A Phase III, Open-Label, Multicenter, Three-Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy vs. Regorafenib in Patients With Previously Treated Unresectable Locally Advanced or Metastatic Colorectal Adenocarcinoma
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: Hoffmann-La Roche

 
Official Title: A Phase III, Open-Label, Multicenter, Three-Arm, Randomized Study 
to Investigate the Efficacy and Safety of Cobimetinib Plus 
Atezolizumab and Atezolizumab Monotherapy vs. Regorafenib in 
Patients With Previously Treated Unresectable Locally Advanced or 
Metastatic Colorectal Adenocarcinoma 
NCT Number: NCT02788279 
Document Date: Protocol Version 5: 28-Nov-2017 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 plus Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol GO30182, Version 5
PROTOCOL
TITLE:
A Phase III, open-label, multicenter, three-arm, 
randomized study to investigate the efficacy and 
safety of cobimetinib plus atezolizumab and
atezolizumab monotherapy vs. regorafenib in 
patients with previously treated unresectable 
locally advanced or metastatic colorectal 
adenocarcinoma
PROTOCOL NUMBER: GO30182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-000202-11
IND NUMBER:
130,091
TEST PRODUCT:
Cobimetinib (RO5514041); atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
22 January 2016
DATE AMENDED:
Version 2:  30 March 2016
Version 3:  4 May 2016
Version 4:  21 October 2016
Version 5: See electronic date stamp below.
 
28-Nov-2017 21:09:59
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Changes to Protocol GO30182, along with a rationale for each change, are summarized 
below:

The protocol has been amended to reflect the update to the Statistical Analysis Plan 
(SAP). Overall survival (OS) will remain the primary endpoint. However, the 
hierarchical testing procedure will only include the OS comparisons between arms. 
The secondary endpoints (progression-free survival [PFS] and objective response 
rate [ORR]) will be deleted from the testing hierarchy and analyzed based on the 
methodologies stated in the revised SAP. The rationale for this amendment is to test 
the primary endpoint (OS) in both comparisons, (Arm A versus Arm C and Arm B 
versus Arm C) while maintaining type-1 error (Section 6.1, Figure 3).  The time of 
analysis has been updated accordingly and will be conducted when there are 
approximately 235 deaths in the study, which is expected to occur 23 months after 
the first patient is randomized (Sections 3.2 and 6.1).

References to Foundation Medicine have been removed from Section 4.5.7.1
because Foundation Medicine is no longer being used for centralized confirmation of 
RAS and microsatellite testing.

References to guidelines for managing cobimetinib-specific adverse events have 
been updated (Sections 5.1.1.1, 5.1.1.2, and 5.1.1.3).

The reporting of adverse events after initiation of study drug has been updated to 
align with the Schedule of Assessments and to align with current model document 
language (Section 5.3.1).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

Event reporting for hospitalization has been clarified (Section 5.3.5.11).

Contact information regarding Medical Monitors has been updated (Section 5.4.1).

Language has been added to clarify that the end of the adverse event reporting is 
defined as 90 days after the last dose of study drug or initiation of a new anti-cancer 
treatment, whichever comes first (Sections 5.4.2.2 and 5.6).

The reference document for assessing the expectedness of adverse events for 
regorafenib has been updated from local prescribing information to Summary of 
Product Characteristics (Section 5.7).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).

The web address for the Roche Global Policy on Sharing of Clinical Trials Data 
(Section 9.5).

Guidelines for managing patients who experience atezolizumab-associated adverse 
events have been revised to include guidelines for hypophysitis and myocarditis and 
have been provided in an appendix so there is no longer a need to consult the 
Atezolizumab Investigator's Brochure for management guidelines (Appendix 9).  The 
list of risks was updated in Section 5.1.2 and cross-references have been updated 
(Sections 1.4.2.2, 4.3.2.2, 5.1.2, 5.1.4.2, 5.1.4.3, 5.1.4.4, and Appendix 3).
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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PROTOCOL AMENDMENT, VERSION 5:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
SECTION 1.4.2.2:  Ongoing Clinical Studies
ImmuneMediated Adverse Events
Refer to the atezolizumab Investigator’s Brochure and Appendix 9 for details regarding 
immunemediated adverse events and identified risks (adverse drug reactions)
observed in patients treated with atezolizumab as well as recommended management 
guidelines for atezolizumab-specific immunemediated adverse events.
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY
The OS final analysis will be conducted when there are approximately 235 deaths in the 
study.  178 deaths for the comparison of Arm A versus Arm C and approximately 127 
deaths for the comparison of Arm B versus Arm C.  This is expected to occur 
approximately 2123 months after the first patient is randomized.
SECTION 4.3.2.2:  Atezolizumab
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events 
associated with cobimetinib and atezolizumab are provided in Section 5.1.4 and 
Appendix 3.  For information regarding management of atezolizumab-associated 
adverse events, please refer to the atezolizumab Investigator’s Appendix 9.
SECTION 4.5.7.1:  Archival and Fresh Tumor Sample for Screening
Extended RAS mutation is defined as mutations occurring in KRAS and NRAS gene 
codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4 
(Allegra et al. 2016).  Local RAS testing results will be accepted with a copy of the 
results and interpretation as part of the screening process with a requirement for central 
confirmation. by Foundation Medicine NGSbased genomic profiling.
MSI status can be defined by several methods such as IHC detection of hMLH1 and 
hMSH2 gene products, NGS testing, or PCR testing by the fraction of MSI loci that 
exhibit differently sized repeats (Lindor et al. 2002; Salipante et al. 2014).  Local MSI 
testing results will be accepted with a copy of the results and interpretation as part of the 
screening process with a requirement for central confirmation.  by Foundation Medicine 
NGSbased genomic profiling.
SECTION 5.1.1.1:  Important Identified Risks Associated with Cobimetinib
Serous Retinopathy
Guidelines for management of patients who develop Grade2 visual disorders or 
retinopathy are provided in Appendix 3Section5.1.4.3.

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Left Ventricular Dysfunction
Most left ventricular ejection fraction reduction events in patients on cobimetinib plus 
vemurafenib (62%) improved or resolved with management according to the 
dose-modification guidelines (see Appendix 3Section5.1.4.3).
Photosensitivity (when Administered with Vemurafenib)
Grade3 photosensitivity events in the cobimetinib plus vemurafenib arm were 
primarily treated with topical medication in conjunction with interruption of study agents.  
Refer to Section 5.1.4.3 for photosensitivity management guidelines.
Pneumonitis
There were no reported Grade3 events in either study arm.  Serious events were 
reported in 2 patients (0.8%) treated with cobimetinib plus vemurafenib.  Refer to 
Appendix 3 for pneumonitis management guidelines.
SECTION 5.1.1.2:  Potential Risks Associated with Cobimetinib
Liver Laboratory Abnormalities and Severe Hepatotoxicity
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines.  In both study arms, the majority of Grade3 liver laboratory test 
abnormalities resolved.  Refer to Appendix 3 for hepatotoxicity management guidelines.
SECTION 5.1.1.3:  Other Risks with Cobimetinib
Rash
Generally, Grade3 rash events were effectively managed with dose modification 
guidelines.  In Study GO28141, approximately 90% of Grade3 rash events resolved in 
both arms.  Refer to Appendix 3 for rash management guidelines.
Gastrointestinal Toxicity
The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake. In the majority of cases, diarrhea has been effectively 
managed with antidiarrheal agents and supportive care. Routine antiemetic prophylaxis 
is not recommended. Refer to Appendix 3 for gastrointestinal toxicity management 
guidelines.
SECTION 5.1.2:  Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as IRRs and immune-related hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis, myocarditis, and hypophysitis.  In addition, systemic 
immune activation is a potential risk associated with atezolizumab.  Refer to Section 6 of 
the Atezolizumab Investigator's Brochure for a detailed description of anticipated safety 
risks for atezolizumab and Appendix 9.

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SECTION 5.1.4.2:  Atezolizumab Dose Modifications
Additional guidelines for specific adverse events delineated by the different study arms 
are provided in the subsections below and the specific management guidelines are 
highlighted in Appendix 3 for cobimetinib plus atezolizumab.  For information regarding 
management of atezolizumab-associated adverse events, please refer to the 
atezolizumab Investigator’s Brochure Appendix 9.
SECTION 5.1.4.3:  Management of Cobimetinib- and Atezolizumab-Specific 
Adverse Events (Arm A)
Toxicities associated or possibly associated with cobimetinib plus atezolizumab 
treatment should be managed according to standard medical practice.  See 
Section 5.1.4.4 for management of adverse events related to atezolizumab.
Guidelines for management of patients who experience atezolizumab-associated 
adverse events, including infusion-related reactions and immune-related events (e.g., 
endocrine, ocular, pancreatic, and neurologic events), are provided in the Atezolizumab 
Investigator’s BrochureAppendix 9.
SECTION 5.1.4.4:  Management of Adverse Events in the Atezolizumab 
Monotherapy Arm (Arm B)
Guidelines for management of patients who experience specific adverse events 
associated with atezolizumab, including infusion-related reactions and immune-related 
events (e.g., pulmonary, hepatic, gastrointestinal, endocrine, ocular, pancreatic, 
dermatologic, and neurologic events), are provided in the Atezolizumab Investigator's 
Brochure Appendix 9.
SECTION 5.3.1:  Adverse Event Reporting Period
After initiation of study drug, all serious adverse events and Adverse Events of Special 
Interest, regardless of relationship to study drug, will be reported until 90 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs 
first.  All other adverse events, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug or initiation of new anti-cancer 
therapy, whichever occurs first.adverse events will be reported until 90 days after the 
last dose of study drug.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment Instructions 
for reporting adverse events that occur after the adverse event reporting period are 
provided in (see Section 5.6).
SECTION 5.3.5.8:  Deaths
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 

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without preexisting heart disease, within 1 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.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization
The following hospitalization scenarios are not considered to be adverse events: An 
event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:The following hospitalization scenario is not considered to be a serious adverse 
event, but should be reported as an adverse event instead:
SECTION 5.4.1:  Emergency Medical Contacts
For all other non-emergency medical questions, please contact your clinical study 
monitor or one of the following Medical Monitors:

, M.D.:  

, Ph.D.:  
 
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug or initiation of 
another anti-cancer drug, whichever comes first.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system.
SECTION 5.6:  POST-STUDY ADVERSE EVENTS
After the end of the reporting period for serious adverse events and adverse events of 
special interest After the end of the adverse event reporting period (defined as 90 days 
after the last dose of study drug or initiation of a new anti-cancer treatment whichever 
comes first), 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 a 
serious adverse event that is believed to be related to prior study drug treatment, the 
event should be reported through use of the Adverse Event eCRF.

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SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Local prescribing informationSummary of Product Characteristics (SPC) for 
regorafenib (StigvaraSPC 2017)
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE
The OS final analysis will be conducted when there are approximately 235 deaths in the 
study.  This is expected to occur approximately 23 months after the first patient is 
randomized.  At that time, it is expected that approximately 178 deaths for the 
comparison of Arm A versus Arm C and approximately 127 deaths for the comparison 
of Arm B versus Arm C will have occurred.  The OS final analysis will be conducted 
when there are approximately 178 deaths for the comparison of Arm A versus Arm C 
and approximately 127 deaths for the comparison of Arm B versus Arm C.  This is 
expected to occur approximately 22 months after the first patient is randomized.  If 178th
event from Arms A and C occurs after 127 h event from Arms B and C, the OS final 
analysis will be conducted after 178th event from Arms A and C has occurred.
SECTION 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.
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdfhttp://www.roche.com/r
oche global policy on sharing of clinical study information.pdf
Figure 3:  Overview of Hierarchical Testing Sequence for Type I Error a
Control (2-Sided) 
Figure 3 was updated to indicate that overall survival (OS) will be tested at a 2-sided 
significance level 0.05 only if the result of previous testing is positive (i.e., statistically 
significant). The testing of secondary endpoints (PFS and ORR) have been removed.
Appendix 3: Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A)
All references to the Atezolizumab Investigator’s Brochure have been updated to 
Appendix 9.

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Appendix 9:  Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab
Appendix 9 was added.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 17
PROTOCOL SYNOPSIS .................................................................................... 18
1.
BACKGROUND .......................................................................................... 31
1.1
Background on Metastatic Colorectal Cancer........................ 31
1.1.1
Incidence and Treatment of Metastatic Colorectal 
Cancer................................................................................... 31
1.1.2
Management of Metastatic Colorectal Cancer 
Beyond Second-Line Chemotherapy..................................... 31
1.2
The Programmed T-Cell Death Ligand-1 
Pathway................................................................................. 32
1.3
The MAPK Signaling Pathway and Regulation of 
the Immune Tumor Microenviroment..................................... 33
1.4
Background on Atezolizumab Monotherapy .......................... 33
1.4.1
Summary of Nonclinical Studies with 
Atezolizumab......................................................................... 33
1.4.2
Clinical Experience with Atezolizumab .................................. 34
1.4.2.1
Ongoing Clinical Studies........................................................ 34
1.4.2.2
Clinical Safety as a Single Agent........................................... 34
1.4.3
Clinical Activity of Atezolizumab ............................................ 35
1.4.4
Clinical Pharmacokinetics and Immunogenicity of 
Atezolizumab......................................................................... 36
1.5
Background on Cobimetinib Monotherapy............................. 36
1.5.1
Summary of Nonclinical Studies with Cobimetinib................. 36
1.5.2
Summary of Clinical Studies with Cobimetinib 
Monotherapy.......................................................................... 37
1.6
Combined Inhibition of PD-l1 and MAPK 
Signaling Pathways as Potential Anti-Cancer 
Therapy in Metastatic Colorectal Cancer............................... 38
1.7
Clinical Data of Cobimetinib plus Atezolizumab in 
Metastatic Colorectal Cancer – Study GP28363 ................... 40
1.8
Study Rationale and Benefit-Risk Assessment...................... 41
2.
OBJECTIVES AND ENDPOINTS ............................................................... 41
2.1
Efficacy Objectives ................................................................ 41

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2.1.1
Primary Efficacy Objective..................................................... 41
2.1.2
Secondary Efficacy Objectives .............................................. 42
2.2
Safety Objective .................................................................... 42
2.3
Pharmacokinetic Objective .................................................... 42
2.4
Immunogenicity Objectives.................................................... 42
2.5
Biomarker Objectives............................................................. 43
2.6
Patient-Reported Outcomes Objectives................................. 43
2.7
Pharmacoeconomic Objectives ............................................. 43
3.
STUDY DESIGN......................................................................................... 43
3.1
Description of the Study......................................................... 43
3.2
End of Study and Length of Study......................................... 46
3.3
Rationale for  Study Design................................................... 46
3.3.1
Rationale for Overall Survival as Primary 
Endpoint ................................................................................ 47
3.3.2
Rationale for Open-Label Study ............................................ 47
3.3.3
Rationale for Patient Population, Stratification 
Factors, and Capping ............................................................ 47
3.3.4
Rationale for Cobimetinib plus Atezolizumab Arm................. 48
3.3.5
Rationale for Atezolizumab Monotherapy Arm ...................... 49
3.3.6
Rationale for Regorafenib as Control Arm............................. 49
3.3.7
Rationale for Dose and Schedule for Cobimetinib 
plus Atezolizumab and for Atezolizumab 
Monotherapy.......................................................................... 49
3.3.8
Rationale for Allowing Patients to Continue 
Treatment until Loss of Clinical Benefit.................................. 50
3.3.9
Rationale for Patient-Related Outcomes 
Assessments ......................................................................... 50
3.3.10
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens, Stratification Criteria, and 
Biomarker Assessments........................................................ 50
3.3.11
Rationale for Blood Sampling for Biomarker 
Assessments ......................................................................... 51
3.3.11.1
Rationale of Optional Whole Genome 
Sequencing............................................................................ 51
4.
MATERIALS AND METHODS .................................................................... 52

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4.1
Patients.................................................................................. 52
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment.......................................... 57
4.3
Study Treatment.................................................................... 58
4.3.1
Formulation, Packaging, and Handling.................................. 58
4.3.1.1
Cobimetinib............................................................................ 58
4.3.1.2
Atezolizumab......................................................................... 58
4.3.1.3
Regorafenib (Stivarga)......................................................... 59
4.3.2
Dosage, Administration, and Compliance.............................. 59
4.3.2.1
Cobimetinib............................................................................ 59
4.3.2.2
Atezolizumab......................................................................... 59
4.3.2.3
Regorafenib........................................................................... 60
4.3.2.4
Dosing of Study Treatment Beyond Disease 
Progression ........................................................................... 61
4.3.3
Investigational Medicinal Product Accountability ................... 61
4.3.4
Post-Trial Access to Cobimetinib and 
Atezolizumab......................................................................... 62
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 63
4.4.1
Permitted Therapy................................................................. 63
4.4.2
Prohibited Therapy ................................................................ 64
4.5
Study Assessments ............................................................... 65
4.5.1
Informed Consent Forms and Screening Log........................ 66
4.5.2
Medical History and Demographic Data ................................ 66
4.5.3
Physical Examinations........................................................... 66
4.5.4
Vital Signs.............................................................................. 67
4.5.4.1
Vital Signs for Patients Assigned to Receive 
Atezolizumab with or without Cobimetinib 
(Arms A and B)...................................................................... 67
4.5.4.2
Vital Signs for Patients Assigned to Receive 
Regorafenib (Arm C) ............................................................. 67
4.5.5
Tumor and Response Evaluations......................................... 67
4.5.6
Laboratory, Biomarker, and Pharmacokinetic 
Samples................................................................................. 68

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4.5.6.1
Local Laboratory Assessments.............................................. 68
4.5.6.2
Central Laboratory Assessments........................................... 69
4.5.7
Tumor Tissue Samples.......................................................... 70
4.5.7.1
Archival and Fresh Tumor Sample for Screening.................. 71
4.5.7.2
Optional Tumor Biopsy on Treatment.................................... 72
4.5.7.3
Tumor Biopsy at Time of Progression ................................... 72
4.5.8
Left Ventricular Ejection Fraction........................................... 73
4.5.9
Ophthalmologic Examination................................................. 73
4.5.10
Patient-Reported Outcomes .................................................. 74
4.5.10.1
European Organization for Research and 
Treatment of Cancer Quality of Life-C30 
Questionnaire and Additional Items....................................... 75
4.5.10.2
EuroQoL 5 Dimensions.......................................................... 75
4.5.11
Timing of Assessments.......................................................... 75
4.5.11.1
Screening .............................................................................. 75
4.5.11.2
On Treatment ........................................................................ 75
4.5.11.3
Treatment Discontinuation..................................................... 76
4.5.11.4
Follow-Up .............................................................................. 76
4.5.11.5
Unscheduled Visits ................................................................ 76
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 76
4.6.1
Patient Discontinuation.......................................................... 76
4.6.2
Study Treatment Discontinuation........................................... 77
4.6.3
Study and Site Discontinuation.............................................. 77
5.
ASSESSMENT OF SAFETY....................................................................... 78
5.1
Safety Plan ............................................................................ 78
5.1.1
Risks Associated with Cobimetinib........................................ 79
5.1.1.1
Important Identified Risks Associated with 
Cobimetinib............................................................................ 79
5.1.1.2
Potential Risks Associated with Cobimetinib ......................... 81
5.1.1.3
Other Risks with Cobimetinib................................................. 82
5.1.2
Risks Associated with Atezolizumab ..................................... 83
5.1.3
Risks Associated with Regorafenib ....................................... 84

