countries reporting at least doubling of melanoma 
incidence over the last two decades particularly within fair-skinned populations 
(Australian Institute of Health and Welfare 2016, Centers for Disease Control and 
Prevention 2015, World Health Organization 2018). 
Cutaneous melanoma arises from melanocyte cells of skin. If recognized early, primary 
lesions can be excised without significant sequelae. Once metastatic however, the 
disease is characterized by mortality and morbidity. 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 two months, and median overall survival 
(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-α (IFN-α) or interleukin-2 (IL-2), although showing improved response rates, 
did not result in improved OS (Chapman et al. 1999; Ives et al. 2007). 
Unfortunately, brain metastases are common in melanoma. Central nervous system 
(CNS) disease detected due to symptoms or surveillance imaging occurs in 
approximately 37-44% of metastatic patients and autopsy studies show brain 
metastases in 75% of fatal melanoma cases (Sloan et al. 2009, Goyal et al. 2015). Brain 
metastases represent a unique therapeutic challenge due to limitations in drug delivery 
across the blood-brain barrier (Agarwala et al. 2000). Surgery, whole brain radiation 
(WBRT) and stereotactic radiotherapy (SRT) have been mainstays of melanoma brain 
metastases treatment, but these approaches do not dramatically ameliorate outcomes 
as shown by a median OS of 6.7 months determined in a retrospective analysis of this 
patient population (Sperduto et al. 2012). Difficulties in treating melanoma brain 
metastases patients are exacerbated by their exclusion from large clinical trials (Larkin 
et al. 2015, Long et al. 2015, Robert et al. 2015a, Robert et al. 2015b, Ascierto et al. 
2016). 
The RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade is a key 
intracellular signalling network that transduces multiple proliferative and differentiating 
signals from the extracellular environment to cell nuclei to activate cellular growth and 
differentiation (Johnson and Lapadat 2002, Roberts and Der 2007). Mutations in the 
V600 codon of the BRAF oncogene (BRAFV600) occur in approximately 50% of all 


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cutaneous melanomas and, though mostly mutually exclusive to these BRAF mutations, 
NRAS is mutated in 15–25% of melanomas (Davies et al. 2002, Lee et al. 2011, Goel et 
al. 2006).  These BRAF and NRAS mutations trigger constitutive activation of the MAPK 
pathway resulting in growth factor-independent cellular proliferation and survival
characteristic of oncogenesis. Notably, the presence of BRAF mutations has been 
associated with an increased risk of CNS metastases in patients with advanced 
melanoma as indicated by a 24% rate of CNS metastases in BRAF mutation-positive
melanoma versus a 12% rate in patients with BRAF wild-type disease (Jakob et al. 
2012). 
In the last decade, immunotherapies disrupting cytotoxic T-lymphocyte–associated 
antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways as well as agents 
targeting the MAPK pathway have been introduced into the treatment of advanced 
melanoma leading to improved outcomes. In one large randomized study comparing 
PD-1 pathway blockade with pembrolizumab to CTLA-4 blockade with ipilimumab, 
24-month survival rates of 55% were observed (Schachter et al. 2017). In studies of 
BRAF inhibitors alone or combined with MEK inhibitors in patients with BRAFV600
mutations, OS of 22.3 to 25.1 months were observed (McArthur et al. 2014, Long et al. 
2015). 
The activity of these agents in melanoma brain metastases has been shown in clinical 
trials limited to patients with CNS disease. In a study of PD-1 pathway blockade with 
pembrolizumab, intracranial responses were observed in 4/18 (22%) of melanoma 
patients enrolled. A tolerable safety profile was observed (Goldberg et al. 2016).  In an 
open-label trial comparing nivolumab (an anti-PD-1 monoclonal antibody) with or without 
ipilimumab in patients unselected for BRAF mutation, at a median follow-up of 
16.4 months, complete or partial intracranial responses were observed in 11/26 (42%) 
patients receiving both agents and 5/25 (20%) patients receiving nivolumab alone. PFS
at six months was 46% and 29% respectively (Long et al. 2017). Combined 
nivolumab/ipilimumab showed similar activity in another single arm trial with an 
intracranial objective response rate (ORR) of 55% and 6-month PFS greater than 60% at 
9 months median follow-up in 75 patients (Tawbi et al. 2017). No new or unexpected 
adverse events were observed in these studies.
In a clinical trial of 146 patients with BRAFV600 mutation-positive disease (n=90 with no 
prior treatment for brain metastases, n=56 with prior treatment for brain metastases), 
MAPK pathway disruption via BRAF inhibition with vemurafenib (Zelboraf®) produced an 
intracranial ORR of 18% in both prior treated and untreated patient cohorts. Median OS 
was 9.6 months (range 0.6–34.5) in the prior treatment cohort and 8.9 months (range 
0.7–34.3) in the cohort of patients who had not received prior treatment for brain 
metastases. Study treatment was reported as well tolerated (McArthur et al. 2017). In a 
study of dual MAPK pathway blockade with combined BRAF and MEK inhibition with 
dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) in patients with BRAFV600
mutation-positive disease, intracranial responses were observed in 58% of the patients 


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with asymptomatic disease and no prior treatment. Preliminary OS analyses in this 
patient subset found median survival ranging from approximately 10 to 24 months. No 
unexpected safety issues were observed (Davies et al. 2017). 
These results suggest that immunotherapy and BRAF-MEK targeted approaches may 
provide systemic alternatives to established, but arguably inadequate, local methods for 
treating melanoma patients with intracranial disease.
1.2
BACKGROUND ON STUDY MEDICATIONS
1.2.1
Background on Cobimetinib
Cobimetinib (Cotellic®) is a potent and highly selective inhibitor of mitogen-activated 
protein kinases MEK1 and MEK2, central components of the MAPK pathway. Activated 
MEK triggers downstream signalling to promote growth. Cancer cells transformed by 
BRAFV600 mutation 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 
tumours that harbour the BRAFV600 mutation (Solit et al. 2006). 
Cobimetinib shows anti-tumour 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. 
Cobimetinib is approved in the United States, European Union and multiple other 
countries across the world for combined use with vemurafenib for the treatment of 
advanced BRAFV600 mutation-positive melanoma.
Refer to the Cobimetinib Investigator’s Brochure for details on nonclinical and clinical 
studies.
1.2.2
Background on Atezolizumab
Atezolizumab (Tecentriq®) is a humanized immunoglobulin (Ig) G1 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 tumour-specific 
T cell responses, resulting in improved anti-tumour activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016).  Atezolizumab has minimal binding to Fcγ receptors, thus 
eliminating detectable Fc-effector function and associated antibody-mediated clearance 
of activated effector T cells.


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Atezolizumab shows anti-tumour activity in both nonclinical models and cancer patients 
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 in the United States and the European Union for the treatment 
of patients with locally advanced or metastatic urothelial bladder carcinoma and 
metastatic non−small cell lung cancer (NSCLC) who have disease progression during or 
following platinum-containing chemotherapy (see current Tecentriq Summary of Product 
Characteristics [SmPC]). Atezolizumab has also received United States FDA approval 
and Committee for Medicinal Products Human Use (CHMP) opinion for extensive-stage 
small-cell lung cancer and for triple-negative breast cancer. Atezolizumab is approved 
for the treatment of hepatocellular carcinoma and melanoma in some countries. 
Atezolizumab is also currently in clinical development for other indications.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.3
Background on Vemurafenib
Vemurafenib is a compound that selectively inhibits oncogenic BRAF kinase. Discovery 
of oncogenic BRAF mutations highlights the central role of this kinase in signalling 
pathways that control cellular proliferation. Oncogenic mutations in BRAF result in 
constitutive activation of BRAF kinase, which causes dysregulated downstream 
signalling via MEK and ERK, leading to increased cell proliferation and survival. 
Vemurafenib is approved as a treatment for adult patients with unresectable or 
metastatic BRAFV600 mutation−positive melanoma in numerous countries worldwide, 
including the European Union, Switzerland, Canada, Australia, New Zealand and Israel, 
and as a treatment for BRAFV600 mutation−positive melanoma in the United States, Brazil 
and Korea. 
Refer to the Vemurafenib Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The rationale for evaluating combination advanced melanoma treatment with 
PD-1/PD-L1 pathway blockade via atezolizumab and MAPK pathway blockade via
cobimetinib and, in BRAFV600 mutation-positive disease, vemurafenib, is based upon 
preclinical evidence for synergistic anti-tumoural effects of these approaches (see
Section 1.3.1), clinical evidence of efficacy of each approach in advanced melanoma
with and without CNS disease (see Section 1.1), and preliminary clinical data showing 
activity and tolerability of combined immunotherapy/MAPK pathway inhibition regimens
in melanoma (see Section 1.3.2). 


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1.3.1
Immunomodulation and the MAPK Pathway in Melanoma: 
Preclinical Data
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer. 
PD- L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1. PD-1 is an inhibitory receptor expressed on T cells 
following T cell activation. PD-1 expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008). B7-1 is a molecule expressed on antigen presenting 
cells and activated T cells. Binding of PD-L1 to PD-1 and B7-1 inhibits T cell proliferation 
and activation, cytokine production and cytolytic activity, leading to the functional 
inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011). Overexpression 
of PD-L1 on tumour cells has been reported to impede anti-tumour immunity, resulting in 
immune evasion (Blank and Mackensen 2007). Melanoma tumour cells are highly 
immunogenic highlighting the applicability of immunomodulation as a potential treatment 
for melanoma. Removal of suppression of T cell activation through PD-1/PD-L1 
blockade may render tumours especially prone to elimination by an active immune 
response (Zito et al. 2012). Importantly, studies of excised melanoma brain metastases 
show PD-L1 expression and lymphocytic infiltration within the intracranial tumour 
microenvironment. These findings were independent of BRAFV600 status (Berghoff et al. 
2015).
There is preclinical evidence of MAPK pathway involvement in the regulation of the 
immune microenvironment of tumours. In cell lines, increased antigen expression and 
enhanced reactivity to antigen-specific T cells is observed with MAPK pathway inhibition 
(Boni et al. 2010). MEK inhibition has also been shown to increase tumour major 
histocompatibility complex expression and PD-L1 expression in triple-negative breast 
cancer cells in vivo and in vitro (Loi et al. 2016). In BRAFV600 mutation-positive 
melanoma, nonclinical studies show induction of an immunosuppressive tumour
microenvironment that can be reversed by BRAF or MEK inhibition (Sumimoto et al. 
2006). Furthermore, BRAF and MEK inhibitors, alone or in combination, have been 
shown to increase melanoma antigen expression, MHC expression, T cell infiltration and 
PD-L1 expression in tumour biopsies from melanoma patients (Wilmott et al. 2012; 
Frederick et al. 2013; Kavakand et al. 2015; Liu et al. 2015; Hu Lieskovan et al. 2015). 
Additional effects of MAPK inhibition that may further modulate the microenvironment to 
enable enhanced anti-tumour immune reactivity 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 
myeloid-derived suppressor cells), as well as suppression of angiogenesis (Phan et al. 
2013; Ebert et al. 2016; Ciuffreda et al. 2009; Chang et al. 2013; Mohan et al. 2015).
Synergistic anti-tumoural activity with combined anti-PD-L1 or anti-PD-1 and MAPK 
inhibitory agents has been shown in murine cancer model studies. The MEK inhibitor 
G-38963, which is mechanistically similar to cobimetinib, has been shown to promote the 


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effector phenotype and longevity of tumour-infiltrating T cells and combine synergistically 
with anti−PD-L1 in inhibiting tumour growth (Ebert et al. 2016). In addition, concurrent 
administration of the MEK inhibitor trametinib and an anti-PD-1 immunomodulator has 
been shown to produce enhanced anti-tumoural activity over these agents alone (Liu et 
al. 2015).
1.3.2
Clinical Experience with Cobimetinib, Atezolizumab and 
Vemurafenib in Melanoma
1.3.2.1
Study PCD4989g: Atezolizumab Monotherapy
Study PCD4989g is an ongoing Phase Ia trial evaluating the safety and 
pharmacokinetics of single agent atezolizumab in patients with locally advanced or
metastatic solid tumours or hematologic malignancies. Response within melanoma 
patients evaluated thus far is comparable to that of two PD-1 inhibitors that are currently 
approved for the treatment of melanoma (pembrolizumab and nivolumab) (Hodi et al. 
2014). 
As of a December 15, 2015 data cut-off, patients with metastatic non-ocular melanoma 
(n=37) enrolled in this study who received doses of at least 10 mg/kg atezolizumab 
every three weeks (n=37), ORR by Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1) was 32% and median PFS was 5.5 months (Roche data on 
file). In addition, atezolizumab monotherapy was well tolerated by patients with 
metastatic melanoma.
Further details of safety findings in this study are found in the current Atezolizumab 
Investigator’s Brochure.
1.3.2.2
Study GP28363:  Cobimetinib plus Atezolizumab
Study GP28363 is an ongoing Phase Ib, open-label, multicentre, global study of 
cobimetinib and atezolizumab in patients with metastatic or locally advanced solid 
tumours, including those who carry a KRAS or BRAFV600 mutation, for which no 
recognized standard therapy exists.
As of a January 17, 2017, clinical data cut-off, there were 20 metastatic melanoma 
patients (10 with BRAFV600 mutation-positive disease) enrolled in the dose escalation or 
expansion stages who were evaluable for efficacy. These patients had received one or 
more prior lines of treatment for advanced disease. The median duration of survival 
follow-up at data cut-off was 25.1 months. The investigator-assessed ORR per RECIST 
v1.1 was 45.0% (9 of 20; 4 of whom were BRAFV600 mutation-positive) for all patients,
with all nine responders having a partial response (PR). The comparable ORRs in 
BRAFV600 mutation-positive and wild-type subgroups suggests that all patients may 
receive benefit regardless of BRAFV600 status. This observation is also supported by the 
median PFS observed in each subgroup (16.2 months in BRAFV600 mutation subgroup, 
15.7 months in BRAF wild-type subgroup).


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Safety data up to January 17, 2017, are available for 150 safety-evaluable patients with 
various tumour types including colorectal cancer, metastatic melanoma and NSCLC. Of 
these, 148 (98.7%) experienced an adverse event. The most frequently observed 
adverse events (≥30%) were diarrhoea (70.7%), fatigue (56%), rash (48%), vomiting 
(42%), nausea (36%), pruritus (35.3%), decreased appetite (34.7%) and constipation 
(29.3%). 
Grade 3/4 adverse events were observed in 96 (64%) of these patients. The most 
common (≥2.7% or 4 patients) included fatigue (10%), anaemia (9.3%), diarrhoea (8%), 
abdominal pain (5.3%), rash and blood creatine phosphokinase (CPK) increased 
(4.7% each), dyspnoea and aspartate aminotransferase (AST) increased (4% each), 
amylase increased and hypertension (3.3% each), and ascites, vomiting, peripheral 
oedema, asthenia, pleural effusion, pulmonary embolism, blood bilirubin increased, 
neutrophil count decreased and hypophosphatemia (2.7% each).
Seven patients (4%) were reported to have had Grade 5 adverse events. The following 
events led to death in 7 patients (4.7%): pneumonia, large intestine perforation, small 
intestinal perforation, sepsis, road traffic accident and respiratory failure. Sixty-seven 
safety-evaluable patients (44.7%) had a serious adverse event (SAE), most of which 
were single reports. The exceptions were pneumonia (6%), pyrexia (4%), abdominal 
pain and dyspnoea (3.3% each), vomiting (2.7%), sepsis and pulmonary embolism 
(2% each), and bacteraemia, cellulitis, lung infection, ascites, intestinal obstruction, 
nausea, fatigue, peripheral oedema, pain, pleural effusion, pneumonitis, dehydration and 
fall (1.3% each). 
These findings are consistent with the known adverse event profiles for cobimetinib and 
atezolizumab and did not represent additive toxicity.
Further details of this study are found in the current Cobimetinib and Atezolizumab 
Investigator’s Brochures.
1.3.2.3
Study GP28384:  Cobimetinib plus Atezolizumab and
Vemurafenib in BRAFV600 Mutation-Positive Melanoma
Study GP28384 is an ongoing multicentre study expected to enrol a total of 
approximately 70 patients with previously untreated BRAFV600 mutationpositive 
melanoma. There are two stages in this study:  a dose escalation stage and an 
expansion stage. The study objectives are to assess the safety, tolerability and 
pharmacology of combined cobimetinib, atezolizumab and vemurafenib (the triplet 
regimen). Following dose-escalating evaluation of combined atezolizumab and 
vemurafenib, evaluation of the triplet regimen was initiated and is ongoing. Preliminary 
safety and efficacy information are currently available for the atezolizumab plus 
vemurafenib cohorts (median follow-up of approximately 1 year, data cut-off March 1, 
2016) and for the triplet cohorts (median follow-up of approximately 10 months, data 
cut-off January 17, 2017).


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The study enrolled four dose-escalation cohorts and is currently enrolling three 
expansion cohorts. Approximately 24 to 30 patients evaluable for dose-limiting toxicities 
were enrolled in the dose-escalation cohorts according to a modified 3 + 3 dose-
escalation design to evaluate the safety, tolerability and pharmacokinetics of the 
regimens. There were no dose-limiting toxicities observed in any of the dose-escalation 
cohorts.  
Based on data from the preceding cohorts, treatment in the fourth escalation cohort and 
expansion cohorts has been established as an initial 28-day run-in with 21 days 960 mg 
vemurafenib twice daily (BID) then seven days 720 mg vemurafenib BID plus 60 mg 
cobimetinib once daily (QD) Days 1-21. Following completion of the 28-day run-in, 
atezolizumab is added to the combination for a final regimen of 60 mg cobimetinib QD 
(21 days on, 7 days off each cycle) plus 800 mg atezolizumab every two weeks (Q2W) 
plus 720 mg vemurafenib BID (Days 1-28 of each cycle).
As of the January 17, 2017 clinical cut-off date, 38 patients had received combination 
treatment with cobimetinib, atezolizumab and vemurafenib and the median survival 
follow-up was 10.1 months (95% confidence interval [CI]: 8.6, 11.0). Approximately 
two-thirds (25/38 or 65.8%) of the efficacy-evaluable patients had a confirmed response 
as assessed by the investigator per RECIST v1.1, with the majority (19/25) as partial 
responders. The median duration of response (DOR) could not yet be estimated based 
on only 28.0% of patients reporting a PFS event. 
Thirty-nine patients receiving the triplet regimen were evaluable for safety at the clinical 
cut-off.  Thirty-eight of these patients reported an adverse event. The most common 
adverse events (≥20%) following completion of the run-in period included diarrhoea
(59%), nausea and arthralgia (56.4% each), pyrexia (53.8%), photosensitivity reaction 
and fatigue (48.7% each), AST increased (46.2%), pruritus and alanine 
aminotransferase (ALT) increased (38.5% each), oedema peripheral (35.9%), 
constipation and hypertension (33.3% each), vomiting, influenza-like illness and cough 
(30.8% each), chills, rash maculopapular and anaemia (28.2% each), decreased 
appetite (25.6%), myalgia and back pain (23.1% each), and dry skin, blood creatinine 
increased, hypophosphatemia and headache (20.5% each).
Grade 3/4 events were reported in 22 patients (56.4%). These events were generally 
reported in one patient each, with the exception of ALT increased (5 patients [12.8%]), 
AST increased and hypophosphatemia (4 patients [10.3%] each), and sepsis, rash 
macular, rash, blood bilirubin increased, blood CPK increased, hyponatremia, urinary 
tract infection, hypertension and diarrhoea (2 patients [5.1%] each). Eleven patients 
experienced SAEs, which were each reported in a single patient (2.6%), with the 
exception of sepsis, which was reported in two patients (5.1%). One patient died as a 
result of Grade 5 duodenitis.


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Overall, there were no unexpected adverse events or apparent additive effects and the 
majority of adverse events were mild or moderate in severity, manageable with dose 
modification, and generally reversible. In summary, treatment with cobimetinib, 
atezolizumab and vemurafenib was associated with a safety profile that appears 
tolerable and manageable.  
Further details of this study are found in the current Cobimetinib, Atezolizumab and 
Vemurafenib Investigator’s Brochures.
1.3.2.4
Ongoing Phase III Studies CO39722 and CO39262  
Combined treatment with cobimetinib and atezolizumab with/without vemurafenib, are 
currently being evaluated in two ongoing, randomized, placebo-controlled, Phase III 
studies. Study CO39722 is comparing cobimetinib plus atezolizumab versus 
pembrolizumab in approximately 450 patients with advanced BRAFV600 wild-type 
melanoma. On 18 June 2019, F. Hoffmann-La Roche Ltd. reviewed the results of the 
primary analysis for Study CO39722 (IMspire170) that showed cobimetinib plus 
atezolizumab combination did not meet the study primary endpoint of improved 
progression-free survival by independent review committee compared to 
pembrolizumab. Safety for the combination of cobimetinib plus atezolizumab was 
consistent with the known safety profile of the individual medicines, and no new safety 
signals were identified with the combination. As expected, the overall incidence of 
adverse events was higher in the combination therapy arm than in the single-agent 
pembrolizumab arm. 
Study CO39262 is comparing combined cobimetinib, atezolizumab and vemurafenib 
versus cobimetinib, vemurafenib and placebo in approximately 500 patients with 
previously untreated BRAFV600 mutation-positive metastatic melanoma. A significant and 
clinically meaningful improvement in the primary endpoint of PFS was demonstrated in 
the study, showing that adding atezolizumab to cobimetinib and vemurafenib helped 
reduce the risk of disease worsening or death, compared to placebo plus cobimetinib 
and vemurafenib. The safety profile observed was consistent with the known safety 
profiles of the individual medicines.
These studies do not allow patients with untreated, actively progressing CNS disease;
patients with metastases to the brain stem (study CO39722 only), midbrain, pons or 
medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm); patients who 
have received prior WBRT; or patients who require corticosteroids. Patients with 
melanoma CNS metastases are therefore largely excluded from these studies.
Further details of these studies are found in the current Cobimetinib, Atezolizumab and 
Vemurafenib Investigator’s Brochures.


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1.3.3
Benefit-Risk Assessment
As described in Section 1.1, melanoma patients with CNS metastases suffer poor 
outcomes and are largely excluded from trials that investigate potentially efficacious 
treatments for advanced melanoma. MAPK inhibition and immune checkpoint blockade 
are treatment approaches known to be efficacious and tolerable in advanced melanoma. 
Smaller studies in CNS melanoma metastases populations specifically have shown 
these approaches exert anti-tumoural activity within the CNS when used as treatment 
strategies on their own. 
Preclinical and preliminary clinical data outlined in Sections 1.3.1 and 1.3.2 indicate the 
potential for synergistic anti-tumoural activity when these approaches are combined.
Based on these data, Phase III studies evaluating combined cobimetinib and 
atezolizumab treatment in BRAFV600 wild-type melanoma and combined cobimetinib, 
atezolizumab and vemurafenib treatment in BRAFV600 mutation-positive disease have 
been initiated. Study MO39136 will address the exclusion of most CNS melanoma 
metastases patients from these studies (see Section 1.3.2.4). 
Preliminary safety data from studies of combined cobimetinib and atezolizumab with or 
without vemurafenib outlined in Section 1.3.2 indicate safety profiles of these agents are 
as expected and without additive toxicity. Importantly, BRAFV600 mutation status is 
required for enrollment and will be the basis by which patients are assigned to treatment
cohort thereby ensuring only patients with the potential to benefit from added 
vemurafenib are exposed to the drug.
Patients enrolled in Study MO39136 will be closely monitored for safety during the study. 
Guidelines for adverse event management (including dose modifications, interruptions or 
discontinuations) that are currently used in ongoing trials (see Section 1.3.2.4) will be 
followed. In addition to Medical Monitor oversight, an Internal Monitoring Committee 
(IMC) will monitor patient safety throughout the study. The IMC will review cumulative 
safety data at regular intervals throughout the study as well as the results of an interim 
safety review conducted for each treatment cohort after approximately 10 patients 
enrolled in the cohort have completed their first tumour assessment.
As described in the Dear Investigator Letter dated 9 July 2019, the Sponsor concluded 
based on results from Study CO39722 that the benefit-risk of atezolizumab in 
combination with cobimetinib in first-line treatment for patients with BRAFV600 wild-type 
melanoma was uncompelling (see Section 1.3.2.4) when compared to pembrolizumab 
monotherapy.  
Nevertheless, the benefit-risk assessment for cobimetinib in combination with 
atezolizumab and vemurafenib or in combination with other agents, or in other disease
indications remains unchanged, with no new safety signals derived from ongoing 
studies. Also, the overall benefit-risk profile of cobimetinib or atezolizumab for the 
currently approved indications is not impacted.


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In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, it is unclear 
whether or how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation 
of the host immune response to acute infection, which may result in immunopathology 
or dysregulated immune system defenses. In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012). However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy.
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines IL-6, IL-10, IL-2, and IFN-
(Merad and Martin 2020). While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute 
SARS-CoV-2 infection while receiving atezolizumab. At this time, there is insufficient 
evidence for causal association between atezolizumab and an increased risk of severe 
outcomes from SARS-CoV-2 infection.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2related interstitial pneumonia. Thus, investigators should 
use their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.
Overlapping toxicities of the combination use of atezolizumab, cobimetinib, and 
vemurafenib may include gastrointestinal toxicity, liver laboratory abnormalities and 
hepatotoxicity, dermatologic toxicity, pancreatitis, nephritis or increased creatinine, 
hyperglycemia, ocular events, and pneumonitis. While vemurafenib is thought to have 
some immune modulating effect, it is not expected that there will be any interaction 
between vemurafenib and SARS-CoV-2 infection in the approved indications and 
ongoing clinical studies. In addition, it is also not expected that there will be any 
interaction between vemurafenib cobimetinib and SARS-CoV-2 infection. Clinical 
trials with the treatments in this study are ongoing during this pandemic and, although 
the study numbers are small, have not shown any increased risk of developing 
COVID-19 or of having a worse outcome in patients on the treatments used in this 
study. 


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There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy of Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021). Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19
vaccination in patients who are receiving cancer immunotherapy (SITC 2020). For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.
The SITC and NCCN recommendations along with institutional guidelines should be 
used by the investigator when deciding on administering COVID-19 vaccines. When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label. Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1).
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in 
patients with BRAFV600 wild-type melanoma with CNS metastases and of cobimetinib
plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients 
with CNS metastases. Specific objectives and corresponding endpoints for the study are 
outlined Table 1 below.








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Following provision of informed consent, potential patients will be screened for study 
eligibility over a 28-day period. Eligible patients will be assigned to a treatment cohort at 
enrollment.  Study treatment in Cohort 1 will consist of orally administered cobimetinib 
and intravenously (IV) administered atezolizumab (see Section 4.3.2.1). Study treatment 
in Cohort 2 will consist of orally administered cobimetinib and vemurafenib for an initial 
28-day treatment run-in period, followed by cobimetinib, vemurafenib and IV 
atezolizumab for subsequent 28-day cycles (Section 4.3.2.2). Disease status for the 
purposes of treatment decisions will be determined by the investigator. Study treatment 
for all patients in both cohorts will be continued until investigator-determined disease 
progression according to RECIST v1.1 (with two exceptions as described below), death, 
unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first. 
Study treatment may be continued beyond progression per RECIST v1.1 if 
pseudoprogression due to the effects of immunotherapy is suspected to have occurred 
or if disease progression is limited to ≤3 intracranial lesions that can be controlled with 
SRT. Clinically stable patients who have a favourable benefit-risk ratio may continue 
study treatment beyond progression per RECIST v1.1 if all of the following criteria are 
met:

Clinically stable patient with evidence of clinical benefit and favourable benefit−risk 
ratio as determined by the investigator 

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 tumour progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Documented investigator/patient discussion of treatment options alternative to 
continuing study treatment at the time of RECIST v1.1-defined disease progression

Consultation with the Medical Monitor is advised
Study treatment will be discontinued in patients who continue treatment beyond disease 
progression per RECIST v1.1 if clinical deterioration because of disease progression 
occurs at any time subsequently or if persistent disease growth is confirmed on follow-up 
disease assessments performed approximately four weeks later. Post-progression 
assessments may be conducted sooner if necessary e.g., due to clinical progression.
The disease status of patients who continued study treatment and underwent intracranial 
SRT will be determined by the investigator according to RECIST v1.1 modified by 
excluding any treated lesions from the sum of largest diameters from baseline onwards.
Patients will attend a Study Treatment Discontinuation Visit after 28 ± 7 days of their last 
study treatment dose. All adverse events will be reported until 30 days after the last 
study treatment dose. After the Study Treatment Discontinuation Visit, patients who have 


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not yet progressed will be followed every 8 or 12 weeks for disease status until disease 
progression is confirmed, and all patients will be followed every three months for survival 
and new anti-cancer treatments. 
Figure 2 presents an overview of the study design.  
Efficacy will be assessed in intracranial disease alone (primary efficacy endpoint) as well 
as in extracranial and overall (both intracranial and extracranial) disease (secondary and 
exploratory efficacy endpoints). Disease status will be determined according to RECIST 
v1.1 with a modified measurability definition for intracranial lesions (≥0.5 cm by 
magnetic resonance imaging [MRI]) and allowing up to five intracranial target lesions (in 
addition to any extracranial target lesions). Exploratory analyses of disease status will 
include evaluations by immune-modified RECIST, RECIST v1.1 modified by excluding 
any SRT-treated lesions from the sum of largest diameters from baseline onwards (if 
applicable), and immunotherapy Response Assessment for Neuro-Oncology (iRANO) 
criteria. Disease status for the primary endpoint will be determined by an Independent 
Review Committee (IRC). IRC membership and procedures will be described in the IRC 
Charter. All other efficacy endpoints will be analysed according to investigator disease 
status determinations. Disease responses for all endpoints will be confirmed by two 
consecutive assessments at least four weeks apart. Regardless of whether patients 
continue treatment beyond disease progression per RECIST v1.1, tumour assessments 
must be repeated approximately four weeks later (or sooner if necessary e.g., due to 
clinical progression).
Efficacy will also be evaluated according to patient-reported outcomes (PROs) 
measured at baseline and during study treatment. Patients will complete the European 
Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 
30 (EORTC QLQ-C30) and brain cancer module (QLQ-BN20) to assess disease and/or 
treatment-related symptoms (e.g., headache, seizure, diarrhoea, functioning, and health-
related quality of life [HRQoL]). After study treatment discontinuation, a subset of the 
EORTC QLQ-C30 only will be administered. 
Safety will be assessed by regular evaluation of adverse events and conduct of physical 
examinations, vital signs, clinical laboratory tests (haematology, blood chemistry) and 
electrocardiograms (ECGs). Adverse events will be reported and graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v4.0. An IMC will monitor patient safety throughout the study (see 
Section 3.1.2).
To evaluate molecular biomarkers associated with disease outcomes including response 
to study treatment, tumour tissue obtained prior to treatment initiation will be collected (if 
available) and plasma will be collected at baseline and at the time of disease 
progression.  