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5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 84
5.1.4.1
Cobimetinib and Regorafenib Dose Modifications................. 84
5.1.4.2
Atezolizumab Dose Modifications.......................................... 85
5.1.4.3
Management of Cobimetinib- and 
Atezolizumab-Specific Adverse Events (Arm A).................... 86
5.1.4.4
Management of Adverse Events in the 
Atezolizumab Monotherapy Arm (Arm B) .............................. 86
5.1.4.5
Management of RegorafenibAssociated 
Adverse Events (Arm C)........................................................ 86
5.2
Safety Parameters and Definitions ........................................ 88
5.2.1
Adverse Events ..................................................................... 89
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 89
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 90
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91
5.3.1
Adverse Event Reporting Period ........................................... 91
5.3.2
Eliciting Adverse Event Information....................................... 92
5.3.3
Assessment of Severity of Adverse Events ........................... 92
5.3.4
Assessment of Causality of Adverse Events ......................... 92
5.3.5
Procedures for Recording Adverse Events............................ 93
5.3.5.1
Infusion-Related Reactions.................................................... 93
5.3.5.2
Diagnosis vs. Signs and Symptoms ...................................... 93
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 94
5.3.5.4
Persistent or Recurrent Adverse Events................................ 94
5.3.5.5
Abnormal Laboratory Values ................................................. 94
5.3.5.6
Abnormal Vital Sign Values ................................................... 95
5.3.5.7
Abnormal Liver Function Tests.............................................. 96
5.3.5.8
Deaths ................................................................................... 96
5.3.5.9
Preexisting Medical Conditions.............................................. 97
5.3.5.10
Lack of Efficacy or Worsening of Colorectal 
Cancer................................................................................... 97
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 97

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5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 98
5.3.5.13
Patient-Reported Outcome Data ........................................... 98
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 99
5.4.1
Emergency Medical Contacts................................................ 99
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 99
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 99
5.4.2.2
Events That Occur after Study Drug Initiation...................... 100
5.4.3
Reporting Requirements for Pregnancies............................ 100
5.4.3.1
Pregnancies in Female Patients.......................................... 100
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 101
5.4.3.3
Abortions ............................................................................. 101
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 101
5.5
Follow-Up of Patients after Adverse Events ........................ 101
5.5.1
Investigator Follow-Up......................................................... 101
5.5.2
Sponsor Follow-Up .............................................................. 102
5.6
Post-Study Adverse Events................................................. 102
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 102
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 102
6.1
Determination of Sample Size ............................................. 103
6.2
Summaries of Conduct of Study.......................................... 104
6.3
Summaries of Treatment Group Comparability ................... 105
6.4
Efficacy Analyses ................................................................ 105
6.4.1
Primary Efficacy Endpoint.................................................... 105
6.4.2
Secondary Efficacy Endpoints............................................. 106
6.5
Patient-Reported Outcomes Analyses................................. 107
6.6
Safety Analyses................................................................... 107
6.7
Pharmacokinetic Analyses................................................... 108
6.8
Immunogenicity Analyses.................................................... 108
6.9
Exploratory Biomarker Analyses.......................................... 109

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7.
DATA COLLECTION AND MANAGEMENT ............................................. 109
7.1
Data Quality Assurance....................................................... 109
7.2
Electronic Case Report Forms............................................. 109
7.3
Electronic Patient-Reported Outcome Data......................... 109
7.4
Source Data Documentation................................................ 110
7.5
Use of Computerized Systems ............................................ 110
7.6
Retention of Records........................................................... 111
8.
ETHICAL CONSIDERATIONS.................................................................. 111
8.1
Compliance with Laws and Regulations .............................. 111
8.2
Informed Consent................................................................ 111
8.3
Institutional Review Board or Ethics Committee.................. 112
8.4
Confidentiality...................................................................... 113
8.5
Financial Disclosure ............................................................ 113
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 113
9.1
Study Documentation .......................................................... 113
9.2
Protocol Deviations.............................................................. 113
9.3
Site Inspections ................................................................... 114
9.4
Administrative Structure....................................................... 114
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 114
9.6
Protocol Amendments ......................................................... 115
10. REFERENCES ......................................................................................... 116
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
Atezolizumab .............................................................................. 60
Table 2
Proposed Non-Inherited Biomarkers for Exploratory 
Research..................................................................................... 70
Table 3
Recommended Cobimetinib and Regorafenib Dose 
Modifications............................................................................... 84
Table 4
Guidelines for Management of Patients Who Experience 
Adverse Events in Arm A and Arm B .......................................... 85

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Table 5
Recommended Dose Modification and Measure for 
HandFoot Skin Reaction/Palmar-Plantar 
Erythrodysesthesia Syndrome .................................................... 87
Table 6
Recommended Measures and Dose Modifications in Case of 
DrugRelated Liver Function Test Abnormalities........................ 88
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 92
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 45
Figure 2
Treatment Schedule.................................................................... 46
Figure 3
Overview of Hierarchical Testing Sequence for Type I Error
Control (2-Sided)....................................................................... 104
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................ 122
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples... 135
Appendix 3
Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) ........................................................... 136
Appendix 4
Anaphylaxis Precautions.......................................................... 155
Appendix 5 
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication.............................................. 156
Appendix 6 
Eastern Cooperative Oncology Group Performance Status...... 168
Appendix 7
EuroQoL 5 Dimensions Health Questionnaire ......................... 169
Appendix 8
European Organisation for Research and Treatment of 
Cancer 30-Item Quality of Life Questionnaire (Version 3)......... 173
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 176

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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A Phase III, open-label, multicenter, three-arm, 
randomized study to investigate the efficacy and 
safety of cobimetinib plus atezolizumab and
atezolizumab monotherapy vs. regorafenib in 
patients with previously treated unresectable 
locally advanced or metastatic colorectal 
adenocarcinoma
PROTOCOL NUMBER:
GO30182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-000202-11
IND NUMBER:
130,091
TEST PRODUCT:
Cobimetinib (RO5514041); atezolizumab 
(RO5541267)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy 
as instructed by your local site monitor.

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PROTOCOL SYNOPSIS
TITLE:
A Phase III, open-label, multicenter, three-arm, randomized study 
to investigate the efficacy and safety of cobimetinib plus 
atezolizumab and atezolizumab monotherapy vs. regorafenib in 
patients with previously treated unresectable locally advanced 
or metastatic colorectal adenocarcinoma
PROTOCOL NUMBER:
GO30182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-000202-11
IND NUMBER:
130,091
TEST PRODUCT:
Cobimetinib (RO5514041); atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Previously treated unresectable locally advanced or metastatic 
colorectal adenocarcinoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of cobimetinib plus 
atezolizumab compared to regorafenib (standard of care) in patients with previously treated, 
unresectable locally advanced or metastatic colorectal cancer (CRC) on the basis of overall 
survival (OS).  Atezolizumab monotherapy will also be evaluated compared to regorafenib on 
the basis of OS.
Secondary Efficacy Objectives
The secondary efficacy objectives include:

Investigator-assessed progression-free survival per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 of patients in the cobimetinib plus atezolizumab arm and the 
atezolizumab monotherapy arm compared to the regorafenib arm.

Investigator-assessed objective response rate per RECIST v1.1 of patients in the 
cobimetinib plus atezolizumab arm and atezolizumab monotherapy arm compared to the 
regorafenib arm

Duration of response of patients in the cobimetinib plus atezolizumab arm and atezolizumab 
monotherapy arm compared to the regorafenib arm

Impact on functioning as measured by changes from baseline on the five-item physical 
functioning sub-scale of the patientcompleted European Organization for Research and 
Treatment of Cancer Quality of Life Core 30 questionnaire (EORTC QLQ-C30)

Impact on healthrelated quality of life as measured by changes from baseline on the 
two-item global health status/quality of life sub-scale of the EORTC QLQ-C30
Safety Objective
The safety objective for this study is to evaluate the safety profile and adverse events 
encountered by patients in the cobimetinib plus atezolizumab arm and atezolizumab 
monotherapy arm compared to the regorafenib arm. 

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Pharmacokinetic Objective
The PK objective for this study is to characterize the cobimetinib and atezolizumab PK profiles 
on the basis of the following:

Plasma concentration of cobimetinib at timepoints specified in Appendix 2

Serum concentration of atezolizumab in both the cobimetinib plus atezolizumab arm and 
the monotherapy atezolizumab arm at timepoints specified in Appendix 2
Immunogenicity Objective
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab 
on the basis of the following endpoint:

Incidence of anti-therapeutic antibodies (ATAs) during the study relative to the prevalence 
of ATAs at baseline in both the cobimetinib plus atezolizumab arm and the atezolizumab 
monotherapy arm.
The exploratory immunogenicity objective for this study is to evaluate potential effects of ATAs 
on efficacy, safety, or pharmacokinetics.
Biomarker Objectives
The exploratory biomarker objectives for this study are as follows:

To assess the following molecular characteristics in tumor samples during pretreatment, on 
treatment, and at progression: 
–
Genetic profile including but not limited to somatic mutations and microsatellite (MSI)
status or mutation load as identified through next-generation sequencing or other 
genetic analysis. 
–
Immune contextures, such as programmed death-ligand 1 (PD-L1), CD8 T cells or 
major histocompatibility complex expression, as identified by immunohistochemistry 
and gene signature profiling
–
CRC molecular subtyping as defined by genetic and RNA and protein profiles

To evaluate the relationship between circulating tumor biomarkers (including but not limited 
to carcinoembryonic antigen [CEA], tumor-associated mutations in cell-free DNA) and 
measures of efficacy
Patient-Reported Outcomes Objectives
The additional patient-reported outcome objective of the study is to assess treatment impact 
and disease symptoms from the sub-scales of the EORTC QLQ-C30 that assess diarrhea, 
constipation, lack of appetite, fatigue, and two additional items from the EORTC item bank that 
assess bloating and abdominal pain associated with cobimetinib plus atezolizumab compared 
with regorafenib in patients with metastatic CRC (mCRC).
Pharmacoeconomic Objectives
In addition, a study objective is to obtain general measures of health as measured by the 
EuroQoL 5 Dimensions questionnaire for health economic modeling of cobimetinib plus 
atezolizumab or atezolizumab monotherapy compared with regorafenib in patients with mCRC.  
This information is not intended to be included in the clinical study report.
Study Design
Description of Study
This is a Phase III, multicenter, open-label, three-arm, randomized study in patients with 
unresectable locally advanced or metastatic CRC who have received at least two prior regimens 
of cytotoxic chemotherapy for metastatic disease.  The study compares regorafenib, a standard 
of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.
The primary objective of the study is to evaluate the efficacy of cobimetinib plus atezolizumab 
compared to regorafenib in patients with unresectable locally advanced or metastatic CRC who 
have received at least two prior regimens of chemotherapy in the metastatic setting.  
The efficacy of atezolizumab monotherapy compared to regorafenib in the same patient 
population will also be evaluated as a primary objective.

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This study will be conducted globally and approximately 360 patients will be randomized in a 
2:1:1 ratio to receive: 

Arm A:  cobimetinib 60 mg orally on Days 121 plus atezolizumab 840 mg intravenous (IV) 
on Day 1 and Day 15 in a 28-day cycle (n ≈ 180), or

Arm B:  atezolizumab monotherapy 1200 mg IV on Day 1 in a 21-day cycle (n ≈90), or 

Arm C:  regorafenib 160 mg orally on Days 121 in a 28-day cycle (n ≈ 90).
At least 50% patients with extended RAS-mutant tumors will be enrolled in each arm.  
Enrollment of patients with MSI-high status will be limited to approximately 5% to reflect the 
natural prevalence in mCRC.
Stratification factors are extended RAS mutation status of the tumor and time since diagnosis of 
first metastasis (18 months vs. 18 months).  Permuted-block randomization will be applied to 
ensure a balanced assignment to each treatment arm.  Randomization and stratification will be 
managed through an interactive voice/web response system.
The Sponsor will monitor the enrollment for each region (North America, Europe, and 
Pacific/Asia).  To ensure balanced global enrollment, the Sponsor may institute temporary 
limitations on enrollment in certain regions in the event of disproportionate accrual of patients.
After signing informed consent, patients will undergo screening procedures that include testing 
the tumor for extended RAS mutation status and MSI status (local tests accepted but 
confirmatory centralized testing required); laboratory tests (e.g., hematology, chemistries, liver 
function tests); left-ventricular function evaluation (echocardiogram or multigated acquisition 
scan); contrast-enhanced computed tomography scan or magnetic resonance imaging of the 
chest, abdomen, and pelvis; and ophthalmologic assessments.  
All eligible patients will be randomized to treatment in either Arm A (cobimetinib plus 
atezolizumab), Arm B (atezolizumab monotherapy) or Arm C (regorafenib).  
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at the 
treatment discontinuation visit, and during the follow-up period.  The National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 will be used to 
characterize the toxicity profile of the study treatments on all patients.  Patients will be assessed 
for adverse events according to the schedule of assessments and as necessary throughout the 
study.
Tumor response will be evaluated according to RECIST v1.1.  Any evaluable and measurable 
disease must be documented at screening and re-assessed at each subsequent tumor 
evaluation.  Investigators will assess tumor response at 8-week intervals, regardless of any 
dose delays or treatment cycle. 
Treatment will continue until the patient has disease progression according to RECIST v1.1, 
unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever 
occurs first.  A rising CEA level alone is not considered disease progression.  No crossover will 
be allowed.  Patients are allowed to receive study treatment beyond disease progression if 
certain conditions are met.
After discontinuation of study treatment, patients may receive any subsequent line therapy as 
directed by their treating physician.
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) 
will continue scheduled tumor assessments until disease progression, withdrawal of consent, 
study termination by Sponsor, or death, whichever occurs first.  In the absence of disease 
progression, tumor assessments should continue regardless of whether patients start a new 
anti-cancer therapy, unless consent is withdrawn.  All patients will be followed for survival 
unless consent is withdrawn.
Number of Patients
Approximately 360 patients with unresectable locally advanced or metastatic CRC who have 
received at least two different chemotherapy regimens for metastatic disease will be enrolled in 
this study.   

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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-specific inclusion criteria:

Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage IV 
American Joint Committee on Cancer 7th edition)

Experienced disease progression on at least two prior systemic chemotherapy regimens for 
mCRC
1.
Prior systemic cytotoxic chemotherapy must include ALL of the following agents: 
a)
Fluoropyrimidines
b)
Irinotecan 
c)
Oxaliplatin
2. Patients who have received prior anti-angiogenic therapy (e.g., bevacizumab) and/or 
anti-epidermal growth factor receptor therapy (e.g., cetuximab) are eligible.
3. Patients must have had documented disease progression within 3 months of the last 
systemic therapy administration. 
4. Patients who were intolerant to prior systemic chemotherapy regimens are eligible if 
there is documented evidence of clinically significant intolerance despite adequate 
supportive measures. 
5. For patients who had disease recurrence within 6 months of completing adjuvant 
chemotherapy, the adjuvant regimen can be considered as one chemotherapy 
regimen for metastatic disease.
General inclusion criteria:

Signed Informed Consent Form

Age 18 years

In the investigator’s judgment, patient is able to comply with the requirements and 
assessments of the study protocol

Eastern Cooperative Oncology Group performance status of 0 or 1

Anticipated life expectancy 3 months

Able to comply with the requirements and assessments of the study protocol

Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to first dose of study drug treatment:
1. Hemoglobin 9 g/dL, platelet count 100,000/mm3, ANC 1500/mm3
2. Creatinine clearance 30 mL/min
3. Amylase and lipase 1.5 the upper limit of normal (ULN) 
4. Serum bilirubin 1.5ULN; patients with known Gilbert’s disease may have a bilirubin 
≤ 3.0x ULN
5. AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN with the following exceptions:
a)
Patients with documented liver metastases: AST and/or ALT 5 ULN
b)
Patients with documented liver or bone metastases:  ALP 5 ULN
6. INR and PTT 1.5 ULN.  Patients who are on therapeutic doses of anti-coagulants 
are eligible if they are on a stable dose of anti-coagulant for 28 days with stable INR 
and PTT values. 

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
Women of childbearing potential must agree to appropriately use an effective form of 
contraception (failure rate of 1% per year) during the treatment period, within 5 months 
after the last dose of atezolizumab, and within 3 months after the last dose of cobimetinib
and regorafenib.
1.
A woman of childbearing potential is defined as a sexually mature woman without prior 
oophorectomy or hysterectomy who have had menses within the last 12 months. 
2.
A woman is not considered to be of childbearing potential if she has become 
amenorrheic for 12 months and has a follicle-stimulating hormone level 40 IU/L.

Men must agree not to donate sperm or have intercourse with a female partner without 
using appropriate barrier contraception during the treatment period and for 3 months after 
the last dose of either cobimetinib or regorafenib.

Available and adequate baseline tumor tissue sample (archival or newly obtained biopsy)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-related exclusion criteria:

After the approximate 5% cap for MSI-high patients is reached, only MSI-stable patients will 
be eligible.

Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant 
patients will be eligible.

Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of 
needing such procedure while receiving study treatment.

Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1

Uncontrolled tumor-related pain.  Patients requiring narcotic pain medication must be on a 
stable regimen at study entry.
1.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to start of 
study treatment.
2.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to the start of study treatment.

Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage 
more than once every 28 days.  Indwelling drainage catheters (e.g., PleurX) are allowed.