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SAEs, deaths, and laboratory abnormalities performed by the investigator and the 
Medical Monitor, the IMC will review cumulative data at regular intervals throughout the 
conduct of the study.
At the time of each review, the IMC will make appropriate recommendations (e.g., the 
study should continue as planned, additional analyses should be performed, enrollment
should be held pending further safety evaluations). 
Decisions will be made in consideration of the totality of the available data. Ad hoc 
meetings may be called in addition to scheduled meetings, as necessary, to provide 
recommendations on management of any potential new safety signals. Specific 
operational details such as the committee’s composition, frequency and timing of 
meetings, members' roles and responsibilities, and data to be reviewed will be described 
in the IMC charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The study will end when all patients enrolled have either completed the study (been 
followed for at least 24 months), died, withdrawn consent, or been lost to follow-up; or 
the Sponsor decides to end the trial; whichever occurs first.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Cobimetinib and Atezolizumab Dosing in 
Cohort 1
In Cohort 1, cobimetinib will be administered at a dose of 60 mg QD for Days 1-21 of 
each 28-day cycle. Atezolizumab will be administered at a dose 840 mg Q2W on Days 1 
and 15 of every 28-day cycle. These doses and schedule are also being assessed in the 
ongoing CO39722 study in advanced melanoma (see Section 1.3.2.4).
Cobimetinib is approved for administration at a dose 60 mg QD for Days 1-21 of each 
28-day cycle in combination with vemurafenib for the treatment of BRAFV600
mutation-positive metastatic melanoma (see the current Cotellic Summary of Product 
Characteristics). 
Atezolizumab will be administered at a fixed dose of 840 mg Q2W (840 mg on Days 1 
and 15 of each 28-day cycle), which is an approved dosage for atezolizumab, as 
outlined in the prescribing information. The average concentration following the 840 mg 
Q2W dosage is expected to be equivalent to that of 1200 mg Q3W.  Anti-tumor activity 
has been observed across doses ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study 
PCD4989g, the maximum tolerated dose of atezolizumab was not reached and no 
dose-limiting toxicities were observed at any dose. The fixed dose of 1200 mg Q3W 
(equivalent to an average body weightbased dose of 15 mg/kg Q3W) was selected on 


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the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).
Concomitant administration of cobimetinib 60 mg QD for Days 1-21 of each 28-day cycle 
and atezolizumab 800 mg IV Q2W has been shown to be safe and tolerable in Study 
GP28363 (see Section 1.3.2.2). Atezolizumab is formulated at a concentration of 
60 mg/mL; thus, 800 mg corresponds to a volume of 13.33 mL. To ensure consistent, 
precise and clinically feasible administration in this study and Study CO39722 (see 
Section 1.3.2.4), the volume has been rounded up to 14 mL, corresponding to a dose of 
840 mg. This nominal increase is further supported by nonclinical dosing data and is not 
expected to be different from the 800 mg dose.
3.3.2
Rationale for Cobimetinib, Atezolizumab and Vemurafenib 
Dosing in Cohort 2
In Cohort 2, treatment will begin with a 28-day run-in period wherein only vemurafenib 
and cobimetinib will be administered. During the run-in, cobimetinib will be administered
at a dose of 60 mg QD Days 1-21. Vemurafenib will be administered at a dose of 
960 mg BID Days 1-21 and at a dose of 720 mg BID Days 22-28. Following completion 
of the 28-day run-in, atezolizumab will be added to the combination for a final regimen of 
60 mg cobimetinib QD (Days 1-21) plus 840 mg atezolizumab Q2W plus 720 mg 
vemurafenib BID (Days 1-28). These doses and schedule are also being assessed in the 
ongoing CO39262 study in advanced melanoma (see Section 1.3.2.4).
Cobimetinib is approved for administration at a dose 60 mg QD for Days 1-21 of each 
28-day cycle in combination with vemurafenib for the treatment of BRAFV600
mutation-positive metastatic melanoma (see the current Cotellic Summary of Product 
Characteristics). 
Atezolizumab will be administered at a fixed dose of 840 mg Q2W (840 mg on Days 1 
and 15 of each 28-day cycle), which is an approved dosage for atezolizumab, as 
outlined in the prescribing information (also see Section 3.3.1). 
Vemurafenib is approved for administration as monotherapy at a dose of 960 mg BID for 
the treatment of BRAFV600 mutation-positive advanced melanoma (see the current 
Zelboraf Summary of Product Characteristics).
Concomitant administration of cobimetinib 60 mg QD (Days 1-21), atezolizumab 800 mg 
IV (Days 1 and 15) and vemurafenib 720 mg QD (Days 1-28) following the 28-day run-in 
dosing and schedule as described above is being studied in Study GP28384 (see 
Section 1.3.2.3). Cobimetinib, atezolizumab and vemurafenib have been found to be 
safe and tolerable at these doses. Atezolizumab is formulated at a concentration of 
60 mg/mL; thus, 800 mg corresponds to a volume of 13.33 mL. To ensure consistent, 
precise and clinically feasible administration in this study and Study CO39262 (see 


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Section 1.3.2.4), the volume has been rounded up to 14 mL, corresponding to a dose of 
840 mg. This nominal increase is further supported by nonclinical dosing data and is not 
expected to be different from the 800 mg dose.
3.3.3
Rationale for Patient Populations
Brain metastases represent a significant therapeutic challenge and are particularly 
common in advanced melanoma (see Section 1.1). Immunotherapy and MAPK targeted 
treatments have shown promise in the treatment of advanced melanoma including in 
patients with CNS disease (see Sections 1.1 and 1.3.2) and are being studied in 
combination in large, randomized Phase III studies that unfortunately exclude most 
patients with CNS disease  (see Section 1.3.2.4).  Study MO39136 will enrol patients 
with CNS disease that may otherwise be excluded from research into this dual-pronged 
treatment approach that has the potential to be of benefit in this hard-to-treat population.
BRAFV600 status must be known prior to study enrollment in order to determine 
appropriate treatment cohort assignment. Patients with BRAFV600 mutation-positive 
disease will be assigned to Cohort 2 wherein treatment includes the BRAF inhibitor 
vemurafenib that abrogates constitutive MAPK activation due to BRAFV600 mutation. 
Patients whose disease does not harbour a BRAFV600 mutation will be assigned to 
treatment in Cohort 1.
All patients must have measurable CNS disease to enable assessment of the primary 
study endpoint, intracranial ORR. Though consistent with RECIST v1.1, the criteria for 
CNS disease measurability have been adapted as in other trials of CNS melanoma 
metastases to ensure CNS lesions can be accurately assessed (Tawbi et al. 2017).  
To enable inclusion of patients who have few other treatment options, prior systemic 
treatment for advanced disease and local treatments for brain metastases, with the 
exception of treatments that may directly affect the experimental regimens in this study
or assessment of efficacy, are allowed. Additional study eligibility criteria have been 
established to ensure adequate health to undergo experimental therapy and ensure the 
absence of potential contraindications to the study regimens.
3.3.4
Rationale for Intracranial Objective Response Rate as Primary 
Endpoint
The primary endpoint of IRC-assessed intracranial ORR was selected in this hypothesis 
generating, Phase II study in order to identify the activity of the experimental regimens
within the CNS in particular. If found promising, additional studies required to evaluate 
the effect of these treatments on PFS and OS may be conducted.


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3.3.5
Rationale for Treatment beyond Disease Progression per 
RECIST v1.1
Patients in either study cohort may continue treatment beyond disease progression per 
RECIST v1.1 for two reasons: possible pseudoprogression due to immunotherapy, or 
disease progression is limited to ≤3 intracranial lesions that may be controlled by SRT.
In studies of immunotherapeutic agents, complete response (CR), PR and stable 
disease (SD) have each been shown to occur after radiographic evidence of an apparent 
increase in tumour burden.  This initial increase in tumour burden caused by immune-
cell infiltration in the setting of a T cell response has been termed pseudoprogression 
(Hales et al. 2010).  In single agent atezolizumab studies (Study PCD4989g – see 
Atezolizumab Investigator’s Brochure), evidence of tumour growth followed by a 
response was observed in several tumour types.  In addition, in some responding 
patients with radiographic evidence of progression, biopsies of new lesions or areas of 
new growth in existing lesions revealed infiltrating immune cells and no viable cancer 
cells.  Because of the potential for a response after pseudoprogression, this study will 
allow treatment in either cohort to continue after apparent radiographic progression per 
RECIST v1.1, provided the benefit-risk ratio is judged to be favourable (see criteria in 
Section 3.1).
The blood brain barrier limits drug delivery to intracranial disease sites (Agarwala et al. 
2000). A probable result of this sequestration is that, while disease outcomes have 
improved with the introduction of new systemic agents (see Section 1.1), intracranial 
disease progression despite stable or responding extracranial disease has become more 
common (Soliman et al. 2015). Though randomized studies evaluating systemic 
treatment with SRT are limited, the practice of managing brain lesions with SRT in 
patients whose extracranial disease is controlled by systemic treatment has become a 
common clinical practice. The value of this approach has been supported by multiple 
retrospective analyses in melanoma patients receiving SRT with immunotherapy and/or 
targeted agents (Anderson et al. 2017; Choong et al. 2017, Ahmed et al. 2016; Mathew 
et al. 2013; Knisely et al. 2012). 
Study treatment will be discontinued in any study patient who continues treatment 
beyond disease progression per RECIST v1.1 if clinical deterioration because of disease 
progression occurs at any time or if persistent disease growth is confirmed on follow-up 
disease assessments performed approximately four weeks later (or sooner if indicated 
due to clinical progression). Notably, the disease status of patients who continued study 
treatment and underwent intracranial SRT will be determined by the investigator 
according to RECIST v1.1 modified by excluding any treated lesions from the sum of 
largest diameters from baseline onwards.
3.3.6
Rationale for Patient-Reported Outcome Assessments
The goal of cancer treatment is to increase survival and delay of tumour progression not 
at the expense of the patients’ quality of life (Peppercorn et al. 2011). Melanoma has 


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one the highest percentage of brain metastases relative to other primary tumours. The 
role of immunotherapy in treatment of brain metastases is unknown because most trials 
exclude patients with active brain lesions (Preusser et al. 2012, Section 1.1). Therefore, 
assessing the impact of treatment and disease burden on patients’ HRQoL and activities 
of daily living provides a holistic view of how the full treatment profile impacts patients’ 
lives.  
The EORTC QLQ-C30, a generic cancer questionnaire that assesses commonly 
reported symptoms, functioning, and Global Health Status (GHS)/HRQoL; and the brain 
cancer module (QLQ-BN20) are validated instruments selected for this study to obtain 
patient-relevant information. Secondary efficacy PRO endpoints evaluated in this study 
will be based on changes detected in the QLQ-C30 or QLQ-BN20 symptoms subscale 
scores that are perceived by patients as clinically significant (Osoba et al. 1998). These 
data will therefore provide meaningful measures of patients’ experience with melanoma 
treatment.  
Assessment of the effects of combination treatment with cobimetinib and atezolizumab 
or with cobimetinib, atezolizumab and vemurafenib in relation to disease and treatment 
burden will allow oncologists to appropriately educate patients on the benefits and risks 
of treatment with these regimens.
3.3.7
Rationale for Biomarker Assessments
Melanoma is a heterogeneous disease driven by aberrations in cancer-related genes 
including BRAF and NRAS gene mutations. Differences in the genetic makeup of 
melanoma is likely to influence clinical response and changes in the genetic makeup 
give insights into potential mechanisms of acquired resistance. The aim is to 
characterize melanoma disease among patients, to better understand clinical responses, 
and to assess potential mechanisms of acquired resistance.
Tumour tissue obtained from study participants prior to study treatment initiation will be 
collected only if such samples are already available. It will be examined for the 
expression of PD-L1 protein.  In addition, if sufficient tumour material is available, an 
analysis of cancer related genes (such as, but not limited to, BRAF and NRAS) may be 
performed using next-generation sequencing (NGS).  The results will be analysed in 
relation to clinical response to identify those patients with a greater likelihood of 
benefiting from study treatment.  
Factors in plasma hold important clues regarding the disease pathobiology of cancer 
patients and may serve as a surrogate for tumour tissue in cases where tissue is not 
easily accessible.  An exploratory objective of this study is to assess biomarkers in 
plasma at baseline and at the time of relapse. Analysis of plasma may include the 
analysis of cancer related genes by performing NGS of circulating tumour DNA.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 60 patients with BRAFV600 mutation-positive melanoma patients with CNS 
metastases (Cohort 2) will be enrolled in this study. Enrollment has been discontinued 
into Cohort 1 (BRAFV600 wild-type cohort).
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry.
Disease-specific criteria

Histologically confirmed melanoma with radiologically confirmed brain metastases

Documented BRAFV600 mutation status of melanoma tumour tissue using a validated 
genetic test.  

Measurable brain metastases defined as any lesion that can be accurately 
measured in at least one dimension as ≥0.5 cm by MRI. Patients who have 
received prior SRT or surgery for brain metastases must have untreated brain 
lesions that can be accurately measured in at least one dimension as ≥0.5 cm by 
MRI. 

Prior anti-cancer therapy for metastatic melanoma is allowed, with the following 
exceptions:
–
Prior BRAF or MEK inhibitors are not allowed in either the metastatic or 
adjuvant settings
–
Prior immunotherapy is not allowed. As an exception, for patients in Cohort 1 
(BRAFv600 wild-type) prior immunotherapy is allowed in the adjuvant setting if 
completed ≥90 days prior to study treatment initiation. Examples of 
immunotherapy include, but are not limited to, nivolumab, pembrolizumab and 
ipilimumab.
–
Any anti-cancer therapy, including chemotherapy, hormonal therapy and 
radiotherapy, is prohibited within two weeks prior to initiation of study treatment

Prior SRT or surgical therapy of ≤10 brain metastases is allowed but prior WBRT is 
not allowed. 

Adverse effects of all prior systemic or local treatment must have either returned to 
baseline or become stable and manageable prior to initiation of study treatment.
General criteria

Willing and able to provide informed consent and have signed the study Informed 
Consent Form

Age 18 years at time of signing Informed Consent Form

Able to comply with the study protocol, in the investigator’s judgment

ECOG Performance Status ≤2

Life expectancy of > 3 months


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
Willing and able to complete health and quality of life questionnaires required by the 
protocol

Adequate hematologic and end-organ function, defined using the following 
laboratory results obtained within 14 days prior to first dose of study treatment with 
the exception of amylase and lipase which may be obtained within 28 days prior to 
study treatment initiation:
–
Absolute neutrophil count ≥1.5 × 109/L without granulocyte colony-stimulating 
factor support
–
White blood cell count ≥2.5 × 109/L
–
Lymphocyte count ≥0.5 × 109/L 
–
Platelet count ≥100 × 109/L without transfusion
–
Haemoglobin ≥90 g/L without transfusion
–
Serum albumin ≥25 g/L 
–
Total bilirubin ≤1.5 × upper limit of normal (ULN)
–
Aspartate transaminase and ALT ≤2.0 × ULN, or for patients with documented 
liver metastases, ≤5.0 ULN 
–
For patients assigned to Cohort 2 only: Amylase and lipase ≤1.5 × ULN
–
Alkaline phosphatase (ALP) ≤2.5 × ULN or, for patients with documented liver 
or bone metastases ALP ≤5 × ULN 
–
Serum creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥40 mL/min on 
the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault 
glomerular filtration rate estimation as follows:
CrCl =
(140 − age) × (weight in kg) (× 0.85 if female)
72 × (serum creatinine in mg/dL)
–
For patients not receiving therapeutic anticoagulation: international normalised 
ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN within 28 
days prior to initiation of study treatment
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
that does not include coumarin anticoagulants, stable INR and stable aPTT 
during the 28 days immediately preceding initiation of study treatment.  

Female patients of childbearing potential and male patients with partners of 
childbearing potential must agree to always use two effective forms of contraception 
including at least one method with a failure rate of 1% per year during the course 
of this study and for at least six months after completion of study therapy.
–
Females of childbearing potential are defined as sexually mature women 
without prior oophorectomy or hysterectomy who have had menses within the 
last 12 months.
–
Females are not considered to be of childbearing potential if amenorrhoeic
for > 12 months and follicle-stimulating hormone (FSH) level ≥ 40 IU/L. For 


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females who have been amenorrhoeic for ≥ 2 years, the requirement for FSH 
measurement at screening will be waived.
–
Examples of effective contraception methods with a failure rate of < 1% per 
year include bilateral tubal ligation and male surgical sterilization; hormonal 
contraceptives that inhibit ovulation; hormone-releasing intrauterine devices; 
and copper intrauterine devices.  A reliable barrier method may be used as the 
second contraceptive method.  Hormonal contraceptive methods must be 
supplemented by a barrier method. Please note that potential interactions 
between vemurafenib and hormonal contraceptives may decrease the 
effectiveness of hormonal contraceptives.
–
Male patients who are surgically sterilized are required to use barrier methods 
of contraception.

Female patients of childbearing potential must agree to refrain from donating eggs 
during the course of the study and for at least 5 months after their final dose of 
atezolizumab 

Male patients must agree to refrain from donating sperm during the course of the 
study and for at least six months after the last dose of cobimetinib
4.1.2
Exclusion Criteria
Patients who meet any of the following cancer-related or general criteria will be excluded 
from study entry:
Cancer-related criteria

Ocular melanoma

Leptomeningeal involvement

Uncontrolled tumour-related pain
Patients requiring narcotic pain medication must be on a stable regimen at start of 
study treatment.
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. Note: indwelling drainage catheters 
(e.g., PleurX®) are allowed.

Prior WBRT treatment for CNS disease

Increasing corticosteroid dose during the seven days prior to initiation of study 
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
Prior treatment with a BRAF or MEK inhibitor 

Major surgical procedure other than for diagnosis within four weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during the 
course of the study 

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster 
ovary cells or to any formulation component of cobimetinib or atezolizumab or, for 
patients assigned to Cohort 2 only, vemurafenib.

Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants 
other than gabapentin, vigabatrin and levetiracetam

Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days 
prior to initiation of study treatment unless the patient has an absolute 
contraindication to the use of non-steroidal anti-inflammatory drugs (NSAIDs) or 
aspirin (i.e., severe allergy or reactive airway disease sensitive to NSAIDs or 
aspirin).

Active malignancy (other than melanoma) or a prior malignancy within the past 
three years
Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma (cuSCC), cervical carcinoma in situ, breast carcinoma in situ, prostate 
cancer in situ or limited stage bladder cancer, and patients with isolated elevation in 
prostate-specific antigen in the absence of radiographic evidence of metastatic 
prostate cancer are eligible for the study.
General criteria

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 baseline

History of clinically significant cardiac dysfunction, including the following:
–
Unstable angina or new-onset angina within three months prior to initiation of 
study treatment
–
Current symptomatic congestive heart failure, defined as New York Heart 
Association Class II or higher
–
Myocardial infarction within three months prior to initiation of study treatment
–
Unstable arrhythmia
–
Left ventricular ejection fraction below the institutional lower limit of normal or 
below 50%, whichever is lower
–
Poorly controlled hypertension, defined as sustained, uncontrolled, 
non-episodic baseline hypertension consistently above 159/99 mmHg despite 
optimal medical management
–
For patients assigned to Cohort 2 only: History of congenital long QT syndrome


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–
For patients assigned to Cohort 2 only: Mean (average of triplicate
measurements) QTc interval corrected using Fridericia’s method (QTcF)
≥480 ms at screening, or uncorrectable abnormalities in serum electrolytes
(sodium, potassium, calcium, magnesium and phosphorus)

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered 
medications

Traumatic injury within two weeks prior to initiation of study treatment

Prior allogeneic stem cell or solid organ transplantation

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 complete list in Appendix 10), 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 from the study) 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 12 months of study treatment initiation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Uncontrolled diabetes or symptomatic hyperglycaemia

Any Grade ≥ 3 haemorrhage or bleeding event within 28 days of study treatment 
initiation

History of stroke, reversible ischemic neurological defect, or transient ischemic 
attack within six months prior to study treatment initiation

Positive human immunodeficiency virus (HIV) test at screening 


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
Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test at screening or a positive quantitative HBV 
DNA test.
If a patient has a negative HBsAg test and a positive total hepatitis B core antibody 
(HBcAb) test at screening, a quantitative HBV DNA test must be performed.  If 
positive, the patient is not eligible.

Patients receiving anti-viral therapy for HBV are not eligible for study enrollment.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test and a positive HCV RNA test at screening

Active tuberculosis

History of severe allergic, anaphylactic or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Severe infection within four weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteraemia, or severe 
pneumonia, or any active infection that, in the opinion of the investigator, could 
impact patient safety

Signs or symptoms of infection within two weeks prior to initiation of study treatment

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

Any psychological, familial, sociological, or geographical condition that may hamper 
compliance with the protocol and follow-up after treatment discontinuation

Pregnancy, breastfeeding, or intention of becoming pregnant during the study. 
Women of childbearing potential must have a negative serum pregnancy test result 
within seven days prior to initiation of study treatment.

Treatment with therapeutic oral or IV antibiotics within two weeks prior to initiation of 
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.

Administration of a live, attenuated vaccine within four weeks prior to initiation 
of study treatment or anticipation of need for such a vaccine during the study

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is shorter, prior 
to study treatment initiation

Treatment with systemic immunosuppressive medications (including, but not limited 
to cyclophosphamide, azathioprine, methotrexate and thalidomide) within two weeks 
prior to study treatment initiation.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 


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corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the 
study.

Treatment with investigational drug within 28 days or 5 half-lives of the drug, 
whichever is longer, prior to initiation of study treatment

For patients to be assigned to Cohort 2 only: anticipated use of any concomitant 
medication during or within seven days prior to initiation of study treatment that is 
known to cause QT prolongation 

Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 
enzyme inducers or inhibitors at least seven days prior to initiation of 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 
Study patients will be assigned to study treatment cohort based on locally determined 
BRAFV600 disease status. Patients with BRAFV600 mutation-positive disease will be 
assigned to treatment with cobimetinib plus atezolizumab and vemurafenib in Cohort 2.
As per the Dear Investigator Letter dated 9 July 2019, no new patients will be enrolled
into Cohort 1.  Ongoing patients in Cohort 1 may continue study treatment as per 
protocol, according to investigator’s medical judgement.
4.3
STUDY TREATMENT
Cobimetinib and atezolizumab are the investigational medicinal products (IMPs) in 
Cohort 1 and cobimetinib, atezolizumab and vemurafenib are the IMPs in Cohort 2. 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e. atezolizumab and cobimetinib in Cohort 1, and 
cobimetinib, atezolizumab and vemurafenib in Cohort 2). 
4.3.1
Study Treatment Formulation, Packaging and Handling
4.3.1.1
Cobimetinib
Cobimetinib will be supplied by the Sponsor as 20-mg, film-coated, immediate-release 
tablets. 
For information on the formulation and handling of cobimetinib, see the pharmacy 
manual and the Cobimetinib Investigator’s Brochure.
4.3.1.2
Atezolizumab
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.


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4.3.1.3
Vemurafenib
Vemurafenib will be supplied by the Sponsor as 240-mg, film-coated tablets.
For information on the formulation and handling of vemurafenib, see the vemurafenib
pharmacy manual and the Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration and Compliance
4.3.2.1
Study Treatment Dosage – Cohort 1
Patients in Cohort 1 will receive cobimetinib and atezolizumab in 28-day treatment 
cycles as outlined in Table 2:
Table 2
Cohort 1 Treatment Regimen 
Cobimetinib:
60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 
1−21 of each 28-day cycle. 
Atezolizumab:
840 mg intravenously (IV) on Days 1 and 15 of each treatment cycle
Study treatment will be continued until investigator-determined disease progression 
according to RECIST v1.1, death, unacceptable toxicity, withdrawal of consent, or 
pregnancy, whichever occurs first. Clinically stable patients who have a favourable 
benefit-risk ratio may continue study treatment beyond progression per RECIST v1.1 if 
pseudoprogression due to the effects of immunotherapy is suspected to have occurred 
or if disease progression is limited to ≤3 intracranial lesions that can be controlled with 
SRT and if all of the criteria listed in Section 4.3.2.3 are met. No change to the 
administration of Cohort 1 study treatment is required during intracranial SRT (if 
applicable).
Study treatment will be discontinued in patients who continue treatment beyond disease 
progression per RECIST v1.1 if clinical deterioration because of disease progression 
occurs at any time subsequently or if persistent disease growth is confirmed on follow-up 
disease assessments performed approximately four weeks later (or sooner if necessary 
e.g., due to clinical progression). The disease status of patients who continued study 
treatment and underwent intracranial SRT will be determined by the investigator 
according to RECIST v1.1 modified by excluding any treated lesions from the sum of 
largest diameters from baseline onwards. 
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
Cohort 1 patients who experience adverse events are provided in Section 5.1.6.1 and in 
the respective Investigator's Brochures.  


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4.3.2.2
Study Treatment Dosage – Cohort 2
Patients in Cohort 2 will receive vemurafenib, cobimetinib and atezolizumab in 28-day 
treatment cycles. Treatment will include a 28-day run-in period wherein patients will 
receive vemurafenib and cobimetinib only. Upon completion of the 28-day run-in period, 
atezolizumab will be added to their treatment regimen. 
Study treatment administration in Cohort 2 is outlined in Table 3:
Table 3
Cohort 2 Treatment Regimen
Cobimetinib
Run-in Period (Cycle 1)
Days 1−21 
60 mg (three tablets of 20 mg each) PO QD
≥Cycle 2
Days 1-21 
60 mg (three tablets of 20 mg each) PO QD
Vemurafenib
Run-in Period (Cycle 1)
Days 1-21 
960 mg (four 240-mg tablets) PO twice daily 
(BID)
Days 22−28 
720 mg dose (three 240-mg tablets) PO BID
≥Cycle 2
Days 1-28 
720 mg dose (three 240-mg tablets) PO BID
Atezolizumab
Run-in Period (Cycle 1)
Not administered during run-in period
≥Cycle 2
Days 1 and 15 
840 mg IV
Study treatment will be continued until investigator-determined disease progression 
according to RECIST v1.1, death, unacceptable toxicity, withdrawal of consent, or 
pregnancy, whichever occurs first. Clinically stable patients who have a favourable 
benefit-risk ratio may continue study treatment beyond progression per RECIST v1.1 if 
pseudoprogression due to the effects of immunotherapy is suspected to have occurred 
or if disease progression is limited to ≤3 intracranial lesions that can be controlled with
SRT and if all of the criteria listed in Section 4.3.2.3 are met. No change to the 
administration of cobimetinib and atezolizumab are required during intracranial SRT (if 
applicable). Caution should be used when administering vemurafenib during SRT and 
standard local treatment practices should be followed. It is recommended that 
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after the procedure. Please refer to Section 5.1.3.10 and to the Vemurafenib 
Investigator’s Brochure for information regarding the risks associated with concomitant 
vemurafenib and radiation treatment.
Study treatment will be discontinued in patients who continue treatment beyond disease 
progression per RECIST v1.1 if clinical deterioration because of disease progression 
occurs at any time subsequently or if persistent disease growth is confirmed on follow-up 
disease assessments performed approximately four weeks later (or sooner if necessary 
e.g., due to clinical progression). The disease status of patients who continued study 
treatment and underwent intracranial SRT will be determined by the investigator 
according to RECIST v1.1 modified by excluding any treated lesions from the sum of 
largest diameters from baseline onwards. 
Any overdose or incorrect administration of any of the study treatments and any adverse 
events associated with an overdose or incorrect study drug administration should be 
reported as described in Section 5.3.5.12. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
Cohort 2 patients who experience adverse events are provided in Section 5.1.6.2 and in 
the respective Investigator's Brochures.
4.3.2.3
Dosing of Study Treatment Beyond Disease Progression 
Study treatment may be continued beyond progression per RECIST v1.1 if 
pseudoprogression due to the effects of immunotherapy is suspected to have occurred 
or if disease progression is limited to ≤3 intracranial lesions that can be controlled with 
SRT. Clinically stable patients in either cohort who have a favourable benefit-risk ratio 
may continue study treatment beyond progression per RECIST v1.1 for either reason if 
all of the following criteria are met: 

Clinically stable patient with evidence of clinical benefit and favourable benefit−risk 
ratio as determined by the investigator 

Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal disease progression

No decline in ECOG Performance Status that can be attributed to disease 
progression

Absence of tumour progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Documented investigator/patient discussion of treatment options alternative to 
continuing study treatment at the time of RECIST v1.1-defined disease progression

Consultation with the Medical Monitor is advised
Study treatment will be discontinued in any patient who continues treatment beyond 
disease progression per RECIST v1.1 if clinical deterioration because of disease 
progression occurs at any time or if persistent disease growth is confirmed on follow-up 


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disease assessments performed approximately four weeks later. Post-progression 
assessments may be conducted sooner if necessary e.g., due to clinical progression. 
The disease status of patients who continued study treatment and underwent intracranial 
SRT will be determined by the investigator according to RECIST v1.1 modified by 
excluding any treated lesions from the sum of largest diameters from baseline onwards.
Note that it is recommended that vemurafenib be interrupted at last one day prior to 
SRT, and to resume at least 1 day after the procedure. 
4.3.2.4
Cobimetinib Administration
Cobimetinib should be taken at the same time every day. It can be taken with or without 
food. Cobimetinib should be swallowed whole with a glass of water and should not be 
chewed, cut, or crushed. If a daily dose of cobimetinib is missed (i.e. is not taken within 
12 hours after the scheduled dosing time), or if vomiting occurs when the dose is taken, 
resume dosing with the next scheduled dose. Missed or vomited doses will not be made 
up.
4.3.2.5
Atezolizumab Administration
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions. For anaphylaxis precautions, see Appendix 11.  
Atezolizumab infusions will be administered per the instructions outlined in Table 4.