Active or untreated CNS metastases are excluded.  Patients with treated and asymptomatic 
CNS metastases are eligible, if they meet all of the following:
1.
Evaluable or measurable disease outside the CNS
2.
No metastases to midbrain, pons, medulla or within 10 mm of the optic nerves and 
chiasm
3.
No history or evidence of intracranial hemorrhage or spinal cord hemorrhage 
4.
No evidence of clinically significant vasogenic edema
5.
Not on corticosteroids for 2 weeks; anti-convulsants at a stable dose are allowed.
6.
No evidence of clinical and radiographic disease progression in the CNS for 3 weeks 
after radiotherapy or surgery.
Exclusion criteria related to study medication:
1.
Any cancer immunotherapy including CD137 agonists, antiprogrammed death-1, 
antiPD-L1, or anti-CTLA4
2.
Any MEK or ERK inhibitor 
3.
Regorafenib

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
Patients with active malignancy (other than CRC) or a prior malignancy within the past 
3 years are excluded.  Patients with completely resected cutaneous melanoma (early stage), 
basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, 
breast carcinoma in-situ, and localized prostate cancer are eligible.
Exclusion criteria based on organ function or medical history:
Cardiovascular:

Unstable angina, new onset angina within last 3 months, myocardial infarction within last 
6 months and current congestive heart failure New York Heart Association Class II or higher.

Left ventricular ejection fraction below institutional lower limit of normal or below 50%, 
whichever is lower. 

Poorly controlled hypertension, defined as a blood pressure consistently above 
150/90 mmHg despite optimal medical management.
Infections:

HIV infection

Active tuberculosis infection

Severe infections within 2 weeks prior to Cycle 1 Day 1

Signs or symptoms of significant infection within 2 weeks prior to Cycle 1 Day 1

Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or 
chronic obstructive pulmonary disease) are eligible

Active or chronic viral hepatitis B or C infection
1.
Patients with hepatitis B virus (HBV) infection are eligible if test for hepatitis B surface 
antigen and HBV DNA are negative
2.
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain reaction 
test for HCV RNA is negative.
Ocular:

History of or evidence of retinal pathology on ophthalmologic examination that is considered 
a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular 
degeneration

Patients will be excluded if they currently have any of the following risk factors for retinal 
vein occlusion:
1.
Uncontrolled glaucoma with intra ocular pressure 21 mmHg
2.
Uncontrolled hypercholesterolemia 300 mg/dL or 7.75 mmol/L
3.
Uncontrolled hypertriglyceridemia 300 mg/dL or 3.42 mmol/L
4.
Fasting hyperglycemia 160 mg/dL or 8.9 mmol/L
Autoimmune conditions and immunomodulatory drugs:

History of autoimmune disease except for the following: 
1.
Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement 
hormone are eligible. 
2.
Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible. 

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis) are permitted provided that they 
meet the following conditions:
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations
Rash must cover less than 10% of body surface area

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Disease is well controlled at baseline and only requiring lowpotency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 
0.05%, aclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months (not requiring 
PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, 
drug-induced pneumonitis, or idiopathic pneumonitis 
Patients with radiation pneumonitis within the radiation field are eligible.

History of organ transplantation including allogeneic bone marrow transplantation
Other medical conditions or medications:

Any hemorrhage or bleeding event CTCAE Grade 3 or higher within 28 days of Cycle 1 
Day 1

History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 
6 months prior to Day 1

Proteinuria 3.5 g/24 hours

Serum albumin 2.5 g/dL

Foods, supplements or drugs that are potent CYP3A4 enzyme inducer or inhibitors are 
prohibited at least 7 days prior to Cycle 1 Day 1 and during study treatment. These include 
St. John’s wort or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent 
cytochrome P450 CYP3A4 enzyme inhibitor).
General exclusion criteria:

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered medications 

Pregnant, lactating, breastfeeding, or intending to become pregnant during the study

History of severe hypersensitivity reactions to components of:
1.
Cobimetinib formulation
2.
Regorafenib formulation
3.
Atezolizumab formulation

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation of a live attenuated vaccine will be required during the study

Any anti-cancer therapy, including chemotherapy, or hormonal therapy within 2 weeks prior 
to initiation of study treatment

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
IL-2) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1 Day 1

Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor agents) within 2 weeks prior to Cycle 1 Day 1
End of Study
The OS final analysis will be conducted when there are approximately 235 deaths in the study. 
This is expected to occur approximately 23 months after the first patient is randomized.   
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis (i.e., OS) or safety follow-up is 
received from the last patient, whichever occurs later.    
Length of Study
LPLV is expected to occur 3 years after the first patient is enrolled.  The study will end at any 
time if the Sponsor decides to end the trial.

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Investigational Medicinal Products and Non-Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are cobimetinib and atezolizumab.  
Regorafenib is an approved treatment for mCRC and is considered a standard of care in this 
disease setting and administered in this study at the same dose that was used in the pivotal 
clinical trials and the approved and marketed dose for this indication.  In this study, regorafenib 
is considered a non-investigational medicinal product, unless depending on local classification, 
regorafenib is deemed an IMP. If considered an IMP, then appropriate information on 
formulation, packaging, handling, and administration will be provided.
Test Products (Investigational Drugs)
Patients randomized to cobimetinib will receive 60 mg (three tablets of 20 mg each) orally once 
daily for Days 121 of a 28-day cycle.  This 4-week period is considered a treatment cycle.
Atezolizumab dose and schedule will depend on the treatment arm:

Arm A:  cobimetinib plus atezolizumab 840 mg IV every 2 weeks 

Arm B:  atezolizumab 1200 mg IV every 3 weeks as monotherapy
Comparator
Patients randomized to Arm C:  regorafenib, will receive 160 mg (four tablets of 40 mg each) of 
regorafenib to be taken orally once daily on Days 121 of a 28-day cycle.  This 4-week period is 
considered a treatment cycle.
Other Non-Investigational Medicinal Products
The following therapies are permitted in the study:

Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low-molecular weight heparin 
or warfarin at a stable dose level)

Palliative radiotherapy (e.g., treatment of known bone metastases) provided it does not 
interfere with assessment of tumor target lesions
It is not required to withhold atezolizumab during palliative radiotherapy.  

Inactive influenza vaccinations during influenza season ONLY

Megastrol administered as an appetite stimulant

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone)
Anti-emetics and anti-diarrheal medications should not be administered prophylactically before 
initial treatment with study drugs.  At the discretion of the investigator, prophylactic anti-emetic 
and anti-diarrheal medication(s) may be used per standard clinical practice before subsequent 
doses of study drugs.  Hematopoietic growth factors should not be administered prophylactically 
before initial treatment with study drugs. Hematopoietic growth factors may be administered 
according to local guidelines if indicated during the course of the study. 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated, as per local standards.  Patients who experience infusion-associated symptoms may 
be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine 
or another H2 receptor antagonist as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious infusionassociated 
events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies as 
clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists).

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Statistical Methods
Primary Analysis
The primary efficacy endpoint is OS, which is defined as the time (in months) between the date 
of randomization and the date of death due to any cause.  Patients who have not died at the 
time of analysis will be censored at the date when they were last known to be alive.  
Comparisons with respect to OS between two treatment arms (i.e., Arm A vs. Arm C, Arm B vs. 
Arm C) will be tested based on a stratified log-rank test.  The stratification factors will be 
extended RAS mutation status of the tumor and time since diagnosis of first metastasis 
(18 months and 18 months).
Each comparison will be tested at a 2-sided significance level of 0.05 within the intent-to-treat
(ITT) population:

Test to reject the null hypothesis of no difference in OS between either experimental arm 
(i.e., Arm A or Arm B) and the control arm (Arm C) in the ITT population.  If the 2sided 
p-value corresponding to the stratified log-rank test is less than 0.05, the null hypothesis will 
be rejected.
The hazard ratio (HR) for OS will be estimated using a stratified Cox model.  Two-sided 
95% CIs for the HR will be provided.  The stratified analyses will incorporate extended RAS 
mutation status and time since diagnosis of first metastasis as stratification factors.  Results 
from an unstratified log-rank test and the unstratified HR will also be presented.  Kaplan-Meier 
methodology will be used to estimate median OS for each treatment arm, and the Kaplan-Meier 
curves will be provided.  The Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median OS for each treatment arm.
The comparison between the two experimental arms (Arm A vs. Arm B) will be conducted for 
descriptive purposes.
Determination of Sample Size  
The study will randomize approximately 360 patients, including a minimum of 180 patients with 
extended RAS-mutant mCRC (assuming a prevalence of at least 50%), to cobimetinib plus 
atezolizumab (Arm A), atezolizumab monotherapy (Arm B), and regorafenib (Arm C) with the 
randomization ratio of 2:1:1, respectively.
The type 1 error () for the analysis of the primary endpoint of OS in the comparison of 
cobimetinib plus atezolizumab (Arm A) against the control arm of regorafenib (Arm C) is 
0.05 (2-sided).  If OS in the comparison of Arm A against Arm C is statistically significant, then 
the OS in the comparison of Arm B against Arm C will be tested at a 2-sided level of 0.05. 
The sample size of this study is determined on the basis of the number of events required to 
demonstrate efficacy with regard to OS in both comparisons (Arm A vs. Arm C and Arm B vs. 
Arm C).
The estimate of the number of events required to demonstrate efficacy with regard to OS is 
based on the following assumptions:

Two-sided significance level of 0.05

Arm A versus Arm C:  87% power to detect an HR of 0.61, corresponding to an 
improvement in median OS from 6.4 months in Arm C to 10.5 months in Arm A

Arm B versus Arm C:  80% power to detect an HR of 0.61, corresponding to an 
improvement in median OS from 6.4 months in Arm C to 10.5 months in Arm B 

No interim analysis for OS

Dropout rate of 10% in 24 months

Hierarchical testing of Arm A versus Arm C followed by Arm B versus Arm C to control the 
overall level of 5%
With these assumptions, approximately 360 patients in total will be randomized into this study, 
with approximately 270 patients for the comparison of Arm A versus Arm C and approximately 
180 patients for the comparison of Arm B versus Arm C.  The OS final analysis will be 
conducted when there are approximately 235 deaths in the study.  This is expected to occur 

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approximately 23 months after the first patient is randomized.  At that time, it is expected 
that approximately 178 deaths for the comparison of Arm A versus Arm C and approximately 
127 deaths for the comparison of Arm B versus Arm C will have occurred.
This number of events corresponds to a minimum detectable difference in HR of approximately 
0.73 for the Arm A versus Arm C comparison and approximately 0.71 for the Arm B versus 
Arm C comparison.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
14/14
14 days on/14 days off
21/7
21 days on/7 days off
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ATA
anti-therapeutic antibody
AUC
area under the concentration-time curve
BOR
best overall response
BRAFi
BRAF inhibitor
CEA
carcinoembryonic antigen
cfDNA
cell-free DNA
Cmax
maximum concentration
Cmin
minimum concentration
CR
complete response
CRC
colorectal cancer
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organization for Research and Treatment of 
Cancer Quality of Life-C30 questionnaire
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL 5 Dimensions
E.U.
European Union
FFPE
formalin-fixed paraffin-embedded 
GWAS
genome-wide association studies
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act

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Abbreviation
Definition
HR
hazard ratio
HRQoL
healthrelated quality of life
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
IL
Interleukin
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IxRS
interactive Web/voice response system
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
mCRC
metastatic colorectal cancer
MDSC
myeloidderived suppressive cells
MEKi
MEK inhibitor
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
MSI
microsatellite
MSS
microsatellite stable
MTD
maximum-tolerated dose
MUGA
multigated acquisition (scan)
NCI
National Cancer Institute
NGS
next-generation sequencing
NIMP
noninvestigational medicinal product
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
programmed cell death
PD-1
programmed cell death-1
PD-L1
programmed cell death ligand-1
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome

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Abbreviation
Definition
PVC
polyvinylchloride
q2w
every 2 weeks
q3w
every 3 weeks
QD
once daily
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SD
stable disease
TNF
tumor necrosis factor
ULN
upper limit of normal
VEGF
vascular epidermal growth factor
WGS
whole genome sequencing

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1.
BACKGROUND
1.1
BACKGROUND ON METASTATIC COLORECTAL CANCER
1.1.1
Incidence and Treatment of Metastatic Colorectal Cancer 
Globally, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males 
and second in females. CRC also is the fourth leading cause of cancer mortality in 
males and third in females (Torre et al. 2016).  The estimated incidence of new cases in 
2012 in developed countries was 736,900, and mortality was 333,200, with the highest 
incidence rates in North America, Europe, and Australia/New Zealand (Torre et al. 2016).
In the United States, about 40% of CRC patients are diagnosed with early-stage disease,
with another 40% diagnosed with regional disease, and 20% diagnosed with distant 
metastasis.  Five-year survival rates are 90%, 70%, and 13%, respectively, with most of 
these patients dying from metastatic disease (Alberts and Wagman 2008; 
American Cancer Society 2015; Kennecke et al. 2014).  
Without treatment, the median survival for patients with metastatic CRC (mCRC) is less 
than 1 year (Liu et al. 2003).  Surgical resection of metastases can improve outcomes.
The 5-year survival rates of the small fraction of patients eligible for resection of 
metastatic lesions are around 27%41% (Mandalà et al. 2007; Zaydfudim et al. 2015).  
In the vast majority of mCRC patients, systemic cytotoxic chemotherapy is the mainstay 
of treatment and median overall survival (OS) is only around 30 months.  Anti-vascular 
endothelial growth factor (VEGF) therapies such as bevacizumab, ramucirumab, and 
ziv-aflibercept, and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies
(mAb) such as cetuximab and panitumumab can be used in combination with 
chemotherapy in first-, second-, and third-line therapies, though treatment combinations
vary by region (Petrelli et al. 2015).  In the United States and Western Europe, 
anti-VEGF and anti-EGFR therapy is used 30%50% and 17%30% of patients during 
the course of treatment, respectively (Zhao et al 2012; Abrams et al. 2014).
1.1.2
Management of Metastatic Colorectal Cancer Beyond 
Second-Line Chemotherapy
Once patients have exhausted standard chemotherapy regimens, their survival is less 
than 6 months.  Recently two agents, regorafenib (Stivarga) and trifluridine and tipiracil 
(TAS-102; LONSURF) have been approved in these previously treated 
chemotherapy-refractory mCRC patients.
Regorafenib is a multikinase inhibitor that was approved in heavily pretreated mCRC 
patients based on an international, multicenter, randomized, double-blind, 
placebo-controlled trial in 760 patients.  The median OS for regorafenib plus best 
supportive care was 6.4 months compared to 5 months for placebo plus best supportive 
care (hazard ratio [HR]0.77; p0.0102).  Common side effects were 
hand-foot syndrome, fatigue, rash, diarrhea, hemorrhage, hypertension, mucositis, and 
infection (Grothey et al. 2013).

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Trifluridine/tipiracil is an orally administered combination of a thymidinebased nucleic 
acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. 
It has recently been approved in the United States based upon an international, 
multicenter, randomized, double-blind, placebo-controlled trial in 800 patients.  
The median OS was 7.1 months (95% CI, 6.5 to 7.8) in the trifluridine and tipiracil group
and 5.3 months (95% CI, 4.6 to 6.0) in the placebo group (HR0.68; p0.001).  Notable 
side effects were neutropenia, anemia, and thrombocytopenia as well gastrointestinal 
toxicity (Mayer et al. 2015).
Even with the recent approvals of these two agents, a high unmet need remains in this 
patient population for more efficacious treatment options with better safety profiles.
1.2
THE PROGRAMMED T-CELL DEATH LIGAND-1 PATHWAY
Encouraging clinical data in the field of tumor immunotherapy have demonstrated that 
therapies that are focused on enhancing T-cell responses against cancer can result in 
significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010).  Therefore, immunomodulation represents a promising new strategy 
for cancer therapy that may result in improved anti-tumor activity.
Programmed T-cell death ligand-1 (PD-L1) expression is prevalent in many human 
tumors (e.g., lung, ovarian, melanoma, colon carcinoma), and its overexpression has 
been associated with poor prognosis in some cancers (Thompson et al. 2006; 
Hamanishi et al. 2007; Ozaki and Honjo 2007; Hino et al. 2010).  PD-L1 is one of two 
ligands (PD-L1 and PD-L2) that bind programmed cell death-1 (PD-1). The PD-1 
receptor is an inhibitory receptor expressed on T cells following T-cell activation in states 
of chronic stimulation, such as chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity that lead to the functional inactivation of T cells.  
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore,
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumorspecific T-cell immunity.
Blockade of PD-L1 or PD-1 with mAbs results in strong and often rapid anti-tumor effects 
in several mouse tumor models (Iwai et al. 2002; Strome et al. 2003) and has 
demonstrated clinical activity with drugs such as atezolizumab (Besse et al. 2015; 
Rosenberg et al. 2015; Vansteenkiste et al. 2015). 
Atezolizumab is a humanized IgG1 mAb that targets PD-L1 and inhibits its interaction 
with its receptors, PD-1 and B7-1 (also known as CD80).  Both of these interactions are 
reported to provide inhibitory signals to T cells. Atezolizumab was engineered to impair 
its binding to Fc receptors, thus eliminating detectable Fc-effector function and 
associated antibody-mediated clearance of activated effector T cells. Section 1.4
describes the nonclinical and clinical data of atezolizumab.

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1.3
THE MAPK SIGNALING PATHWAY AND REGULATION OF THE 
IMMUNE TUMOR MICROENVIROMENT
The MAPK signaling cascade is a key intracellular signaling network that transduces 
multiple proliferative and differentiating signals from the extracellular environment to the 
nucleus of cells to activate cellular growth and differentiation.  Signaling through ERK is 
one major MAPK pathway that has been identified that plays a significant role in normal 
cellular regulation (Johnson and Lapadat 2002; Roberts and Der 2007).  Given the 
central role that the MAPK pathway plays in normal cellular development, abnormal 
regulation of this signaling pathway could lead to tumorigenesis through contribution to 
uncontrolled proliferation, invasion, metastasis, and angiogenesis as well as diminished 
apoptosis.
The MAPK pathway has also been implicated in the regulation of the immune 
microenvironment of tumors.  In in vitro cell lines, blocking the MAPK pathway was 
shown to increase antigen expression and enhance reactivity to antigenspecific 
T lymphocytes (Boni et al. 2010).  In melanoma patients who are treated with a 
combined BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi), increased intratumoral 
lymphocytes (CD4- and CD8-positve T cells) were observed compared to pre-treatment 
biopsy samples (Kakavand et al. 2015).  Furthermore, pre-treatment biopsies where 
there were increased tumor-infiltrating lymphocytes demonstrated a larger increase in 
tumor-infiltrating lymphocytes and PD-1 expression after treatment with a BRAFi and 
MEKi (Cooper et al. 2015; Kakavand et al. 2015; Liu et al. 2015).  The inhibition of the 
MAPK pathway leads to an increase in immune effector cells in the tumor, thus priming 
the microenvironment to enable to immune system to attack the tumor.
Inhibition of the MAPK pathway has focused on the suppression of targets within this
signaling network, such as MEK1 and MEK2.  There are multiple upstream activating 
signals, but multiple alternative pathways exist to bypass their inhibition and still activate 
ERK1 and ERK2. ERK1 and ERK2 can only be activated and phosphorylated by MEK1 
and MEK2, which therefore render MEK1 and MEK2 as key signaling hubs for the 
inhibition of the MAPK pathway.  
Cobimetinib is an orally dosed, potent and highly selective inhibitor of MEK. Section 1.5
describes the nonclinical and clinical data of cobimetinib.
1.4
BACKGROUND ON ATEZOLIZUMAB MONOTHERAPY
See the atezolizumab Investigator’s Brochure for additional details on nonclinical and 
clinical studies.
1.4.1
Summary of Nonclinical Studies with Atezolizumab
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetics, to demonstrate an acceptable 
safety profile, and to identify a Phase I starting dose. Comprehensive pharmacology, 

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pharmacokinetic (PK), and toxicology evaluations were thus undertaken with 
atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in 
projecting the appropriate starting dose in humans. Based on the similar binding affinity 
and pharmacologic activity of atezolizumab for cynomolgus monkey and human PD-L1, 
the cynomolgus monkey was selected as the relevant nonclinical model for 
understanding the safety, pharmacokinetics, and toxicokinetics of atezolizumab.  
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses. The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies in patients.
1.4.2
Clinical Experience with Atezolizumab
1.4.2.1
Ongoing Clinical Studies
In the United States, atezolizumab is approved for the treatment of locally advanced or 
metastatic urothelial bladder cancer who have progressed during or following platinum-
containing chemotherapy and for metastatic nonsmall cell lung cancer (NSCLC) who 
have progressed during or following platinum-containing chemotherapy and if harboring 
an EGFR or ALK aberration have progressed on U.S. Food and Drug 
Administration-approved therapy for these aberrations.  Atezolizumab is currently being 
tested in multiple Phase I, II, and III studies, both as monotherapy and in combination 
with several anti-cancer therapies (see the atezolizumab Investigator’s Brochure for 
study descriptions). Much of the safety and efficacy data summarized below is from 
Phase I Study PCD4989g, a multicenter, first-in-human, open-label, dose-escalation 
study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion once every three weeks (q3w) to patients 
with locally advanced or metastatic solid malignancies or hematologic malignancies.
1.4.2.2
Clinical Safety as a Single Agent
The safety data for atezolizumab have been derived mainly from the treatment of 
patients in Study PCD4989g. As of 10 May 2015, the clinical database contained 
preliminary safety data from 558 patients who have received any amount of 
atezolizumab at doses between 0.01 and 20 mg/kg across multiple tumor types. 
No dose-limiting toxicities (DLTs) have been observed at any dose level, and no 
maximum tolerated dose (MTD) has been established.
Adverse Events
Of the 558 treated patients,520 (93.2%) reported an adverse event regardless of 
attribution to atezolizumab. The majority of these adverse events were Grade 1 or 2 in 
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for Adverse Events, Version 4.0 (NCI CTCAE v4.0). The most frequently observed 
adverse events (occurring in 10% of treated patients) included fatigue, nausea, 
decreased appetite, pyrexia, dyspnea, diarrhea, constipation, cough, headache, back 
pain, vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, 
pruritus, generalized pain, and peripheral edema.
There were 66 patients (11.88%) who experienced Grade ≥ 3 adverse events that were 
assessed as related to study drug by the investigators. Grade 3 and 4 adverse events 
considered related by the investigator included dyspnea, pneumonitis, increased ALT, 
increased AST, increased -glutamyl transferase, lymphocyte count decreased, cardiac 
tamponade, asthenia, autoimmune hepatitis, pneumonia, influenza, and hypoxia.
ImmuneMediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immunemediated adverse events have been closely monitored during the 
atezolizumab clinical program. These include potential dermatologic, hepatic, 
gastrointestinal, endocrine, neurologic, and respiratory events as well as events of 
hepatitis/elevated liver function tests and influenza-like illness that are considered 
potential adverse drug reactions associated with atezolizumab.
Refer to the atezolizumab Investigator’s Brochure and Appendix 9 for details regarding 
immunemediated adverse events and identified risks (adverse drug reactions) 
observed in patients treated with atezolizumab as well as recommended management 
guidelines for atezolizumab-specific immunemediated adverse events.
1.4.3
Clinical Activity of Atezolizumab
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)−based responses (i.e., RECIST v1.1 responses), have been observed in 
patients with different tumor types, including NSCLC, renal cell carcinoma (RCC), 
melanoma, bladder cancer, CRC, head and neck cancer, gastric cancer, breast cancer, 
and sarcoma treated with atezolizumab monotherapy in Study PCD4989g. 
Analyses of PD-L1 expression on baseline tumor tissue have been performed for 
Study PCD4989g, with results suggesting that PD-L1 expression is likely to be 
associated with response to atezolizumab.
Among 345 efficacy evaluable patients treated as of 21 October 2013 (data cutoff of 
21 April 2014), with a median of 30.4 weeks of follow-up, 62 patients experienced 
objective responses per RECIST v1.1, with an overall response rate (ORR) of 
18% (95% CI: 14.1%, 22.3%). Objective responses with atezolizumab monotherapy 
were observed in a broad range of malignancies, including NSCLC, RCC, melanoma, 
bladder cancer, CRC, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma. The atezolizumab—F. Hoffmann-La Roche Ltd 29/Protocol GO30140, 
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97.9weeks, for which the “” denotes a censored value). The majority of these 
responses have been durable, with 72.6% of responses (45 of 62 patients) ongoing as of 
the clinical cutoff date.
1.4.4
Clinical Pharmacokinetics and Immunogenicity of 
Atezolizumab
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses 1 mg/kg. For the 1- and 20-mg/kg dose 
groups, the mean apparent clearance and the mean volume of distribution at steady 
state ranged from 3.20 to 4.44 mL/day/kg and 48.165.7 mL/kg, respectively, which is 
consistent with the expected pharmacokinetics of an IgG1 antibody in humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg). The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses ranging from 
1020 mg/kg. Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have 
maintained the expected target trough levels of drug despite the detection of ATAs.
To date, no clear relationship between detection of ATAs and adverse events or infusion 
reactions has been observed.
1.5
BACKGROUND ON COBIMETINIB MONOTHERAPY
Cobimetinib is a reversible, potent, and highly selective inhibitor of MEK1 and MEK2.
Cobimetinib is approved in the United States, European Union, Switzerland, and in 
multiple other countries across the world for use with vemurafenib for the treatment of 
advanced BRAF-mutated melanoma.
1.5.1
Summary of Nonclinical Studies with Cobimetinib
Cobimetinib inhibits proliferation of a variety of human tumor cell lines through inhibition 
of MEK1 and MEK2.  In addition, cobimetinib inhibits ERK phosphorylation in xenograft 
tumor models and stimulates apoptosis.  Cobimetinib accumulates in tumor xenografts 
and remains at high concentrations in the tumor after plasma concentrations have 
declined.  The activity of cobimetinib to inhibit ERK1 phosphorylation is more closely 
correlated with its concentration in tumor tissue than in plasma; in general, there is a 
good correlation between reduced ERK1 phosphorylation and efficacy in tumor 
xenograft models.  Tumor regression has been observed in several human tumor 
xenograft models.  This regression was dose dependent with up to 100% regression at 
the highest doses tested.  The models studied included CRC, malignant melanoma, 
breast carcinoma, and anaplastic lung carcinoma.
A characterization of the pharmacologic and PK properties of cobimetinib was performed 
in a series of nonclinical studies that are summarized in the cobimetinib Investigator’s 
Brochure.

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The nonclinical toxicity of cobimetinib was characterized in singleand repeatdose 
general toxicity studies in rats and dogs, in vitro genotoxicity studies, 
embryolethality/teratogenicity studies in rat, and cardiovascular, neurobehavioral, and 
respiratory safety pharmacology studies.  The studies are summarized in the cobimetinib 
Investigator’s Brochure.
1.5.2
Summary of Clinical Studies with Cobimetinib Monotherapy
As of October 2015, cobimetinib had been administered alone or with other agents to 
more than 1000 adult cancer patients and approximately 120 healthy volunteers in 18 
clinical trials; the vast majority of patients had been treated with cobimetinib plus other 
agents, such as vemurafenib.  These include one trial of cobimetinib as a single agent, 
seven clinical pharmacology studies, and nine trials of cobimetinib with other agents. 
Study MEK4592g was a Phase I, non-randomized, open-label, safety and PK
dose-escalation study. The study was conducted in patients with metastatic or
unresectable solid tumors for which standard curative or palliative measures did not exist
or were no longer effective. A total of 115 patients were treated, and the study has 
since been completed.
The study consisted of five treatment stages:

Stage I: Dose-escalation cohorts; patients were treated on a 21-days-on, 7-days-off
(21/7) schedule to determine the MTD. 

Stage IA: Dose-escalation cohorts; patients were treated on a 14-days-on,
14-days-off (14/14) schedule to determine the MTD on an alternate dosing regimen.

Stage II: Expansion cohort with the MTD determined in Stage I (60 mg daily [QD]
21/7) in patients harboring a BRAF, NRAS, or KRAS mutation.

Stage IIA: Expansion cohort with the MTD determined in Stage IA (100 mg QD 
14/14) in patients harboring a BRAF, NRAS, or KRAS mutation.

Stage III: A dedicated drug-drug interaction study at the MTD determined in Stage I 
(60 mg QD 21/7) in approximately 20 patients with solid tumors.
Dose-Limiting Toxicities
Four DLTs were observed in Stage I (21/7 dosing schedule) of Study MEK4592g. At the 
40-mg dose level, a DLT of Grade 4 hepatic encephalopathy and Grade 3 elevated 
ammonia was reported in a patient with pre-existing liver metastases. At the 60-mg 
dose level, a DLT of Grade 3 rash was reported that improved with skin toxicity 
management and drug holiday. At the 80-mg dose level, two DLTs were reported: 
1 patient with Grade 3 diarrhea despite treatment with anti-diarrheal medications and 
1 patient with Grade 3 rash.
Two DLTs were observed in Stage IA (14/14 dosing schedule), both at the 125-mg dose 
level. One patient had Grade 3 rash and another had Grade 3 blurred vision associated 
with neurosensory detachment of the retina.

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Adverse Events
All patients in Study MEK4592g experienced an adverse event. The most frequent 
adverse events were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea and
vomiting (33.9% each), and edema peripheral (28.7%). Other events that occurred 
in 10% of patients included anemia, abdominal pain, constipation, hypokalemia, 
decreased appetite, headache, dizziness, back pain, increased AST, dermatitis 
acneiform, pruritus, and dry skin.  Among the patients who received cobimetinib 60 mg 
21/7, the most frequent treatmentemergent adverse events were diarrhea (64.4%),
rash (53.3%), fatigue (48.9%), nausea and edema peripheral (31.1% each), and 
vomiting (28.9%).
Grade3 Adverse Events
Among all cobimetinib-treated patients, 5 patients (4.3%) experienced a 
Grade 4 adverse event, and 53 patients (46.1%) experienced a Grade 3 adverse event.
The most frequent Grade 3 and Grade 4 adverse events were hyponatremia (9.6%), 
fatigue (8.7%), anemia (7.8%), and diarrhea and hypokalemia (6.1% each). 
Serious Adverse Events 
A total of 49 patients (42.6%) experienced a serious adverse event. The most common 
types of serious adverse events were gastrointestinal disorders (n17), but there were 
no trends in specific preferred terms. The gastrointestinal serious adverse events, such 
as intestinal obstructions and gastrointestinal hemorrhages, occurred in patients with 
gastrointestinal malignancies. Serious adverse events reported for more than 2 patients
among all patients in the study were anemia, bile duct obstruction, dehydration,
syncope, and respiratory arrest (3 patients each [2.6%]).
Efficacy
Best overall response (BOR) was assessed for 74 of 97 patients in Stages I, IA, II, and 
IIA.  Overall 6 patients (all of whom had melanoma; 6.2%) had a confirmed partial 
response (PR), 28 patients (28.9%) had stable disease (SD), and 40 patients (41.2%) 
had progressive disease. Out of the 14 CRC patients, all patients experienced 
progressive disease. In Stage III of Study MEK4592g, 18 patients were accrued and 
BOR was assessed for 14 of 18 patients. Four patients (22.2%) had SD as their BOR,
and 2 patients (11.1%) had unconfirmed tumor responses.
For further clinical information on cobimetinib as monotherapy or with other anti-cancer 
agents, please see the cobimetinib Investigator’s Brochure.
1.6
COMBINED INHIBITION OF PD-L1 AND MAPK SIGNALING 
PATHWAYS AS POTENTIAL ANTI-CANCER THERAPY IN 
METASTATIC COLORECTAL CANCER
Because of the high unmet medical need in heavily pretreated advanced mCRC, where 
OS is only 6 months, several clinical studies have tested checkpoint inhibitors in this 

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setting with disappointing results (Brahmer et al. 2012; Topalian et al. 2012; 
Poulin-Costello et al. 2013).  
Recently, immune checkpoint inhibitors have been shown to have clinical benefit in 
microsatellite (MSI) unstable mCRC but not in MSI stable cohorts (Le et al. 2015). 
This preferential effect of checkpoint inhibitors on MSI-high CRCs has been postulated 
to be due to an increase in neo-antigens from a greater somatic mutation load.  This 
increase in somatic mutations amplifies upstream pathways required for an immune 
response, such as recruitment of immune effector or antigen presenting cells 
(Llosa et al. 2015; Zhang et al. 2015).  Furthermore, the mismatch repairdeficient 
cancers have increased CD8-positive T cells and PD-L1 expression in the tumor, which 
may explain why they are responsive to checkpoint inhibitors (Li et al. 2015; 
Smedt et al. 2015).
One potential mechanism to convert otherwise resistant cancers is to recruit immune 
cells to the tumor sites so that the anti-PD L1 can be effective in activating the local 
immune system against the cancer cells. Nonclinical models suggest that MEK 
inhibition may have pleiotropic effects that could impact the tumor immune 
microenvironment, as the MAPK pathway has been implicated in the immune resistance 
of tumors and inhibition of this pathway can lead to increase CD8positive T-cell 
infiltration (Kakavand et al. 2015; Liu et al. 2015).    
Within the tumor, MEK inhibition results in increased major histocompatibility complex 
(MHC) class I expression and tumor antigen presentation, which acts to enhance tumor 
recognition by the immune system.  Interestingly, MEK inhibition in tumors also 
increases expression of the checkpoint receptor PD-L1, which could counteract the 
increased presentation of tumor antigens.  Lastly, the MAPK pathway is known to 
regulate a number of cytokines and chemokines, such as VEGF, interleukin (IL)-6 (IL-6), 
IL-8, and granulocytemacrophage colony-stimulating factor, which may impact 
recruitment of vascular and other stromal cell types, including myeloidderived 
suppressive cells (MDSCs) that can inhibit the anti-tumor activity of T cells 
(Bancroft et al. 2001; Sano et al. 2001; Bancroft et al. 2002; Phan et al. 2013).  Activity 
of MEK inhibition outside of the tumor cells may further contribute to the modulation of 
the immune microenvironment that could enable a more permissive immune reaction 
against the tumor.  These effects include inhibition of tumor vascular maturity and 
integrity, tumor infiltration, activity of MDSCs, neutrophils, increased activity of 
antigen-presentation cells, such as macrophage and dendritic cells, and recruitment and 
activation status of T-cell subsets, including CD8-positive cytolytic and CD4positive 
helper cells (Giordano et al. 2015; Liu et al. 2015; Loi et al. 2015).  
Collectively, these effects enable tumors to demonstrate stronger anti-tumor responses 
with the combination of a MEKi and PD-L1/PD-1 blockade in multiple mouse models, 
including colorectal, breast, and melanoma models (Liu et al. 2015; Loi et al. 2015).  
Increased anti-tumor activity is associated with increased CD8positive T-cell infiltration 

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of tumors that express markers consistent with tumorcell cytolytic activity.  These data 
suggest that MEK inhibition can modulate the tumor immune microenvironment and 
enable better tumor recognition and killing by the immune system, particularly when 
paired with a checkpoint inhibitor against the PD-1/PD-L1 axis.
1.7
CLINICAL DATA OF COBIMETINIB PLUS ATEZOLIZUMAB IN 
METASTATIC COLORECTAL CANCER – STUDY GP28363
Study GP28363 is a Phase Ib, open-label, multicenter study designed to assess the 
safety, tolerability, and pharmacokinetics of cobimetinib plus atezolizumab in patients 
with advanced solid tumors.
The study has two stages:  Stage 1 (dose escalation) and Stage 2 (expansion).
Stage 1 is designed to establish the combination MTD for cobimetinib plus atezolizumab.
In Stage 2, the recommended Phase II dose and schedule were investigated in 
tumorspecific expansion cohorts: KRAS-mutant mCRC, NSCLC, and metastatic 
melanoma.
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.8
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The rationale for specific details of the study design are discussed in Section 3.3.
The combination of a MEKi and PD-L1 inhibitor has nonclinical and clinical data that 
strongly support further evaluation in previously treated mCRC patients.  Both in vitro 
and in vivo models have shown that the MAPK pathway plays an important role in the 
immune tumor microenvironment, and MEK inhibition leads to increases in MHC-1 and 
PD-L1 expression as well as increases in CD8positive lymphocyte recruitment into the 
tumor microenvironment.  This enhancement of the local immune system in combination 
with a PD-L1 inhibitor has demonstrated increased efficacy in nonclinical and clinical 
models.  The Phase Ib clinical trial evaluating cobimetinib plus atezolizumab in 
previously treated KRASmutated mCRC patients shows an efficacy of a 13% PR rate 
and a 26% SD rate, with some responses lasting more than 1 year.  The regimen is well 
tolerated, and the safety profile is manageable and tolerable.
There is clearly a high medical need in this patient population of previously treated 
mCRC patients, where OS is less than 6 months and treatment options are very limited 
and often poorly tolerated.  Cobimetinib plus atezolizumab has shown clinically efficacy 
in these mCRC patients and is well tolerated; thus, further study in this clinical trial is 
warranted.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of: 1) cobimetinib plus 
atezolizumab or 2) atezolizumab monotherapy, compared to regorafenib in patients with 
unresectable locally advanced or metastatic CRC who have been previously treated with 
at least two lines of chemotherapy.  Specific objectives and corresponding endpoints for 
the study are outlined in Sections 2.12.7.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of cobimetinib plus 
atezolizumab compared to regorafenib (standard of care) in patients with previously 
treated, unresectable locally advanced or metastatic CRC on the basis of OS. 
Atezolizumab monotherapy will also be evaluated compared to regorafenib on the basis 
of OS.