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4.3.2.7
Assessment of Compliance
To assess patient compliance with self-administration of cobimetinib in Cohort 1 and 
cobimetinib and vemurafenib in Cohort 2, 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 [Cohort 1] and Appendix 2
[Cohort 2]) 
for assessments of compliance.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (cobimetinib and atezolizumab in Cohort 1 
and cobimetinib, atezolizumab and vemurafenib in Cohort 2) will be provided by the 
Sponsor where required by local health authority regulations. The study site should 
follow all instructions included with each shipment of IMP. The study site will 
acknowledge receipt of IMPs supplied by the Sponsor, by returning the appropriate 
documentation to confirm the shipment condition and content. Any damaged shipments 
will be replaced. The investigator or designee must confirm that appropriate 
temperature conditions have been maintained during transit, either by time monitoring 
(shipment arrival date and time) or temperature monitoring, for all IMPs received and 
that any discrepancies have been reported and resolved before use of the IMPs. All 
IMPs must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions, with access 
limited to the investigator and authorized staff.  
The IMPs will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or be returned to the Sponsor (if supplied by 
the Sponsor) with the appropriate documentation. The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor. The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form.
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.
4.3.4
Continued Access to Cobimetinib, Atezolizumab and
Vemurafenib
The Sponsor will offer continued access to Roche IMPs cobimetinib, atezolizumab and 
vemurafenib 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 Roche IMPs atezolizumab and cobimetinib (Cohort 1 
and Cohort 2 patients) and vemurafenib (Cohort 2 patients only) after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
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
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 Roche IMPs cobimetinib and atezolizumab 
(Cohort 1 and Cohort 2 patients) and vemurafenib (Cohort 2 patients only) after 
completing the study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for metastatic melanoma

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
metastatic melanoma 

Provision of the Roche IMP 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
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from seven days prior to initiation 
of study treatment until 28 days after the last dose of study treatment. All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF). 
4.4.1
Permitted Therapy 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic 
anticoagulation therapy (such as low-molecular-weight heparin at a stable dose level), or 
other allowed maintenance therapy should continue their use. Male and female patients 
of reproductive potential should use highly effective means of contraception (see 
Section 4.1.1). 
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy such as low-molecular-weight 
heparin. Note that coumarin anticoagulants are not permitted during the study.


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
Vaccinations (such as influenza, COVID-19); however, live, attenuated vaccines 
are not permitted (see Section 4.4.5)

Megestrol acetate administered as an appetite stimulant 

Inhaled corticosteroids administered for COPD or asthma

Mineralocorticoids (e.g., fludrocortisone)

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Pain medications as indicated, as per standard practice
In general, investigators should manage a patient’s care (including pre-existing 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.5) as clinically indicated, per local 
standard practice. 
Anti-emetic medications, antidiarrheal medications and hematopoietic growth factors are 
not to be administered prophylactically prior to initiation of study treatment. However, at 
the discretion of the investigator, anti-emetic medications, antidiarrheal medications and 
hematopoietic growth factors may be administered prophylactically per standard local 
practice before the second and subsequent doses of study treatment. In addition, 
premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
Patients who experience infusion-associated symptoms may be treated symptomatically 
with ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice (acetaminophen is 
prohibited for patients in Cohort 2 only - see Section 4.4.5). Serious infusion-associated 
events manifested by dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation or respiratory distress should be managed with supportive 
therapies as clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists; 
see Appendix 11 ).
4.4.2
Cautionary Therapy 
4.4.2.1
Antiplatelet Agents 
Antiplatelet agents should be used with caution during study treatment. 
4.4.2.2
Systemic Corticosteroids, Immunosuppressive Medications,
and TNF-Inhibitors
Systemic corticosteroids, immunosuppressive medications, and TNF-α inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab. If 
feasible, alternatives to these agents should be considered. 


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Corticosteroids administered to control symptoms of cerebral oedema and mass effect 
must be reported in the eCRF. Dosage, frequency, dates of administration and route of 
administration must be recorded in the dedicated eCRF pages.
For treatment of vemurafenib-related adverse events in Cohort 2 (other than 
hepatotoxicity as outlined in Section 5.1.5.2), systemic corticosteroids may be 
administered at the lowest effective dose and for the shortest possible duration deemed 
necessary by the investigator.
Topical corticosteroids are allowed for suspected cutaneous autoimmune reactions. 
Megestrol may be administered as an appetite stimulant during the study. In situations in 
which systemic corticosteroids, immunosuppressive medications, or TNF-α inhibitors 
would be routinely administered, alternatives, including antihistamines, should be 
considered. If the alternatives are not feasible, systemic corticosteroids, 
immunosuppressive medications, and TNF-α inhibitors may be administered at the 
discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to the Atezolizumab Investigator's Brochure
for details).
4.4.2.3
Bisphosphonates 
Patients who are receiving bisphosphonates to enrollment should be maintained on 
bisphosphonate during study treatment. Initiation of bisphosphonates is discouraged 
during study treatment because of their potential immunomodulatory properties. 
However, initiation of such treatment should not result in study treatment discontinuation.
4.4.2.4
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
Cautionary therapies applicable to patients receiving cobimetinib (Cohorts 1 and 2):

Concomitant use of strong and moderate inhibitors of CYP3A (e.g., clarithromycin, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) should 
be avoided during cobimetinib treatment because 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). 

Strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine,
and phenobarbital) should be avoided during cobimetinib treatment because 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.


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Cautionary therapies applicable to patients receiving vemurafenib (Cohort 2 only):

Vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer. Concomitant 
use of vemurafenib with agents with a narrow therapeutic window that are 
metabolized by CYP1A2 and CYP3A4 is not recommended. If co-administration 
cannot be avoided, exercise caution, as vemurafenib may increase plasma 
exposure of CYP1A2 substrate drugs and decrease plasma exposure of CYP3A4 
substrate drugs. Dose reduction of the concomitant CYP1A2 substrate drug may be 
considered, if clinically indicated. Acetaminophen is a CYP1A2 substrate and is 
prohibited for patients in Cohort 2 (see Section 4.4.5). 

In two drug-drug interaction studies, vemurafenib increased the exposure of a 
single, oral dose of digoxin. An approximate 1.8- and 1.5-fold increase in digoxin 
area under the concentration-time curve (AUC) from Time 0 to the last measurable 
concentration and maximum concentration, respectively, was observed in a prior 
study (Study GO28394). Digoxin and other p-glycoprotein substrates with a narrow 
therapeutic window are prohibited within seven days prior to initiation of 
vemurafenib, during vemurafenib treatment, and for 28 days after the last dose of 
vemurafenib. 

In vitro data have demonstrated that vemurafenib is a moderate inhibitor of 
CYP2C8. CYP2C8 substrates with a narrow therapeutic window should be used 
with caution, as their concentration may be increased when co-administered with 
vemurafenib. 

In vitro data have demonstrated that vemurafenib is a substrate of CYP3A4. Thus, 
strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfainavir, 
voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital) should be used with caution when co-administered with 
vemurafenib
The above lists of medications are not necessarily comprehensive. The investigator 
should consult the prescribing information when determining whether a concomitant 
medication can be safely administered with study treatment.  In addition, the Medical 
Monitor is available to advise if questions arise regarding medications not listed above.
4.4.2.5
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, herbal therapies not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator.
4.4.2.6
Medications Affecting the QT Interval – Cohort 2 Only
Caution should be exercised when Cohort 2 study treatment is co-administered with 
drugs that cause QT prolongation or cardiac arrhythmia, especially in patients with a 
pre-existing cardiac disease or ECG abnormality that may predispose them to cardiac 
dysrhythmia. Investigators should closely monitor patients who are on medications or 


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supplements that may affect the QT interval. Alternative treatment options for 
medications known to affect QT interval should be discussed with each patient prior to 
their enrollment in this study. Additional information is available at the following Internet 
site: 
https://crediblemeds.org/healthcare-providers/
The effect of vemurafenib 960 mg BID on QT interval was evaluated in a multicentre, 
open-label, single-arm study in 132 previously-treated patients with BRAFV600
mutation−positive metastatic melanoma (Study NP22657). No large changes from 
baseline in mean QTc interval (i.e., > 20 ms) were detected in the study. However, 
vemurafenib is associated with concentration-dependent QT prolongation. 
Although nonclinical studies showed a low potential for QT-interval prolongation with 
cobimetinib, no additive effect on QT-interval prolongation was observed when patients 
were treated with cobimetinib in combination with vemurafenib in Study GO28141. A 
combined cobimetinib and vemurafenib concentration-QTcF model (for which 
433 patients contributed 1031 cobimetinib and vemurafenib observations) provided no 
evidence that cobimetinib prolonged QTcF interval when co-administered with 
vemurafenib.
4.4.3
Stereotactic Radiation in Cohort 2
Stereotactic radiation is permissible as described in Section 4.3.2.3. Due to vemurafenib 
radiation recall and radiation sensitization (see Section 5.1.3.10), caution should be used 
when giving vemurafenib concomitantly or sequentially with radiation treatment.
4.4.4
Cautionary Food
Due to a possible increased risk of liver toxicity, the consumption of alcohol during study 
treatment is not recommended.
4.4.5
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Other than SRT as described in Section 4.3.2.3, concomitant therapy intended for 
the treatment of cancer (including, but not limited to, chemotherapy, hormonal 
therapy, immunotherapy, radiotherapy for palliative or other purposes, 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), and during study treatment.

Investigational therapy is prohibited within 28 days (or 5 half-lives of the drug, 
whichever is longer), prior to initiation of study treatment and during study treatment.

Anti-emetic medications, antidiarrheal medications and hematopoietic growth 
factors are not to be administered prophylactically prior to initiation of study 
treatment. 


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
Anti-arrhythmic agents and medications with a risk of torsades de pointes are 
prohibited within seven days prior to initiation of study treatment, during study 
treatment, and for 28 days after the last dose of study treatment. 

Denosumab (a RANKL inhibitor) is prohibited during atezolizumab treatment 
because it could potentially alter the efficacy and safety of atezolizumab. Patients 
who are receiving denosumab prior to enrollment must be willing and eligible to 
receive a bisphosphonate instead while in the study. 

Live, attenuated vaccines (e.g., FluMist) are prohibited within four weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the last dose of atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 28 days or 5 half-lives of the drug (whichever is longer)
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab.

St. John's wort is prohibited during study treatment and for two weeks after the last 
dose of cobimetinib or vemurafenib (whichever is later)

Coumarin anticoagulants are prohibited during study treatment

For patients in Cohort 2 only, acetaminophen is prohibited within seven days prior to 
initiation of study treatment, during study treatment, and for 28 days after the last 
dose of study treatment, unless the patient has an absolute contraindication to the 
use of NSAIDs or aspirin (i.e., severe allergy or reactive airway disease sensitive to 
NSAIDs or aspirin). See Section 4.4.2.4.
4.4.6
Prohibited Food
Use of grapefruit juice, a potent CYP3A4 enzyme inhibitor, is prohibited during the study 
and for 30 days after the last dose of study treatment. 
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
(Cohort 1) and Appendix 2 (Cohort 2). 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.
Safety assessments specified in this section are for the purposes of monitoring and 
management of toxicities known to be associated with the study treatment included in 
this study (see Section 5.1 for further information).


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before any 
study-specific screening procedure is performed. All signed Informed Consent Forms
(i.e., including for those patients not subsequently enrolled) will be maintained at the 
study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. The investigator will maintain a detailed record of 
all patients screened and will document eligibility or record reasons for screening 
failure, as applicable.
Screening Window and Screening Window Extension
All screening assessments must be performed within 28 days prior to study treatment 
initiation. Exceptionally, results of standard-of-care tests or examinations performed 
before obtaining informed consent and within 28 days prior to study treatment initiation 
may be used for screening assessments; such tests do not need to be repeated for 
screening.
The screening window may be extended for an agreed upon and acceptable period to 
allow re-evaluation of assessments at the investigator’s discretion.
Re-screening
Re-screening may be allowed in certain cases (e.g., patients not initially enrolled due to 
an aberrant laboratory value, washout of a prior medication, unavailability of study drug, 
or inability to complete screening within the screening window). Such patients cannot 
have been previously enrolled in the study nor have received study treatment. Patients 
may be re-screened only once for the study.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases and surgeries within five years 
prior to initiation of study treatment, cancer history (including prior cancer therapies, 
surgeries, and procedures), 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 treatment will be recorded. At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. 
Demographic data will include age, sex and self-reported race/ethnicity (where 
permissible).


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4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, throat (HEENT), neck, and 
the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary and neurological systems. HEENT examination should include visual 
inspection and/or palpation of the oral cavity and oropharynx, and palpation of the 
draining lymph nodes of the neck. Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations, consisting of an evaluation of the oral 
cavity, oropharynx, head and neck (including lymph nodes), lungs, heart, abdomen and 
skin, should be performed at specified post-baseline visits and as clinically indicated. 
Patients should be asked specifically about skin and vision changes as part of each 
physical examination. Changes from baseline abnormalities should be recorded at each 
subsequent physical examination. New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
As part of tumour assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly and splenomegaly.
4.5.4
Vital Signs
Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure and 
temperature. Blood pressure and heart 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.
Vital signs should be measured within 60 minutes prior to each atezolizumab infusion 
and, if clinically indicated, during or after the infusion. In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities (see 
Appendix 1 and Appendix 2).
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.
Weight and height will be measured at the timepoints specified in the schedule of 
activities (see Appendix 1 and Appendix 2).
4.5.5
ECOG Performance Status
See Appendix 4
4.5.6
Tumour and Response Evaluations
All measurable and non-measurable lesions must be documented at screening (within 
28 days prior to initiation of study treatment). Previously irradiated lesions should not be 


selected as measurable (target) lesions. Tumour assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening. All measurable and evaluable lesions 
should be re-assessed at each subsequent tumour evaluation. Intracranial and 
extracranial tumour assessments after end of Cycle 2 should be conducted every 
8 weeks ± 1 week regardless of study treatment delays through 24 months and then 
every 12 weeks ± 1 week thereafter until confirmed disease progression per RECIST 
v1.1, initiation of a new anti-cancer treatment, withdrawal of consent, study termination 
by the Sponsor or death, whichever occurs first.
Tumour assessments must be performed independently of changes to the study 
treatment administration schedule (i.e. when treatment is withheld). If a tumour 
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. 
Tumour assessments are to continue according to schedule in patients who discontinue 
treatment for reasons other than disease progression (unless subsequent anti-cancer 
therapy is initiated). 
Intracranial disease must be followed by MRI. Extracranial tumour 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. If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed along with MRI scans of the abdomen, pelvis and head. 
In the event a positron emission tomography (PET)/CT scanner is used for tumour 
assessments, the CT portion of the PET/CT must meet criteria for diagnostic quality. 
Clinical disease assessments by physical examination should be performed for patients 
with palpable/superficial lesions. Tumour measurements for each patient should be 
made by the same investigator or radiologist, if feasible, ideally using the same 
assessment technique or procedure throughout the study. Results must be reviewed by 
the investigator before dosing at the next cycle.
Disease status will be determined according to RECIST v1.1 (see Appendix 5) with a 
modified measurability definition for intracranial lesions (≥ 0.5 cm by MRI) and allowing 
up to five intracranial target lesions (in addition to any extracranial target lesions). 
Exploratory analyses of disease status will include evaluations by immune-modified 
RECIST (see Appendix 6), RECIST v1.1 modified by excluding any SRT lesions from 
the sum of largest diameters from baseline onwards (if applicable), and iRANO criteria 
(see Appendix 7).
Disease responses for all endpoints will be confirmed by two consecutive assessments 
at least four weeks apart. Tumour assessments showing disease progression must be 
repeated approximately four weeks later regardless of whether treatment is continued 
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beyond progression. If disease progression is not confirmed, the subsequent tumour 
assessment should occur at least four weeks later. However, post-progression 
assessments may be conducted sooner for patients continuing study treatment beyond 
progression if necessary e.g., due to clinical progression. Objective response (CR or PR) 
must be confirmed by repeat assessments ≥4 weeks after initial documentation. In the 
case of SD, tumour measurements must meet criteria for SD ≥6 weeks after initiation of 
study treatment.
Disease status for the primary endpoint will be determined by an IRC. Disease status for 
the purposes of treatment decisions will be determined by the investigator. All other 
efficacy endpoints will be analysed according to investigator disease status 
determinations.
4.5.7
Study-Specific Safety Monitoring Assessments (Cohorts 1 and 
2)
4.5.7.1
Ophthalmologic Examinations
Patients will undergo ophthalmologic examinations at specified timepoints during the 
study. Patients will be evaluated at screening for risk factors for neurosensory retinal 
detachment, RVO, or neovascular macular degeneration. Risk factors for RVO include 
history of serous retinopathy or history of RVO, or evidence of ongoing serous 
retinopathy or RVO at baseline. Patients with such conditions will be excluded from the 
study as detailed in Section 4.1.2. 
Ophthalmologic examinations will include visual acuity testing, intraocular pressure 
measurements by tonometry, slit-lamp ophthalmoscopy, indirect ophthalmoscopy, and 
spectral domain optical coherence tomography (OCT). If spectral domain OCT is not 
available, time-domain OCT may be performed instead. Ophthalmologic examination 
must be performed by a qualified ophthalmologist.
4.5.7.2 
Cardiac Monitoring
Evaluation of Left Ventricular Function 
Patients will undergo evaluation of left ventricular ejection fraction (LVEF), either by 
ECHO or MUGA, at specified timepoints during the study, and as clinically indicated for 
new or worsening symptoms. Any patient who develops clinical signs or symptoms 
suspicious of cardiac failure should undergo an LVEF assessment. Evaluation of left 
ventricular function must be performed using the same method for each patient. 
Guidelines for management of symptomatic or asymptomatic decreased LVEF are 
provided in Sections 5.1.6.4 (Cohort 1) and 5.1.6.5 (Cohort 2). All patients who restart 
treatment with a reduced dose of cobimetinib because of a decrease in LVEF, should 
have LVEF measurements taken more frequently as per Appendix 1 (Cohort 1) or 
Appendix 2 (Cohort 2) before resuming regular LVEF monitoring every 12 weeks 
(three cycles).  
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
Skin examination for cuSCC, BCC, actinic keratosis, keratoacanthoma (KA), and/or 
second primary melanoma 

Appropriate mapping of any suspicious lesions that may represent cuSCC, BCC, 
actinic keratosis, KA, or second primary melanoma 

Biopsy and/or excision of any suspicious lesions and submission of specimen 
blocks or sections for pathologic examination by the local laboratory including the 
local pathology report if available

Treatment of identified skin neoplasms or conditions per local standard of care
Head and Neck Examination 
To monitor for the occurrence of squamous cell carcinoma (SCC) in the upper 
aerodigestive tract, a head and neck examination will be performed by the investigator or 
his or her designee at screening, specified timepoints during the study, and as clinically 
indicated (e.g., if any new head and neck lesions are suspected of being non-cuSCC). 
Assessments will include (at a minimum) examination of the HEENT and neck, visual 
inspection of the oral mucosa and lymph node palpation. 
Any suspicious lesions that are identified will be evaluated according to local standard of 
care and biopsied or excised if indicated. Specimens must be sent for pathological 
examination, and appropriate follow-up must be instituted.
Lung Examination 
Patients will undergo CT or MRI scans of the chest to monitor for the occurrence of lung 
SCC. The chest CT or MRI scans performed as part of regularly scheduled tumour 
assessments may be used for lung SCC surveillance.
Anal Examination 
To monitor for anal SCC, visual inspection and digital examination of the anus and anal 
canal will be performed by the investigator or his or her designee at specified timepoints 
during the study and as clinically indicated. Colonoscopy, sigmoidoscopy, or anoscopy is 
not required but may be performed if clinically indicated. Any suspicious lesions that are 
identified will need to be evaluated according to local standard of care and biopsied if 
indicated. 
Gynaecological Examination 
To monitor for cervical carcinoma, all female patients will undergo a pelvic examination, 
including visual inspection of the uterine cervix and Papanicolaou (Pap) smear, at 
specified timepoints during the study and as clinically indicated. Pelvic examinations 
performed within 12 months prior to screening need not be repeated if found to be 
normal.


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4.5.9
Laboratory, Biomarker and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 

BRAFV600 mutation status determined in tumour tissue by a validated genetic test 

Haematology: white blood cell count, red blood cell count, haemoglobin, 
haematocrit, reticulocyte count, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).

Chemistry panel (serum or plasma): sodium, potassium, magnesium, chloride, 
bicarbonate or total carbon dioxide (bicarbonate and total carbon dioxide are not 
mandatory if unavailable at site), glucose (non-fasting), BUN or urea, creatinine, 
albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, lactate 
dehydrogenase and CPK, amylase and lipase.

Both blood glucose and lipid panel must be obtained after at least an 8-hour fast, at 
screening only. Lipid panel should include total cholesterol, low-density lipoprotein 
and triglycerides.

Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria).

Coagulation: INR, aPTT 

Thyroid function testing: thyroid-stimulating hormone, free T3 (or total T3 for sites 
where free T3 is not performed), free thyroxine. 

HBV serology: HBsAg, hepatitis B surface antibody, total HBcAb. If a patient has a 
negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test 
should be performed at screening.

HCV serology: HCV antibody and (if HCV antibody test is positive) HCV RNA. If a 
patient has a positive HCV antibody test at screening, an HCV RNA test must also 
be performed to determine if the patient has an active HCV infection.

HIV serology 

Pregnancy test: All women of childbearing potential will have a negative serum 
pregnancy test within seven days prior to initiation of study treatment. Urine 
pregnancy tests (serum pregnancy test if urine test is not available) will be 
performed at specified subsequent visits. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.
Females of childbearing potential are defined as sexually mature women without 
prior oophorectomy or hysterectomy who have had menses within the last 
12 months. Females are not considered to be of childbearing potential if 
amenorrhoeic for > 12 months and FSH level ≥40 IU/L. For females who have been 
amenorrhoeic for ≥2 years, the requirement for FSH measurement at screening will 
be waived.


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The following samples will be sent to one or several central laboratories or to the 
Sponsor for analysis: 

Formalin-fixed paraffin embedded tumour tissue block or 10 consecutively cut 
sections from the primary tumour or a metastatic lesion (decalcified tissue is not 
allowed) obtained any time prior to entry in this study (e.g., archival material).

Two 10 mL whole blood for plasma obtained at baseline and again at the time of 
disease progression.
Analyses at central laboratories will include assessment of PD-L1 protein expression 
and targeted NGS of cancer-related genes (including but not limited to BRAF and 
NRAS) to evaluate the relationship between molecular biomarkers and clinical efficacy 
parameters. 
Next-generation sequencing will be performed in collaboration with University Hospital 
Zurich. The investigator can obtain results from these analyses in the form of an NGS 
report. If allowed by local laws, the investigator may share and discuss the results with 
the patient, unless the patient chooses otherwise. The NGS report is generated for 
research purposes and is not provided for the purpose of guiding future treatment 
decisions.
For sampling procedures, storage conditions and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
no later than five years after the final Clinical Study Report has been completed, with the 
following exception:

Formalin-fixed paraffin embedded tissue blocks will be returned to the site upon 
request or 18 months after final closure of the study database, whichever occurs 
first.  
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analysed, 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 these analyses will be subject to the 
confidentiality standards described in Section 8.4.
4.5.10
Patient-Reported Outcomes
To more fully characterize disease burden and clinical benefit of study treatment in 
patients with BRAFV600 mutation-positive or negative melanoma with CNS metastases, 
PRO data will be obtained through the EORTC QLQ-C30 and QLQ-BN20
questionnaires. Paper versions of the questionnaires will be used, and the 
questionnaires will be translated as appropriate in the local language. 




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4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.12) will not be 
applicable at that site.
4.5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to cobimetinib, 
atezolizumab, vemurafenib or diseases:

remaining plasma or derivatives thereof (such as DNA)

left over cut sections of tumour tissue or derivatives thereof (such as DNA)
The above samples may be sent to one or more laboratories for analysis of germline or
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), NGS, or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 


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opportunity for developing new therapeutic approaches. Data will be analysed in the 
context of this study but will also be explored in aggregate with data from other studies. 
The availability of a larger dataset will assist in identification of important biomarkers and 
pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted. However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.12.4
Confidentiality
Specimens and associated data will be labelled with a unique patient identification 
number.
Patient medical information associated with RBR specimens 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.
Given the complexity and exploratory nature of the analyses of RBR specimens, 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 Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorized designee will explain to each patient the 
objectives, methods and potential hazards of participation in the RBR. Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period. A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.


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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason. However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data. If a patient wishes to withdraw consent to the testing of his or her 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the RBR Research Sample Withdrawal of 
Informed Consent eCRF. The patient will be provided with instructions on how to 
withdraw consent after the trial is closed. A patient's withdrawal from Study MO39136
does not, by itself, constitute withdrawal of specimens from the RBR. Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study MO39136.
4.5.12.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor. The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment (cobimetinib, atezolizumab ±
vemurafenib) if they experience any of the following:

Confirmed disease progression per investigator assessment according to RECIST 
v1.1 
Note: Study treatment may be continued beyond progression per RECIST v1.1 if 
pseudoprogression due to the effects of immunotherapy is suspected to have 
occurred or if disease progression is limited to ≤3 intracranial lesions that can be 
controlled with SRT. Patients considered for continuation beyond progression per 
RECIST v1.1 must meet criteria described in Section 4.3.2.3. However, study 
treatment will be discontinued in patients who continue treatment beyond disease 


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progression per RECIST v1.1 if persistent disease growth is confirmed on follow-up 
disease assessments performed approximately four weeks later (or sooner if 
necessary e.g., due to clinical progression). The disease status of patients who 
continued study treatment and underwent intracranial SRT will be determined by the 
investigator according to RECIST v1.1 modified by excluding any treated lesions 
from the sum of largest diameters from baseline onwards.

Clinical deterioration due to disease progression 
Note: patients who continued study treatment beyond documented disease 
progression must also discontinue study treatment if clinical deterioration because 
of disease progression occurs at any time

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any adverse event that requires study treatment discontinuation including as per the 
guidelines in Section 5.1

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues study treatment

Investigator or Sponsor determines it is in the best interest of the patient (e.g., 
unwillingness to comply with study assessments that compromise their safety)

Withdrawal of consent

Use of an anti-cancer therapy (outside of study treatment per protocol)

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will attend a Study Treatment Discontinuation Visit after 28 ± 7 days of their last 
study treatment dose. All adverse events will be reported until 30 days after the last 
study treatment dose. After the Study Treatment Discontinuation Visit, patients who have 
not yet progressed will be followed every 8 or 12 weeks for disease status until disease 
progression has been confirmed. Survival, PROs and anti-cancer treatments will be 
collected via telephone calls and/or clinic visits every three months until death, loss to 
follow-up, or study termination by the Sponsor.
4.6.2
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

Patient non-compliance, defined as failure to comply with protocol requirements as 
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
Study termination or site closure
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. If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 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.
4.6.3
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, 
atezolizumab and vemurafenib in completed and ongoing studies. The anticipated 
important safety risks are outlined below (see Section 5.1.1 for cobimetinib, Section
5.1.2 for atezolizumab, Section 5.1.3 for vemurafenib, and Sections 5.1.4 and 5.1.5 for 
combination use). Cohort-specific guidelines for dose modifications and treatment 
interruption, as well as management of patients who experience specific adverse events, 
are provided in Section 5.1.6. 


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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. 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. Cobimetinib and 
vemurafenib will be dispensed with instructions for appropriate self-administration 
including handling of missed doses. Adverse events will be reported as described in 
Sections 5.2-5.7. 
Patients with active infection are excluded from study participation. In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020). If a 
patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or 
radiologic evaluations per investigator judgment. If a diagnosis of SARS-CoV-2 
infection is confirmed, the disease should be managed as per local or institutional 
guidelines.
During the study, a Medical Monitor and the IMC will be responsible for ongoing safety 
oversight. In addition, a safety interim analysis will be performed by the Sponsor and 
reviewed by the IMC once at least 10 patients per cohort have completed their first 
tumour assessment. The analysis will be conducted by the Sponsor according to the 
Sponsor’s standard operating procedures for safety reviews. The conduct of all IMC 
reviews and meetings will be as described in the IMC charter.
5.1.1
Risks Associated with Cobimetinib
The following adverse events are classified as identified risks associated with 
cobimetinib: serous retinopathy, left ventricular dysfunction, photosensitivity (when 
administered with vemurafenib), severe haemorrhage, rhabdomyolysis and pneumonitis. 
The following adverse events are classified as potential risks for cobimetinib: severe 
hepatotoxicity (Grade ≥ 3), impaired female fertility, and teratogenicity and 
developmental toxicity. In addition, there is the possibility of drug-drug interactions in 
patients treated with cobimetinib (see Section 4.4 for details). Refer to Section 6 of the 
Cobimetinib Investigator's Brochure for a detailed description of all anticipated risks for 
cobimetinib.
Guidelines for management of patients who develop specific adverse events associated 
with cobimetinib are provided in Sections 5.1.6.4 (Cohort 1) and 5.1.6.5 (Cohort 2).


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5.1.1.1
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK inhibitors, including cobimetinib. Manifestations of serous 
retinopathy include visual disturbances, findings of retinal detachment and retinopathy. 
Serous retinopathy events may also be asymptomatic. 
To address serous retinopathy with cobimetinib treatment, all patients are required to 
undergo a baseline ophthalmologic examination to evaluate for risk factors for 
neurosensory retinal detachment, RVO, or neovascular macular degeneration. Patients 
will also undergo complete ophthalmologic examinations at specified timepoints 
throughout the study and as clinically indicated if a patient notes any visual disturbances. 
Details regarding baseline and subsequent ophthalmologic examinations are provided in 
Section 4.5.7.1. 
5.1.1.2
Left Ventricular Dysfunction
Decrease from baseline in left ventricular ejection fraction has been reported in patients 
receiving cobimetinib. Decreased left ventricular ejection fraction may be symptomatic or 
asymptomatic. 
All patients will undergo evaluation of left ventricular ejection fraction, either by 
echocardiography or multigated acquisition scan at baseline, at specified timepoints 
during treatment, at the end of treatment, and as clinically indicated. 
5.1.1.3
Photosensitivity (When Administered with Vemurafenib)
No evidence of photosensitivity has been observed with cobimetinib as a single agent. 
However, photosensitivity has been observed when cobimetinib was given in 
combination with vemurafenib. 
5.1.1.4
Pneumonitis 
Events of pneumonitis have been reported in cobimetinib clinical studies. Most reported 
events were reported as non-serious and a lower severity (grade). 
5.1.1.5
Rhabdomyolysis 
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents. The majority of CPK 
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, and rhabdomyolysis has been reported in post-marketing experience. CPK 
will be monitored at baseline and monthly during treatment or as clinically indicated. 
5.1.1.6
Haemorrhage 
Haemorrhage, including major haemorrhages defined as symptomatic bleeding in a 
critical area or organ, can occur with cobimetinib. In clinical studies with cobimetinib, 
events of cerebral haemorrhage, gastrointestinal tract haemorrhage, reproductive tract 
haemorrhage and haematuria, have been reported.


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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). Coumarin anticoagulants are 
not permitted during the study.
5.1.1.7
Severe Hepatotoxicity (Grade ≥ 3) 
Liver laboratory test abnormalities, including increases in ALT, AST and ALP, have been 
reported as adverse events and SAEs 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. 
5.1.1.8
Impaired Female Fertility 
Results from nonclinical studies indicate that there is a potential for effects on female 
fertility. While no dedicated fertility studies have been conducted with cobimetinib in 
animals, degenerative changes were observed in reproductive tissues of dogs. These 
changes were reversible upon discontinuation of cobimetinib. 
5.1.1.9
Teratogenicity and Developmental Toxicity 
There are no data regarding the use of cobimetinib in pregnant women. When 
cobimetinib was administered to pregnant rats, cobimetinib caused embryolethality and 
foetal malformations of the great vessels and skull at similar systemic exposures to 
those observed in patients administered the 60-mg dose. Therefore, teratogenicity and 
developmental toxicity is a potential risk for cobimetinib, and cobimetinib use is not 
recommended during pregnancy.
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following: IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis,
myocarditis, 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 
Appendix 14 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab. 


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Guidelines for management of patients who develop specific adverse events associated 
with atezolizumab are provided in Sections 5.1.6.4 (Cohort 1) and 5.1.6.5 (Cohort 2).
5.1.3
Risks Associated with Vemurafenib
The following adverse events are classified as identified risks associated with 
vemurafenib: cuSCC, new primary melanoma, progression of RAS-mutant malignancy, 
photosensitivity and sunburn, liver injury, QT prolongation, hypersensitivity and severe 
cutaneous reactions, uveitis, VIIth nerve paralysis, radiation recall and radiation 
sensitization and acute kidney injury. The following adverse events are classified as 
potential risks for vemurafenib: non-cuSCC, bone marrow toxicity, drug-drug interaction, 
second primary malignancy, gastrointestinal polyps and RVO. In addition, neutropenia,
pancreatitis, Dupuytren’s contracture and plantar fascial fibromatosis have been 
identified as adverse drug reactions in the post-marketing setting. Descriptions of 
identified risks and selected other risks are provided below. Refer to Section 6 of the 
Vemurafenib Investigator's Brochure for a detailed description of all identified and 
potential risks for vemurafenib, including adverse drug reactions in the post-marketing 
setting.
Guidelines for management of patients who develop specific adverse events associated 
with vemurafenib are provided in Section 5.1.6.5.
5.1.3.1
Cutaneous Squamous Cell Carcinoma and New Primary 
Melanoma 
Cases of cuSCC, which include those classified as keratoacanthomas or mixed 
keratoacanthoma subtype, have been reported in patients treated with vemurafenib, 
usually early in the course of treatment. Potential risk factors associated with cuSCC in 
three vemurafenib clinical trials included age (≥ 65 years), prior skin cancer and chronic 
sun exposure. Cases of new primary malignant melanoma have also been reported in 
patients treated with vemurafenib. Cutaneous SCC and new primary malignant 
melanoma were managed with excision, and patients were able to continue treatment 
without dose adjustment. 
For patients in Cohort 2, evaluations of the skin by a dermatologist, or qualified 
equivalent medical specialist, will be performed at specified timepoints during the study 
(see Section 4.5.8.1 for details). All new primary neoplasms, including new primary 
melanoma, will be reported until six months after the last dose of vemurafenib. 
5.1.3.2
Non-Cutaneous Squamous Cell Carcinoma 
Cases of SCC of the head and neck have been reported in patients treated with 
vemurafenib. 
To monitor for the occurrence of SCC, Cohort 2 patients will undergo a head and neck 
examination, CT or MRI scans of the chest, and visual inspection and digital examination 
of the anus and anal canal at specified timepoints during the study. To monitor for 


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cervical carcinoma, all female patients in Cohort 2 will undergo a pelvic examination, 
including visual inspection of the uterine cervix and Papanicolaou smear, at specified 
timepoints during the study. See Section 4.5.8.1 for details of monitoring assessments. 
All new primary neoplasms will be reported until six months after the last dose of 
vemurafenib.
5.1.3.3
RAS-Mutant Malignancies 
On the basis of its mechanism of action, vemurafenib may cause progression of cancers 
associated with RAS mutations. In addition, progression of pre-existing RAS-mutant 
malignancies (chronic myelomonocytic leukaemia, pancreatic cancer) have been 
reported in patients treated with vemurafenib. Vemurafenib should be used with caution 
in patients with a prior or concurrent cancer associated with RAS mutation.
5.1.3.4
Photosensitivity and Sunburn 
Mild to severe skin photosensitivity has been reported in patients treated with 
vemurafenib. All patients should be advised to minimize sun exposure, wear protective 
clothing, and use a broad-spectrum ultraviolet A/ultraviolet B sunscreen and lip balm 
(SPF ≥ 30), reapplied every 2 to 3 hours, when outdoors during vemurafenib treatment 
and for at least 5−10 days after discontinuing vemurafenib. 
5.1.3.5
Liver Injury 
Liver injury, including cases of severe liver injury, have been reported in patients treated 
with vemurafenib. ALP, ALT, AST and bilirubin will be monitored at specified timepoints 
throughout the study. 
5.1.3.6
QT Prolongation 
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label 
Phase II QT sub-study in patients with metastatic melanoma. QT prolongation may lead 
to an increased risk of ventricular arrhythmias, including torsades de pointes. 
Patients with a history of congenital long QT syndrome, QTcF ≥ 480 ms, or 
uncorrectable abnormalities in serum electrolytes will be excluded from study inclusion. 
ECG and electrolytes, including potassium, magnesium and calcium, will be monitored 
throughout the study. In addition, investigators should closely monitor patients who are 
on medications or supplements that may affect the QT interval. Alternative treatment 
options for medications known to affect QT interval should be discussed with each 
patient prior to their enrollment in this study. 
5.1.3.7
Hypersensitivity and Severe Cutaneous Reactions 
Serious hypersensitivity reactions, including anaphylaxis, have been reported in 
association with vemurafenib and upon re-initiation of treatment. Severe hypersensitivity 
reactions included generalized rash and erythema or hypotension. Drug reaction with 
eosinophilia and systemic symptoms has been reported in association with vemurafenib 
in the post-marketing setting. Severe dermatologic reactions have been reported in 


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patients receiving vemurafenib, including cases of Stevens-Johnson syndrome and toxic 
epidermal necrolysis. 
5.1.3.8
Uveitis and Retinal Vein Occlusion 
Serious ophthalmologic reactions, including uveitis, have been reported in patients 
treated with vemurafenib. Retinal vein occlusion has been observed and is a potential 
risk. 
Patients will under ophthalmologic examinations at specified timepoints during the study 
(see Section 4.5.7.1). Patients will be evaluated at screening for risk factors for 
neurosensory retinal detachment, RVO, or neovascular macular degeneration. Risk 
factors for RVO include history of serous retinopathy or history of RVO, or evidence of 
ongoing serous retinopathy or RVO at baseline. Patients with such conditions are
excluded from the study. 
5.1.3.9
VIIth Nerve Paralysis 
Cases of VIIth nerve paralysis have been observed in patients treated with vemurafenib. 
In clinical trials, these events resolved without sequelae. 
5.1.3.10
Radiation Recall and Radiation Sensitization 
An adverse drug reaction of potentiation of radiation treatment toxicity has been 
identified in patients treated with radiation prior to, during, or subsequent to vemurafenib 
treatment. The nature and severity were evaluated as worse than expected for the 
normal tissue tolerance to therapeutic radiation. The reaction was seen in the skin, 
oesophagus, lung, liver, rectum and urinary bladder. Most cases were cutaneous in 
nature, but some cases involving visceral organs had fatal outcomes. Further details of 
radiation recall and sensitization events are provided in the current Vemurafenib 
Investigator’s Brochure. Vemurafenib should be used with caution when given 
concomitantly or sequentially with radiation treatment. Radiation therapy should not be 
administered unless the possible benefits outweigh the possible risks.
It is recommended that vemurafenib be interrupted at least one day prior to SRT, and to 
resume at least 1 day after the procedure. 
Other than SRT applicable as described in Section 4.3.2.3, radiotherapy is not permitted 
during the study.
5.1.3.11
Acute Kidney Injury and Renal Function Alterations 
Acute kidney injury, including interstitial nephritis, has been observed in patients treated 
with vemurafenib. The majority of these cases have been characterized by mild to 
moderate increases in serum creatinine (some observed in the setting of dehydration 
events), with recovery after dose modification. 
Serum creatinine will be monitored throughout the study. Vemurafenib acute kidney 
injury dose modification guidelines should be utilized when applicable and it is 


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recommended to routinely monitor serum creatinine levels in all patients undergoing 
vemurafenib therapy.
5.1.3.12
Drug-Drug Interaction 
Drug-drug interactions are a potential risk for vemurafenib. Prohibited therapies and food 
and cautionary therapies are described in Section 4.4. 
5.1.3.13
Gastrointestinal Polyps 
Rare cases of colonic polyps have been reported in patients treated with vemurafenib for 
two or more years while enrolled in a clinical study (Chapman et al. 2012). 
5.1.3.14
Neutropenia 
Neutropenia has been identified as an uncommon adverse drug reaction associated with 
the use of vemurafenib, typically occurring during the first 6−12 weeks of treatment. It 
appears to be reversible usually within two weeks, with temporary interruption, dose 
reduction, or discontinuation of vemurafenib, and in some cases has been managed with 
granulocyte colony-stimulating factor.
5.1.3.15
Pancreatitis 
Pancreatitis has been identified as an uncommon adverse drug reaction in patients 
being treated with vemurafenib. The clinical presentation in terms of severity, mild to 
moderate, was consistent with the clinical picture of drug-induced pancreatitis (Lankisch 
et al.1995). 
The Sponsor recommends that serum amylase and lipase testing be conducted as part 
of the workup of any suspected case of pancreatitis in addition to other appropriate 
testing (e.g., abdomen CT scan). 
5.1.3.16
Dupuytren’s Contracture and Plantar Fascial Fibromatosis
Dupuytren’s contracture and plantar fascial fibromatosis have been reported with 
vemurafenib. The majority of cases were Grade 1 or 2, but severe, disabling cases of 
Dupuytren’s contracture have also been reported.
5.1.4
Risks Associated with Combination Use of 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 as described below. Please also refer to the 
Cobimetinib Investigator’s Brochure and Atezolizumab Investigator’s Brochure 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 


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evidence of overlapping and/or potentiation of the above toxicities is observed, patients 
should receive maximal supportive care as clinically indicated. 
Guidelines for management of patients who develop these toxicities are provided in
Section 5.1.6.4.
5.1.4.1
Dermatologic Toxicity 
Treatment-emergent rash has been reported with single-agent atezolizumab. The 
majority of these cases were mild in severity and self-limited, with or without pruritus. 
Because rash has been observed with cobimetinib, this is a potentially overlapping 
toxicity and should be closely monitored. A dermatologist should evaluate persistent 
and/or severe rash or pruritus. A biopsy should be considered unless contraindicated. 
5.1.4.2
Ocular Toxicity 
Uveitis or episcleritis and other immune-mediated ocular disease may be associated 
with atezolizumab. Ophthalmologic reactions have been observed with cobimetinib 
(serous retinopathy). Thus, this is a potential overlapping toxicity with this treatment 
combination. 
5.1.4.3
Hepatic Toxicity 
Liver laboratory abnormalities and hepatotoxicity have been observed with cobimetinib 
(with vemurafenib) and atezolizumab monotherapy. Generally, liver laboratory 
abnormalities following treatment with cobimetinib + vemurafenib are manageable with 
dose modifications. Rare cases of immune-mediated hepatitis have been associated 
with the administration of atezolizumab. 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases. Patients with known liver disease that could 
increase susceptibility to or exacerbate the effect of any potential hepatotoxicity of study 
treatment, including those with active hepatitis B or active hepatitis C viral infection, are 
excluded from the study. 
Liver function will be monitored throughout the study. Patients with right upper-quadrant 
abdominal pain and/or unexplained nausea or vomiting should have liver function tests 
performed immediately and reviewed before administration of the next dose of study 
treatment. For patients with elevated liver function tests, concurrent medication, viral 
hepatitis, and toxic or neoplastic aetiologies should be considered and addressed, as 
appropriate. 
5.1.4.4
Pulmonary Toxicity 
Dyspnoea, cough, fatigue, hypoxia, pneumonitis and pulmonary infiltrates have been 
associated with the administration of atezolizumab. Pneumonitis is an identified risk for 
cobimetinib and is therefore a potential overlapping toxicity with this treatment 
combination. Patients will be assessed for pulmonary signs and symptoms throughout 


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the study and will also have CT scans of the chest performed at every tumour 
assessment. All pulmonary events should be thoroughly evaluated for other commonly 
reported aetiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. 
5.1.4.5
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of atezolizumab. In 
addition, because diarrhoea has been commonly observed with cobimetinib, 
gastrointestinal reactions are a potential overlapping toxicity with this treatment 
combination. Diarrhoea can frequently be managed with anti-diarrheal agents but can 
also progress to clinically significant dehydration and/or electrolyte imbalances with 
effects on other organs, possibly resulting in renal, hepatic and/or cardiac failure. 
Patients should be instructed to promptly contact the investigators if they develop 
diarrhoea. Investigators should treat diarrhoea and intervene promptly for patients who 
appear to be at increased risk of developing significant dehydration, electrolyte 
imbalances, or multi-organ failure. Patients should receive maximum supportive care per 
institutional guidelines. 
5.1.5
Risks Associated with Combination Use of Cobimetinib, 
Atezolizumab and Vemurafenib
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. Gastrointestinal toxicity, liver laboratory abnormalities and hepatotoxicity, 
dermatologic toxicity, pancreatitis, nephritis or increased creatinine, hyperglycaemia, 
ocular events, and pneumonitis represent potential overlapping toxicities with combined 
cobimetinib, atezolizumab and vemurafenib. These are described below. Please also 
refer to Investigator’s Brochures for cobimetinib, atezolizumab and vemurafenib for more 
details regarding these adverse events.
Patients treated with cobimetinib, atezolizumab and vemurafenib 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 above toxicities is 
observed, patients should receive maximal supportive care as clinically indicated.
Guidelines for management of patients who develop these toxicities are provided in
Section 5.1.6.5.
5.1.5.1
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of atezolizumab. In 
addition, because diarrhoea has been commonly observed with vemurafenib, 
cobimetinib, and cobimetinib + vemurafenib, gastrointestinal reactions are a potential 
overlapping toxicity with this treatment combination. Diarrhoea can frequently be 
managed with anti-diarrheal agents but can also progress to clinically significant 


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dehydration and/or electrolyte imbalances with effects on other organs, possibly 
resulting in renal, hepatic and/or cardiac failure. Patients should be instructed to 
promptly contact the investigators if they develop diarrhoea. Investigators should treat 
diarrhoea and intervene promptly for patients who appear to be at increased risk of 
developing significant dehydration, electrolyte imbalances, or multi-organ failure. 
Patients should receive maximum supportive care per institutional guidelines. 
5.1.5.2
Hepatic Toxicity 
Liver laboratory abnormalities and hepatotoxicity have been observed with cobimetinib 
with vemurafenib, vemurafenib monotherapy, and atezolizumab monotherapy. 
Generally, liver laboratory abnormalities following treatment with cobimetinib + 
vemurafenib, as well as vemurafenib monotherapy, are manageable with dose 
modifications. Rare cases of immune-mediated hepatitis have been associated with the 
administration of atezolizumab. It appears that Grade ≥ 3 ALT or AST elevations may 
occur at a higher frequency with atezolizumab + cobimetinib + vemurafenib. 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases. Patients with known liver disease that could 
increase susceptibility to or exacerbate the effect of any potential hepatotoxicity of study 
treatment, including those with active hepatitis B or active hepatitis C viral infection, are 
excluded from the study. 
Liver function will be monitored throughout the study. Patients with right upper-quadrant 
abdominal pain and/or unexplained nausea or vomiting should have liver function tests 
performed immediately and reviewed before administration of the next dose of study 
treatment. For patients with elevated liver function tests, concurrent medication, viral 
hepatitis, and toxic or neoplastic aetiologies should be considered and addressed, as 
appropriate. 
5.1.5.3
Dermatologic Toxicity 
Treatment-emergent rash has been reported with single-agent atezolizumab. The 
majority of these cases were mild in severity and self-limited, with or without pruritus. 
Because rash has been observed with vemurafenib and cobimetinib + vemurafenib, this 
is a potentially overlapping toxicity and should be closely monitored. A dermatologist 
should evaluate persistent and/or severe rash or pruritus. A biopsy should be considered 
unless contraindicated. 
5.1.5.4
Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab. Pancreatitis is an adverse drug reaction for vemurafenib and could 
therefore represent an overlapping toxicity. The differential diagnosis of acute abdominal 
pain should include pancreatitis. Appropriate work-up should include an evaluation for 
ductal obstruction, as well as serum amylase and lipase tests. 


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5.1.5.5
Renal Events 
Renal failure, ranging from creatinine elevation to acute interstitial nephritis and acute 
tubular necrosis, has been observed with vemurafenib treatment. Nephritis is a rare risk 
for atezolizumab. Creatinine will be monitored according to the schedule of activities 
during study treatment. 
5.1.5.6
Hyperglycaemia 
Increased blood sugar has been rarely observed with cobimetinib treatment. Rare cases 
of immune-related diabetes have been observed with atezolizumab treatment. Blood 
glucose will be assessed throughout the study. Patients with uncontrolled diabetes or 
symptomatic hyperglycaemia will be excluded.
5.1.5.7
Ocular Toxicity 
Uveitis or episcleritis and other immune-mediated ocular disease may be associated 
with atezolizumab. Ophthalmologic reactions have been observed with vemurafenib 
(uveitis and RVO) and cobimetinib (serous retinopathy). Thus, this is a potential 
overlapping toxicity with this treatment combination. 
Patients will under ophthalmologic examinations at specified timepoints during the study. 
An ophthalmologist should evaluate visual complaints. 
5.1.5.8
Pulmonary Toxicity 
Dyspnoea, cough, fatigue, hypoxia, pneumonitis and pulmonary infiltrates have been 
associated with the administration of atezolizumab. Pneumonitis is an identified risk for 
cobimetinib and is therefore a potential overlapping toxicity with this treatment 
combination. Patients will be assessed for pulmonary signs and symptoms throughout 
the study and will also have CT scans of the chest performed at every tumour
assessment. All pulmonary events should be thoroughly evaluated for other commonly 
reported aetiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. 
5.1.6
Management of Patients Who Experience Specific Adverse 
Events
5.1.6.1
Dose Modifications – Cohort 1
General dose modification guidelines for cobimetinib are provided in Table 5. Dose 
modification guidelines for specific adverse events with combination treatment in this 
cohort are provided in Appendix 12. Additional guidelines for the management of 
adverse events associated with atezolizumab are provided in Appendix 14 . 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 modification to ≤Grade 1 and provided there are no safety 
concerns.




Triplet treatment period (Cycles ≥2)
The dose of cobimetinib can be reduced by 20 mg QD (one dose level) decrements up 
to two times for management of drug-related toxicities (i.e. from 60 to 40 mg and then 
from 40 to 20 mg), except during the run-in period when only one dose reduction is 
allowed. If further dose reduction is indicated after two dose reductions, the patient must 
discontinue cobimetinib but may continue treatment with atezolizumab and/or 
vemurafenib at the investigator’s discretion. The dose of cobimetinib may be escalated 
by a maximum of one dose level (20 mg) from 20 mg QD to 40 mg QD at the 
investigator's discretion in patients who have previously undergone dose reduction, 
provided there are no safety concerns and the adverse event that resulted in the dose 
reduction has resolved to ≤ Grade 1.  Dose escalation from 40 mg QD to 60 mg QD is 
not permitted.
There will be no dose modifications for atezolizumab in this study.
The dose of vemurafenib dose can be reduced during the triplet combination treatment 
period from 720 mg BID to 480 mg BID. If further dose reduction is indicated, the patient 
must discontinue vemurafenib but may continue treatment with atezolizumab and/or 
cobimetinib at the investigator’s discretion.
Dose modification guidelines for specific adverse events with combination treatment in 
this cohort are provided in Appendix 13 . Additional guidelines for the management of 
adverse events associated with atezolizumab are provided in Appendix 14.
5.1.6.3 
Treatment Interruption or Discontinuation 
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, the patient will be discontinued from atezolizumab. Study treatment 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 patient is likely to derive clinical benefit. The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures). The acceptable length of treatment 
interruption must be based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
Cobimetinib (Cohort 1) or cobimetinib and vemurafenib (Cohort 2) treatment may be 
temporarily suspended in patients who experience toxicity considered to be related to 
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study treatment. If cobimetinib or vemurafenib (if applicable) has been withheld 
for > 28 days because of toxicity, the patient should be discontinued from that drug, 
unless the patient is likely to derive clinical benefit. The decision to re-challenge 
patients with study treatment should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed. The Medical Monitor should be 
consulted for any major surgery (e.g., involving a body cavity), and cobimetinib and 
vemurafenib (if applicable) should generally be withheld for two days prior to the 
procedure and for two weeks afterwards.
For dose interruptions required in the run-in period (Cycle 1) in Cohort 2, refer to 
Section 5.1.6.2.
5.1.6.4
Management Guidelines – Cohort 1
In general, toxicities should be managed with supportive care, dose modifications (as 
permitted), and treatment interruptions applied to the component of the study treatment 
judged to be the primary cause. Additional tests or procedures, such as autoimmune
serology or biopsies to obtain tissue samples, may be performed to determine a possible 
immunogenic aetiology. This also applies to cases where the severity exceeds 
previously observed toxicities, or nature of the toxicity encountered differs from the 
known safety profile. Special attention to cases of severe cutaneous hypersensitivity 
reactions, such as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is 
warranted from study investigators.
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 
haemorrhage, see Appendix 12. Additional guidelines for the management of adverse 
events associated with atezolizumab are provided in Appendix 14 .
5.1.6.5
Management Guidelines – Cohort 2
In general, toxicities should be managed with supportive care, dose modifications (as 
permitted), and treatment interruptions applied to the component of the study treatment 
judged to be the primary cause. Additional tests or procedures, such as autoimmune 
serology or biopsies to obtain tissue samples, may be performed to determine a possible 
immunogenic aetiology. 
Cohort 2 patients should be monitored closely upon initiation of atezolizumab as a third 
treatment component on Days 1 and 15 of Cycles 2 and 3, as well as the days 
immediately following these visits. Regular telephone contact and, if needed, 
unscheduled laboratory tests are strongly recommended. 
Guidelines for management of patients who experience specific adverse events in this 
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
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)
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.
SAEs 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).  
These events may or may not be SAEs and they may or may not be considered related 
to study medication. Regardless of relationship or severity, these events will be recorded 
if they start from the time of the first dose of study treatment and will be followed until 
resolution. 
After the end of the adverse event reporting period, the Sponsor should be notified if the 
Investigator becomes aware of any adverse events of special interest that are believed 
to be related to prior study treatment.


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Adverse events of special interest for this study are as follows:
Events specific to cobimetinib and vemurafenib

Any RVO

Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment or central serous 
chorioretinopathy 

Grade ≥ 3 photosensitivity 

Rhabdomyolysis or Grade ≥ 3 CPK elevation 

Grade ≥ 3 haemorrhage or any grade cerebral haemorrhage 

Grade ≥ 3 rash 

Grade ≥ 3 diarrhoea 

Grade ≥ 3 QT interval prolongation 

Symptomatic heart failure and/or Grade ≥ 2 left ventricular ejection fraction 
reduction

Pneumonitis

Hepatitis, including AST or ALT 10 × ULN
Events specific to atezolizumab

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, or hypophysitis

Hepatitis, including AST or ALT 10 × ULN

Systemic lupus erythematosus

Neurological disorders: Guillain-Barré syndrome, myasthenia gravis, 
meningoencephalitis 

Nephritis

Events suggestive of hypersensitivity, IRRs, CRS, influenza-like illness, HLH, and 
MAS

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune haemolytic anaemia


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Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)
Other adverse events of special interest

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)

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.
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 
treatment, only SAEs caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see
Section 5.4.2 for instructions for reporting SAEs).
After initiation of study treatment, all adverse events as follows:

All adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs
first

SAEs and adverse events of special interest will continue to be reported until 
90 days after the last dose of study treatment or until initiation of new systemic 
anti-cancer therapy, whichever occurs first.




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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 study treatment, indicating "yes" or "no"
accordingly. The following guidance should be taken into consideration (see also 
Table 7):

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as
applicable)

Known association of the event with study treatment 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
Table 7
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment 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 study treatment, 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 study treatment; and/or the adverse 
event abates or resolves upon discontinuation of study treatment or dose reduction and, 
if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfils the criteria specified below.  
Evidence exists that the adverse event has an aetiology other than study treatment
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed two days after 
first dose of study treatment).
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.


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5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF. If possible, 
avoid ambiguous terms such as "systemic reaction." Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF. If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
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 haemorrhage 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 SAEs.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
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 
hypokalaemia) or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
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 "hyperkalaemia."


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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 an SAE 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 metastatic melanoma should be recorded on the 
Death Attributed to Progressive Disease eCRF. All other on-study deaths, 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. The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
pre-existing heart disease, within one hour after the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable. 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. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Pre-existing Medical Conditions
A pre-existing 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 pre-existing 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 pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
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.


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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 an SAE (per the 
definition of SAEs 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 an SAE:

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 pre-existing 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 an SAE, 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
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 
quality 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.


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Special situations are not in themselves adverse events, but may result in adverse 
events. 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 or qualifies as an adverse event of special interest, 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).  
For atezolizumab, cobimetinib, and vemurafenib, 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.

Drug misuse that qualifies as an overdose: Enter the adverse event term. Check the 
“Intentional overdose” and “Drug misuse” boxes.
In addition, all special situations associated with atezolizumab, cobimetinib, and 
vemurafenib, regardless of whether they result in an adverse event, should be recorded 
on the Adverse Event eCRF 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.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one entry to report the accidental 
overdose and one entry to report the headache. The "Accidental overdose" and 
"Medication error" boxes would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data 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.
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 treatment:

SAEs (defined in Section 5.2.2; see Section 5.4.2 for details on reporting 
requirements)


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
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 5.3.5.12 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 SAEs to the local 
health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, an Emergency Medical Call Centre Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
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 Centre 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. 
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 Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported. The paper 
Clinical Trial Adverse Event/Special Situations 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 Treatment Initiation
After initiation of study treatment, SAEs and adverse events of special interest will be 
reported until 90 days after the last dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first. New primary neoplasms other than 
cuSCC (which qualify as SAEs) will continue to be reported until six months after the last 


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dose of vemurafenib. 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 Adverse 
Event/Special Situations 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 SAEs 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 through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within six months after the last dose of study treatment. A paper 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.  Pregnancy should not be recorded on the Adverse 
Event eCRF. The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the foetus.  
Monitoring of the patient should continue until conclusion of the pregnancy. Any SAEs 
associated with the pregnancy (e.g., an event in the foetus, 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 six
months after the last dose of study treatment.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form 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 study treatment. When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 


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Information to allow for follow-up on her pregnancy. If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form with additional
information on the pregnant partner and the course and outcome of the pregnancy as it 
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 foetus, 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.
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 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as an SAE, 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).
5.5
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 SAEs considered to be related to study treatment 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.


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5.5.2
Sponsor Follow-Up
For SAEs, 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 reporting period for SAEs and adverse events of special interest 
(defined as 90 days after the last dose of study treatment), all deaths, regardless of 
cause, should be reported through use of the Long-Term Survival Follow-Up eCRF.  
In addition, if the investigator becomes aware of an SAE that is believed to be related to 
prior exposure to study 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 Adverse Event/Special Situations 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 SAEs 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 safety 
information in the documents listed below:

Cobimetinib Investigator's Brochure 

Atezolizumab Investigator's Brochure 

Vemurafenib Investigator's Brochure
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.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
A primary study analysis that includes analyses of all efficacy endpoints and safety 
summaries will be conducted based on data collected up to six months after the last 
patient is enrolled in the study (last patient in [LPI]). The final study analysis including 
updated analyses of safety and efficacy endpoints will be conducted based on data 
collected up to 24 months after LPI.
Unless otherwise indicated, efficacy analyses will be based upon the Evaluable Patient 
population in each cohort consisting of all enrolled patients who received study 
medication and have at least two post-baseline tumour assessments for response 
evaluation. Analyses of safety, PRO, survival, timing of change in corticosteroid use, and 
time to subsequent intracranial or systemic anti-cancer treatment endpoints will be 
conducted based upon the Safety population in each cohort consisting of all patients 
who received at least one dose of study medication.
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this Phase II study is estimation and hypothesis generation regarding the 
effect of cobimetinib plus atezolizumab on CNS metastases from BRAFV600 wild-type 
melanoma and the effect of cobimetinib plus atezolizumab and vemurafenib on CNS 
metastases from BRAFV600 mutation-positive melanoma. There are no reference data 
available on the use of these combination therapies in these patient populations.  
There is no formal statistical hypothesis in this study. The originally planned total sample 
size of approximately 60 patients per cohort was based on an estimated study drop-out 
rate of 15%, the primary endpoint and 95% CIs for each treatment regimen. No power 
calculation has been performed.  
In a Dear Investigator Letter dated 9 July 2019, the Sponsor communicated the decision 
to discontinue enrollment in the BRAFv600 wild-type cohort (Cohort 1). As of 9 July 2019, 
15 patients were enrolled in Cohort 1. The 15 patients enrolled into the BRAFV600
wild-type cohort at the time of recruitment stop will be analysed descriptively only.
Point estimates and 95% CIs for a range of possible outcomes produced using nQuery 
(version 7) with 50 evaluable patients in the BRAFV600 mutation-positive cohort are 
provided in Table 8 below.




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A sensitivity analysis of the primary endpoint that includes patients with unconfirmed CR 
or PR will also be conducted in each cohort based upon the Safety population in order to 
detect a potential bias with regard to the primary analysis. 
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are listed in Table 1.
Intracranial ORR is defined as the proportion of patients with either a CR or PR in their 
intracranial disease based on two consecutive assessments ≥ 4 weeks apart as 
determined by investigator according to RECIST v1.1.
Extracranial ORR is defined as the proportion of patients with either a CR or PR in their 
extracranial disease based on two consecutive assessments ≥ 4 weeks apart, as 
determined by the investigator according to RECIST v1.1. For extracranial response rate 
a 95% Pearson-Clopper CI will be calculated and presented.
Overall ORR is defined as the proportion of patients with either a CR or PR in their 
overall disease (i.e. including intracranial and extracranial disease) based on two 
consecutive assessments ≥ 4 weeks apart, as determined by the investigator according 
to RECIST v1.1. For overall ORR a 95% Pearson-Clopper CI will be calculated and 
presented.
Intracranial, extracranial and overall PFS are defined as the time from study treatment 
initiation to the first occurrence of disease progression or death from any cause, 
whichever occurs first, as determined by the investigator according to RECIST v1.1.
Kaplan-Meier methodology will be used to estimate median intracranial, extracranial and 
overall PFS; Kaplan-Meier curves will be provided. Data for patients who have not 
experienced disease progression or have died will be censored at the last tumour 
assessment date.
Intracranial, extracranial and overall DOR are defined as the time from the first 
occurrence of a documented objective response based on two consecutive assessments 
≥4 weeks apart to disease progression or death from any cause (whichever occurs 
first), as determined by the investigator according to RECIST v1.1. The censoring 
method for DOR is the same as 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.
Intracranial, extracranial and overall disease control rates (DCR) are defined as the 
proportion of patients with a CR or PR or SD at 16 weeks from study treatment initiation, 
as determined by the investigator according to RECIST v1.1. For DCR, a 95% 
Pearson-Clopper CI will be calculated and presented.