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2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives include:

Investigator-assessed progression-free survival (PFS) per RECIST v1.1 
(see Appendix 5) of patients in the cobimetinib plus atezolizumab arm and the 
atezolizumab monotherapy arm compared to the regorafenib arm.

Investigator-assessed objective response rate (ORR) per RECIST v1.1
(see Appendix 5) of patients in the cobimetinib plus atezolizumab arm and 
atezolizumab monotherapy arm compared to the regorafenib arm

DOR of patients in the cobimetinib plus atezolizumab arm and atezolizumab 
monotherapy arm compared to the regorafenib arm

Impact on functioning as measured by changes from baseline on the five-item 
physical functioning sub-scale of the patientcompleted European Organization for 
Research and Treatment of Cancer Quality of Life Core 30 questionnaire
(EORTC QLQ-C30)

Impact on healthrelated quality of life (HRQoL) as measured by changes from 
baseline on the two-item global health status/quality of life sub-scale of the EORTC
QLQ-C30
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety profile and adverse events 
encountered by patients in the cobimetinib plus atezolizumab arm and atezolizumab 
monotherapy arm compared to the regorafenib arm. 
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the cobimetinib and atezolizumab PK 
profiles on the basis of the following:

Plasma concentration of cobimetinib at timepoints specified in Appendix 2

Serum concentration of atezolizumab in both the cobimetinib plus atezolizumab arm
and the monotherapy atezolizumab arm at timepoints specified in Appendix 2
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab on the basis of the following endpoint:

Incidence of ATAs during the study relative to the prevalence of ATAs at baseline in 
both the cobimetinib plus atezolizumab arm and the atezolizumab monotherapy arm.
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ATAs on efficacy, safety, or pharmacokinetics.

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2.5
BIOMARKER OBJECTIVES
The exploratory biomarker objectives for this study are as follows:

To assess the following molecular characteristics in tumor samples during 
pretreatment, on treatment, and at progression:
–
Genetic profile including but not limited to somatic mutations and MSI status or 
mutation load as identified through next-generation sequencing (NGS) or other 
genetic analysis.
–
Immune contextures, such as PD-L1, CD8 T cells or MHC expression, as 
identified by immunohistochemistry (IHC) and gene signature profiling
–
CRC molecular subtyping as defined by genetic and RNA and protein profiles

To evaluate the relationship between circulating tumor biomarkers (including but not 
limited to carcinoembryonic antigen [CEA], tumor-associated mutations in cell-free 
DNA [cfDNA]) and measures of efficacy
2.6
PATIENT-REPORTED OUTCOMES OBJECTIVES
Refer to Section 2.1.2 for patientreported secondary efficacy objectives.
The additional patient-reported outcome (PRO) objective of the study is to assess 
treatment impact and disease symptoms from the sub-scales of the EORTC QLQ-C30 
that assess diarrhea, constipation, lack of appetite, fatigue, and two additional items
from the EORTC item bank that assess bloating and abdominal pain associated with
cobimetinib plus atezolizumab compared with regorafenib in patients with mCRC.
2.7
PHARMACOECONOMIC OBJECTIVES
In addition, a study objective is to obtain general measures of health as measured by the 
EuroQoL 5 Dimensions (EQ-5D-5L) questionnaire for health economic modeling of 
cobimetinib plus atezolizumab or atezolizumab monotherapy compared with regorafenib 
in patients with mCRC. This information is not intended to be included in the clinical 
study report.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, multicenter, open-label, three-arm, randomized study in patients with 
unresectable locally advanced or metastatic CRC who have received at least two prior 
regimens of cytotoxic chemotherapy for metastatic disease. The study compares 
regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab
and atezolizumab monotherapy.
The primary objective of the study is to evaluate the efficacy of cobimetinib plus 
atezolizumab compared to regorafenib in patients with unresectable locally advanced or 
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metastatic setting.  The efficacy of atezolizumab monotherapy compared to regorafenib 
in the same patient population will also be evaluated as a primary objective.
This study will be conducted globally and approximately 360 patients will be randomized 
in a 2:1:1 ratio to receive (Figure 1 and Figure 2):

Arm A:  cobimetinib 60 mg orally on Days 121 plus atezolizumab 840 mg IV on 
Day 1 and Day 15 in a 28-day cycle (n ≈ 180), or

Arm B:  atezolizumab monotherapy 1200 mg IV on Day 1 in a 21-day cycle (n ≈90), 
or 

Arm C:  regorafenib 160 mg orally on Days 121 in a 28-day cycle (n ≈ 90).
At least 50% patients with extended RAS-mutant tumors (see Section 4.5.7.1 for 
definition) will be enrolled in each arm. Enrollment of patients with MSI-high status
(see Section 4.5.7.1 for definition) will be limited to approximately 5% to reflect the 
natural prevalence in mCRC (Goldstein et al. 2014).
Stratification factors are extended RAS mutation status of the tumor and time since 
diagnosis of first metastasis (18 months vs.18 months). Permuted-block 
randomization will be applied to ensure a balanced assignment to each treatment arm.
Randomization and stratification will be managed through an interactive voice/web 
response system (IxRS).
The Sponsor will monitor the enrollment for each region (North America, Europe, and 
Pacific/Asia).  To ensure balanced global enrollment, the Sponsor may institute 
temporary limitations on enrollment in certain regions in the event of disproportionate 
accrual of patients.
The schedule of study assessments and procedures are detailed in Appendix 1.
After signing informed consent, patients will undergo screening procedures that include 
testing the tumor for extended RAS mutation status and MSI status (local tests accepted 
but confirmatory centralized testing required); laboratory tests (e.g., hematology, 
chemistries, liver function tests); left-ventricular function evaluation (echocardiogram
[ECHO] or multigated acquisition scan [MUGA]); contrast-enhanced computed 
tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, 
and pelvis; and ophthalmologic assessments. 
All eligible patients will be randomized to treatment in either Arm A (cobimetinib plus 
atezolizumab), Arm B (atezolizumab monotherapy) or Arm C (regorafenib). The dosing 
regimen and schedule for each treatment arm is shown in Figure 2 and Section 4.3.
All patients will be closely monitored for safety and tolerability during all cycles of therapy, 
at the treatment discontinuation visit, and during the follow-up period. The NCI CTCAE 
v4.0 will be used to characterize the toxicity profile of the study treatments on all patients.

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Patients will be assessed for adverse events according to the schedule of assessments
in Appendix 1 and as necessary throughout the study.
Tumor response will be evaluated according to RECIST v1.1 (see Appendix 5).
Any evaluable and measurable disease must be documented at screening and 
re-assessed at each subsequent tumor evaluation. Investigators will assess tumor 
response at 8-week intervals, regardless of any dose delays or treatment cycle.
Treatment will continue until the patient has disease progression according to RECIST 
v1.1, unacceptable toxicity, death, patient or physician decision to withdraw, or 
pregnancy, whichever occurs first. A rising CEA level alone is not considered disease 
progression. No crossover will be allowed. Patients are allowed to receive study 
treatment beyond disease progression if certain conditions are met (Section 4.3.2.4).
After discontinuation of study treatment, patients may receive any subsequent line 
therapy as directed by their treating physician.
Patients who discontinue treatment for reasons other than disease progression 
(e.g., toxicity) will continue scheduled tumor assessments until disease progression, 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
In the absence of disease progression, tumor assessments should continue regardless 
of whether patients start a new anti-cancer therapy, unless consent is withdrawn.  
All patients will be followed for survival unless consent is withdrawn.   
Figure 1
Study Schema
mCRCmetastatic colorectal cancer; MSI-Hmicrosatellite high.

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Figure 2
Treatment Schedule
Dday; IVintravenous; PO orally (by mouth).
3.2
END OF STUDY AND LENGTH OF STUDY
The OS final analysis will be conducted when there are approximately 235 deaths in the 
study.  This is expected to occur approximately 23 months after the first patient is 
randomized.  
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis (i.e., OS) or safety 
follow-up is received from the last patient, whichever occurs later. LPLV is expected to 
occur 3 years after the first patient is enrolled. The study will end at any time if the 
Sponsor decide s to end the trial.
3.3
RATIONALE FOR STUDY DESIGN
This Phase III study is designed to assess the efficacy of immunotherapy and 
MEK inhibition over regorafenib in unresectable mCRC patients who have received at 
least two prior lines of chemotherapy in this setting. Despite recent improvements in 

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treatment, the prognosis for these heavily pretreated patients remains dismal, with a 
median OS of approximately 6 months.  Approved therapies are associated with 
significant toxicities. Therefore, there is a continuing need for more efficacious and
better-tolerated treatments.
3.3.1
Rationale for Overall Survival as Primary Endpoint 
Overall survival was chosen as the primary endpoint because it is the gold standard 
endpoint for cancer. Measurement of this endpoint is not questionable and patients with 
either measurable or non-measurable disease can be evaluated without the possibility of 
discrepancies in interpretations. This patient population has very few treatment options 
that would confound the assessment of OS, thus making OS a particular meaningful 
endpoint.
3.3.2
Rationale for Open-Label Study
The primary endpoint of the study is OS, and an open-label design would have minimal 
impact on OS. Given that this study is being conducted in a patient population with 
almost no treatment options that could affect the endpoints of the study, an open-label 
study design is unlikely to impart a significant bias to the study results. Furthermore, the 
study utilizes three study drugs with two administration routes and schedules, which 
introduces substantial challenges to blinding and can result in erroneous drug 
administration. 
3.3.3
Rationale for Patient Population, Stratification Factors, and 
Capping
The Phase Ib trial (GP28363) evaluated the cobimetinib and atezolizumab in 
KRAS-mutated mCRC patients and demonstrated promising clinical activity (Section 1.7).
RAS−mutated mCRC, in general, have a relatively poor immune cell infiltration and low 
immune inhibitory molecule expression compared to RAS wild-type colorectal tumors 
(Lal et al. 2015).
The proposed mechanism of action would predict that this combination would be just as 
effective or potentially more efficacious in patients with RAS-wild type mCRC who 
generally have a more favorable tumor immune microenvironment. Therefore, given the 
promising clinical activity and high unmet need, this Phase III study will include both 
RAS mutant and RAS wild-type mCRC patients.
This Phase III study will stratify patients based on their tumor extended RAS mutation 
status and time since diagnosis of first metastasis. These are important predictive and 
prognosis factors for mCRC and may potentially affect treatment outcomes.
RAS mutation status has important implications in treatment and prognosis of mCRC 
(Karapetis et al. 2008; De Roock et al. 2010; Sorich et al. 2015; Allegra et al. 2016).
Several studies have demonstrated that RAS mutations are associated with a worse 
prognosis compared to RAS wild type cohorts (Sorbye et al. 2015; Sorich et al. 2015; 

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Vincenzi et al. 2015). This bears particular importance for regorafenib, which is the 
treatment in the control arm of this Phase III study. In the CORRECT study (regorafenib 
monotherapy for previously treated mCRC), subgroup analysis showed a treatment 
effect for OS in favor of regorafenib over placebo for patients with KRAS wild-type 
tumors whereas a numerically lower effect was reported in patients with KRAS-mutant 
tumors (Grothey et al. 2013). The HR (95% CI) of OS was 0.653 (0.476 to 0.895) for 
patients with KRAS wild-type tumors and 0.867 (0.670 to 1.123) for patients with 
KRAS-mutant tumors. Given that RAS mutation status has substantial prognostic 
significance, patients on this study will be stratified by their tumor RAS mutation status.
Time since diagnosis of first metastasis (<18 months,18 months) also will be used as 
a stratification factor.  This stratification is commonly used when studying this patient 
population (Gothrey et al. 2014; Mayer et al 2015).  The percent survival of mCRC 
patients is dramatically reduced from the first year from diagnosis to the second year 
from diagnosis of metastatic disease (Golan 2013; van der Geest 2015;
Roder et al. 2015). Because time from diagnosis has great prognostic implications on 
survival, this trial will stratify accordingly.
In the mCRC setting, the natural frequency of tumors with MSI-high status is 
approximately 5% (Goldstein et al. 2014). In order to ensure generalizability of the study 
results, this Phase III study will limit the patients with MSI-high tumors to approximately
5%. Similarly, the frequency of extended RAS mutations in the previously treated 
mCRC patient population ranges from 50%−65%; thus, to reflect this prevalence, this 
study will enroll at least 50% mCRC patients with RAS-mutated tumors.
MSI status in CRC has important implications in both the treatment and prognosis for 
mCRC (Goldstein et al. 2014). In particular, recent data has shown that antiPD-1 
mAbs may be more efficacious in patients with MSI-high mCRC tumors (Le et al. 2015; 
Oh et al. 2015).  Atezolizumab, an anti-PD-L1 mAb, inhibits the PD-L1 ligand, thereby
blocking the interaction of PD-L1 with PD-1 and B7-1. Given that atezolizumab inhibits
the interaction between PD-L1 and PD-1, patients with MSI-high mCRC tumors will likely 
experience differential efficacy compared to patients with microsatellite stable (MSS) 
mCRC tumors. In this study, the number of MSI-high patients will be capped at 
approximately 5% to represent the prevalence in this patient population. Stratification by 
MSI/MSS will not be necessary as the small number of MSI-high patients will likely not 
affect the overall results of the trial.
3.3.4
Rationale for Cobimetinib plus Atezolizumab Arm
Both nonclinical and clinical data from the Phase Ib Study GP28363 showed promising 
efficacy of cobimetinib plus atezolizumab in heavily pretreated KRAS−mutated mCRC 
patients.  All the patients tested had MSI-stable tumors, unlike results from other 
checkpoint inhibitors (see Section 1.6). Because cobimetinib plus atezolizumab was 
well tolerated, and the efficacy data are promising, this combination will be further 
explored in this setting of high medical need.

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3.3.5
Rationale for Atezolizumab Monotherapy Arm
Recent data showed that antiPD-1 mAbs may be more efficacious in patients with 
MSI-high mCRC tumors (Le et al. 2015; Oh et al. 2015).  In contrast to antiPD-1 agents, 
atezolizumab is an antiPD-L1 mAb, which is capable of inhibiting the interaction of 
PD-L1 with PD-1 and also PD-L1 with B7-1. Given that atezolizumab inhibits PD-L1 
ligand from binding the PD-1 receptor and another immunomodulatory receptor (B7-1), 
the activity of atezolizumab may not be limited to MSI-high mCRC tumors. 
 
 
.
Therefore, the atezolizumab monotherapy was included in this Phase III study to further 
evaluate the activity of atezolizumab in mCRC. 
3.3.6
Rationale for Regorafenib as Control Arm
Regorafenib and trifluridine/tipiracil are approved treatments for previously treated
mCRC patients. Regorafenib was approved based on a Phase III trial that showed an 
improvement of OS compared to best supportive care of 1.4 months and a PFS of 
0.3 months (Grothey et al. 2013). Regorafenib is approved in numerous countries 
worldwide, including the United States and European Union. 
Trifluridine/tipiracil was recently approved in September 2015 in the United States. 
The approval was based on a Phase III trial demonstrating median OS improvement
from 5.3 months with placebo to 7.1 months with trifluridine/tipiracil (Mayer et al. 2015).
As this is a global trial and regorafenib has been established as a standard of care 
treatment in patients in this setting in numerous countries, regorafenib is an appropriate 
treatment for the control arm.
The dosing and schedule for regorafenib that will be used in this study is the same as 
the dose that was used in the pivotal clinical trials (Grothey et al. 2013; Li et al. 2015) 
and the approved and marketed dose for this indication.  Regorafenib will be 
administered at the recommended dose of 160 mg regorafenib (four 40 mg tablets) 
taken orally once daily for the first 21 days of each 28-day cycle.
3.3.7
Rationale for Dose and Schedule for Cobimetinib plus 
Atezolizumab and for Atezolizumab Monotherapy
In Arm A (cobimetinib plus atezolizumab), concomitant administration of atezolizumab 
and cobimetinib was studied in the Phase Ib Study GP28363. Cobimetinib 60 mg on a
21/7 schedule is the approved dose and schedule of cobimetinib. For administration 
with cobimetinib, on a 28-day cycle, a dose of 840 mg atezolizumab administered every 
2 weeks has the equivalent dose exposure as the 1200 mg every 3 weeks (21–day 
cycle), the planned dose for the atezolizumab monotherapy arm.  In Study GP28363, 
atezolizumab was dosed concurrently with cobimetinib at 800 mg IV q2w. The 840 mg
dose is expected to be similar to the 800 mg dose of atezolizumab dose and selected in 
this study to simplify dose administration. 

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In Arm B (atezolizumab monotherapy), atezolizumab will be dosed at 1200 mg IV q3w.
This is the dosing schedule that is being used in multiple Phase III studies of 
atezolizumab monotherapy across multiple tumor types. This dose and schedule of 
atezolizumab has been demonstrated to be safe and tolerable in over 1000 treated 
patients. 
3.3.8
Rationale for Allowing Patients to Continue Treatment until 
Loss of Clinical Benefit
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents as increase in tumor size does not consistently reflect 
therapeutic failure (Wolchok et al. 2009).  The phenomena of pseudo progression or 
infiltration of tumor by immune cells may mimic tumor progression. Therefore, as this 
study is evaluating an immunotherapy, the study will allow patients to continue to receive 
study treatment after documented RECIST v1.1defined radiographic disease 
progression, provided the benefit-risk ratio for the patient remains favorable as assessed 
by the physician and study monitor (see Section 4.3.2.4).  
3.3.9
Rationale for Patient-Related Outcomes Assessments
The patient experience of mCRC includes impacts on symptoms (disease and treatment 
burden), functioning, and HRQoL. Disease-specific symptoms (e.g., bloating, abdominal 
pain, diarrhea, constipation, loss of appetite) and other symptoms (e.g., fatigue) that 
negatively impact patients’ functioning and quality of life are relevant in this population.  
Patient-completed questionnaires are included to characterize the impact of disease and 
treatment on patients. The collection of this type of data will provide greater insights for 
both the medical and patient communities to understand disease and treatment burden 
and resulting HRQoL when patients are exposed to cobimetinib plus atezolizumab or 
atezolizumab monotherapy treatments in the mCRC setting (Marventano et al. 2013).
The EQ-5D-5L will be included to derive utility to inform pharmacoeconomic models.
3.3.10
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens, Stratification Criteria, and Biomarker Assessments
Tumor tissue samples will be collected at baseline for genetic and histopathological 
assessments at DNA, RNA, protein, and tissue levels to add to researchers' 
understanding of disease pathobiology.  Genebased CRC classification increasingly 
has been proposed as a way of differentiating various subtypes of CRC and may have 
profound effects on both treatment and prognosis.  These subtypes have been shown to 
have different immunomodulatory affects and may influence the efficacy of this 
combination (Guinney et al. 2015; Kocarnik et al. 2015; Lal et al. 2015).  As these 
biomarkers may also have prognostic value, their potential association with disease 
progression will also be explored.  Archival/baseline tumor analysis and classification of 
different CRC subtypes will be performed to further assess this possible relationship.