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OS is defined as the time from study treatment initiation to death from any cause. For 
patients who are alive at the time of analysis data cut-off, 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 one day after the study treatment 
initiation date. Kaplan-Meier methodology will be used to estimate median OS and 
Kaplan-Meier curves will be provided. 
6.4.2.1
Patient-reported Secondary Efficacy Endpoints
Time from study treatment initiation to cognitive symptom deterioration is defined as the 
time from baseline to the first time a patient’s score shows a ≥10-point increase above 
baseline in any of the following EORTC QLQ-BN20 transformed symptom subscale 
scores (whichever comes first): visual disorder, motor dysfunction, communication 
deficit, headaches, seizures and drowsiness. 
Time from study treatment initiation to symptom and function deterioration is defined as 
the time from baseline to the first time a patient’s score shows a ≥10-point increase 
above baseline in any of the following EORTC QLQ-C30 transformed symptom subscale 
scores (whichever comes first): fatigue or physical, cognitive and role functioning scales.
Duration of Stable/Improved HRQoL scores is assessed through use of the two-item 
GHS/HRQoL subscale (Questions 29 and 30) of the EORTC QLQ-C30. Patients 
post-baseline PRO scores will be classified as “improved”, “stable”, or “worsened” 
according to a ≥ 10-point change in the GHS/QoL, functional, and symptom scores of 
the EORTC QLQ-C30 and the QLQ-BN20. 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 time point, including progression, treatment discontinuation and 
post-study treatment.
Only patients with a non-missing baseline assessment and at least one non-missing 
post-baseline assessment will be included in PRO analyses. Questionnaire completion 
and compliance will be summarized at each time point by treatment arm.
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are listed in Table 1 and are as follows:

Intracranial ORR defined as the proportion of patients with either a CR or PR in their 
intracranial disease as assessed by the investigator according to iRANO criteria 
based on two consecutive assessments ≥ 4 weeks apart. 

Objective response rate in intracranial, extracranial and overall disease as
determined by investigator according to immune-modified RECIST with modified 
measurability definition for intracranial lesions (≥0.5 cm by MRI) and allowing up to 
five intracranial target lesions.  

Intracranial, extracranial and overall PFS is determined by the investigator 
according to immune-modified RECIST. 


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
Intracranial, extracranial and overall DOR is determined by the investigator 
according to immune-modified RECIST 
Objective response, PFS and DOR, as determined by the investigator according to 
immune modified RECIST, will be analysed using the same methods as described
in Section 6.4.2.

Radiotherapy-assisted PFS defined as time from study treatment initiation to the first 
occurrence of disease progression or death from any cause, whichever occurs first, 
as determined by the investigator according to RECIST v1.1 modified by excluding 
≤3 lesions that can be treated by SRT from the sum of largest diameters from 
baseline onwards 

Timing of increase or change in corticosteroid use during treatment will be based on 
corticosteroid used for symptomatic control as indicated in the eCRF

Time from study treatment initiation to subsequent intracranial and systemic 
anti-cancer treatment

Change from baseline scores over time in treatment/disease-related symptoms as 
evaluated by the EORTC QLQ-C30 and QLQ-BN20 questionnaires will be 
summarized descriptively including the mean change from baseline of 
linear-transformed scores for all subscales of the EORTC QLQ-C30 and QLQ-BN20
according to the EORTC scoring manual guideline at each assessment time point 
for each cohort, including progression, treatment discontinuation and post-study 
discontinuation. The mean (and 95% CI) and median of the absolute scores and the 
change from baseline will be reported for interval and continuous variables. Only 
patients with a non-missing baseline assessment and at least one non-missing post-
baseline assessment will be included in PRO analyses.
6.5
SAFETY ANALYSES
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs and study treatment exposures, presented by cohort. 
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 dose of study treatment will be summarized by 
cohort and NCI CTCAE grade. In addition, SAEs, severe adverse events (Grades 3, 4,
and 5), adverse events of special interest, and adverse events leading to discontinuation 
or interruption of study treatment 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 
cohort. 
Exposure to study treatment, including treatment duration, number of cycles and dose 
intensity, will be summarized for each cohort using descriptive statistics. Number of dose 
reductions, treatment interruptions and cycle delays will also be summarized by 
treatment cohort.


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All deaths and causes of death will be summarized by cohort. 
Laboratory data with values outside the normal ranges will be identified. In addition, 
relevant laboratory data and vital signs will be summarized by cohort. 
6.6
BIOMARKER ANALYSES
The relationship between clinical efficacy parameters and biomarkers in tumour tissue 
and plasma (including, but not limited to; PD-L1, BRAF and NRAS) will be explored at 
the conclusion of this study. 
6.7
INTERIM ANALYSIS
A safety interim analysis will be performed after at least 10 patients in both cohorts have 
completed their first tumour assessment (i.e. approximately eight weeks after start of 
study treatment). The analysis will be conducted by the Sponsor according to the 
Sponsor’s standard operating procedures for safety reviews. The results of the interim 
analysis will be reviewed by the IMC as described in the IMC charter.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) 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 CRO will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system.
The Sponsor will perform oversight of the data management of this study. The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates including 
quality checking to be performed on the data.
Central laboratory data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
The 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. 
The 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 CRO.
All eCRFs should be completed by designated, trained site staff. The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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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.
The PRO data will be collected on paper questionnaires. The data from the 
questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
Electronic CRFs 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. The 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. The 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
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, 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 7.5.


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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.
7.4
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.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study or for 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.
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 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 


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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.
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.
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 


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responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting SAEs to the local health 
authority and IRB/EC. Investigators may receive written IND safety reports 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 9.6).
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 one year after completion of the study (see definition of end 
of study in Section 3.2).


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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.
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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks. Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters. Detection of deviations from quality tolerance limits will trigger an evaluation 
to determine if action is needed. Details on the establishment and monitoring of quality 
tolerance limits will be provided in a Quality Tolerance Limit Management Plan.
9.4
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.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
will provide clinical operations management, data management and medical monitoring.


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Approximately 23 sites worldwide will participate to enrol approximately 120 patients. 
Screening and enrollment will occur through an IxRS.  
Central facilities will be used for biomarker analyses as specified in Section 4.5.9. 
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An SC will provide scientific oversight of the trial. Disease status for the primary endpoint 
will be determined by an IRC.
9.6
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, at scientific 
congresses, in clinical trial registries and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request. For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 six 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 multicentre trials only in their entirety and not as individual centre
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 


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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.
9.7
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).
10.
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brain metastases: lessons learned from the EORTC Brain Metastases Strategic 
Meeting 2012. Eur J Cancer. 2012 Dec;48(18):3439-47.
Revicki DA, van den Eertwegh AJ, Lorigan P, et al. Health related quality of life 
outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab 
treatment. Health Qual Life Outcomes 2012;10:66.
Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with 
combined dabrafenib and trametinib. N Engl J Med. 2015a Jan 1;372(1):30-9. doi: 
10.1056/NEJMoa1412690.
Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med. 2015b Jun 25;372(26):2521-32. doi: 
10.1056/NEJMoa1503093.
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 2011;364:2517−26.
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Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
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treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:1909-20.
Schachter J, Ribas A, Long GV et al. Pembrolizumab versus ipilimumab for advanced 
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10.1016/S0140-6736(17)31601-X


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2012;113:725-34.






Appendix 1
Schedule of Activities for Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
139 / Protocol MO39136, Version 5.0
Notes: All safety assessments (laboratory tests, ECGs, etc) should be performed within three days prior to Day 1. Unless otherwise specified, other 
assessments should be performed within seven days of the scheduled visit. On treatment days, all assessments should be performed prior to 
dosing, unless otherwise specified. If a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit 
should be scheduled on the nearest following feasible date.
a.
Exceptionally, results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to initiation 
of study treatment may be used; such tests do not need to be repeated for screening.  
b.
Patients who discontinue study treatment will return to the clinic for a Study Treatment Discontinuation Visit after 28 days (± 7 days) after their 
last dose of any study drug.
c.
Survival, patient-reported outcomes and anti-cancer treatments will be collected via telephone calls and/or clinic visits every three months until 
death, loss to follow-up, or study termination by the Sponsor.
d.
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment.
e.
HIV, HBV and HCV tests will be conducted locally.
f.
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure and temperature. Blood pressure and heart 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. Vital signs 
should be measured within 60 minutes prior to each atezolizumab infusion and, if clinically indicated, during or after the infusion. 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.
g.
Includes evaluation of the head, eyes, ears, nose and throat (HEENT), neck, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary and neurologic systems. 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.
Submission of formalin-fixed paraffin embedded tumour tissue (one block or 10 consecutively cut sections) from the primary tumour or a metastatic 
lesion (decalcified tissue is not allowed) obtained any time prior to study entry (e.g., archival material).
i.
Left ventricular dysfunction will be evaluated by ECHO or MUGA at screening, on Day 1 of Cycle 2 (± 1 week) and on Day 1 of every three 
treatment cycles thereafter starting at Cycle 5 (± 2 weeks for each), at the treatment discontinuation visit (unless evaluation performed within the 
previous 12 weeks showed no clinically significant findings or changes from baseline) and as clinically indicated. All patients who restart treatment 
with a reduced dose of cobimetinib because of a decrease in LVEF should have LVEF measurements taken after approximately 2, 4, 10 and 
16 weeks (or as clinically indicated) and then resume monitoring LVEF every 12 weeks (three cycles).  
j.
During the study treatment period, paper versions of the EORTC QLQ-C30 and QLQ-BN20 questionnaires will be self-administered before the 
patient receives any information on disease status and prior to the performance of any non-patient reported outcome assessments and prior to 
atezolizumab administration (if applicable). After the treatment discontinuation visit, patients will complete Questions 29 and 30 of the EORTC 
QLQ-C30 only. Post-treatment discontinuation visit questionnaires may be administered over the telephone. 


Appendix 1
Schedule of Activities for Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
140 / Protocol MO39136, Version 5.0
k.
Perform a limited, symptom-directed examination including an evaluation of the oral cavity, oropharynx, head and neck (including lymph nodes), 
lungs, heart, abdomen and skin at specified time points or as clinically indicated. Patients should be asked specifically about skin and vision 
changes as part of each physical examination. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
l.
Haematology includes white blood cell count, red blood cell count, haemoglobin, haematocrit, reticulocyte count, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). If screening haematology is performed within 7 days of initiation of 
study treatment, it does not need to be repeated for Day 1 of Cycle 1.
m. Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, bicarbonate or total carbon dioxide (bicarbonate and total 
carbon dioxide are not mandatory if unavailable at site), glucose (non-fasting), BUN or urea, creatinine, albumin, phosphorus, calcium, total 
bilirubin, ALP, ALT, AST, lactate dehydrogenase and CPK, amylase and lipase. If screening blood chemistry is performed within 7 days of initiation 
of study treatment, it does not need to be repeated for Day 1 of Cycle 1.
n.
All women of childbearing potential will have a negative serum pregnancy test within seven days prior to initiation of study treatment. Women 
without prior oophorectomy or hysterectomy who have been amenorrhoeic for >12 months but < 2 years must have a FSH level test to determine 
childbearing potential. Urine pregnancy tests will be performed on Day 1 of each treatment cycle, at the treatment discontinuation visit and at 
study follow up until six months post-study treatment discontinuation. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
o.
Includes thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), free thyroxine. Thyroid-function tests are to 
be performed at screening, on Day 1 of Cycles 1-5 and every second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.), and at the treatment 
discontinuation visit.
p.
Both blood glucose and lipid panel must be obtained after at least an 8-hour fast, at screening only. Lipid panel should include total cholesterol, 
low-density lipoprotein and triglycerides
q.
Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).
r.
Ophthalmologic examinations should be performed at screening; on Day 1 of Cycle 2 (± 1 week), Cycles 5, 8, 11, 15, 19, 23, and every six cycles 
thereafter (i.e., Cycles 29, 35, 41, etc.) (± 2 weeks for each); at the treatment discontinuation visit; and as clinically indicated (including in the 
event of any visual changes). 
s.
Intracranial disease must be followed by magnetic resonance imaging (MRI). Extracranial tumour 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. Intracranial and extracranial 
tumour assessments after end of Cycle 2 should be conducted every 8 weeks ± 1 week regardless of study treatment delays through 24 months 
and then every 12 weeks ± 1 week thereafter until confirmed disease progression per RECIST v1.1, withdrawal of consent, study termination by 
the Sponsor or death, whichever occurs first. Tumour assessments showing disease progression must be repeated approximately four weeks 
later regardless of whether treatment is continued beyond progression. Post-progression assessments may be conducted sooner if necessary 
e.g., due to clinical progression. Objective response (complete or partial response) must be confirmed by repeat assessments ≥4 weeks after 


Appendix 1
Schedule of Activities for Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
141 / Protocol MO39136, Version 5.0
initial documentation. In the case of stable disease, tumour measurements must meet criteria for stable disease ≥6 weeks after initiation of study 
treatment.
t.
Two 10 mL whole blood samples will be collected for preparation of EDTA plasma.
u.
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from seven days prior to initiation of study treatment until 28 days after the last dose of study 
treatment.
v.
After informed consent has been obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should 
be reported. After initiation of study treatment, all adverse events will be reported until 30 days after the last study treatment dose. 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 SAEs considered to be related to study 
treatment or trial-related procedures until a final outcome can be reported. In addition, the Sponsor should be notified if the investigator becomes 
aware of any SAE that is believed to be related to prior study treatment.
w.
Medication diaries should be collected and reviewed and unused medications should be collected for assessment of compliance.










Appendix 2
Schedule of Activities for Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
146 / Protocol MO39136, Version 5.0
Notes: All safety assessments (laboratory tests, ECGs, etc) should be performed within three days prior to Day 1. Unless otherwise specified, other 
assessments should be performed within seven days of the scheduled visit. On treatment days, all assessments should be performed prior to dosing, 
unless otherwise specified. If a protocol mandated study visit coincides with a holiday and/or weekend that preclude the visit, the visit should be 
scheduled on the nearest following feasible date.
a.
Results of standard-of-are tests or examinations performed prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment may be used; such tests do not need to be repeated for screening.  
b.
Patients who discontinue study treatment will return to the clinic for a Study Treatment Discontinuation Visit after 28 days (± 7 days) after their 
last dose of any study drug.
c.
Survival, patient-reported outcomes and anti-cancer treatments will be collected via telephone calls and/or clinic visits every three months until 
death, loss to follow-up, or study termination by the Sponsor.
d.
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment.
e.
HIV, HBV and HCV tests will be conducted locally.  
f.
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure and temperature. Blood pressure and heart 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. Vital signs 
at screening must be performed within seven days prior to initiation of study treatment. Vital signs should be measured within 60 minutes prior 
to each atezolizumab infusion and, if clinically indicated, during or after the infusion. 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.
g.
Includes evaluation of the head, eyes, ears, nose and throat (HEENT), neck, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary and neurologic systems. 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.
Submission of formalin-fixed paraffin embedded tumour tissue (one block or 10 consecutively cut sections) from the primary tumour or a 
metastatic lesion (decalcified tissue is not allowed) obtained any time prior to study entry (e.g., archival material).
i.
Left ventricular dysfunction will be evaluated by ECHO or MUGA at screening, on Day 1 of Cycle 2 (± 1 week) and on Day 1 of every three 
treatment cycles thereafter starting at Cycle 5 (± 2 weeks for each), at the treatment discontinuation visit (unless evaluation performed within the 
previous 12 weeks showed no clinically significant findings or changes from baseline), and as clinically indicated. All patients who restart 
treatment with a reduced dose of cobimetinib because of a decrease in LVEF should have LVEF measurements taken after approximately 2, 4, 
10 and 16 weeks (or as clinically indicated) and then resume monitoring LVEF every 12 weeks (three cycles).  
j.
During the study treatment period, paper versions of the EORTC QLQ-C30 and QLQ-BN20 questionnaires will be self-administered before the 
patient receives any information on disease status and prior to the performance of any non-patient reported outcome assessments and prior to 


Appendix 2
Schedule of Activities for Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
147 / Protocol MO39136, Version 5.0
atezolizumab administration (if applicable). After the treatment discontinuation visit, patients will complete Questions 29 and 30 of the EORTC 
QLQ-C30 only. Post-treatment discontinuation visit questionnaires may be administered over the telephone. 
k.
Perform a limited, symptom-directed examination including an evaluation of the oral cavity, oropharynx, head and neck (including lymph nodes), 
lungs, heart, abdomen and skin, at specified time points or as clinically indicated. Patients should be asked specifically about skin and vision 
changes as part of each physical examination. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
l.
During the treatment period, ECG recordings must be obtained prior to the morning doses of cobimetinib and vemurafenib on Day 15 (± 3 days) 
of Cycles 1, 2, 3 and 4. Thereafter ECG recordings will be obtained on Day 15 of every three cycles (i.e. Day 15 of Cycles 7, 10, 13, etc.) 
(± 3 days); at the treatment discontinuation visit (± 3 days); and as clinically indicated. EGCs should be performed prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws unless pre-authorized by the Medical Monitor) and after the patient has 
been resting in a supine position for at least 10 minutes.
m.
Haematology includes white blood cell count, red blood cell count, haemoglobin, haematocrit, reticulocyte count, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). If screening haematology is performed within seven days of initiation 
of study treatment, it does not need to be repeated for Day 1 of Cycle 1.
n.
Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, bicarbonate or total carbon dioxide (bicarbonate and total 
carbon dioxide are not mandatory if unavailable at site), glucose (non-fasting), BUN or urea, creatinine, albumin, phosphorus, calcium, total 
bilirubin, ALP, ALT, AST, lactate dehydrogenase and CPK, amylase and lipase. If screening blood chemistry is performed within seven days of 
initiation of study treatment, it does not need to be repeated for Day 1 of Cycle 1.
o.
All women of childbearing potential will have a negative serum pregnancy test within seven days prior to initiation of study treatment. Women 
without prior oophorectomy or hysterectomy who have been amenorrhoeic for >12 months but < 2 years must have a FSH level test to determine 
childbearing potential. Urine pregnancy tests will be performed on Day 1 of each treatment cycle, at the treatment discontinuation visit and at 
study follow up until six months post-study treatment discontinuation. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
p.
Includes thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), free thyroxine. Thyroid-function tests are to 
be performed at screening, on Day 1 of Cycles 2−6 and every second cycle thereafter (e.g., Day 1 of Cycles 8, 10, 12, etc.), and at the treatment 
discontinuation visit.
q.
Both blood glucose and lipid panel must be obtained after at least an 8-hour fast, at screening only. Lipid panel should include total cholesterol, 
low-density lipoprotein and triglycerides
r.
Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).
s.
To monitor for the occurrence of squamous cell carcinoma (SCC) in the upper aerodigestive tract, a head and neck examination will be performed 
at screening, Day 1 of Cycle 4 and every three cycles thereafter during treatment (i.e., Day 1 of Cycles 7, 10, 13, etc.), at the treatment 
discontinuation visit (unless performed within the previous 12 weeks), at 3 and 6 months (± 2 weeks) after the last dose of study treatment, and 


Appendix 2
Schedule of Activities for Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
148 / Protocol MO39136, Version 5.0
as clinically indicated (e.g., if any new head and neck lesions are suspected of being non-cuSCC). Assessments will include (at a minimum) 
examination of the HEENT and neck, visual inspection of the oral mucosa, and lymph node palpation.
t.
To monitor for anal SCC, visual inspection and digital examination of the anus and anal canal will be performed at screening, at the treatment 
discontinuation visit, 6 months (± 2 weeks) after the last dose of vemurafenib, and as clinically indicated. Colonoscopy, sigmoidoscopy, or 
anoscopy is not required but may be performed if clinically indicated. To monitor for cervical carcinoma, all female patients will undergo a pelvic 
examination, including visual inspection of the uterine cervix and Papanicolaou (Pap) smear, at screening, at the treatment discontinuation visit, 
6 months (± 2 weeks) after the last dose of vemurafenib, and as clinically indicated. Pelvic examinations performed within 12 months prior to 
screening need not be repeated if found to be normal.
u.
A complete dermatologic evaluation should be performed at screening, on Day 1 of Cycle 2 and every three cycles thereafter during treatment 
(i.e., Day 1 of Cycles 5, 8, 11, etc.) (± 1 week), at the treatment discontinuation visit (unless performed within the previous 12 weeks), 6 months 
(± 2 weeks) after the last dose of study treatment, and as clinically indicated. 
v.
Ophthalmologic examinations should be performed at screening; on Day 1 of Cycle 2 (± 1 week), Cycles 5, 8, 11, 15, 19, 23, and every six cycles 
thereafter (i.e., Cycles 29, 35, 41, etc.) (± 2 weeks for each); at the treatment discontinuation visit; and as clinically indicated (including in the
event of any visual changes). 
w.
Intracranial disease must be followed by magnetic resonance imaging (MRI). Extracranial tumour 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. Intracranial and extracranial 
tumour assessments after end of Cycle 2 should be conducted every 8 weeks ± 1 week regardless of study treatment delays through 24 months 
and then every 12 weeks ± 1 week thereafter until confirmed disease progression per RECIST v1.1, initiation of a new anti-cancer treatment, 
withdrawal of consent, study termination by the Sponsor or death, whichever occurs first. Tumour assessments showing disease progression 
must be repeated approximately four weeks later regardless of whether treatment is continued beyond progression. If disease progression is not 
confirmed, the subsequent scheduled tumour assessment should occur not earlier than 4 weeks since the confirmatory scan. Post-progression 
assessments may be conducted sooner if necessary e.g., due to clinical progression. Objective response (complete or partial response) must 
be confirmed by repeat assessments ≥ 4 weeks after initial documentation. In the case of stable disease, tumour measurements must meet 
criteria for stable disease ≥ 6 weeks after initiation of study treatment.
Chest CT or MRI scans will be used to monitor for lung SCC. An additional chest CT or MRI scan must be performed 6 months (± 2 weeks) after 
study treatment discontinuation for SCC monitoring. 
x.
Two 10 mL whole blood samples will be collected for preparation of EDTA plasma.
y.
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from seven days prior to initiation of study treatment until 28 days after the last dose of study 
treatment.
z.
After informed consent has been obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should 
be reported. After initiation of study treatment, all adverse events will be reported until 30 days after the last study treatment dose. The investigator 


Appendix 2
Schedule of Activities for Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
149 / Protocol MO39136, Version 5.0
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 SAEs considered to be related to study 
treatment or trial-related procedures until a final outcome can be reported. In addition, the Sponsor should be notified if the investigator becomes 
aware of any SAE that is believed to be related to prior study treatment.
aa.
All patients will receive vemurafenib at a dose of 960 mg (four 240-mg tablets) PO BID on Days 1-21 of Cycle 1. Patients will receive vemurafenib 
at a dose of 720 mg (three 240-mg tablets) on Days 1-28 of all subsequent treatment cycles. Vemurafenib will be dispensed on Day 1 of each 
treatment cycle and on Day 21 or 22 of the run-in period.
bb.
For patients in Cohort 2, atezolizumab will be administered beginning in Cycle 2 only.
cc.
Medication diaries should be collected and reviewed and unused medications should be collected for assessment of compliance.






Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
152 / Protocol MO39136, Version 5.0
Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1)
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 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
153 / Protocol MO39136, Version 5.0
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.
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 four 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.


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
154 / Protocol MO39136, Version 5.0
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 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 
used 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 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
155 / Protocol MO39136, Version 5.0
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 should 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").
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.


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
156 / Protocol MO39136, Version 5.0
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 
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 


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
157 / Protocol MO39136, Version 5.0
evaluations. In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the CRF 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
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 


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
158 / Protocol MO39136, Version 5.0
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 pre-existing 
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.
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.


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
159 / Protocol MO39136, Version 5.0
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 
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 


Appendix 5Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
160 / Protocol MO39136, Version 5.0
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
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.  


Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
161 / Protocol MO39136, Version 5.0
Appendix 6
Immune-Modified Response Evaluation Criteria in Solid Tumors
(imRECIST)
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, 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 (imRECIST), 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 imRECIST and RECIST v1.1 are summarized in Table 1.
Table 1
Comparison of RECIST v1.1 and imRECIST
RECIST v1.1
imRECIST
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 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
162 / Protocol MO39136, Version 5.0
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.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
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163 / Protocol MO39136, Version 5.0
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.
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 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
164 / Protocol MO39136, Version 5.0
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 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 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 
used 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.


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
165 / Protocol MO39136, Version 5.0
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").
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 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
166 / Protocol MO39136, Version 5.0
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 
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 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
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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 
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 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
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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 imRECIST 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 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 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. 


Appendix 6:Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST)
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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 
having "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 1.
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.  
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 Cancer Res 
2009;15:741220.
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 Cancer 2014;2:17.


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Appendix 7
Immunotherapy Response Assessment for Neuro-Oncology 
(iRANO) Criteria
The iRANO criteria are summarized in Table 1 below. For a complete description, please 
refer to: Okada H, Weller M, Huang R et al. Immunotherapy response assessment in 
neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015 
Nov;16(15):e534-42; located at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638131
Table 1: iRANO criteria
Brain metastases
Complete 
response
Disappearance of all enhancing target and non-target lesions for ≥4 week; 
no new lesions; no steroids; clinically stable or improved
Partial response
≥30% decrease in sum of longest diameters of target lesions for ≥4 weeks; 
no new lesions; stable or decreased steroid dose; clinically stable or 
improved
Minor response
Not applicable
Stable disease
Does not qualify for complete response, partial response, or progressive 
disease
Progressive 
disease
≥20% decrease in the sum of longest diameters of target lesions; or 
unequivocal progression of enhancing non-target lesions; or new lesions; or 
substantial clinical decline
The iRANO criteria integrate into the existing RANO criteria for malignant glioma, 
low-grade glioma, and brain metastases by providing recommendations for the 
interpretation of progressive imaging changes. Speciﬁcally, iRANO recommends 
conﬁrmation of disease progression on follow-up imaging three months after initial 
radiographic progression if there is no new or substantially worsened neurological 
deﬁcits that are not due to comorbid events or concurrent medication, and it is six
months or less from starting immunotherapy. If follow-up imaging conﬁrms disease 
progression, the date of actual progression should be back-dated to the date of initial 
radiographic progression. The appearance of new lesions six months or less from the 
initiation of immunotherapy alone does not deﬁne progressive disease. 




Appendix 7:Immunotherapy Response Assessment for Neuro-Oncology 
(iRANO) Criteria
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Figure 1:
iRANO treatment algorithm for the assessment of progressive 
imaging findings in patients with neuro-oncological malignancies 
undergoing immunotherapy.
iRANO = immunotherapy Response Assessment in Neuro-Oncology.
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments 
to be completed in this study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Appendix 8:European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30
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Appendix 9
EORTC QLQ-BN20 Questionnaire
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments 
to be completed in this study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 


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Appendix 10
Pre-existing 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 where 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).  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.  
The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anaemia
Autoimmune haemolytic
anaemia
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 anaemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cholangitis
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 11
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

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.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
5.
Continue to observe the patient and document observations.


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Appendix 12
Guidelines for Management of Patients Who Experience Specific 
Adverse Events in Cohort 1
Table 1: General Guidance and Infusion-Related Reactions
General guidance and infusion-related reactions
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 the patient is likely 
to derive clinical benefit.  The decision to re-challenge patients with 
study treatment should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.

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.  Study treatment 
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 patient is likely to 
derive clinical benefit.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.  
Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures). The acceptable length of 
treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
Grade 1 or Grade 2 
(tolerable) treatment 
related events not 
described below

No dose reduction. Maintain cobimetinib at the same dose of 60 mg 
QD (3 tablets).


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
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General guidance and infusion-related reactions
Event
Action to be taken
Grade 3 or 4 or 
intolerable Grade 2 
treatment-related 
toxicities not described 
below

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. Cobimetinib dose reductions should be as
follows:
o
First appearance:  interrupt treatment until Grade ≤ 1: restart
treatment at 40 mg
o
Second appearance: interrupt treatment until Grade ≤ 1: restart
treatment at 20 mg
o
Third appearance: consider permanent discontinuation.
IRRs, anaphylaxis and 
hypersensitivity 
reaction

Guidelines for management of IRRs are provided in the Atezolizumab 
Investigator's Brochure.

For anaphylaxis precautions, see Appendix 11.

For severe hypersensitivity reactions, permanently discontinue all 
study treatment. 
IRR infusion-related reaction; QD once a day.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have
fully recovered from the event.  The decision to re-challeng patients with atezolizumab should be
based on investigator’s assessment of benefit-risk and documented by the investigator (or an
appropriate delegate).  The Medical Monitor is available to advise as needed.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
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Table 2: Gastrointestinal Toxicity
Gastrointestinal toxicity
Event
Action to be taken
Gastrointestinal 
events: general 
guidance

All events of diarrhoea or colitis should be thoroughly evaluated for 
more common aetiologies 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 
diarrhoea or loose stool, initiate maximal anti-diarrheal supportive 
care (Lomotil® and loperamide).

Suggested regimen:
o
Loperamide: Initiate dose with 4 mg, then 4 mg/6 hr around the 
clock, alternating with Lomotil.®
o
Lomotil® (diphenoxylate and atropine): Dispense 2 tablets 
(diphenoxylate 5 mg, atropine 0.05 mg) every 6 hours around the 
clock.
o
Continue Lomotil® and loperamide until no loose stools for 24 hours.
o
If Grade ≤ 2 diarrhoea persists after 48 hours of total treatment with 
Lomotil® and loperamide, consider second-line agents 
(e.g., octreotide, budesonide, tincture of opium).

Oral supplementation:
o
Initiate oral supplementation of potassium and/or magnesium if 
serum levels are < LLN.
o
Consider oral rehydration therapy (e.g., Pedialyte®) for Grade ≥1 
diarrhoea or vomiting.

Dietary modifications:
o
Stop all lactose-containing products and instruct patient to eat small 
meals.
o
Suggest the BRAT diet (banana, rice, apples, toast) diet, without 
fibre (other vegetables and fruits).
o
Encourage adequate hydration with salt-containing liquids, such as 
broth or Gatorade®.
Diarrhoea, Grade 1 or
Grade 2 (tolerable)

Continue atezolizumab and cobimetinib.