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Tumor biopsies while on treatment and at progression are scheduled to further elucidate 
the possible mechanism of action or mechanisms of resistance (innate or acquired) of 
this regimen and may include evaluation of CD8positive T-cell infiltrate, PD-L1 
expression, and biomarkers of enhanced immune response, MAPK activation, and 
others involved in apoptosis or inflammation.
3.3.11
Rationale for Blood Sampling for Biomarker Assessments
An exploratory objective of this study is to evaluate biomarkers (including but not limited 
to cytokines, whole genome sequencing [WGS], cfDNA, and cancer-specific biomarkers,
such as CEA) in blood samples.  The evaluation of blood biomarkers may provide 
evidence for biologic activity of cobimetinib plus atezolizumab and atezolizumab 
monotherapy in patients with mCRC and may allow for the early prediction of clinical 
benefit of cobimetinib and atezolizumab use.
In addition, potential correlations of these biomarkers with the safety and activity of 
cobimetinib and atezolizumab will be explored.
3.3.11.1
Rationale of Optional Whole Genome Sequencing
Genomics is increasingly informing understanding of disease pathobiology and rationale 
for the development of new therapeutic approaches. WGS provides comprehensive 
characterization of the genome and, along with clinical data collected in this study, may 
increase the opportunity for making these discoveries.
Relevant literature on genomic analyses shows ample examples of genetic variations 
and their implications in immune responses. For instance, a recent report identified 
20 genes linked to variability of the immune response to seasonal influenza vaccination,
seven of which were shown to be involved in intracellular antigen transport, processing, 
and presentation (Franco et al. 2013). Similarly, genomewide association studies
(GWAS) have identified specific genetic variants that are associated with differences in 
WBC, neutrophil, and monocyte counts among individuals (Knight 2013). Furthermore, 
GWAS in autoimmune diseases have led to novel insights, an example of which is the 
role of autophagy in Crohn’s disease, which was elucidated based on variation at two 
loci and has now become a major therapeutic target in this disease (Hu and Daly 2012).
It is also established that genetic variants of drug-metabolizing enzymes and 
transporters can affect the pharmacokinetics of drugs, which affects safety and efficacy. 
For example, patients who carry defective alleles of the gene encoding uridine 
diphosphate glucuronosyltransferase 1A1, which facilitates the metabolism and 
excretion of SN-38 (the active metabolite of irinotecan), are at a higher risk for adverse 
effects associated with the use of standard doses of irinotecan 
(O’Dwyer and Catalano 2006).
In addition to the link between genetic variation in drug-metabolizing enzymes and 
transporters and pharmacokinetics, recent studies have also identified genetic variants 

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that increase the likelihood of (or are protective of) developing druginduced adverse 
events. For example, HLA has been demonstrated to play an important role in the 
development of drug-induced rash for some drugs (carbamazepine, abacavir, and 
allopurinol; Michels et al. 2015; Shirzadi et al. 2015; Stamp et al. 2015). In addition, 
mutations in GSTP1, CTLA4, and FDG4 have been associated with development of 
druginduced peripheral neuropathy of various small molecules (Lecomte et al. 2006; 
Ruzzo et al 2007; Favis et al. 2011; Baldwin et al. 2012).
Therefore, determining host genetic variation by performing WGS on patient samples 
collected in this study and assessing the relationship with response to treatment and
observed adverse events may enable a further understanding of efficacy and safety for 
cancer immunotherapy and other therapeutic approaches. To this end, a blood sample 
may be collected from patients enrolled in this study for DNA extraction to enable WGS 
analysis. The WGS testing is an optional component of this study; patients can decline 
this sample collection and test.
WGS is contingent upon the review and approval by each site's IRB/EC and, if 
applicable, an appropriate regulatory body. If a site has not been granted approval for 
WGS, this assessment will not be applicable at that site.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 360 patients with unresectable locally advanced or metastatic CRC who 
have received at least two different chemotherapy regimens for metastatic disease will 
be enrolled in this study (see Section 4.5.2 for definition of chemotherapy regimen).
The patients will be stratified for extended RAS status and time since diagnosis of first 
metastasis (<18 months vs. ≥18 months).  MSI-high status will be capped at
approximately 5%, and at least 180 patients with extended RAS will be enrolled in the 
study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-specific inclusion criteria:

Histologically confirmed adenocarcinoma originating from the colon or rectum
(Stage IV American Joint Committee on Cancer [AJCC] 7th edition)

Experienced disease progression on at least two prior systemic chemotherapy 
regimens for mCRC
1.
Prior systemic cytotoxic chemotherapy must include ALL of the following agents: 
a)
Fluoropyrimidines
b)
Irinotecan 
c)
Oxaliplatin

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2. Patients who have received prior anti-angiogenic therapy (e.g., bevacizumab) 
and/or anti-EGFR therapy (e.g., cetuximab) are eligible.
3. Patients must have had documented disease progression within 3 months of 
the last systemic therapy administration. 
4. Patients who were intolerant to prior systemic chemotherapy regimens are 
eligible if there is documented evidence of clinically significant intolerance 
despite adequate supportive measures. 
5. For patients who had disease recurrence within 6 months of completing 
adjuvant chemotherapy, the adjuvant regimen can be considered as one 
chemotherapy regimen for metastatic disease.
General inclusion criteria:

Signed Informed Consent Form

Age18 years

In the investigator’s judgment, patient is able to comply with the requirements and 
assessments of the study protocol

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
(see Appendix 6)

Anticipated life expectancy3 months

Able to comply with the requirements and assessments of the study protocol

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to first dose of study drug treatment:
1. Hemoglobin9 g/dL, platelet count100,000/mm3, ANC1500/mm3
2. Creatinine clearance 30 mL/min
3. Amylase and lipase1.5the upper limit of normal (ULN)
4. Serum bilirubin 1.5ULN; patients with known Gilbert’s disease may have a 
bilirubin 3.0 ULN
5. AST, ALT, and alkaline phosphatase (ALP) 2.5ULN with the following 
exceptions:
a)
Patients with documented liver metastases: AST and/or ALT5ULN
b)
Patients with documented liver or bone metastases:  ALP5ULN
6. INR and PTT1.5ULN. Patients who are on therapeutic doses of 
anti-coagulants are eligible if they are on a stable dose of anti-coagulant for 
28 days with stable INR and PTT values. 

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
Women of childbearing potential must agree to appropriately use an effective form 
of contraception (failure rate of 1% per year) during the treatment period, within 
5 months after the last dose of atezolizumab, and within 3 months after the last dose 
of cobimetinib and regorafenib.
1.
A woman of childbearing potential is defined as a sexually mature woman 
without prior oophorectomy or hysterectomy who have had menses within the 
last 12 months. 
2.
A woman is not considered to be of childbearing potential if she has become 
amenorrheic for 12 months and has a follicle-stimulating hormone 
level 40 IU/L.

Men must agree not to donate sperm or have intercourse with a female partner
without using appropriate barrier contraception during the treatment period and for 
3 months after the last dose of either cobimetinib or regorafenib.

Available and adequate baseline tumor tissue sample (archival or newly obtained 
biopsy; see Section 4.5.7)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-related exclusion criteria:

After the approximate 5% cap for MSI-high patients is reached, only MSI-stable 
patients will be eligible.

Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant 
patients will be eligible.

Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of 
needing such procedure while receiving study treatment.

Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1

Uncontrolled tumor-related pain.  Patients requiring narcotic pain medication must 
be on a stable regimen at study entry.
1.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
start of study treatment.
2.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to the start of study treatment.

Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated 
drainage more than once every 28 days. Indwelling drainage catheters 
(e.g., PleurX) are allowed.

Active or untreated CNS metastases are excluded.  Patients with treated and 
asymptomatic CNS metastases are eligible, if they meet all of the following:
1.
Evaluable or measurable disease outside the CNS

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2.
No metastases to midbrain, pons, medulla, or within 10 mm of the optic nerves 
and chiasm
3.
No history or evidence of intracranial hemorrhage or spinal cord hemorrhage 
4.
No evidence of clinically significant vasogenic edema
5.
Not on corticosteroids for2 weeks; anti-convulsants at a stable dose are 
allowed.
6.
No evidence of clinical and radiographic disease progression in the CNS
for3 weeks after radiotherapy or surgery.

Exclusion criteria related to study medication:
1.
Any cancer immunotherapy including CD137 agonists, antiPD-1, antiPD-L1, 
or anti-CTLA4
2.
Any MEK or ERK inhibitor 
3.
Regorafenib

Patients with active malignancy (other than CRC) or a prior malignancy within the 
past 3 years are excluded. Patients with completely resected cutaneous melanoma 
(early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical 
carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are 
eligible.
Exclusion criteria based on organ function or medical history:
Cardiovascular:

Unstable angina, new onset angina within last 3 months, myocardial infarction within 
last 6 months and current congestive heart failure New York Heart Association 
Class II or higher.

Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or 
below 50%, whichever is lower. 

Poorly controlled hypertension, defined as a blood pressure consistently above 
150/90 mmHg despite optimal medical management.
Infections:

HIV infection

Active tuberculosis infection

Severe infections within 2 weeks prior to Cycle 1 Day 1

Signs or symptoms of significant infection within 2 weeks prior to Cycle 1 Day 1

Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract 
infection or chronic obstructive pulmonary disease) are eligible

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
Active or chronic viral hepatitis B or C infection
1.
Patients with hepatitis B virus (HBV) infection are eligible if test for hepatitis B 
surface antigen (HBsAg) and HBV DNA are negative
2.
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain 
reaction (PCR) test for HCV RNA is negative.
Ocular:

History of or evidence of retinal pathology on ophthalmologic examination that is 
considered a risk factor for central serous retinopathy, retinal vein occlusion, or 
neovascular macular degeneration

Patients will be excluded if they currently have any of the following risk factors for 
retinal vein occlusion:
1.
Uncontrolled glaucoma with intra ocular pressure21 mmHg
2.
Uncontrolled hypercholesterolemia300 mg/dL or 7.75 mmol/L
3.
Uncontrolled hypertriglyceridemia300 mg/dL or 3.42 mmol/L
4.
Fasting hyperglycemia160 mg/dL or 8.9 mmol/L
Autoimmune conditions and immunomodulatory drugs:

History of autoimmune disease except for the following:
1.
Patients with autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone are eligible.
2.
Patients with controlled type 1 diabetes mellitus on a stable dose of insulin 
regimen are eligible.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis) are permitted 
provided that they meet the following conditions:
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and only requiring lowpotency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 
0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis 
obliterans, drug-induced pneumonitis, or idiopathic pneumonitis 
Patients with radiation pneumonitis within the radiation field are eligible.

History of organ transplantation including allogeneic bone marrow transplantation

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Other medical conditions or medications:

Any hemorrhage or bleeding event CTCAE Grade 3 or higher within 28 days of 
Cycle 1 Day 1

History of stroke, reversible ischemic neurological defect, or transient ischemic 
attack within 6 months prior to Day 1

Proteinuria3.5 g/24 hours

Serum albumin2.5 g/dL

Foods, supplements or drugs that are potent CYP3A4 enzyme inducer or inhibitors 
are prohibited at least 7 days prior to Cycle 1 Day 1 and during study treatment. 
These include St. John’s wort or hyperforin (potent CYP3A4 enzyme inducer) and 
grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
General exclusion criteria:

Inability to swallow medications

Malabsorption condition that would alter the absorption of orally administered 
medications

Pregnant, lactating, breastfeeding, or intending to become pregnant during the study

History of severe hypersensitivity reactions to components of:
1.
Cobimetinib formulation
2.
Regorafenib formulation
3.
Atezolizumab formulation

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation of a live attenuated vaccine will be required during the study

Any anti-cancer therapy, including chemotherapy, or hormonal therapy within 
2 weeks prior to initiation of study treatment

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is shorter, 
prior to Cycle 1 Day 1

Treatment with systemic immunosuppressive medications (including but not limited 
to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1 Day 1
4.2
METHOD OF TREATMENT ASSIGNMENT 
After written informed consent has been obtained and eligibility established, each patient 
will be assigned an identification number and be randomized to 2:1:1 to one of the three
treatment arms through use of an IxRS (see Figure 1 in Section 3.1).

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Permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by the following criteria:

Tumor extended RAS status (RAS mutated or RAS wild-type).  Extended RAS 
mutation is defined as mutations occurring in KRAS and NRAS gene codons 12 and 
13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4

Time since diagnosis of first metastasis (<18 months vs. ≥18 months)
Once the limit of patients with MSI-high tumors has been reached (approximately 5% of 
patients; see Section 3.3.3), only patients whose tumors are MSI-stable or MSI-low will 
be enrolled and randomized.  
Once the limit of patients with extended RAS wild type (50%) has been reached (see 
Section 3.3.3), only patients whose tumors are extended RAS mutant will be enrolled 
and randomized.
Patients should receive their first dose of study treatment as soon as possible and within 
3 days of randomization.
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are cobimetinib and 
atezolizumab.  
Regorafenib is an approved treatment for mCRC in this disease setting and can be
considered standard of care.  Regorafenib is a noninvestigational medicinal product 
(NIMP) in this study unless local regulations require it to be an IMP.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Cobimetinib
Cobimetinib will be supplied by the Sponsor as tablets.  The 20-mg cobimetinib drug 
product is a film-coated, white, round, immediate-release tablet.  Cobimetinib will be 
packaged in blister packs.  The inactive ingredients in cobimetinib are as follows:  
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate for the tablet core.  The tablet coating consists of polyvinyl alcohol, 
part hydrolyzed, titanium dioxide, polyethylene glycol 3350, and talc.  Cobimetinib should 
not be stored above 25°C (77°F).  If the study drug is stored outside of the permitted 
temperature ranges, quarantine the affected supply and contact the monitor.
For further details, see the cobimetinib Investigator’s Brochure.
4.3.1.2
Atezolizumab
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials. 
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may 
contain more than the stated volume to enable delivery of the entire 20 mL volume.
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840-mg dose. For information on the formulation and handling of atezolizumab, refer to 
the Investigator's Brochure and Pharmacy Manual.
4.3.1.3
Regorafenib (Stivarga)
The control arm (Arm C) is regorafenib. In countries where regorafenib is considered an 
NIMP by local regulations and is commercially available, the commercial formulation of 
regorafenib (Stivarga) will be provided by the local institution as part of standard of care 
treatment.  It will be provided or reimbursed by the Sponsor if it is considered an IMP by 
local regulations (see Section 4.3.3) or not commercially available.
For information on the formulation, packaging, and handling of regorafenib, see the 
Stivarga (regorafenib) Prescribing Information.  
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Cobimetinib
Patients randomized to cobimetinib will receive 60 mg (three tablets of 20 mg each) 
orally once daily for Days 121 of a 28-day cycle as stated in Section 3.1, including 
Figure 2.  This 4-week period is considered a treatment cycle.
Cobimetinib should be taken at the same time every day.  It can be taken with or without 
food. If a dose of cobimetinib is missed or if vomiting occurs when the dose is taken, 
resume dosing with the next scheduled dose.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF (See Section 5.3).
4.3.2.2
Atezolizumab
Atezolizumab dose and schedule will depend on the treatment arm:

Arm A:  cobimetinib plus atezolizumab 840 mg IV q2w

Arm B:  atezolizumab 1200 mg IV q3w as monotherapy
Both dosing schedules will be administered in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  
For more detailed information on drug preparation, storage, and administration, refer to 
the Investigator’s Brochure and Pharmacy Manual.
Atezolizumab infusions will be administered per the instructions outlined in Table 1.

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Table 1
Administration of First and Subsequent Infusions of 
Atezolizumab
First Infusion
Subsequent Infusions
Premedication is allowed.
If patient experienced IRR during any previous 
infusion, pre-medication with antihistamines 
may be administered for Cycles 2 at the 
discretion of the treating physician.
Record vital signs (HR, RR, BP, and T) within 
60 min before starting infusion.        
Record patient’s vital signs (HR, RR, BP, and 
T) within 60 min before starting infusion.
Infuse atezolizumab (one vial in 250 mL NaCl) 
over 60 (15) min
If the patient tolerated the first infusion well 
without infusion-associated AEs, the second 
infusion may be delivered over 30 (10) min.
Record vital signs (HR, RR, BP, and T) during 
the infusion or after the infusion if clinically
indicated
If the patient had an IRR during the previous 
infusion, the subsequent infusion must be 
delivered over 60 (15) min.
Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed 
to contact their study physician if they develop 
such symptoms.
Record patient’s vital signs (HR, RR, BP, and 
T) during the infusion or after the infusion if 
clinically indicated or patient experienced 
symptoms during the previous infusion.
If no reaction occurs, continue subsequent 
infusions over 30 (10) min with same 
schedule for recording vital signs.
AEadverse event; BPblood pressure; HRheart rate; IRRinfusion-related reaction; 
NaClsodium chloride; RR respiratory rate; T temperature. 
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events 
associated with cobimetinib and atezolizumab are provided in Section 5.1.4 and
Appendix 3. For information regarding management of atezolizumab-associated 
adverse events, please refer to Appendix 9.
For anaphylaxis precautions, see Appendix 4. 
See the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF
(See Section 5.3).
4.3.2.3
Regorafenib
Regorafenib will be used in the commercially available formulation.

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Patients randomized to regorafenib (Arm C), will receive regorafenib at the approved 
dose level of 160 mg (four tablets of 40 mg each) orally once daily on Days 121 of a 
28-day cycle (see Section 3.3 and Figure 2 in Section 3.1 ). This 4-week period is 
considered a treatment cycle.
Regorafenib should be taken at the same time each day. The tablets should be 
swallowed whole with water after a light meal that contains 30% fat. An example of a 
light (low-fat) meal would include one portion of cereal (about 30 g), one glass of 
skimmed milk, one slice of toast with jam, one glass of apple juice, and one cup of coffee 
or tea (520 calories, 2 g fat).
The study investigator may implement dose interruption or dose reduction in response to 
adverse events to ensure patient safety and tolerability.  Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.1.4.1.  
Please refer to the Stivarga (regorafenib) prescribing information for more details.
Any overdose or incorrect administration of regorafenib should be noted on the 
Regorafenib Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of regorafenib should be recorded on the Adverse Event eCRF
(See Section 5.3).
4.3.2.4
Dosing of Study Treatment Beyond Disease Progression
Dosing of study treatment beyond RECIST v1.1defined disease progression is allowed 
for patients on all treatment arms. Patients must meet all of the following criteria to be 
allowed to receive study treatment beyond disease progression:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs indicating unequivocal progression of disease. 
Patients may continue to receive treatment beyond disease progression in the 
absence of clinical signs or symptoms of progression despite a rising CEA level.

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocolallowed medical interventions

Patients must provide written consent to acknowledge deferring these treatment 
options in favor of continuing study treatment at the time of RECIST v1.1-defined 
disease progression

Approved by the study Medical Monitor
4.3.3
Investigational Medicinal Product Accountability
The IMPs required for completion of this study (i.e., cobimetinib, atezolizumab, and 
regorafenib if considered an IMP by local regulations) will be supplied or reimbursed by 
the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of cobimetinib and atezolizumab using the IxRS to confirm the 

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shipment condition and content.  Any damaged shipments will be replaced. Where 
regorafenib is supplied by the Sponsor, shipment receipt will be documented using IxRS; 
otherwise, it will be documented per local practice.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
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
Post-Trial Access to Cobimetinib and Atezolizumab
The Sponsor will offer post-trial access to the study drugs cobimetinib and atezolizumab 
free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, as outlined below.  Note that 
regorafenib will not be offered free of charge after study completion. 
A patient will be eligible to receive cobimetinib and atezolizumab after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug 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 study drug or data suggest that 
the study drug is not effective for colorectal cancer

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for CRC

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND
ADDITIONAL RESTRICTIONS
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1
Permitted Therapy 
The following therapies are permitted in the study:

Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low-molecular weight 
heparin or warfarin at a stable dose level)

Palliative radiotherapy (e.g., treatment of known bone metastases) provided it does 
not interfere with assessment of tumor target lesions
It is not required to withhold atezolizumab during palliative radiotherapy.  

Inactive influenza vaccinations during influenza season ONLY

Megastrol administered as an appetite stimulant

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone)
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drugs. At the discretion of the investigator, 
prophylactic anti-emetic and anti-diarrheal medication(s) may be used per standard 
clinical practice before subsequent doses of study drugs. Hematopoietic growth factors 
should not be administered prophylactically before initial treatment with study drugs. 
Hematopoietic growth factors may be administered according to local guidelines if 
indicated during the course of the study. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2 receptor antagonist as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusionassociated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and b2-adrenergic agonists).

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All medications must be recorded on the Concomitant Medications eCRF.
4.4.2
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited for various time periods prior to starting 
study treatment, depending on the anti-cancer agent (see Section 4.1.2), and during 
study treatment until disease progression is documented and patient has discontinued 
study treatment.  This includes but is not limited to chemotherapy, hormonal therapy, 
immunotherapy, radiotherapy, investigational agents, or herbal therapy.
The following medications are prohibited while receiving study treatment, unless 
otherwise noted:

Traditional herbal medicines as their use may result in unanticipated drug-drug 
interactions that may cause or confound assessment of toxicity.

Denosumab: Patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while in the study.

Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to randomization or 
at any time during the study or within 5 months following the last infusion of 
atezolizumab.

For patients on atezolizumab:
–
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); 
in such patients, MRIs of the chest, abdomen, and pelvis with a non-contrast 
CT scan of the chest must be performed. 
–
Immunomodulatory agents, including but not limited to interferons or IL-2, 
during the entire study; these agents could potentially increase the risk for 
autoimmune conditions when received in combination with atezolizumab
–
Immunosuppressive medications, including but not limited to 
cyclophosphamide, azathioprine, methotrexate, and thalidomide; these agents 
could potentially alter the activity and the safety of atezolizumab
–
Systemic corticosteroids and TNF-inhibitors may attenuate potential 
beneficial immunologic effects of treatment with atezolizumab.  Therefore, in 
situations where systemic corticosteroids or TNF-inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered first 
by the treating physician.  If the alternatives are not feasible, systemic 
corticosteroids and TNF-inhibitors may be administered at the discretion of 
the treating (see Section 4.4.2)

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
For patients on cobimetinib:
–
Concomitant use of strong and moderate inhibitors of CYP3A 
(e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, 
telithromycin, and voriconazole) should be avoided as cobimetinib is a sensitive 
substrate of CYP3A and exposures will be increased in presence of these 
agents (approximately 7-fold increase in presence of itraconazole in healthy 
subjects).
–
Avoid strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, and St. John’s wort) as they increase the 
metabolism of cobimetinib.  Strong inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product, with no or minimal 
potential to induce CYP3A4 should be considered.

For patients on regorafenib:
–
Avoid use of strong and moderate inhibitors of CYP3A (e.g., clarithromycin, 
grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and 
voriconazole) as mean AUC of regorafenib was increased by 33% (Stivarga 
[regorafenib] Prescribing Information).
–
Avoid strong UGT1A9 inhibitor (e.g., mefenamic acid, diflunisal, and niflumic 
acid) during regorafenib treatment as their influence on the steady-state 
exposure of regorafenib and its metabolites has not been studied. 
–
Avoid strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, and St. John’s wort) as they increase the 
metabolism of regorafenib.  Strong inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product, with no or minimal 
potential to induce CYP3A4 should be considered. 
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP3A or UGT1A9.  
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM292362.pdf
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study.

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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 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed by the investigator to confirm 
that patients meet all eligibility criteria before randomization.  The investigator will 
maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, prior surgeries, reproductive 
status, and use of alcohol, and drugs of abuse.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study drug will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity. Baseline 
disease characteristics data will include AJCC disease stage at enrollment, ECOG 
performance status, date of diagnosis of first metastatic disease, site of primary disease, 
RAS status, MSI status, history of metastasectomy, location of metastasis at enrollment, 
number of prior chemotherapy regimens, and prior therapy (5-fluorouracil, oxaliplatin, 
irinotecan, trifluridine and tipiracil, anti-EGFR, anti-VEGF), 
A chemotherapy regimen is defined as a set of chemotherapy agents with an initial 
defined dose and frequency that are given in a prescribed order, which may be 
concurrently.  A regimen can consist of only one chemotherapy agent or multiple agents.  
If one of the agents is discontinued because of toxicity or other concerns, the remaining 
chemotherapy combination is not considered a new regimen.  Maintenance therapy is 
also not considered a separate regimen.  If a chemotherapy regimen is held and 
restarted at a later date, this is considered one regimen and not two separate 
chemotherapy regimens.
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptomdirected physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF (See Section 5.2).

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Patients on cobimetinib plus atezolizumab will be asked specifically about vision 
changes as part of each physical examination in addition to interval medical history.  
Note:  If physical examinations are performed within 7 days of Cycle 1 Day 1, they do 
not have to be repeated on Cycle 1 Day 1 (see Section 4.5.11).
4.5.4
Vital Signs
Vital signs are defined as:  temperature (°C), heart rate, respiratory rate, and systolic 
and diastolic blood pressure.  Height and weight will be recorded on Cycle 1 Day 1.
4.5.4.1
Vital Signs for Patients Assigned to Receive Atezolizumab with 
or without Cobimetinib (Arms A and B)
Vital signs will be measured and recorded at the following timepoints:

Within 60 minutes prior to infusion

During infusion and/or after infusion if clinically indicated
For patients in the atezolizumab arm who experienced an infusion-related reaction 
during the previous atezolizumab infusion, refer to Section 5.1.4.
4.5.4.2
Vital Signs for Patients Assigned to Receive Regorafenib 
(Arm C)
Monitor vital signs weekly for the first 6 weeks and then with every cycle, especially 
systolic and diastolic blood pressure as indicated by the Stivarga (regorafenib) 
Prescribing Information as uncontrolled hypertension has been known to occur.
4.5.5
Tumor and Response Evaluations
Baseline tumor assessments should be performed 35 days before Cycle 1 Day 1 and 
assessed according to RECIST v 1.1 (see Appendix 5). The same procedure used to 
assess disease sites at baseline should be used throughout the study (e.g., the same 
contrast protocol for CT scans or MRI scans). To the extent that it is feasible, the same 
assessor should read and evaluate the tumor assessments for the same patient 
throughout the study. CT or MRI scans should include chest, abdomen, and pelvic 
scans; CT or MRI scans of the neck should be included if clinically indicated. At the 
investigator’s discretion, CT scans may be repeated at any time if progressive disease is 
suspected. 
Evaluation of tumor response conforming to RECIST v1.1 must be documented every 
8 weeks1 week no matter where the patient is in the chemotherapy treatment cycle
(this can occur mid-treatment) until documented investigatordetermined progressive 
disease, loss of clinical benefit, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  Schedule of tumor assessments are independent of 
any changes to the study treatment administration schedule (e.g., dose delay) and may 
occur mid-cycle depending on length of cycle.  If a tumor assessment has to be 
performed early or late, subsequent assessments should be conducted according to the 
original schedule based on the date of first study drug administration (Cycle 1 Day 1).  

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Confirmation of response (PR or complete response [CR]) will be done no earlier than 
28 days from study entry.  In the case of SD, measurements must have met the SD 
criteria at least once after study entry at a minimum interval not less than 6 weeks.  
Patients who discontinue study treatment for any reason other than disease progression 
will continue to undergo tumor response evaluations (approximately every 8 weeks) until 
progressive disease.  A rising CEA alone without radiological evidence of progression is 
not considered progressive disease. 
Patients who continue to experience clinical benefit in all three arms, despite evidence of 
radiographic progression as defined by RECIST v1.1, may continue treatment (see 
Section 4.3.2.4) and will continue tumor assessments as per the schedule listed above.
4.5.6
Laboratory, Biomarker, and Pharmacokinetic Samples
4.5.6.1
Local Laboratory Assessments
Screening

Hematology (CBC, hemoglobin, hematocrit, WBC count with differential [neutrophils,
eosinophils, lymphocytes], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, CPK, lipase, 
amylase, LDH, and albumin)

Coagulation (INR and aPTT)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation.
–
A woman is not considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (defined as 
12 continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone permanent surgical sterilization (removal 
of bilateral ovaries and/or uterus.

Thyroid function testing (thyroid-stimulating hormone, free T3, free T4)

HBV serology:  HBsAg, antibodies against HBsAg, anti-hepatitis B core antibody 
(anti-HBcAb)

HBV DNA should be obtained prior to randomization if patient has a negative 
serology for HbsAg and a positive serology for anti-HBcAb.

HCV serology:  HCV antibody (anti-HCV)

HCV RNA should be obtained prior to randomization if patient tests positive for 
anti-HCV

HIV testing
–
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study.

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On Study Treatment

Hematology (CBC, hemoglobin, hematocrit, WBC count with differential [neutrophils, 
eosinophils, lymphocytes, and platelet count])

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, CPK, lipase, and
amylase)

CEA
4.5.6.2
Central Laboratory Assessments
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories.  Instruction manuals and supply kits will 
be provided for all central laboratory assessments.  Residual atezolizumab PK and ATA 
samples will be retained for further method development, validation, and characterization.  
Samples will be stored until they are no longer needed or until they are used up.  
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

ATA assays, provided that it does not cause undue hardship to the patient (e.g., the 
patient is in hospice care and not able to come in for a visit)

Serum samples also may be assayed for other anti-atezolizumab antibodies with 
use of validated immunoassays

Auto-antibody testing:  baseline sample to be collected on Cycle 1 Day 1 prior to the 
first dose of study drug.  For patients who show evidence of immune-mediated 
toxicity, additional samples may be collected, and all samples will be analyzed 
centrally.
–
Anti-nuclear antibody
–
Antidouble-stranded DNA
–
Circulating antineutrophil cytoplasmic antibody
–
Perinuclear antineutrophil cytoplasmic antibody

PK assay, provided that it does not cause undue hardship to the patient (e.g., the 
patient is in hospice care and not able to come in for a visit)
–
Serum samples will be assayed for atezolizumab concentrations with use of a 
validated immunoassay.  
–
Plasma samples for cobimetinib concentrations will be measured using 
validated liquid chromatography combined with tandem mass spectrometry 
method.

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
Biomarker assays in blood samples
–
Blood samples will be obtained for biomarker evaluation (including but not limited 
to biomarkers that are related to CRC or tumor immune biology) from all eligible 
patients according to the schedule in Appendix 1.  Samples will be processed to 
obtain plasma for the determination of changes in blood-based biomarkers.  Blood 
samples may be processed to obtain peripheral blood mononuclear cells and their 
derivatives (e.g., RNA and DNA) and may be evaluated for immune-related, 
tumor-type related, and other exploratory biomarkers (e.g., alterations in gene 
expression or single nucleotide polymorphisms; see Table 2).  Optional blood 
sample for WGS may also be obtained.
Table 2
Proposed Non-Inherited Biomarkers for Exploratory Research
Sample Type
Timing
Proposed Non-Inherited Biomarkers
Plasma
Baseline and subsequent 
timepoints during treatment 
●Cytokines
●cfDNA
Tissue (e.g., tumor)
Prior to study (archival) or 
baseline (fresh); on 
treatment (optional) and at 
progression
●NGS
●Biomarkers that may predict 
response, elucidate mechanism of 
response, or predict resistance 
(including but not limited to: CD8, 
MHC1, PD-L1, -catenin)
●RNAseq for CRC subtyping
cfDNAcell-fee DNA; CRC colorectal cancer; MHCmajor histocompatibility complex; 
NGSnext-generation sequencing; PD-L1programmed death ligand-1; RNAseqRNA 
sequencing.
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual.
The remainder of samples obtained for study-related procedures (including blood 
samples and tumor tissues) will be destroyed no later than 5 years after the final Clinical 
Study Report has been completed or earlier depending on local regulations. Archival 
blocks will be returned to sites following biomarker testing.
4.5.7
Tumor Tissue Samples
A central laboratory will coordinate the sample collection of tissue samples for research 
related testing at central laboratories or at the Sponsor.  Instruction manuals and supply 
kits will be provided for all central laboratory assessments.
See the laboratory manual for additional details on tissue sample handling.

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4.5.7.1
Archival and Fresh Tumor Sample for Screening
Representative tumor specimens in paraffin blocks (preferred) or at least 20 serial cut, 
unstained slides with an associated pathology report must be submitted for
determination of extended RAS status and MSI status.
Extended RAS mutation is defined as mutations occurring in KRAS and NRAS gene 
codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4 
(Allegra et al. 2016).  Local RAS testing results will be accepted with a copy of the 
results and interpretation as part of the screening process with a requirement for central 
confirmation.
MSI status can be defined by several methods such as IHC detection of hMLH1 and 
hMSH2 gene products, NGS testing, or PCR testing by the fraction of MSI loci that 
exhibit differently sized repeats (Lindor et al. 2002; Salipante et al. 2014).  Local MSI 
testing results will be accepted with a copy of the results and interpretation as part of the 
screening process with a requirement for central confirmation. 
In addition, NGS for exploratory research on non-inherited (or tumor specific) biomarkers 
(including, but not limited to, cancer-related genes and biomarkers associated with 
common molecular pathways) and exploratory biomarkers (including but not limited to 
markers related to immune, MAP kinase pathway, or CRC biology, such as T-cell 
markers or tumor mutation status) may be evaluated (see Table 2 in Section 4.5.6).
Foundation Medicine NGSbased genomic profiling will be performed.  When performed 
by Foundation Medicine, the investigator can obtain results from the samples collected 
in the form of an NGS report, which is available upon request directly from Foundation 
Medicine.  The investigator may share and discuss the results with the patient, unless 
the patient chooses otherwise.  The Foundation Medicine NGS assay has not been 
cleared or approved by health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.
Archival tumor tissue should be collected as follows:

A representative formalinfixed, paraffin-embedded (FFPE) tumor specimen 
collected at first diagnosis and/or subsequent tumor recurrence(s) consistent with 
the patient’s diagnosis is required for participation in this study (FFPE block 
[preferred], or a minimum of 20 unstained serial sections). This specimen must be 
accompanied by the associated pathology report.  
–
The available tumor sample must be adequate to determine extended RAS 
status and MSI status.
–
The tumor sample and associated pathology report must be confirmed to be 
available prior to any studyspecific screening procedures.  Fine-needle 
aspiration, brushing, cell pellet from pleural effusion, and lavage samples are 
not acceptable.  For core needle biopsy specimens, at least three cores should 
be submitted for evaluation.  

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–
For samples that do not meet the minimum requirements for size/slide number, 
contact the Medical Monitor via site contact with tissue size and tumor 
content/number of slides to determine eligibility.  
–
Alternatively, or if the archival tumor sample does not meet minimum 
requirements, the patient may be offered the option of undergoing a 
pretreatment procedure (excisional or core tumor biopsy) to obtain an adequate 
tumor sample, provided that his or her disease is easily accessible and tumor 
biopsies can be performed with minimal risk and discomfort.
If archival tissue is unavailable, a pretreatment tumor biopsy is required.  
Cytological or fine-needle aspiration samples are not acceptable.  Acceptable samples 
include:

Core needle biopsies for deep tumor tissue; at least three cores, embedded into a 
single paraffin block, should be submitted for evaluation.

Excisional or incisional tumor biopsy

Tumor tissue resection
4.5.7.2
Optional Tumor Biopsy on Treatment
An optional biopsy while on treatment is requested on Cycle 1 Day 155 days provided 
the patient’s disease is easily accessible and tumor biopsies can be performed with 
minimal risk and discomfort.  
This biopsy is for exploratory research on biomarkers associated with the MAP kinase 
pathway and immune-related pathways, and for DNA and RNA extraction on non-
inherited biomarkers (including, but not limited to cancer-related genes).
4.5.7.3
Tumor Biopsy at Time of Progression
Patients will undergo a mandatory tumor biopsy to obtain a tumor sample at time of 
progression unless not clinically feasible and provided that their disease is easily 
accessible and tumor biopsies can be performed with minimal risk and discomfort.  
This biopsy is for DNA, RNA, and protein analysis for exploratory research on 
non-inherited (tumor specific) biomarkers included but not limited to studying 
mechanisms of resistance.  NGS will be performed by Foundation Medicine.  When 
performed by Foundation Medicine, the investigator can obtain results from the samples 
collected in the form of an NGS report, which is available upon request directly from 
Foundation Medicine.  The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay 
has not been cleared or approved by health authorities.  The NGS report is generated 
for research purposes and is not provided for the purpose of guiding future treatment 
decisions.

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4.5.8
Left Ventricular Ejection Fraction
All patients will require evaluation of LVEF at screening, and only patients receiving 
cobimetinib (Arm A) will require subsequent evaluations of LVEF.
Evaluation of LVEF by ECHO or MUGA must be performed at the following timepoints: 

Screening 

Cycle 2 Day 11 week 

Day 1 of every three treatment cycles thereafter starting at Cycle 52 weeks 

Treatment discontinuation visit:  The treatment discontinuation visit evaluation of 
LVEF does not need to be performed at the treatment discontinuation visit if an 
evaluation has been performed within the last 12 weeks and there are no clinically 
significant findings and/or changes from baseline. 