Investigate aetiology, referring patient to GI specialist for evaluation 
of possible colitis if appropriate.

Initiate supportive care and monitor patient closely


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
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Gastrointestinal toxicity
Event
Action to be taken
Diarrhoea, 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 aetiology.

Investigate aetiology 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.
Diarrhoea, 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 aetiology.

Rule out bowel perforation.

Investigate aetiology, 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 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
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Gastrointestinal toxicity
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; IV intravenous; LLN lower limit of normal; 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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
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Table 3: Dermatologic Toxicity
Dermatologic toxicity
Event
Action to be taken
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, if unresponsive to topical corticosteroids, consider 
oral prednisone 0.5 mg/kg/day.

For Grade 2 rash, consider referral to dermatologist.
Acneiform rash:

Consider topical corticosteroids (e.g., hydrocortisone 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline, or 
antibiotics covering skin flora) as clinically indicated.
Dermatologic event, 
Grade 3

Withhold atezolizumab and cobimetinib.

Refer patient to dermatologist. A biopsy should be performed if 
appropriate.

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)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
184 / Protocol MO39136, Version 5.0
Dermatologic toxicity
Event
Action to be taken

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 Steven-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab.
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 12 weeks 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 based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of treatment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challeng patients 
with atezolizumab should be based on investigator’s assessment of benefit-risk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
185 / Protocol MO39136, Version 5.0
Table 4: Elevated Liver Enzymes
Elevated liver enzymes
Event
Action to be taken
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
o
Consider withholding atezolizumab [c]
o
Consider administering 1−2 mg/kg/day oral prednisone or equivalent 
followed by ≥ 1-month taper
o
Restart atezolizumab if event resolves to Grade 1 or better within 
12 weeks [a, b]
o
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:
o
Withhold atezolizumab
o
Consider administering 1−2 mg/kg/day oral prednisone or equivalent 
followed by ≥ 1-month taper
o
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.
o
Permanently discontinue atezolizumab and cobimetinib if event does not 
resolve to Grade 1 or better within 12 weeks [a, b, c]
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-α 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 consultation with the 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.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
186 / Protocol MO39136, Version 5.0
Elevated liver enzymes
Event
Action to be taken
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-α 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 12 weeks 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 based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challeng patients with atezolizumab 
should be based on investigator’s assessment of benefit-risk and documented by the investigator 
(or an appropriate delegate).  The Medical Monitor is available to advise as needed.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
187 / Protocol MO39136, Version 5.0
Table 5: Pulmonary Events
Pulmonary events
Event
Action to be taken
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 aetiologies 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 aetiologies.
Pneumonitis, 
Grade 1 
(asymptomatic)

Continue cobimetinib.

Consider withholding atezolizumab.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.

For recurrent pneumonitis, treat as Grade 3 or 4 event.
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 aetiology, 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 or events with no improvement after 4872 hours of 
corticosteroids, 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 aetiology, initiate 
treatment with 1−2 mg/kg/day IV methylprednisolone 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.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
188 / Protocol MO39136, Version 5.0
Pulmonary events
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
Table 6: Ocular Toxicity
Ocular toxicity
Event
Action to be taken
General guidance and 
NCI CTCAE v4.0 scale 
for Eye Disorders–
Other

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) per 
NCI CTCAE v4.0 (see below). 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 Grade 1 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.

NCI CTCAE v4.0 “Eye Disorders–Other” scale:
o
Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
o
Grade 2: Moderate; minimal, local or non-invasive intervention 
indicated; limiting age appropriate instrumental ADL.
o
Grade 3: Severe or medically significant but not immediately sight 
threatening; hospitalization or prolongation of existing hospitalization 
indicated; disabling; limiting self-care ADL.
o
Grade 4: Sight-threatening consequences; urgent intervention 
indicated; blindness (20/200 or worse) in the affected eye.
Serous retinopathy, 
Grade 1 or 2 
(tolerable) per NCI 
CTCAE v4.0 scale for 
“Eye Disorders–Other”

Continue cobimetinib and atezolizumab without dose change.

Continue ophthalmology follow-up as clinically indicated.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
189 / Protocol MO39136, Version 5.0
Ocular toxicity
Event
Action to be taken
Serous retinopathy, 
Grade 2 (intolerable) 
or Grade 3 or 4 per 
NCI CTCAE v4.0 scale 
for Eye Disorders–
Other”

Interrupt cobimetinib until Grade 1 or better.

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.

The dose of cobimetinib should be reduced by one dose level when 
restarting.

Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite two dose level reductions.
Potential immune-
mediated ocular 
toxicity (e.g., uveitis, 
iritis, episcleritis, or 
retinitis)

Follow guidelines provided in the Atezolizumab Investigator's 
Brochure.

Continue cobimetinib as clinically indicated.
RVO (any grade)

If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines.

Continue atezolizumab.
ADL activities of daily living; OCT optical coherence tomography; Q4W every 4 weeks; 
RVO retinal vein occlusion.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
190 / Protocol MO39136, Version 5.0
Table 7: Left Ventricular Ejection Fraction Decrease from Baseline
Left ventricular ejection fraction 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
Not Applicable
Not Applicable
< 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
Not 
Applicable

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. The
Medical Monitor is 
available to advise as 
needed 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.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
191 / Protocol MO39136, Version 5.0
Table 8: Rhabdomyolysis or CPK Elevation
Rhabdomyolysis or CPK elevation
Event
Action to be taken
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.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
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.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
CPK creatine phosphokinase.


Appendix 12:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 1
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
192 / Protocol MO39136, Version 5.0
Table 9: Haemorrhage
Haemorrhage
Event
Action to be taken
Grade 3 haemorrhage

Interrupt cobimetinib treatment. There are no data on the 
effectiveness of cobimetinib dose modification for haemorrhage 
events. Clinical judgment should be applied when considering 
restarting cobimetinib treatment.

Continue atezolizumab treatment.
Grade 4 haemorrhage 
or any grade cerebral 
haemorrhage

Interrupt cobimetinib treatment. Permanently discontinue cobimetinib 
for haemorrhage events attributed to cobimetinib.

Continue atezolizumab treatment.


Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
193 / Protocol MO39136, Version 5.0
Appendix 13
Guidelines for Management of Patients Who Experience Specific 
Adverse Events in Cohort 2
Table 1: General Guidance and Infusion-Related Reactions
General guidance and infusion-related reactions
Event
Action to be taken
General guidance for 
dose modifications and 
treatment delays and
discontinuation

There will be no dose modifications for atezolizumab.

The dose of cobimetinib and vemurafenib can be reduced by one 
dose level in the run-in period (Cycle 1) (see Section 5.1.6.2).

During the triplet combination period (Cycles ≥ 2), 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 and/or vemurafenib at the investigator’s discretion.

During the triplet combination period (Cycles ≥ 2), vemurafenib dose 
can be reduced from 720 mg BID to 480 mg BID. If further dose 
reduction is indicated, the patient must discontinue vemurafenib but 
may continue treatment with atezolizumab and/or cobimetinib at the 
investigator’s discretion.

If atezolizumab is withheld and corticosteroids are initiated for 
treatment of a toxicity, corticosteroids 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, the patient 
should be discontinued from atezolizumab.  Study treatment 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 patient is likely to 
derive clinical benefit.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.  
Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures). The acceptable length of 
treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.

If either cobimetinib or vemurafenib is withheld for > 28 days because 
of toxicity, the patient should be discontinued from that drug, unless 
the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with study treatment should be based on 
investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
194 / Protocol MO39136, Version 5.0
General guidance and infusion-related reactions
Event
Action to be taken

After dose reduction, consideration may be given to allow for dose 
escalation of cobimetinib or vemurafenib by a maximum of one dose 
level following resolution of the adverse event that resulted in dose 
modification, provided there are no safety concerns. Dose escalation 
is not permitted during the run-in period (Cycle 1). See
Section 5.1.6.2.
IRRs, anaphylaxis and 
hypersensitivity 
reaction

Guidelines for management of IRRs are provided in the Atezolizumab 
Investigator's Brochure for atezolizumab. 

For anaphylaxis precautions, see Appendix 11 .

For severe hypersensitivity reactions, permanently discontinue all 
study treatment.
IRR infusion-related reaction.
Table 2: Gastrointestinal Toxicity
Gastrointestinal toxicity
Event
Action to be taken
Gastrointestinal 
events:  general 
guidance

All events of diarrhoea or colitis should be thoroughly evaluated for 
other more common aetiologies.

For events of significant duration or magnitude or associated with signs 
of systemic inflammation or acute phase reactants (e.g., increased 
CRP, platelet count, or bandemia): 
o
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.
Abdominal pain in 
combination with blood 
or mucus in stool 
and/or 
Grade ≥ 3 diarrhoea 
with possible colitis 
(e.g., peritoneal signs, 
ileus, or fever)

Withhold all study treatment.

Discontinue medications that may exacerbate colitis (e.g., NSAIDS).

Initiate maximum supportive care and monitor patient closely.

Investigate aetiology, ruling out bowel perforation.  Refer patient to GI 
specialist.

If immune-mediated colitis is suspected, 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.  
Consider TNF antagonists for refractory diarrhoea.

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 and vemurafenib with doses reduced by one level.  If not, 
permanently discontinue cobimetinib and vemurafenib.

When study treatment is resumed, administer supportive care and/or 
prophylactic treatment.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
195 / Protocol MO39136, Version 5.0
Gastrointestinal toxicity
Event
Action to be taken
Diarrhoea, 
Grade 1 or 2

Continue all study treatment

Initiate maximum supportive care and monitor patient closely.

Investigate aetiology, referring patient to GI specialist for evaluation of 
possible colitis if appropriate.
Diarrhoea, Grade 3

Withhold all study treatment.

Discontinue medications that may exacerbate colitis (e.g., NSAIDS) 
while investigating aetiology.

Initiate maximum supportive care and monitor patient closely.

Investigate aetiology, referring 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 [a, b, c].

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib and vemurafenib with doses reduced by one level.  If not, 
permanently discontinue cobimetinib and vemurafenib.
Diarrhoea, Grade 4

Permanently discontinue all study treatment and contact Medical 
Monitor [c]

Discontinue medications that may exacerbate colitis (e.g., NSAIDS) 
while investigating aetiology.

Initiate maximum supportive care and monitor patient closely.

Investigate aetiology, referring patient to GI specialist for evaluation of 
possible colitis, including biopsy if 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
CRP C-reactive protein; GI gastrointestinal; NSAID non-steroidal anti-inflammatory drug; 
TNFtumour necrosis factor.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
196 / Protocol MO39136, Version 5.0
Table 3: New Skin Lesion
New skin lesion
Event
Action to be taken
Cutaneous primary 
malignancy or skin 
lesion suggestive of 
cutaneous primary 
malignancy

Continue all study treatment

Treat per institutional guidelines
Table 4: Dermatologic Toxicity
Dermatologic toxicity
Event
Action to be taken
General guidance

A dermatologist should evaluate persistent and/or severe rash or pruritus.  
A biopsy should be considered unless contraindicated.
Photosensitivity, 
Grade 1

Continue all study treatment.

Initiate supportive care.
Photosensitivity, 
Grade 2

Continue atezolizumab.

Initiate supportive care per institutional guidelines.
First episode:

If event does not resolve to Grade 1 or better within 7 days, withhold 
cobimetinib and vemurafenib.

If treatment is withheld and event resolves to Grade 1 or better within 
28 days, resume cobimetinib at current dose and resume vemurafenib 
with dose reduced by one level.

If event does not resolve to Grade 1 or better within 28 days, permanently 
discontinue cobimetinib and vemurafenib.
Subsequent episodes:

Withhold cobimetinib and vemurafenib.

If event resolves to Grade 1 or better within 28 days, resume cobimetinib 
at current dose and resume vemurafenib with dose reduced by one level.

If event does not resolve to Grade 1 or better within 28 days, permanently 
discontinue cobimetinib and vemurafenib.
Photosensitivity, 
Grade 3

Withhold cobimetinib and vemurafenib.  Continue atezolizumab

Initiate supportive care per institutional guidelines.

If event resolves to Grade 1 or better within 28 days, resume cobimetinib 
at current dose and resume vemurafenib with dose reduced by one level.  
If not, permanently discontinue cobimetinib and vemurafenib.
Photosensitivity, 
Grade 4

Initiate supportive care per institutional guidelines.

If event resolves to Grade 1 or better within 28 days, resume cobimetinib 
at current dose and resume vemurafenib with dose reduced by one level.  
If not, permanently discontinue cobimetinib and vemurafenib.

Continue atezolizumab if clinically indicated.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
197 / Protocol MO39136, Version 5.0
Dermatologic toxicity
Event
Action to be taken
Dermatologic event, 
Grade 1

Continue all study treatment.

Initiate maximum supportive care (e.g., antihistamines, topical 
corticosteroids).
Dermatologic event, 
Grade 2

Continue all study treatment.

Consider patient referral to dermatologist.

Initiate maximum supportive care (e.g., antihistamines, topical 
corticosteroids).  If event does not improve, consider treatment with 
higher-potency topical corticosteroids.

If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic event, 
Grade 3

Refer patient to dermatologist.  A biopsy should be performed if 
appropriate and, if possible, photographs of the rash should be obtained 
and submitted to the Sponsor.
Acneiform rash:

Withhold atezolizumab and cobimetinib.  Continue vemurafenib.

Refer patient to dermatologist

If event does not improve within 48−72 hours, consider treatment with 
10 mg/day oral prednisone or equivalent, increasing dose to 
1−2 mg/kg/day if event still does not improve.

If event resolves to Grade 2 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue atezolizumab 
[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.

When study treatment is resumed, consider treatment with topical 
corticosteroids and oral antibiotics.
Non-acneiform (e.g., maculo-papular) rash:

Withhold vemurafenib.  Continue atezolizumab and cobimetinib.

If event resolves to Grade 2 or better within 28 days, resume vemurafenib 
with dose reduced by one level.  If not, permanently discontinue 
vemurafenib.
Dermatologic event, 
Grade 4

Permanently discontinue all study treatment and contact Medical 
Monitor [c].


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
198 / Protocol MO39136, Version 5.0
Dermatologic toxicity
Event
Action to be taken
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade)
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis:

Withhold atezolizumab and vemurafenib 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 and vemurafenib.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
199 / Protocol MO39136, Version 5.0
Table 5: Elevated Liver Enzymes
Elevated liver enzymes
Event
Action to be taken
Elevations in ALT, AST and/or bilirubin during run-in period (Cycle 1)
Elevation in ALT, AST 
and/or bilirubin, 
Grade 1 or 2 (run-in 
period/Cycle 1)

Continue cobimetinib and vemurafenib.
Elevation in ALT, AST 
and/or bilirubin, 
Grade 3 (run-in 
period/Cycle 1)

Withhold vemurafenib.  Continue cobimetinib. 

If event resolves to Grade 1 or better within 28 days, resume 
vemurafenib with dose reduced by one level.  If not, discontinue 
patient from study
Elevation in ALT, AST 
and/or bilirubin, 
Grade 4 (run-in 
period/Cycle 1)
First episode:

Withhold cobimetinib and vemurafenib.

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib and vemurafenib with doses reduced by one level.  If 
not, discontinue patient from study.
Subsequent episodes:

Discontinue patient from study
Elevations in ALT, AST and/or bilirubin during triple combination period (Cycles ≥2)
ALT, AST and bilirubin 
≤ 3 × ULN (triple 
combination 
period/Cycles ≥2)

Continue all study treatment.

Monitor ALT, AST and bilirubin at least weekly.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
200 / Protocol MO39136, Version 5.0
Elevated liver enzymes
Event
Action to be taken
ALT or AST > 3 × ULN
to 5 × ULN in 
combination with 
bilirubin ≤ 3 × ULN 
(triple combination 
period/Cycles ≥ 2)

Consider withholding all study treatment. 

Monitor ALT, AST and bilirubin at least weekly.  If values worsen, 
monitor at least every other day. 

If values have not worsened and have not resolved to ≤ 3 × ULN 
upon re-evaluation 1−20 days after event onset, consider treatment 
with 1−2 mg/kg/day oral prednisone or equivalent. 

If values have not worsened and have not resolved to ≤ 3 × ULN 
upon re-evaluation ≥ 21 days after event onset, initiate treatment 
with 1−2 mg/kg/day oral prednisone or equivalent.

If values have worsened upon re-evaluation, 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 
values do not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If treatment is withheld and values resolve to ≤ 3 × ULN before or 
within 12 weeks after initiation of corticosteroids, resume 
atezolizumab at fixed dose [a, b].

If values do not resolve to ≤ 3 × ULN within 12 weeks after initiation 
of corticosteroids, permanently discontinue atezolizumab [a, b, c].

If treatment is withheld and values resolve to ≤ 3 × ULN before or 
within 28 days after initiation of corticosteroids, resume cobimetinib 
and vemurafenib as follows:
o
If values did not worsen prior to resolution, resume cobimetinib and 
vemurafenib at current doses.
o
If values worsened prior to resolution:
First Episode:  Resume cobimetinib at current dose and resume 
vemurafenib with dose reduced by one level.
Second Episode:  Resume cobimetinib and vemurafenib with doses 
reduced by one level.
Third Episode:  Resume cobimetinib with dose reduced by one level 
and permanently discontinue vemurafenib.
Fourth Episode:  Permanently discontinue cobimetinib.

If values do not resolve to ≤ 3 × ULN within 28 days after initiation of 
corticosteroids, permanently discontinue cobimetinib and 
vemurafenib.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
201 / Protocol MO39136, Version 5.0
Elevated liver enzymes
Event
Action to be taken
ALT or AST > 5 × ULN 
to 10 × ULN in 
combination with 
bilirubin ≤ 1.5 × ULN 
(triple combination 
period/Cycles ≥ 2)

Withhold all study treatment.

Monitor ALT, AST and bilirubin at least every other day.

If values do not improve within 48 hours, 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 
values do not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 

If values improve within 48 hours but subsequently worsen or do not 
resolve to ≤ 3 × ULN within 14 days after event onset, 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 values do not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If values resolve to ≤ 3 × ULN before or within 12 weeks after 
initiation of corticosteroids, resume atezolizumab at fixed dose [a, b].

If values do not resolve to ≤ 3 × ULN within 12 weeks after initiation 
of corticosteroids, permanently discontinue atezolizumab [a, b, c].

If values resolve to ≤ 3 × ULN before or within 28 days after initiation 
of corticosteroids, resume cobimetinib and vemurafenib as follows:
First Episode:  Resume cobimetinib at current dose and resume 
vemurafenib with dose reduced by one level.
Second Episode:  Resume cobimetinib and vemurafenib with doses 
reduced by one level.
Third Episode:  Resume cobimetinib with dose reduced by one level 
and permanently discontinue vemurafenib.
Fourth Episode:  Permanently discontinue cobimetinib.

If values do not resolve to ≤ 3 × ULN within 28 days after initiation of 
corticosteroids, permanently discontinue cobimetinib and 
vemurafenib.
ALT or AST > 5 × ULN 
to 10 × ULN in 
combination with
bilirubin > 1.5 × ULN to 
3 × ULN
or 
ALT or AST ≤ 10 × 
ULN in combination 
with bilirubin > 3 × 
ULN (triple 
combination period)

Withhold all study treatment.

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 values do not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

Monitor ALT, AST and bilirubin at least every other day.

If values resolve to ≤ 3 × ULN within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab [a, b, c].

If values resolve to ≤ 3 × ULN within 28 days, resume cobimetinib at 
current dose and resume vemurafenib with dose reduced by one 
level. If not, permanently discontinue cobimetinib and vemurafenib.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
202 / Protocol MO39136, Version 5.0
Elevated liver enzymes
Event
Action to be taken
ALT > 10 × ULN with 
or without elevation of 
AST or bilirubin 
or 
Confirmed cases of 
Hy's law with no 
identifiable cause 
other than study 
treatment (triple 
combination period)

Permanently discontinue all study treatment and contact Medical 
Monitor [c].

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 values do not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
203 / Protocol MO39136, Version 5.0
Table 6: Pulmonary Events
Pulmonary events
Event
Action to be taken
Pulmonary event, 
Grade 1

Continue all study treatment and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.

For recurrent events, treat as a Grade 3 or 4 event.

For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary event, 
Grade 2

Withhold atezolizumab.  Consider withholding cobimetinib and vemurafenib.

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 within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue atezolizumab 
and contact Medical Monitor [a, b, c].

If cobimetinib and vemurafenib are withheld and event resolves to Grade 1 
or better within 28 days, resume cobimetinib and vemurafenib at current 
doses.

If event does not resolve to Grade 1 or better within 28 days, permanently 
discontinue cobimetinib and vemurafenib.

For recurrent events or events with no improvement after 4872 hours of 
corticosteroids, treat as a Grade 3 or 4 event.
Pulmonary event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor [c].  
Withhold cobimetinib and vemurafenib.

Bronchoscopy or BAL is recommended.

Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 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.

If event resolves to Grade 1 or better within 28 days, cobimetinib and 
vemurafenib may be resumed with doses reduced by one level.  If not, 
permanently discontinue cobimetinib and vemurafenib.
BAL bronchoscopic alveolar lavage.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
204 / Protocol MO39136, Version 5.0
Table 7: Endocrine Disorders
Endocrine disorders
Event
Action to be taken
Asymptomatic 
hypothyroidism

Continue all study treatment.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Symptomatic 
hypothyroidism

Withhold atezolizumab.  Continue cobimetinib and vemurafenib.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

Consider patient referral to endocrinologist.

When symptoms are controlled and thyroid function is improving, resume 
atezolizumab.
Asymptomatic 
hyperthyroidism
TSH ≥ 0.1 mU/L and < 0.5 mU/L:

Continue all study treatment.

Monitor TSH every 4 weeks.

Consider patient referral to endocrinologist.
TSH < 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.

Consider patient referral to endocrinologist.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.  Continue cobimetinib and vemurafenib.

Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed.

Consider patient referral to endocrinologist.

When symptoms are controlled and thyroid function is improving, resume 
atezolizumab.

For life-threatening immune-mediated hyperthyroidism, permanently 
discontinue atezolizumab, withhold cobimetinib and vemurafenib, and 
contact Medical Monitor [c].  If event becomes clinically manageable 
within 28 days, resume cobimetinib and vemurafenib with doses reduced 
by one level.  If not, permanently discontinue cobimetinib and 
vemurafenib.
Adrenal 
insufficiency, 
Grade 2, 3, or 4

Withhold atezolizumab.  Continue cobimetinib and vemurafenib.

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 within 12 weeks, resume atezolizumab at current dose.

If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy within 12 weeks, permanently discontinue 
atezolizumab and contact Medical Monitor [a, b, c].


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
205 / Protocol MO39136, Version 5.0
Endocrine disorders
Event
Action to be taken
Hyperglycaemia, 
Grade 1 or 2

Continue all study treatment.

Initiate treatment with insulin if needed. Consider cobimetinib dose 
modification per general guidelines as clinically indicated.

Monitor for glucose control.
Hyperglycaemia, 
Grade 3 or 4

Withhold atezolizumab.  Continue cobimetinib and vemurafenib.

Initiate treatment with insulin.

Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines.

Monitor for glucose control.

When symptoms resolve and glucose levels are stable, resume 
atezolizumab.
TSH thyroid-stimulating hormone.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
206 / Protocol MO39136, Version 5.0
Table 8: Pancreatic Events
Pancreatic events
Event
Action to be taken
Amylase and/or lipase 
elevation, Grade 1

Continue all study treatment.

Monitor amylase and lipase prior to dosing.
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0 ULN:

Continue all study treatment.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., > 3 weeks), consider treatment with 
10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:

Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab and vemurafenib.  Continue cobimetinib.

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 within 12 weeks, resume 
atezolizumab.  If not, permanently discontinue atezolizumab and 
contact Medical Monitor [a, b, c].

If event resolves to Grade 1 or better within 28 days, resume 
vemurafenib with dose reduced by one level.  If not, permanently 
discontinue vemurafenib.

For recurrent events, permanently discontinue all study treatment 
and contact Medical Monitor [c].
Pancreatitis, Grade 3

Withhold all study treatment.

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 within 12 weeks, resume 
atezolizumab.  If not, permanently discontinue atezolizumab and 
contact Medical Monitor [a, b, c].

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib at current dose and resume vemurafenib with dose 
reduced by one level.  If not, permanently discontinue cobimetinib 
and vemurafenib.

For recurrent events, permanently discontinue all study treatment 
and contact Medical Monitor [c].


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
207 / Protocol MO39136, Version 5.0
Pancreatic events
Event
Action to be taken
Pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor.  
Consider permanently discontinuing cobimetinib and vemurafenib.  

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.

If cobimetinib and vemurafenib are withheld and event resolves to 
Grade 1 or better within 28 days, resume cobimetinib at current dose 
and resume vemurafenib with dose reduced by one level.  If event 
does not resolve to Grade 1 or better within 28 days, permanently 
discontinue cobimetinib and vemurafenib.
GI gastrointestinal.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
208 / Protocol MO39136, Version 5.0
Table 9: Neuropathy Disorders
Neuropathy disorders
Event
Action to be taken
Neuropathy, Grade 1

Continue all study treatment.

Investigate aetiology.
Neuropathy, Grade 2

Withhold atezolizumab.  Continue cobimetinib and vemurafenib.

Investigate aetiology and refer patient to neurologist.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab.  If not, permanently discontinue atezolizumab and 
contact Medical Monitor [a,b,c].
Neuropathy, Grade 3

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Continue cobimetinib and vemurafenib.

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.
Neuropathy, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Withhold cobimetinib and vemurafenib.

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

If patient stabilizes within 28 days, consider resuming cobimetinib at 
current dose and vemurafenib with dose reduced by one level.  If 
not, permanently discontinue cobimetinib and vemurafenib.
Myasthenia gravis or 
Guillain-Barre 
syndrome, Grades 1, 
2, or 3

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Continue cobimetinib and vemurafenib.

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with 1−2 mg/kg/day oral or IV prednisone or 
equivalent.
Myasthenia gravis or 
Guillain-Barré 
syndrome, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Withhold cobimetinib and vemurafenib.

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with 1−2 mg/kg/day oral or IV prednisone or 
equivalent.

If patient stabilizes within 28 days, resume cobimetinib and 
vemurafenib at current doses.  If not, permanently discontinue 
cobimetinib and vemurafenib.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
209 / Protocol MO39136, Version 5.0
Neuropathy disorders
Event
Action to be taken
Immune-mediated
meningoencephalitis, 
any grade

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Withhold cobimetinib and vemurafenib.

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.

If patient stabilizes within 28 days, resume cobimetinib and 
vemurafenib at current doses.  If not, permanently discontinue 
cobimetinib and vemurafenib.
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 12 weeks 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 based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of treatment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
210 / Protocol MO39136, Version 5.0
Table 10: Ocular Toxicity
Ocular toxicity
Event
Action to be taken
Potential immune-mediated
ocular toxicity (e.g., uveitis, 
retinal events), Grade 1

Continue all study treatment.

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.
Potential immune-mediated
ocular toxicity (e.g., uveitis, 
retinal events), Grade 2

Withhold atezolizumab and vemurafenib.  Continue cobimetinib.

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 within 12 weeks, resume 
atezolizumab.  If not, permanently discontinue atezolizumab 
and contact Medical Monitor [a, b, c].

If event resolves to Grade 1 or better within 28 days, resume 
vemurafenib with dose reduced by one level.  If not, 
permanently discontinue vemurafenib.
Potential immune-mediated
ocular toxicity (e.g., uveitis, 
retinal events), Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor [c].  Withhold cobimetinib and vemurafenib.

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.

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib at current dose and resume vemurafenib with dose 
reduced by one level.  If not, permanently discontinue 
cobimetinib and vemurafenib.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
211 / Protocol MO39136, Version 5.0
Ocular toxicity
Event
Action to be taken
Other ocular toxicity 
(i.e., not immune related)

Withhold cobimetinib and vemurafenib.  Continue atezolizumab.

Refer patient to ophthalmologist.
Retinal vein occlusion:

Permanently discontinue cobimetinib and vemurafenib.
Serous retinopathy, Grade 1:

Resume cobimetinib and vemurafenib at current doses.

Continue ophthalmology follow-up.
Serous retinopathy, Grade 2 or 3:

Resume vemurafenib at current dose.

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, permanently 
discontinue cobimetinib.
Serous retinopathy, Grade 4:

Permanently discontinue cobimetinib.  Withhold vemurafenib.   

If event resolves to Grade 1 or better within 28 days, resume 
vemurafenib with dose reduced by one level.  If not, 
permanently discontinue vemurafenib.
All other ocular events, Grade 1:

Resume cobimetinib and vemurafenib at current doses.
All other ocular events, Grade 2, 3, or 4:

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib and vemurafenib at current doses.  If not, 
permanently discontinue cobimetinib and vemurafenib.
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 12 weeks 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 based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of treatment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
212 / Protocol MO39136, Version 5.0
Table 11: QT Interval Prolongation
QT interval prolongation
Event
Action to be taken
QTcF ≤ 500 ms with 
change from baseline 
in QTcF of < 60 ms

Continue all study treatment.
QTcF > 500 ms with 
change from baseline 
in QTcF of < 60 ms
or
QTcF ≤ 500 ms with 
change from baseline 
in QTcF of ≥ 60 ms

Withhold vemurafenib.  Continue atezolizumab and cobimetinib.

Rule out other risk factors for arrhythmia (e.g., myocardial 
ischemia).  Check for electrolyte disturbances (e.g., potassium, 
magnesium and calcium).

Evaluate concomitant medications to determine if there is 
co-administration of drugs that prolong QT interval.

Refer patient to cardiologist.

Monitor ECG weekly.

If QTcF improves to ≤ 500 ms or baseline within 28 days, resume 
vemurafenib with dose reduced by one level.  Repeat ECG at 2 and 
4 weeks after resuming vemurafenib, on Day 15 of each 
subsequent cycle for three cycles, and then every 3 months 
thereafter.

If QTcF does not improve to ≤ 500 ms or baseline within 28 days, 
permanently discontinue vemurafenib.
QTcF > 500 ms with 
change from baseline 
in QTcF of ≥ 60 ms

Permanently discontinue vemurafenib.  Continue atezolizumab and 
cobimetinib.

Rule out other risk factors for arrhythmia (e.g., myocardial 
ischemia).  Check for electrolyte disturbances (e.g., potassium, 
magnesium and calcium).

Evaluate concomitant medications to determine if there is 
co-administration of drugs that prolong QT interval.

Refer patient to cardiologist.

Monitor ECG weekly until QTcF improves to ≤ 500 ms or baseline.
ECG electrocardiogram; QTcF QT interval corrected using Fridericia’s method.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
213 / Protocol MO39136, Version 5.0
Table 12: Left Ventricular Ejection Fraction Decrease from Baseline
Left ventricular ejection fraction decrease from baseline
Patient
LVEF Value
Recommended Action 
with Cobimetinib, 
Atezolizumab and 
Vemurafenib
LVEF Value 
following 
Treatment Break
Recommended 
Cobimetinib 
Daily Dose
Asymptomatic
≥50% 
or
40%−49% and 
< 10% 
absolute 
decrease from 
baseline

Continue all study 
treatment.
Not Applicable
Not Applicable
< 40%
or
40%−49% and 
≥10% 
absolute 
decrease from 
baseline

Withhold 
cobimetinib for at 
least 2 weeks

Continue 
atezolizumab and 
vemurafenib

Re-evaluate LVEF 
at 14 days
< 10% absolute 
decrease from 
baseline
First 
occurrence: 
40 mg [a]
Second 
occurrence: 
20 mg [a]
Third 
occurrence: 
permanent 
discontinuation
< 40% or ≥ 10% 
absolute decrease 
from baseline
Permanent 
discontinuation
For all patients restarting treatment:

re-evaluate LVEF at 2, 4, 10 and 16 weeks and then every 
12 weeks (3 cycles as per protocol) or as clinically indicated 
until treatment discontinuation
For patients who permanently discontinue cobimetinib:

LVEF assessments should continue post treatment every 
6 weeks or as clinically indicated until the LVEF recovers to 
LLN or 50%


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
214 / Protocol MO39136, Version 5.0
Left ventricular ejection fraction decrease from baseline
Patient
LVEF Value
Recommended Action 
with Cobimetinib, 
Atezolizumab and 
Vemurafenib
LVEF Value 
following 
Treatment Break
Recommended 
Cobimetinib 
Daily Dose
Symptomatic
Not Applicable

Withhold 
cobimetinib for at 
least 4 weeks

Continue 
atezolizumab and 
vemurafenib.

Patient referral to 
cardiologist is 
strongly 
recommended

Re-evaluate LVEF 
at 28 days
Asymptomatic and 
< 10% absolute 
decrease from 
baseline
First 
occurrence: 
40 mg [a]
Second 
occurrence: 
20 mg [a]
Third 
occurrence: 
permanent 
discontinuation 
Asymptomatic and 
< 40% or ≥ 10% 
absolute decrease 
from baseline
Permanent 
discontinuation
Symptomatic 
regardless of 
LVEF
Permanent 
discontinuation
For all patients restarting treatment:

re-evaluate LVEF at 2, 4, 10 and 16 weeks and then every 
12 weeks (3 cycles as per protocol) or as clinically indicated 
until treatment discontinuation
For patients (asymptomatic and symptomatic) who permanently 
discontinue cobimetinib:

LVEF assessments should continue post treatment every 6 
weeks or as clinically indicated until the LVEF recovers to 
LLN or 50% and or symptoms resolve
LLN lower limit of normal; LVEF left ventricular ejection fraction.
a.
Patients on a cobimetinib dose less than 60 mg will reduce by one dose level reduction (a 20-mg 
daily reduction), from a 40 mg daily dose to a 20 mg daily dose, and patients on a 20 mg daily 
dose at the time of the interruption (for LVEF decline) should discontinue cobimetinib.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
215 / Protocol MO39136, Version 5.0
Table 13: Rhabdomyolysis or CPK Elevation
Rhabdomyolysis or CPK elevation
Event
Action to be taken
General guidance

Consider withholding cobimetinib while investigating aetiology.  
Continue atezolizumab and vemurafenib.

Assess patient for any history of strenuous physical activity, blunt 
trauma, or recent intramuscular injections.

Evaluate for cardiac injury and rhabdomyolysis.  If evidence of 
clinically significant cardiac injury or rhabdomyolysis, consider 
permanent discontinuation of cobimetinib.
Asymptomatic CPK 
elevation, Grade 1, 2, 
or 3

Continue all study treatment.
Rhabdomyolysis or 
symptomatic CPK 
elevation, Grade 1, 2, 
or 3

Withhold cobimetinib.  Continue atezolizumab and vemurafenib.

If event improves by at least one grade within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, permanently 
discontinue cobimetinib.
Rhabdomyolysis or 
CPK elevation 
(symptomatic or 
asymptomatic), Grade 
4

Withhold cobimetinib.  Continue atezolizumab and vemurafenib.

If event improves to Grade ≤ 3 within 28 days, resume cobimetinib 
with dose reduced by one level.  If not, permanently discontinue 
cobimetinib.
Grade 3 or 4 or 
intolerable Grade 2 
treatment-related 
toxicities not described 
above

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 and vemurafenib with doses reduced by one level.  If 
not, permanently discontinue cobimetinib and vemurafenib.
CPK creatine phosphokinase.
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 12 weeks 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 based on an assessment of benefitrisk by the investigator and
in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
c.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 13:  Guidelines for Management of Patients Who Experience 
Specific Adverse Events in Cohort 2
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
216 / Protocol MO39136, Version 5.0
Table 14: Haemorrhage
Haemorrhage
Event
Action to be taken
Grade 3 events

Interrupt cobimetinib treatment.  There is no data on the 
effectiveness of cobimetinib dose modifications for haemorrhage 
events.

Clinical judgment should be applied when considering restarting 
cobimetinib treatment. 

Vemurafenib dosing can be continued when cobimetinib treatment 
is interrupted, if clinically indicated.

Continue atezolizumab treatment
Grade 4 events or 
cerebral haemorrhage 
(all grades)

Interrupt cobimetinib treatment.

Permanently discontinue cobimetinib for haemorrhage events 
attributed to cobimetinib.

Interrupt vemurafenib and restart if event improves within 28 days.

Continue atezolizumab unless clinically indicated.


Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
217 / Protocol MO39136, Version 5.0
Appendix 14
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 aetiology.  
Although most immune-mediated adverse events observed with immunomodulatory 
agents 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 a given patient may be 
experiencing 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.  The decision to re-challenge patients with atezolizumab 
should be based on investigator’s assessment of benefit-risk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.  Atezolizumab treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures).  The acceptable 
length of treatment interruption must be based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of 


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
218 / Protocol MO39136, Version 5.0
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnoea, 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 tumour assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
aetiologies 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.
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.

For Grade 1 pneumonitis, consider withholding atezolizumab.
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 or events with no improvement after 4872 hours 
of corticosteroids, 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 IV methylprednisolone 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 to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
219 / Protocol MO39136, Version 5.0
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
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.  The decision to re-challeng 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
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 aetiologies 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].
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 aetiology 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.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
220 / Protocol MO39136, Version 5.0

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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhoea or colitis are provided in Table 3.
All events of diarrhoea or colitis should be thoroughly evaluated for other more common 
aetiologies.  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. 
Table 3:
Management Guidelines for Gastrointestinal Events (Diarrhoea or 
Colitis)
Event
Management
Diarrhoea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhoea 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].


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
221 / Protocol MO39136, Version 5.0
Event
Management
Diarrhoea 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].
Diarrhoea 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 to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
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.  The decision to re-challeng 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
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 


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
222 / Protocol MO39136, Version 5.0
(e.g., TSH, growth hormone, luteinizing hormone, FSH, 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.
Table 4:
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

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.

Consider patient referral to endocrinologist.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.

Consider patient referral to endocrinologist.
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].
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].
Hyperglycaemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
223 / Protocol MO39136, Version 5.0
Event
Management

Monitor for glucose control.
Hyperglycaemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose levels 
are stable.
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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients 
with atezolizumab should be based on investigator’s assessment of benefit-risk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
224 / Protocol MO39136, Version 5.0
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 to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
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.  The decision to re-challeng 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
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, 
dyspnoea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
225 / Protocol MO39136, Version 5.0
Myocarditis may also be a clinical manifestation of myositis and should be managed 
accordingly.  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 pre-
existing 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 aetiology, should be treated according to the guidelines in Table 6.
Table 6:
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2-4

Permanently discontinue atezolizumab and contact Medical 
Monitor [a].

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.
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an IRR or CRS with atezolizumab may receive 
premedication with antihistamines, antipyretics and/or analgesics (acetaminophen is 
prohibited for patients in Cohort 2 only; see Section 4.4.5) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
226 / Protocol MO39136, Version 5.0
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.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 
2020).  If a patient develops suspected CRS during the study, a differential diagnosis 
should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or 
radiologic evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 
infection is confirmed, the disease should be managed as per local or institutional 
guidelines.
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.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
227 / Protocol MO39136, Version 5.0
Event
Management

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 [e].

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.

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.
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 

Permanently discontinue atezolizumab and contact Medical Monitor [f].

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).


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
228 / Protocol MO39136, Version 5.0
Event
Management
mask, or Venturi 
mask

Consider anti-cytokine therapy [e].

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 [f].

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 [e]. For patients who are refractory to 
anti-cytokine therapy, experimental treatments [g] may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
229 / Protocol MO39136, Version 5.0
Event
Management
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:  The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a.
Grading system for 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.
There are case reports where anti-cytokine therapy has been used for treatment of CRS 
with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but 
data are limited, and the role of such treatment in the setting of antibody-associated CRS 
has not been established.
f.
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.  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 after consulting the Medical Monitor and considering the benefitrisk 
ratio.
g.
Refer to Riegler et al. (2019).
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 work-up 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.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
230 / Protocol MO39136, Version 5.0
Table 8:
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0 ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:

Treat as a Grade 3 event.
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].
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].


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
231 / Protocol MO39136, Version 5.0
Event
Management
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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  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.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
232 / Protocol MO39136, Version 5.0
Event
Management

Consider treatment with higher-potency topical corticosteroids if event does 
not improve.

If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
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].
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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 work-up is essential for an accurate characterization to 
differentiate between alternative aetiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
233 / Protocol MO39136, Version 5.0
Table 10: Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, Grade 1

Continue atezolizumab.

Investigate aetiology.
Immune-mediated 
neuropathy, Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset [a].

Investigate aetiology and refer patient to neurologist.

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].

Refer patient to neurologist.

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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
234 / Protocol MO39136, Version 5.0
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 
oedema.  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 aetiology, 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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 
aetiologies (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.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
aetiology, should be treated according to the guidelines in Table 12 below.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
235 / Protocol MO39136, Version 5.0
Table 12: Management Guidelines for Renal Events
Event
Management
Renal event, Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine and urine protein, 
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 [c]. 

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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 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.  


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
236 / Protocol MO39136, Version 5.0
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis.
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 to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
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.  The decision to re-challeng 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed. 


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
237 / Protocol MO39136, Version 5.0
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
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 permanently discontinue atezolizumab 
and contact Medical Monitor [c].  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 to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
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.  The decision to re-challeng patients with 
atezolizumab should be based on investigator’s assessment of benefit-risk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
238 / Protocol MO39136, Version 5.0
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 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 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
239 / Protocol MO39136, Version 5.0
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.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from:
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role 
for monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric 
Rheumatology International Trials Organisation Collaborative Initiative. Ann 
Rheum Dis 2016;75:4819.


Appendix 14:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Cobimetinib, atezolizumab, vemurafenib — F. Hoffmann-La Roche Ltd
240 / Protocol MO39136, Version 5.0
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther 
Clin Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.

SAP_001.pdf: 
 
Official Title: 
A Phase II Two Cohort Study Evaluating the Safety and Efficacy of 
Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With 
Central Nervous System Metastases and Cobimetinib Plus 
Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive 
Melanoma With Central Nervous System Metastases 
NCT Number: 
NCT03625141 
Document Date: 
Statistical Analysis Plan (SAP) Version 2: 02-June-2021 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
SPONSOR:
LEGAL REGISTERED 
ADDRESS:
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
DATE FINAL:
See electronic date stamp above
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab, Cobimetinib, and Vemurafenib —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO39136
STATISTICAL ANALYSIS PLAN
STUDY TITLE: A PHASE II TWO COHORT STUDY EVALUATING THE SAFETY 
AND EFFICACY OF COBIMETINIB PLUS ATEZOLIZUMAB IN 
BRAFV600 WILD-TYPE MELANOMA WITH CENTRAL NERVOUS 
SYSTEM METASTASES AND COBIMETINIB PLUS 
ATEZOLIZUMAB AND VEMURAFENIB IN BRAFV600
MUTATION-POSITIVE MELANOMA WITH CENTRAL NERVOUS 
SYSTEM METASTASES
STUDY NUMBER:
MO39136
STUDY NAME:
Tricotel
VERSION NUMBER:
2
ROCHE COMPOUND(S):
Cobimetinib (RO5514041)
Atezolizumab (RO5541267)
Vemurafenib (RO5185426)
EUDRACT NUMBER:
2018-000759-41
IND NUMBER:
117296, 135717, and 111271
PLAN PREPARED BY:
 (Cytel)
Date and Time(UTC)        Reason for Signing                              Name
02-Jun-2021 20:21:18
(
)
Company Signatory


Atezolizumab, Cobimetinib, and Vemurafenib —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO39136
2
STATISTICAL ANALYSIS PLAN VERSION HISTORY
This statistical analysis plan (SAP) was developed based on Roche SAP model 
document updated on 26 October 2020.
SAP Version
Approval Date
Based on Protocol
(Version, Approval Date)
2.0
see electronic date stamp 
on title page
|day month year|
Version 4.0, 26 February 2020
1.0
17 April 2019
Version 2.0, 6 November 2018


Atezolizumab, Cobimetinib, and Vemurafenib —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO39136
3
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
Key changes to the SAP, along with the rationales for each change, are summarized 
below.
Section
Description of 
Change
Rationale for Change
4
Patient-reported 
outcome
(PRO)-evaluable 
population added
for the PRO 
analysis
It is stated in the protocol that “Only patients with a 
non-missing baseline assessment and at least one 
non-missing post-baseline assessment will be included in 
PRO analyses.” For clarify purpose, we added PRO 
population in the Section 4 and clarified that this population 
will be used for PRO analysis to ensure compliance with the 
protocol.
5.1
Only a subset of 
efficacy analysis 
will be done on 
Cohort 1
Given that the recruitment of Cohort 1 was stopped 
prematurely, it is no longer appropriate to produce all the 
efficacy analysis due to small sample size. Thus, the 
Statistical Analysis Plan is updated to limit the efficacy 
analysis.
5.3.1
No analysis on 
primary endpoint 
on Cohort 1
After the premature discontinuation of Cohort 1, it was 
decided to not perform the independent review of scan for 
patients in Cohort 1. Thus, all analyses on the primary 
endpoint will be performed on Cohort 2 only. 
5.3.3
Adding sensitivity 
analysis of primary 
endpoints on all 
treated patients 
(safety population)
The analysis on primary endpoint is planned on evaluable 
population only, which excludes subjects with less than 
2 scans. Excluding these subjects could lead to an inflation 
of the response rate by excluding the early progression or 
death. Therefore, we add an analysis on all treated patients 
to assess the bias introduced by excluding these patients.
5.3.4.1
New subgroup
Additional subgroup added to better explore the effect of 
demographic characteristics and clinical and biological 
prognostic factors on the efficacy endpoint.
5.4
Adding analysis 
secondary efficacy 
endpoints on all 
treated patients 
(safety population)
The analysis on efficacy endpoint (objective response rate
[ORR], progression-free survival [PFS], and disease control 
rate [DCR]) are planned on evaluable population, which 
excludes subjects with less than 2 scans. Excluding these 
subjects could lead to an inflation of the response rate by 
excluding the early progression or death. Therefore, we add 
an analysis on all treated patients to assess the bias 
introduced by excluding these patients.
5.4.2.8
Update the 
definition of time to 
deterioration (TTD) 
to a decrease of 
10 point from 
baseline for 
functional scale
TTD will be 
performed on each 
scale separately
A high score on functional scale and a low score on symptom 
scale is an improvement as per the scoring manual. Thus, a 
deterioration for functioning scale and Global Health Status
(GHS)/ Quality-of-Life (QoL) for Core 30 (QLQ-C30) is 
defined by a decrease of 10 point from baseline. A 
deterioration for symptoms scale for QLQ-C30 and items for 
Quality-of-Life Questionnaire brain cancer module
(QLQ-BN20) is defined by an increase of 10 point from 
baseline.


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Statistical Analysis Plan MO39136
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Each scale measure different functions and symptoms.
Thus, it is more meaningful to evaluate the TTD on each 
symptom and function separately. 
5.5.1.6
Add analysis on 
change in 
corticosteroid use
New analyses are added to explore the change in 
corticosteroid use based on data collected case report form
(CRF).
5.5.1.8
Add PFS, duration 
of response (DoR)
and DCR by 
independent review 
committee (IRC)
To assess the bias introduced on efficacy endpoint as 
determined by investigator using response evaluation criteria 
in solid tumors (RECIST).
5.6
Safety analysis will 
be done separately 
for patients in 
Cohort 2 who 
actually received 
and didn’t receive 
the triplet 
combination during 
the treatment 
period
To evaluate safety on patients who actually received the
triplet combination and those who received only cobimetinib 
and vemurafenib.
Patients in Cohort 2 will receive cobimetinib and vemurafenib
during the run-in period (Cycle 1) and with the triplet 
combination (cobimetinib, atezolizumab, and vemurafenib) 
post run-in (Cycle 2 onwards). 
6.2
Replaced analysis 
of adverse events 
(AEs) by highest 
grade by analysis 
of AE by System 
Organ Class (SOC)
and Preferred Term 
(PT)
Summary of some AEs (such as AE leading to study drug 
discontinuation, etc.) by highest grade are removed when not 
appropriate. They are replaced by a summary of the 
incidence by SOC and PT only.
5.6.2
Add a list of 
suspected 
Coronavirus 
Disease (COVID) 
case
To identify potential COVID case in the study, if any.
5.6.2
Add analysis on AE 
during run-in and 
post run-in in 
Cohort 2
To evaluate safety during triple combination period and 
during the period where only cobimetinib and vemurafenib
are administered.
5.7.1
Add summary of 
pharmacodynamic 
related to COVID
To assess potential impact of COVID.
Additional minor changes have been made throughout to improve clarity and 
consistency.


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 3
1.
INTRODUCTION ........................................................................................ 10
1.1
Objectives and Endpoints...................................................... 10
1.2
Study Design ......................................................................... 13
1.2.1
Treatment Assignment........................................................... 16
1.2.2
Independent Review Facility.................................................. 16
1.2.3
Data Monitoring ..................................................................... 16
2.
STATISTICAL HYPOTHESES.................................................................... 16
3.
SAMPLE SIZE DETERMINATION.............................................................. 16
4.
ANALYSIS SETS ........................................................................................ 17
5.
STATISTICAL ANALYSES ......................................................................... 18
5.1
General Consideration........................................................... 18
5.2
Participant Disposition ........................................................... 18
5.3
Primary Endpoint Analysis..................................................... 18
5.3.1
Definition of Primary Endpoint ............................................... 19
5.3.2
Main Analytical Approach for Primary Endpoint..................... 19
5.3.3
Sensitivity Analyses for Primary Endpoint ............................. 19
5.3.4
Supplementary Analyses for Primary Endpoint ..................... 19
5.3.4.1
Subgroup Analyses for Primary Endpoint.............................. 19
5.4
Secondary Endpoints Analyses............................................. 20
5.4.1
Key/Confirmatory Secondary Endpoint.................................. 20
5.4.2
Supportive Secondary Endpoints .......................................... 20
5.4.2.1
Intracranial Objective Response Rate – RECIST .................. 20
5.4.2.2
Extracranial Objective Response Rate – RECIST................. 20
5.4.2.3
Overall Objective Response Rate – RECIST......................... 20
5.4.2.4
Intracranial, Extracranial and Overall 
Progression-Free Survival – RECIST .................................... 20
5.4.2.5
Intracranial, Extracranial and Overall Duration of 
Response – RECIST ............................................................. 21
5.4.2.6
Intracranial, Extracranial and Overall Disease 
Control Rate at 16 Weeks – RECIST .................................... 21


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5.4.2.7
Overall Survival ..................................................................... 22
5.4.2.8
Patient-Reported Outcomes .................................................. 22
5.5
Exploratory Endpoints Analysis ............................................. 24
5.5.1.1
Intracranial Objective Response Rate - iRANO..................... 24
5.5.1.2
Intracranial, Extracranial and Overall Objective 
Response Rate – Immune-modified RECIST ........................ 24
5.5.1.3
Intracranial, Extracranial and Overall Progression 
Free Survival – Immune-modified RECIST............................ 24
5.5.1.4
Intracranial, Extracranial and Overall Duration of 
Response – Immune-modified RECIST................................. 24
5.5.1.5
Radiotherapy-Assisted Progression Free Survival 
– RECIST .............................................................................. 24
5.5.1.6
Timing of Increase or Change in Corticosteroid 
Use ........................................................................................ 25
5.5.1.7
Time to Subsequent Intracranial and Systemic 
Anti-Cancer Treatment .......................................................... 25
5.5.1.8
DoR, DCR and PFS by IRC – RECIST.................................. 25
5.6
Safety Analyses..................................................................... 26
5.6.1
Extent of Exposure ................................................................ 26
5.6.2
Adverse Events ..................................................................... 26
5.6.3
Laboratory Data..................................................................... 27
5.6.4
Vital Signs.............................................................................. 28
5.7
Other Analyses...................................................................... 28
5.7.1
Summaries of Conduct of Study............................................ 28
5.7.2
Summaries of Treatment Group 
Comparability/Demographics and Baseline 
Characteristics....................................................................... 28
5.8
Interim Analyses .................................................................... 29
5.8.1
Planned Interim Analyses...................................................... 29
5.8.2
Optional Interim Analyses...................................................... 29
6.
SUPPORTING DOCUMENTATION............................................................ 29
7.
REFERENCES ........................................................................................... 29


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LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 10
Table 2
Objective Response Rate Estimates and Confidence 
Intervals with 50 Evaluable Patients per Treatment Cohort ........ 17
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 15


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or 
Term
Description
AE
adverse event
BRAFV600
V600 codon of the BRAF oncogene
CI
confidence interval
CNS
central nervous system
COVID
Coronavirus Disease 
CR
complete response
CRF
case report form
DCR
disease control rate
DoR
duration of response
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EORTC
European Organization for the Research and Treatment of Cancer
GHS
Global Health Status
HRQoL
health-related qualify of life
IMC
Internal Monitoring Committee
iRANO
immunotherapy Response Assessment for Neuro-Oncology
IV
intravenous (ly)
IRC
independent review committee
LDH
Lactic Acid Dehydrogenase 
LPI
last patient in (last patient enrolled)
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NA
not applicable
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-L1
programmed death ligand 1
PFS
progression free survival
PR
partial response
PRO
patient-reported outcome
PT
Preferred Term
QLQ-C30
Quality-of-Life Questionnaire Core 30


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QLQ-BN20
Quality-of-Life Questionnaire - Brain Cancer Module
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum of longest diameter
SOC
System Organ Class
SRT
stereotactic radiotherapy
TEAE
treatment-emergent adverse event
TTD
time to deterioration
ULN
upper limit of normal


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) provides details of the planned analyses and
statistical methods for Study MO39136 (TRICOTEL): A Phase II, two cohort study 
evaluating the safety and efficacy of cobimetinib plus atezolizumab in BRAFV600 wild-type 
melanoma with central nervous system metastases and cobimetinib plus atezolizumab 
and vemurafenib in BRAFV600 mutation positive melanoma with central nervous system 
metastases. The background for the study can be found in the study protocol.
1.1
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in 
patients with BRAFV600 wild-type melanoma with central nervous system (CNS)
metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600
mutation-positive melanoma patients with CNS metastases. Specific objectives and 
corresponding endpoints for the study are outlined Table 1 below. 
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objectives
Corresponding Endpoints

To evaluate intracranial ORR with 
cobimetinib plus atezolizumab in 
BRAFV600 wild-type melanoma as 
assessed by an IRC 

To evaluate intracranial ORR with 
cobimetinib plus atezolizumab and 
vemurafenib in BRAFV600 
mutation-positive melanoma as 
assessed by an IRC 

Intracranial ORR defined as the proportion of 
patients with either a CR or PR in their 
intracranial disease based on two consecutive 
assessments 4 weeks apart. Disease status 
for this endpoint will be determined by an IRC 
in accordance with RECIST v1.1 with modified 
measurability definition for intracranial lesions 
(0.5 cm by MRI) and allowing up to five 
intracranial target lesions 
Secondary Efficacy Objectives
Corresponding Endpoints

To evaluate the efficacy of 
cobimetinib plus atezolizumab in 
BRAFV600 wild-type melanoma 
with CNS metastases 

To evaluate the efficacy of 
cobimetinib plus atezolizumab and 
vemurafenib in BRAFV600
mutation-positive melanoma with 
CNS metastases

Extracranial ORR, defined as the proportion of 
patients with either a CR or PR in their 
extracranial disease based on two consecutive 
assessments 4 weeks apart, as determined 
by the investigator according to RECIST v1.1 

Overall ORR, defined as the proportion of 
patients with either a CR or PR in their overall 
disease (i.e., including intracranial and 
extracranial disease) based on two consecutive 
assessments 4 weeks 


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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives
Corresponding Endpoints
apart, as determined by the investigator 
according to RECIST v1.1

Intracranial, extracranial, and overall PFS 
defined as the time from study treatment 
initiation to the first occurrence of disease 
progression or death from any cause, whichever 
occurs first, as determined by the investigator 
according to RECIST v1.1 

Intracranial, extracranial, and overall DOR, 
defined as the time from the first occurrence of 
a documented objective response based on two 
consecutive assessments 4 weeks apart to 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1 

Intracranial, extracranial, and overall DCR, 
defined as the proportion of patients with a CR 
or PR or SD at 16 weeks from study treatment 
initiation, as determined by the investigator 
according to RECIST v1.1 

OS defined as the time from study treatment 
initiation to death from any cause 

Time from study treatment initiation to cognitive 
symptom deterioration, defined as a change 
(10 points on a 0-100 scale) on selected 
scales of the EORTC-BN20 (visual disorder, 
motor dysfunction, communication deficit, 
headaches, seizures and drowsiness) 

Time from study treatment initiation to symptom 
and function deterioration defined as a change 
(10 points on a 0-100 scale) in fatigue, 
physical functioning, cognitive functioning, or 
role functioning as measured by the Fatigue, 
Physical, Cognitive, Role Functioning scales of 
the EORTC QLQ-C30 

Duration of Stable/Improved HRQoL scores as 
assessed through use of the two-item GHS/QoL 
subscale (Questions 29 and 30) of the EORTC 
QLQ-C30


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Statistical Analysis Plan MO39136
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objective(s)
Corresponding Endpoints

To evaluate the efficacy of 
cobimetinib plus atezolizumab in 
BRAFV600 wild-type melanoma with 
CNS metastases 

To evaluate the efficacy of 
cobimetinib plus atezolizumab and 
vemurafenib in BRAFV600
mutation-positive melanoma with 
CNS metastases 

Intracranial ORR defined as the proportion of 
patients with either a CR or PR in their 
intracranial disease based on two 
consecutive assessments 4 weeks apart. 
Disease status for this endpoint will be 
determined by the investigator according to 
iRANO criteria. 

ORR in intracranial, extracranial, and overall 
disease as determined by investigator 
according to immune-modified RECIST with 
modified measurability definition for 
intracranial lesions (0.5 cm by MRI) and 
allowing up to five intracranial target lesions 

Intracranial, extracranial, and overall PFS as 
determined by the investigator according to 
immune-modified RECIST 

Intracranial, extracranial, and overall DOR as 
determined by the investigator according to 
immune-modified RECIST 

Radiotherapy-assisted PFS defined as time 
from study treatment initiation to the first 
occurrence of disease progression or death 
from any cause, whichever occurs first, as 
determined by the investigator according to 
RECIST v1.1 modified by excluding 
3 lesions that can be treated by SRT from 
the sum of largest diameters from baseline 
onwards 

Timing of increase or change in 
corticosteroid use during treatment 

Time from study treatment initiation to 
subsequent intracranial and systemic 
anti-cancer treatment 

Change from baseline scores over time in 
treatment/disease-related symptoms as 
evaluated by the EORTC QLQ-C30 and 
QLQ-BN20 questionnaires 


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Statistical Analysis Plan MO39136
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Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective(s)
Corresponding Endpoints

To evaluate the safety of cobimetinib 
plus atezolizumab in BRAFV600 wild-type 
melanoma with CNS metastases 

To evaluate the safety of cobimetinib 
plus atezolizumab and vemurafenib in 
BRAFV600 mutation-positive melanoma 
with CNS metastases 

Occurrence and severity of adverse events, 
with severity determined according to 
NCI CTCAE v4.0 

Change from baseline in targeted vital signs 

Change from baseline in targeted clinical 
laboratory test results 
Exploratory Biomarker Objective(s)
Corresponding Endpoints

To perform molecular characterization 
of melanoma disease in plasma and 
tumour tissue 

Relationship between biomarkers 
(including, but not limited to; PD-L1, BRAF 
and NRAS) in plasma and tumour tissue 
and clinical efficacy parameters 
CRcomplete response; DCRdisease control rate; DORduration of response; EORTC 
QLQ-C30 and QLQ-BN20European Organization for Research and Treatment of Cancer 
Quality of Life questionnaire core questionnaire and brain cancer specific module; GHSGlobal 
Health Status; HRQoLhealth-related quality of life; MRImagnetic resonance imaging; 
iRANOimmunotherapy Response Assessment for Neuro-Oncology; IRCIndependent Review 
Committee; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse 
Events; ORRobjective response rate; OSoverall survival; PFSprogression-free survival; 
PRpartial response; PD-L1programmed death ligand 1; PROpatient-reported outcome; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors version 1.1; SDstable disease; 
SRTstereotactic radiotherapy.
1.2
STUDY DESIGN
Study MO39136 is a Phase II, two cohort, efficacy and safety study of BRAFV600
status-specific combination treatment with cobimetinib, atezolizumab and vemurafenib 
for melanoma with CNS metastases. Study patients will be assigned to a study 
treatment cohort based on locally determined BRAFV600 disease status:

Cohort 1: Patients with BRAFV600 wild-type disease will be assigned to treatment 
with cobimetinib plus atezolizumab in Cohort 1. 

Cohort 2: Patients with BRAFV600 mutation-positive disease will be assigned to 
treatment with cobimetinib plus atezolizumab and vemurafenib in Cohort 2. 
The study includes assessment of patient reported quality of life outcomes as well as 
exploratory biomarker evaluations. 
Study treatment will consist of: 

Cohort 1: orally administered cobimetinib and intravenously (IV) administered 
atezolizumab in 28-day cycles. 


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Statistical Analysis Plan MO39136
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
Cohort 2: orally administered cobimetinib and vemurafenib for an initial 28-day 
treatment run-in period, followed by cobimetinib, vemurafenib and IV atezolizumab 
for subsequent 28-day cycles. 
Disease status for the purposes of treatment decisions will be determined by the 
investigator.  Study treatment for all patients in both cohorts will be continued until 
investigator-determined disease progression according to Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST v1.1) (with two exceptions as described below), 
death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs 
first.
Study treatment may be continued beyond progression per RECIST v1.1 if:

pseudoprogression due to the effects of immunotherapy is suspected to have 
occurred or disease progression is limited to 3 intracranial lesions that can be 
controlled with stereotactic radiotherapy (SRT). 

Patient is clinically stable, have a favourable benefit-risk ratio (all the criteria listed in 
the protocol have to be met).
The disease status of patients who continued study treatment and underwent intracranial 
SRT will be determined by the investigator according to RECIST v1.1 modified by 
excluding any treated lesions from the sum of largest diameters from baseline onwards. 
Patients will attend a Study Treatment Discontinuation Visit within 287 days of their last 
study treatment dose. All AEs will be reported until 30 days after the last study treatment 
dose. After the Study Treatment Discontinuation Visit, patients who have not yet 
progressed will be followed every 8 or 12 weeks for disease status until disease 
progression has been confirmed, and all patients will be followed every three months for 
survival and new anti-cancer treatments. 
Figure 1 presents an overview of the study design.


Atezolizumab, Cobimetinib, and Vemurafenib —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO39136
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Figure 1
Study Schema
BRAFV600V600 codon of the BRAF oncogene; Nnumber of patients
Efficacy will be assessed in intracranial disease alone (primary efficacy endpoint) as well 
as in extracranial and overall (both intracranial and extracranial) disease (secondary and 
exploratory efficacy endpoints). Disease status will be determined according to 
RECIST v1.1 with a modified measurability definition for intracranial lesions (0.5 cm by 
magnetic resonance imaging [MRI]) and allowing up to five intracranial target lesions (in 
addition to any extracranial target lesions). Exploratory analyses of disease status will 
include evaluations by immune-modified RECIST, RECIST v1.1 modified by excluding 
any SRT-treated lesions from the sum of largest diameters from baseline onwards (if 
applicable), and immunotherapy Response Assessment for Neuro-Oncology (iRANO) 
criteria. Disease status for the primary endpoint will be determined by an Independent 
Review Committee (IRC). All other efficacy endpoints will be analysed according to 
investigator disease status determinations. Disease responses for all endpoints will be 
confirmed by two consecutive assessments at least four weeks apart. Regardless of 
whether patients continue treatment beyond disease progression per RECIST v1.1, 
tumour assessments must be repeated approximately four weeks later (or sooner if 
necessary e.g., due to clinical progression).
Approximately 60 patients will be enrolled into each treatment cohort for a total of 
120 patients enrolled. With an estimated study drop-out rate of 15%, approximately 
50 patients in each cohort are expected to be evaluable for the primary efficacy 
endpoint. To ensure approximately equal sample sizes in each treatment cohort, study 
eligibility and screening may be adjusted with respect to BRAFV600 status once enrolment 
reaches 60 patients in either treatment cohort.
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Based on the results of the primary analysis for Study CO39722 (IMspire170) of 
cobimetinib plus atezolizumab combination in previously untreated advanced BRAFV600
wild-type melanoma patients (see Section 1.3.2.4 of the study protocol), enrollment in 
the BRAFV600 wild-type cohort has been discontinued. Ongoing patients in this cohort 
may continue study treatment as per protocol, according to investigator’s medical 
judgement.
1.2.1
Treatment Assignment
Study patients will be assigned to study treatment cohort based on locally determined 
BRAFV600 disease status. Patients with BRAFV600 wild-type disease will be assigned to 
treatment with cobimetinib plus atezolizumab in Cohort 1. Patients with BRAFV600
mutation-positive disease will be assigned to treatment with cobimetinib plus 
atezolizumab and vemurafenib in Cohort 2.
1.2.2
Independent Review Facility
Disease status for the primary endpoint will be determined by an IRC. IRC membership 
and procedures will be described in the IRC charter. 
1.2.3
Data Monitoring
The Internal Monitoring Committee (IMC) will monitor patient safety throughout the study
and will assess the benefit-risk, as described in the IMC charter. The IMC will include 
Sponsor representatives from Clinical Science, Drug Safety, and Biostatistics. In addition 
to the ongoing assessment of the incidence and nature of AEs (particularly Grade 3 
events), serious adverse events (SAEs), deaths, and laboratory abnormalities performed 
by the investigator and the Medical Monitor, the IMC will review cumulative data at 
regular intervals throughout the conduct of the study and assess the benefit-risk.
At the time of each review, the IMC will make appropriate recommendations (e.g., the 
study should continue as planned, additional analyses should be performed, enrolment 
should be held pending further safety evaluations). Decisions will be made in 
consideration of the totality of the available data. Ad hoc meetings may be called in 
addition to scheduled meetings, as necessary, to provide recommendations on 
management of any potential new safety signals. Specific operational details such as the 
committee’s composition, frequency and timing of meetings, members’ roles and 
responsibilities, and data to be reviewed are described in the IMC charter.
2.
STATISTICAL HYPOTHESES
There is no formal statistical study hypothesis. All statistical analyses will be entirely 
descriptive.
3.
SAMPLE SIZE DETERMINATION
The purpose of this Phase II study is estimation and hypothesis generation regarding the 
effect of cobimetinib plus atezolizumab on CNS metastases from BRAFV600 wild-type 


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Statistical Analysis Plan MO39136
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melanoma and the effect of cobimetinib plus atezolizumab and vemurafenib on CNS 
metastases from BRAFV600 mutation-positive melanoma. There are no reference data 
available on the use of these combination therapies in these patient populations. 
There is no formal statistical hypothesis in this study. The planned total sample size of 
approximately 120 patients (60 patients/cohort) is based on based on an estimated 
study drop-out rate of 15%, the primary endpoint and 95% confidence intervals (CIs) for 
each treatment regimen. If necessary, study eligibility and screening may be adjusted 
with respect to BRAFV600 status once enrolment reaches 60 patients in either treatment 
cohort. No power calculation has been performed.
Point estimates and 95% CIs for a range of possible outcomes produced using nQuery 
(Version 7) with 100 evaluable patients (50 per treatment cohort) are provided in
Table 2.
Table 2
Objective Response Rate Estimates and Confidence Intervals 
with 50 Evaluable Patients per Treatment Cohort
Intracranial Response Rate in Each Cohort
95% Confidence Interval
35%
(21.8%, 48.2%)
40%
(26.4%, 53.6%)
45%
(31.2%, 58.8%)
50%
(36.1%, 63.9%)
55%
(41.2%, 68.8%)
4.
ANALYSIS SETS
The following populations are defined:
Population
Definition
Safety-evaluable
Population
All participants received at least one dose of study treatment
(e.g., atezolizumab, cobimetinib, or vemurafenib)
Evaluable Population
All enrolled patients who received study medication and have at 
least two post-baseline intracranial tumour assessments for 
response evaluation
PRO-evaluable
Population
All patients who received any amount of any study medication 
(e.g., atezolizumab, cobimetinib, or vemurafenib) and have a 
baseline and at least one post baseline PRO assessment in the 
questionnaire of interest (EORTC QLQ-C30 or EORTC QLQ-
BN20)
EORTC QLQ-C30 and QLQ-BN20European Organization for Research and Treatment of 
Cancer Quality of Life questionnaire core questionnaire and brain cancer specific module; 
PROpatient-reported outcome.


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5.
STATISTICAL ANALYSES
5.1
GENERAL CONSIDERATION
A primary study analysis that includes analyses of all efficacy endpoints and safety 
summaries will be conducted based on data collected up to 6 months after the last 
patient is enrolled in the study (last patient in [LPI]). The final study analysis including 
updated analyses of safety and efficacy endpoints will be conducted based on data 
collected up to 24 months after LPI. 
Unless otherwise indicated, efficacy analyses will be based upon the Evaluable 
population in each cohort consisting of all enrolled patients who received study 
medication and have at least two post-baseline tumour assessments for response 
evaluation. Analyses of safety, survival, corticosteroid use, and time to subsequent 
intracranial or systemic anti-cancer treatment endpoints will be conducted based upon 
the Safety evaluable population in each cohort consisting of all patients who received at 
least one dose of study medication. Analyses of patient-reported outcome (PRO)
endpoints will be conducted based upon the PRO-evaluable population.
Any incomplete or missing death date will be handled separately for safety and efficacy 
analyses. In safety analyses, all deaths will be included, regardless of completeness of 
death date; patients who died with a partial or missing death date will be included as an 
event. In efficacy analyses, a death is considered an event only if a complete death date 
is available; patients who died with only a partial or missing death date will not be 
considered as a death event.
Based on the results of the primary analysis for Study CO39722 (IMspire170) of 
cobimetinib plus atezolizumab combination in previously untreated advanced BRAFV600
wild-type melanoma patients (see Section 1.3.2.4 of the study protocol), enrollment in 
the BRAFV600 wild-type cohort was discontinued. The primary endpoint will not be 
evaluated on Cohort 1. Only a subset of analysis on efficacy secondary endpoints will 
be performed. 
5.2
PARTICIPANT DISPOSITION
The analysis of patient disposition will be based on the safety population.
Study enrollment and reasons for study discontinuation will be summarized by cohort. 
Study treatment administration and reasons for discontinuation from study treatment will 
be summarized.
5.3
PRIMARY ENDPOINT ANALYSIS
The primary endpoint will be derived and analyzed on Cohort 2 only. 


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5.3.1
Definition of Primary Endpoint
Intracranial objective response rate (ORR) is defined as the proportion of patients with a 
complete or partial response in their intracranial disease based on two consecutive 
assessments 4 weeks apart. Disease status will be determined by an IRC according to 
RECIST v1.1 with a modified measurability definition for intracranial lesions (0.5 cm by 
MRI) and allowing up to five intracranial target lesions. 
5.3.2
Main Analytical Approach for Primary Endpoint
The primary efficacy analysis will be the analysis of the intracranial ORR. The 
intracranial ORR will be presented together with a 95% Pearson-Clopper CI using the 
evaluable population.
5.3.3
Sensitivity Analyses for Primary Endpoint
Sensitivity analyses of the primary endpoint will be conducted in order to detect a 
potential bias with regard to the primary analysis.

The analysis on primary endpoint will be replicated on Safety evaluable population 
to assess the response rate of all patients enrolled and treated in this study.

The intracranial ORR will include patients with unconfirmed complete response (CR)
or partial response (PR) based on the safety population. Unconfirmed Intracranial 
ORR will be analyzed using the same methods as described in Section 5.3.2.
In addition, a summary of concordance between investigator and IRC intracranial 
response assessments, according to RECIST v1.1 with a modified measurability 
definition for intracranial lesions (0.5 cm by MRI) and allowing up to five intracranial 
target lesions, will be provided.
5.3.4
Supplementary Analyses for Primary Endpoint
Not applicable.
5.3.4.1
Subgroup Analyses for Primary Endpoint
The consistency of the primary efficacy results will be examined in subgroups defined by 
demographic characteristics and clinical and biological prognostic factors. Summaries of 
intracranial ORR, including 95% Pearson-Clopper CIs, will be produced for each of the 
defined subgroups, and displayed in a Forest plot (Lewis and Clarke 2001).
The subgroups to be considered include, but may not be limited to, the following:

Age (65 years, 65 years) 

Race (non-White, White)

Sex (female, male)

Eastern Cooperative Oncology Group (ECOG) performance status (0, 1)

programmed death ligand 1 (PDL1) status 

Lactic Acid Dehydrogenase (LDH) (upper limit of normal [ULN], ULN)


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
BRAF mutation subtype (V600E, V600K)

Extracranial sum of longest diameter

Number of target lesion (intracranial, extracranial) 

Receiving prior steroid therapy 

Organ involvement (site of target lesion): patients with brain lesion(s) only, patients 
with brain lesion(s) and other lesions. 
5.4
SECONDARY ENDPOINTS ANALYSES
Unless otherwise noted, all efficacy analyses will be performed on both the evaluable 
patient population and all treated patients (safety population).
5.4.1
Key/Confirmatory Secondary Endpoint
Not applicable.
5.4.2
Supportive Secondary Endpoints
5.4.2.1
Intracranial Objective Response Rate – RECIST
Intracranial ORR is defined as the proportion of patients with either a CR or PR in their 
intracranial disease based on two consecutive assessments 4 weeks apart, as 
determined by the investigator according to RECIST v1.1 with a modified measurability 
definition for intracranial lesions (0.5 cm by MRI) and allowing up to five intracranial 
target lesions. 
The intracranial ORR will be presented together with a 95% Pearson-Clopper CI.
5.4.2.2
Extracranial Objective Response Rate – RECIST
Extracranial ORR is defined as the proportion of patients with either a CR or PR in their 
extracranial disease based on two consecutive assessments 4 weeks apart, as 
determined by the investigator according to RECIST v1.1. 
The extracranial ORR will be presented together with a 95% Pearson-Clopper CI.
5.4.2.3
Overall Objective Response Rate – RECIST
Overall ORR is defined as the proportion of patients with either a CR or PR in their 
overall disease (i.e., including intracranial and extracranial disease) based on two 
consecutive assessments 4 weeks apart, as determined by the investigator according 
to RECIST v1.1.
The overall ORR will be presented together with a 95% Pearson-Clopper CI.
5.4.2.4
Intracranial, Extracranial and Overall Progression-Free 
Survival – RECIST
Intracranial, extracranial, and overall progression-free survival (PFS) are defined as the 
time from study treatment initiation to the first occurrence of disease progression, as 


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determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first. Data for patients who have not experienced disease progression 
or death at the time of analysis data cutoff will be censored at the last evaluable tumor 
assessment date.
Kaplan-Meier methodology will be used to estimate median intracranial, extracranial,
and overall PFS. Kaplan-Meier curves will be provided. The 95% CI of the median PFS 
will be constructed using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982).
5.4.2.5
Intracranial, Extracranial and Overall Duration of Response –
RECIST
For patients who achieve respectively an intracranial, extracranial, and objective 
response, intracranial, extracranial, and overall DOR are defined as the time from the 
first occurrence of a documented objective response based on two consecutive 
assessments 4 weeks apart to disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to RECIST v1.1. 
The censoring method for DOR is the same as the one described for PFS analysis in 
Section 5.4.2.4.
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. 
5.4.2.6
Intracranial, Extracranial and Overall Disease Control Rate at 
16 Weeks – RECIST
Intracranial, extracranial, and overall disease control rates (DCR) are defined as the 
proportion of patients with a CR or PR (based on two consecutive assessments 
4 weeks apart) or stable disease (SD) at 16 weeks from study treatment initiation, as 
determined by the investigator according to RECIST v1.1. The denominator is all 
patients in the evaluable population. 
Week 16 occurs at Study Day 112. Allowing 7 days after the exact Week 16, 
assessments that occur between Study Day 112 and Study Day 119 (inclusive) will be 
considered as a Week 16 assessment.
Patients with a CR or PR or SD at 16 weeks from study treatment initiation are patients: 

With a CR or PR assessed within the window of Study Days 112-119 inclusive and 
followed by a consecutive CR or PR assessment in the next 4 weeks.
OR

With a CR or PR assessed prior to the Study Day 112 and followed by a 
consecutive CR or PR assessment in the next 4 weeks and on or after Study
Day 112.
OR

With a SD assessed within the window of Study Days 112-119 inclusive.


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DCR will be presented together with a 95% Pearson-Clopper CI. 
5.4.2.7
Overall Survival
The overall survival (OS) analysis will be based on the safety population (all treated 
patients) only.
OS is defined as the time from study treatment initiation 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. 
Kaplan-Meier methodology will be used to estimate OS. Kaplan-Meier curves will be 
provided. The 95% CI of the median OS will be constructed using the Brookmeyer and 
Crowley method.
5.4.2.8
Patient-Reported Outcomes
The analysis of each questionnaire respectively will be performed on PRO-evaluable 
population only.
The EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30) and Quality-of-Life 
Questionnaire brain cancer module (QLQ-BN20) data will be scored according to the 
EORTC scoring manual (Fayers et al. 2001).
Time from study treatment initiation to cognitive symptom deterioration is defined as the 
time from study treatment initiation to the first time a patient’s score shows a 10-point 
increase above baseline in the following EORTC QLQ-BN20 transformed scale scores: 
visual disorder (items 6, 7, and 8), motor dysfunction (items 10, 15, and 19), 
communication deficit (items 11, 12, and 13), headaches (item 4), seizures (item 9) and 
drowsiness (item 14).
Time from study treatment initiation to symptom deterioration is defined as the time from 
study treatment initiation to the first time a patient’s score shows a 10-point increase 
above baseline in the following EORTC QLQ-C30 transformed symptom subscale 
scores: fatigue (items 10, 12, and 18).
Time from study treatment initiation to function deterioration is defined as the time from 
study treatment initiation to the first time a patient’s score shows a 10-point decrease
from baseline in the following EORTC QLQ-C30 transformed functioning subscale 
scores: physical (items 1 to 5), cognitive (items 20 and 25) and role functioning (items 6 
and 7) scales.
Duration of stable/improved HRQoL scores is assessed through use of the two-item 
Global Health Status (GHS)/ Quality-of-Life (QoL) subscale (items 29 and 30) of the 
EORTC QLQ-C30. Duration of Stable/Improved HRQoL scores is defined for patients 


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who achieve a PRO score of “improved” or “stable” as the time from the first occurrence 
of an “improved” or “stable” score to a “worsened” score. 
Data for patients who do not achieve a 10-point change at the time of analysis data 
cutoff will be censored at the last time PRO data are available.
Patients post-baseline PRO scores will be classified as ”improved”, “stable”, or 
“worsened”as follow:

Symptom scales of the EORTC QLQ-C30 and the QLQ-BN20
o
“Improved” if a 10-point of decrease is observed.
o
“Worsened” if a 10-point of increase is observed.
o
“Stable" if their baseline score changes by any other

The GHS/QoL and functional scales of the EORTC QLQ-C30:
o
"Improved" if their baseline score increases by 10 points,
o
"Worsen" if their baseline score decreases by 10 points,
o
"Stable" if their baseline score changes by any other
Time to deterioration (TTD) in BN20 scales (visual disorder, motor dysfunction, 
communication deficit, headaches, seizures and drowsiness), TTD in symptom (fatigue), 
TTD in each functioning scales (physical, role, cognitive), and duration of 
stable/improved HRQoL scores for GHS/QoL subscale will be analyzed using the same 
method as the analysis of PFS described in Section 5.4.2.4.
The number and proportion of patients who improve, remain stable, or worsen from 
baseline will be summarized by study visit.
Questionnaire completion and compliance (based on the number of patients who were 
expected to reach a given visit) will be summarized at each timepoint.
In the event of incomplete data, for all questionnaire subscales, if more than 50% of the 
constituent items are completed, a pro-rated score will be computed consistent with the 
scoring manuals and published validation reports. For subscales with less than 50% of 
the items completed, the subscale will be considered as missing.
Change from baseline scores over time in treatment/disease-related symptoms as 
evaluated by the EORTC QLQ-C30 and QLQ-BN20 questionnaires will be summarized 
descriptively including the mean change from baseline of linear-transformed scores for 
all subscales of the EORTC QLQ-C30 and QLQ-BN20 according to the EORTC scoring 
manual guideline at each assessment time point for each cohort, including progression, 
treatment discontinuation and follow-up. The mean and median of the absolute scores 
and the change from baseline will be reported for interval and continuous variables. 


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5.5
EXPLORATORY ENDPOINTS ANALYSIS
5.5.1.1
Intracranial Objective Response Rate - iRANO
Intracranial ORR is defined as the proportion of patients with either a CR or PR in their 
intracranial disease as assessed by the investigator according to iRANO criteria based 
on two consecutive assessments 4 weeks apart.
Intracranial ORR will be analyzed using the same methods as described in 
Section 5.3.2.
5.5.1.2
Intracranial, Extracranial and Overall Objective Response Rate 
– Immune-Modified RECIST
ORR in intracranial, extracranial and overall disease are defined as described in 
Sections 5.4.2.1, 5.4.2.2, and 5.4.2.3 but determined by investigator according to 
immune-modified RECIST with modified measurability definition for intracranial lesions 
(0.5 cm by MRI) and allowing up to five intracranial target lesions. 
Intracranial, extracranial, and overall ORR will be analyzed using the same methods as 
described in Section 5.3.2.
5.5.1.3
Intracranial, Extracranial, and Overall Progression-Free 
Survival – Immune-Modified RECIST
Intracranial, extracranial, and overall PFS are defined as described in Section 5.4.2.4 but
determined by the investigator according to immune-modified RECIST.
Intracranial, extracranial, and overall PFS will be analyzed using the same methods as 
described in Section 5.4.2.4.
5.5.1.4
Intracranial, Extracranial, and Overall Duration of Response –
Immune-Modified RECIST
Intracranial, extracranial, and overall DOR are defined as described in Section 5.4.2.5
but determined by the investigator according to immune-modified RECIST.
Intracranial, extracranial, and overall DOR will be analyzed using the same methods as 
described in Section 5.4.2.5.
5.5.1.5
Radiotherapy-Assisted Progression-Free Survival – RECIST
Radiotherapy-assisted intracranial PFS is defined as the time from study treatment 
initiation to the first occurrence of disease progression or death from any cause, 
whichever occurs first, as determined by the investigator according to RECIST v1.1 
modified by excluding 3 lesions that can be treated by SRT from the sum of largest 
diameters from baseline onwards. The censoring method is the same as the one 
described for PFS analysis in Section 5.4.2.4.


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For the purpose of the analysis of radiotherapy-assisted PFS, the disease status will be 
derived by removing the lesions treated by SRT (3 maximum) from sum of longest 
diameters (SLD), from baseline onwards. 
Radiotherapy-assisted PFS will be analyzed using the same methods as described in 
Section 5.4.2.4.
5.5.1.6
Timing of Increase or Change in Corticosteroid Use
The analysis of timing of increase in corticosteroid use during treatment will be based on 
the safety population.
A summary table of the status of corticosteroids (None / Stable or decreased / 
Increased) during treatment, as collected in the ‘iRANO Response assessment’ 
electronic Case Report Form (eCRF) page will be provided by visit. 
The time to increase in corticosteroid use is defined as the time from study treatment 
initiation to the first increase in corticosteroid use during treatment. Data for patients 
who have not experienced any increase in corticosteroid use during treatment, at the 
time of analysis data cutoff, will be censored at the last iRANO response assessment 
date during treatment. Timing of increase or change in corticosteroid use will be 
analyzed using the same methods as described in Section 5.4.2.4.
For patients on corticosteroids for disease control at study entry, the number of patients 
with a change in the corticosteroid use (increase/decrease/off) will be summarized 
descriptively based on the medication case report form (CRF) page if applicable.
5.5.1.7
Time to Subsequent Intracranial and Systemic Anti-Cancer 
Treatment
The analysis of time to subsequent intracranial and systemic anti-cancer treatment will 
be based on the safety population.
Time from study treatment initiation to subsequent intracranial and systemic anti-cancer 
treatment is defined as the time from study treatment initiation to the date of first 
administration of subsequent systemic anti-cancer therapy. Data for patients who have 
not received any subsequent anti-cancer treatment at the time of analysis data cutoff will 
be censored at the time of study termination or at the cutoff data, whichever occurs first.
Time to subsequent intracranial and systemic anti-cancer treatment will be analyzed 
using the same methods as described in Section 5.4.2.4.
5.5.1.8
DoR, DCR and PFS by IRC – RECIST
Intracranial PFS, DoR, and DCR, as determined by the IRC according to RECIST v1.1, 
will be analyzed using the same methods described for intracranial PFS, DoR, and DCR
determined by investigator on all patients who received at least one dose of study 
medication (safety evaluable population).


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5.6
SAFETY ANALYSES
Safety analyses will be performed on the safety evaluable population.
In addition, patients in Cohort 2 will receive cobimetinib and vemurafenib during the 
run-in period (Cycle 1) and the triplet combination (cobimetinib, atezolizumab and 
vemurafenib) from Cycle 2 onwards. For the purpose of safety analyses in Cohort 2, the 
patients will be grouped according to whether they have received the triplet combination:

cobimetinibvemurafenib (Patients who discontinued therapy prior to any 
atezolizumab administration): patients who received any amount of cobimetinib
and/or vemurafenib without any amount of atezolizumab

atezolizumabcobimetinibvemurafenib: patients who received any amount of
atezolizumab in addition to cobimetinibvemurafenib.
5.6.1
Extent of Exposure
Study drug (atezolizumab, cobimetinib, and vemurafenib) exposure will be summarized 
for each cohort using descriptive statistics. 
The overall number of cycles initiated (i.e., for drug combination) and the overall duration 
of treatment (in months) will be provided. 
For each study drug separately, the total number of cycles initiated, the duration of 
treatment (in months), the duration categories in months, the cumulative dose, the dose 
intensity (%), the number of dose modification during the study and the reason for dose 
modification will be summarized. 
5.6.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory
Activities (MedDRA) thesaurus levels and graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.
AEs that occur during or after the first dose of study treatment (i.e., treatment-emergent 
adverse events [TEAEs]) will be included in the summary tables.
Adverse events will be summarized by MedDRA term, appropriate MedDRA levels 
(System Organ Class [SOC] and Preferred Term [PT]), and when specified by NCI 
CTCAE grade. For each patient, multiple occurrences of the same event will be counted 
once at the maximum severity.
The following adverse events will be summarized by SOC or medical concept for AEs of 
special interest (AESIs), PT, and NCI CTCAE grade, for each cohort:

Adverse events (AEs)

AEs and AESIs of Grade 3 or higher

Adverse events related to i) any study treatment, ii) atezolizumab, iii) cobimetinib, iv) 
vemurafenib (Cohort 2 only), v) all study treatment.


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
SAEs

AESIs
The following AEs will be summarized by SOC or medical concept for AESIs and PT for 
each cohort:

AEs

SAEs

AEs and SAEs related to i) any study treatment, ii) atezolizumab, iii) cobimetinib, 
iv) vemurafenib (Cohort 2 only), v) all study treatment.

Adverse events leading to discontinuation of i) any study treatment, ii) atezolizumab, 
iii) cobimetinib, iv) vemurafenib (Cohort 2 only), v) all study treatment.

Adverse events leading to dose modification or interruption of i) any study treatment, 
ii) atezolizumab, iii) cobimetinib, iv) vemurafenib (Cohort 2 only), v) all study 
treatment.

AESIs specific to i) atezolizumab, ii) cobimetinibvemurafenib, iii) the combination, 
based on lists of pre-defined terms.

AESIs leading to discontinuation of i) atezolizumab, ii) cobimetinib, iii) vemurafenib

AESIs leading to dose modification or interruption of i) atezolizumab, ii) cobimetinib, 
iii) vemurafenib

Fatal AEs

Serious AESIs
Adverse events will be summarized by PT for each cohort. In addition, deaths, SAEs, 
AESIs, and AEs during the run-in period and the triple combination period (i.e., post
run-in), will be summarized for Cohort 2 only. 
All listings of AEs will include all AEs. AEs associated with coronavirus disease
(COVID-19) will be listed.
All deaths and causes of death will be summarized by cohort.
5.6.3
Laboratory Data
Laboratory data will be summarized over time including change from baseline. Values 
outside the normal ranges will be summarized. Additionally, selected laboratory data will 
be classified in accordance with NCI CTCAE Version 4.0 and will be summarized by 
grade.
Highest NCI CTCAE grade post-baseline will also be reported, and shift tables from 
baseline to worst value during the study post-baseline will be presented.
Patient meeting the criteria for Hy’s Law will be summarized.


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5.6.4
Vital Signs
Actual values and changes from baseline in selected vital signs will be summarized over 
time.
5.7
OTHER ANALYSES
A shift table presenting the baseline ECOG performance status to worst post-baseline 
value will be provided by cohort.
A shift table presenting the baseline ECG assessment result to post-baseline value will
be displayed by visit for the Cohort 2.
5.7.1
Summaries of Conduct of Study
Major protocol deviations, including violations of inclusion/exclusion criteria and 
deviations during study conduct, will be summarized by cohort.
All COVID-19 related major protocol deviations will be summarized by cohort.
5.7.2
Summaries of Treatment Group Comparability/Demographics 
and Baseline Characteristics
The following analyses will be based on the safety population.
Demographic characteristics such as age, sex, race/ethnicity, ECOG and other relevant 
baseline characteristics will be summarized by cohort. The disease baseline 
characteristics will include:

Time since initial diagnosis (years)

Primary diagnosis (Local regional, Metastasis, Unknown)

Histologically confirmed sites

Histological subtypes

Initial diagnosis staging

Time since initial diagnosis of metastatic melanoma (months)

Stage at study entry

BRAFV600 mutation status and type
Descriptive statistics (mean, median, standard deviation [SD], and range) will be 
presented for continuous data, and frequencies and percentages will be presented for 
categorical data.
The baseline value will be defined as the last available value recorded on or prior to the 
first administration of any study medication.
Prior cancer therapy, prior cancer radiotherapy, prior cancer surgery, follow-up cancer 
therapy, on-study radiotherapy, on-study targeted surgeries and procedures, follow-up 


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cancer radiotherapy, follow-up cancer therapy and follow-up cancer-related surgical 
procedures will be summarized by cohort. Previous and concurrent medical history, as 
well as medications, will also be summarized by cohort. In addition, the prior and 
concomitant anticonvulsants and systemic corticosteroid for disease control will also be 
summarized.
5.8
INTERIM ANALYSES
5.8.1
Planned Interim Analyses
A first safety interim analysis will be performed after at least 10 patients in each of both 
cohorts have completed their first tumor assessment (i.e., approximately eight weeks 
after start of study treatment). The analysis will be conducted by the Sponsor according 
to the Sponsor’s standard operating procedures for safety reviews. The results of the 
interim analysis will be reviewed by the IMC as described in the IMC charter.
Full details on interim analyses are provided in the IMC charter.
5.8.2
Optional Interim Analyses
Not applicable.
6.
SUPPORTING DOCUMENTATION
This section is not applicable, since there is no additional supporting document.
APPENDIX 1: CHANGES TO PROTOCOL-PLANNED ANALYSES
The TTD for functional scale on QLQ-C30 is defined as 10 point of decrease from 
baseline instead of 10 point of increase as defined in the protocol. Indeed, a high score 
on functioning scale represent a high / healthy level of functioning as per the QLQ-C30 
manual, thus an improvement.
The TTD analysis will be performed on the selected symptoms and functional scales for 
QLQ-C30 and BN20 separately since each item measures different level of functioning 
and symptomatology/problems. 
7.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics.
1982;1:29-41.
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 scoring manual (3rd Edition). Published by: 
European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ.
2001;322:147980.