All patients who restart treatment with a reduced dose of cobimetinib because of a 
decrease in LVEF should have LVEF measurements taken after approximately 
2 weeks, 4 weeks, 10 weeks, and 16 weeks and then resume monitoring LVEF 
every 3 cycles.
Any patient who develops clinical signs or symptoms suspicious of cardiac failure should 
undergo an LVEF assessment.  Evaluation of LVEF must be performed by the same 
method (ECHO or MUGA) for each patient.  It is strongly encouraged that the same 
laboratory and operator perform ECHO/MUGA scans for each individual patient.  
Investigators must be aware of local institution regulations regarding repeat MUGA 
scans.  The repeat administration of radioisotopes is limited in some nuclear medicine 
laboratories, and some patients in this study could require monitoring on four or more 
occasions.
4.5.9
Ophthalmologic Examination
All patients will require an ophthalmologic examination at screening and only patients 
receiving cobimetinib (Arm A) will require subsequent ophthalmologic examinations.
Ophthalmologic examination must be performed at the following timepoints:

Screening

Cycle 2 Day 11 week

Day 1 of Cycles 5, 8, and 11 (every 3 cycles)2 weeks

Day 1 of Cycles 15, 19, and 23 (every four treatment cycles)2 weeks

Day 1 of Cycles 29, 35, 41, 47, etc. (every six treatment cycles)2 weeks

Treatment discontinuation visit. If an ophthalmologic evaluation has been performed 
within the last 12 weeks of the treatment discontinuation visit, the ophthalmologic 
examination does not need to be performed during the treatment discontinuation 
visit.

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The objective of baseline ophthalmologic examination is to evaluate for evidence of 
retinal pathology that may be a risk factor for central serous retinopathy or retinal vein 
occlusion. Ophthalmologic examination must be performed by a qualified 
ophthalmologist. Risk factors for retinal vein occlusion include uncontrolled serum 
cholesterol, hypertriglyceridemia, hyperglycemia, hypertension, and glaucoma. Patients 
with such conditions will be excluded from the study as detailed in the 
inclusion/exclusion criteria.
Baseline and serial surveillance ophthalmologic examination will include visual acuity 
testing, intraocular pressure measurements by tonometry, slit-lamp ophthalmoscopy, 
indirect ophthalmoscopy, spectraldomain optical coherence tomography, and 
Humphrey Automatic Visual Field using Swedish interactive threshold algorithm 
Fast 10-2 protocol.
4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30 and two additional items from the 
EORTC item bank (see Section 4.5.10.1) to more fully characterize the clinical profile of 
cobimetinib plus atezolizumab as compared to regorafenib.  In addition, to derive utility 
for pharmacoeconomic models, patients will complete the EQ-5D-5L.  
The questionnaires will be translated as required in the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit will be completed in their 
entirety by the patient prior to the performance of non-PRO assessments and the 
administration of study treatment (where applicable).
Patients will use an electronic PRO (ePRO) device to capture PRO data at in-person 
clinic visits.  The ePRO device and/or instructions for completing the PRO 
questionnaires electronically will be provided by the investigator staff.  The data will be 
transmitted via a pre-specified transmission method (e.g., web or wireless) automatically 
after entry to a centralized database at the ePRO vendor.  The data can be accessed by 
the appropriate sponsor study personnel securely via the Internet.
The questionnaires will be completed on the ePRO tablet at the beginning of each cycle 
upon arrival at the study clinic during treatment period and at the treatment 
discontinuation visit. The assessments should continue until loss of clinical benefit and 
then follow the survival follow-up frequency at 3 and 6 months. If the survival follow-up  
study visits are conducted by telephone, the PRO data (the reduced EORTC QLC 30) 
for that visit will be collected via telephone interview and recorded by the investigative 
staff on the ePRO tablet.
Adverse event reports will not be derived from PRO data by the Sponsor.

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4.5.10.1
European Organization for Research and Treatment of Cancer 
Quality of Life-C30 Questionnaire and Additional Items
The EORTC QLQ-C30 is a self-report questionnaire that assesses multiple dimensions 
of HRQoL among cancer patients.  Responses to this 30-item questionnaire are 
categorized into five functional domains (i.e., physical, role, emotional, cognitive, and 
social) (scored on a 4-point Likert scale), one global health status domain (scored on a 
7-point Likert scale), three symptom domains (i.e., fatigue, nausea/vomiting, pain), and 
six single items (scored on a 4-point Likert scale).  Items that assess abdominal bloating 
and abdominal pain that are issued from the validated EORTC item bank will be added 
to the assessment. Each score is transformed into a 0100-point scale.  In the five 
functional scales and the global health status scale, a high score means a “high level of 
functioning or global health status.”  In the case of symptom scales and single items, a 
higher score implies a “high level of symptoms or problems.”
To maintain validity and minimize patient burden, the EORTC instrument administered 
via telephone interview will consist of a reduced version of the EORTC QLQ items 
(Items 17, 10, 12, 13, 16, 17, 18, 29, and 30 from the C30 and the two additional items 
from the item bank).
4.5.10.2
EuroQoL 5 Dimensions
The EQ-5D questionnaire is a generic, preference-based health utility measure with 
questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  
The EQ-5D will be utilized in this study for economic modeling.  The EQ-5D 
questionnaire takes 5 minutes or less to complete.
To maintain validity and minimize patient burden, the EQ-5D-5L instrument administered 
via telephone interview will consist of the telephone interview version of the EQ-5D-5L.
4.5.11
Timing of Assessments
4.5.11.1
Screening
Screening tests and evaluations will be performed within 35 days prior to Cycle 1 Day 1.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 35 days prior to Cycle 1 Day 1 may be used; such tests do not need 
to be repeated for screening.
See Appendix 1 for the schedule of screening assessments and Appendix 2 for the 
schedule of PK and ATA assessments.
4.5.11.2
On Treatment
All treatment visits must occur within ± 3 days from the scheduled date unless otherwise 
noted (see Appendix 1).  All procedures, tests, and assessments will be performed on 
the day of the specified visit unless a time window is specified.  Assessments scheduled 

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on the day of study treatment administration (Day 1) of each cycle should be performed 
prior to study treatment infusion unless otherwise noted.
4.5.11.3
Treatment Discontinuation
Patients who discontinue study treatment will return to the clinic for a treatment 
discontinuation visit within 30 days after the last dose of study treatment.  The visit at 
which the investigator determines a loss of clinical benefit may be used as the treatment 
discontinuation visit.  In the event that the decision for discontinuation is due to an 
adverse event and this visit also shows progressive disease, discontinuation will be 
marked as due to progressive disease.
See the study flowcharts provided in Appendix 1.
Patients who discontinue study treatment must be followed according to the follow-up 
visit schedule for progression and/or survival until death, loss to follow-up, or withdrawal 
of consent, which will be defined as study discontinuation.
4.5.11.4
Follow-Up
After the treatment discontinuation visit, adverse events should be followed as outlined 
in Section 5.6.  For patients who discontinue study treatment for reasons other than 
disease progression, tumor assessments should continue to be performed as scheduled 
(i.e., every 8 weeks1 week) until patient death or documented disease progression.
Survival follow-up should continue until death, withdrawal of consent, the patient is lost 
to follow-up, or study termination by the Sponsor, whichever occurs first.  If the patient 
withdraws from study, the study staff may use a public information source (e.g., county 
records) when permissible, to obtain information about survival status only.
See the study flowcharts provided in Appendix 1 for assessments to be performed 
during follow-up visits.
4.5.11.5
Unscheduled Visits
Assessments for unscheduled visits related to a patient’s underlying CRC, study 
treatment, or adverse events should be performed as clinically indicated and entered 
into Unscheduled Visit eCRFs.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

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
Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Disease progression (see Section 4.3.2.4 for dosing beyond progression)

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status

Intolerable toxicity related to any study drug

Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment

Use of another nonprotocol anti-cancer therapy (see Section 4.4.2)

Pregnancy
Patients must provide written consent to acknowledge deferring any standard treatment 
options that may exist in favor of continuing treatment at the time of initial progression.
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.
4.6.3
Study and Site 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.  
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

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
Non-compliance with the International Conference on 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 
In the United States, atezolizumab is approved for the treatment of locally advanced or 
metastatic urothelial bladder cancer who have progressed during or following 
platinum-containing chemotherapy and for metastatic nonsmall cell lung cancer who 
have progressed during or following platinum-containing chemotherapy and if harboring 
an EGFR or ALK aberration have progressed on U.S. Food and Drug 
Administration-approved therapy for these aberrations and is currently in clinical 
development for other indications.  The safety plan is based on results from nonclinical 
studies, completed and ongoing clinical studies, and published data on similar molecules.  
Please refer to the atezolizumab Investigator’s Brochure for a complete summary of 
safety information.
Cobimetinib (for use with vemurafenib) is approved in the United States and European 
Union as well as other countries for the treatment of metastatic melanoma. The safety 
plan for patients in this study is based on clinical experience with cobimetinib in 
completed and ongoing studies.  The anticipated important safety risks for cobimetinib 
are outlined below.  Please refer to the cobimetinib Investigator's Brochure for a 
complete summary of safety information. 
Regorafenib is approved in the United States, European Union, and Japan.  Please refer 
to the Stivarga (regorafenib) Prescribing Information for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients who participate in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification, and 
treatment interruption or discontinuation, are provided below.  There are separate 
guidelines for the three different arms as the toxicities and management guidelines are 
distinct for the three different arms.  Please refer to the specific guidelines for each arm 
individually.
5.1
SAFETY PLAN
The risks associated with cobimetinib, atezolizumab, and regorafenib are detailed in 
Section 5.1.1, Section 5.1.2, and Section 5.1.3, respectively.

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5.1.1
Risks Associated with Cobimetinib
Information related to risks attributed to cobimetinib is based on safety data from 
Phase III Study GO28141 (cobimetinib plus vemurafenib), Phase Ib Study NO25395 
(cobimetinib plus vemurafenib), and Phase I Study MEK4592g (cobimetinib 
monotherapy). For further information regarding clinical safety, please refer to the 
current cobimetinib Investigator’s Brochure.
5.1.1.1
Important Identified Risks Associated with Cobimetinib
Hemorrhage
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical 
area or organ, can occur with cobimetinib. In clinical studies with cobimetinib, events of 
cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract hemorrhage, 
and hematuria, have been reported.
In the Phase III Study GO28141, Grade 14 hemorrhagic events were reported in 13.0% 
of patients treated with cobimetinib plus vemurafenib, and in 7.3% of patients treated 
with placebo plus vemurafenib. The majority of hemorrhagic events were Grade 1 or 2 
and non-serious.  Grade 34 hemorrhage events were reported in 1.2% of patients 
receiving cobimetinib plus vemurafenib and 0.8% of patients receiving placebo plus 
vemurafenib. 
Caution should be used in patients with additional risk factors for bleeding, such as brain 
metastases, and/or in patients that use concomitant medications that increase the risk of 
bleeding (including antiplatelet or anticoagulant therapy).
Instructions for dose modification for hemorrhage events are included in Appendix 3.
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK-inhibitors, including cobimetinib (Flaherty et al. 2012). 
Manifestations of serous retinopathy include visual disturbances, findings of retinal 
detachment, and retinopathy. Serous retinopathy events may also be asymptomatic.
Serous retinopathy has been characterized in the Phase III Study GO28141.  The study 
incorporated prospective serial ophthalmic examinations for all enrolled patients.  Serous 
retinopathy was reported more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half the events were asymptomatic Grade 1 events.  Few patients treated 
with cobimetinib plus vemurafenib experienced Grade3 ocular events (2.8%); the 
majority of these were managed with dose modification of both cobimetinib and 
vemurafenib.
To address serous retinopathy with cobimetinib treatment, all patients are required to 
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retinal pathology that is considered to be a risk factor for or indicative of neurosensory 
retinal detachment, central serous chorioretinopathy, neovascular retinopathy, or 
retinopathy of prematurity. Patients will also undergo ophthalmologic examinations at 
specified time points throughout the study (see Appendix 1). Details regarding baseline 
and subsequent ophthalmologic examinations are provided in Appendix 3.
Guidelines for management of patients who develop Grade2 visual disorders or 
retinopathy are provided in Appendix 3.
Left Ventricular Dysfunction
Decrease in left ventricular ejection fraction from baseline has been reported in patients 
receiving cobimetinib. Left ventricular dysfunction may occur with signs and symptoms of 
cardiac failure, or reduction in left ventricular ejection fraction events may be 
asymptomatic.
Left ventricular dysfunction has been characterized in the Phase III Study GO28141.  
The study incorporated prospective serial left ventricular ejection fraction evaluation in all 
patients.   With active surveillance, measured reductions in left ventricular ejection 
fraction were observed more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (8.5% vs. 3.7%, respectively, of Grade 2 or 
3 decrease).  Of the patients treated with cobimetinib plus vemurafenib, 2 patients (0.8%) 
had symptomatic reduction in left ventricular ejection fraction and the remaining patients 
were asymptomatic.  Most left ventricular ejection fraction reduction events in patients on 
cobimetinib plus vemurafenib (62%) improved or resolved with management according 
to the dose-modification guidelines (see Appendix 3). 
Rhabdomyolysis and CPK Elevations
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 
elevations reported were asymptomatic, non-serious, and resolved with or without study 
drug interruption.  One event of rhabdomyolysis was reported in the Phase III 
Study GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported 
in postmarketing experience.
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade3 events).  
CPK will be monitored at baseline and monthly during treatment or as clinically 
indicated. Instructions for Dose Modification for elevated CPK and rhabdomyolysis are 
included in Appendix 3.

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Photosensitivity (when Administered with Vemurafenib)
No evidence of phototoxicity has been observed with cobimetinib as a single agent. 
However, photosensitivity was observed on the GO28141 trial with a higher frequency in 
the cobimetinib plus vemurafenib arm versus placebo plus vemurafenib arm (46.3% vs. 
35.4%, respectively). The majority of events were Grades 1 or 2, with Grade3 events 
occurring in 3.6% of patients in the cobimetinib plus vemurafenib arm versus 0% in the 
placebo plus vemurafenib arm. Grade3 photosensitivity events in the cobimetinib plus 
vemurafenib arm were primarily treated with topical medication in conjunction with 
interruption of study agents. 
Pneumonitis
Events of pneumonitis have been reported in cobimetinib clinical studies. Most reported 
events were considered non-serious and low-severity grade.  In the Phase III 
Study GO28141, pneumonitis events were reported more frequently in patients treated 
with cobimetinib plus vemurafenib than placebo plus vemurafenib (1.6% vs. 0.4%, all 
grades).  There were no reported Grade3 events in either study arm.  Serious events 
were reported in 2 patients (0.8%) treated with cobimetinib plus vemurafenib.  Refer to 
Appendix 3 for pneumonitis management guidelines.
5.1.1.2
Potential Risks Associated with Cobimetinib
Liver Laboratory Abnormalities and Severe Hepatotoxicity
Liver laboratory test abnormalities, including increases in ALT, AST, and alkaline 
phosphatase have been reported as adverse events and serious adverse events in 
patients treated with cobimetinib plus vemurafenib.
In the Phase III Study GO28141, liver laboratory test abnormalities reported as Grade3 
adverse events occurred more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (20.5% vs. 15.1%, respectively).
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines.  In both study arms, the majority of Grade3 liver laboratory test 
abnormalities resolved.  Refer to Appendix 3 for hepatotoxicity management guidelines.
Impaired Female Fertility and Developmental Toxicity
There is a potential for effects on fertility and embryo-fetal toxicity based on results from 
nonclinical studies. 
While no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased 
apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal 
epithelial cells in rats, and epididymal epithelial cells in dogs.  These changes were 
reversible upon discontinuation of cobimetinib administration.
In a dedicated embryo-fetal toxicity study, cobimetinib produced fetal toxicity (resorptions 
and reductions in fetal weight), and teratogenicity (malformations of the great vessels 

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and skull) at similar systemic exposures to those observed in patients administered the 
60 mg dose.
5.1.1.3
Other Risks with Cobimetinib
Rash
In the Phase III Study GO28141, combined rash events of all types and grades were 
reported more frequently in patients treated with cobimetinib plus vemurafenib than 
placebo plus vemurafenib (71.7% vs. 66.7%, respectively), although Grade3 events 
(approximately 16% of patients) and types of rash reported were similar between study 
arms.  Specific events in patients treated with cobimetinib plus vemurafenib included 
rash (39% all grades, 5.9% Grade3, 1.6% serious adverse events) and rash 
maculo-papular (14.6% all grades, 6.3% Grade3, 1.2% serious adverse events).
Generally, Grade3 rash events were effectively managed with dose modification 
guidelines.  In Study GO28141, approximately 90% of Grade3 rash events resolved in 
both arms.  Refer to Appendix 3 for rash management guidelines.
Gastrointestinal Toxicity
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, 
have been reported in all cobimetinib studies in adult cancer patients.
In the Phase III Study GO28141, diarrhea was the most common adverse event 
reported. Diarrhea events of all severity grades were reported in 59.9% of patients and 
Grade 3 or 4 events were reported in 6.5% of patients treated with cobimetinib plus 
vemurafenib versus 30.9% (Grade 3) and 0.8% (Grade 4) in the patients treated with 
placebo plus vemurafenib. No Grade 5 events of diarrhea have been reported. Serious 
adverse events of diarrhea were reported in 1.2% of patients treated with cobimetinib 
plus vemurafenib.
Nausea and vomiting have been reported in association with cobimetinib. Most nausea 
and vomiting events were considered non-serious and low-severity grade. In the 
Phase III Study GO28141, nausea and vomiting events were reported more frequently in 
the active cobimetinib arm than the control arm (nausea 41.3% vs. 25.2%; vomiting 24.3% 
vs. 12.6%). However, of patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea 0.8%, vomiting 1.2%).
In the Phase I single-agent study (MEK4592g), all grades of nausea and vomiting were 
both reported as 33.9% with 0.9% reported for Grade3 nausea and none reported for 
vomiting.
The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake. In the majority of cases, diarrhea has been effectively 
managed with antidiarrheal agents and supportive care. Routine antiemetic prophylaxis 

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is not recommended. Refer to Appendix 3 for gastrointestinal toxicity management 
guidelines.
Hypersensitivity 
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib monotherapy or cobimetinib when used 
with other agents. These have appeared to be isolated reports, and in some cases, 
occurred in patients with histories of drug allergies. Thus, the relationship of cobimetinib 
to these events is unclear.
In the Phase III Study GO28141, Grade 3 hypersensitivity events were reported in 
3 patients in the cobimetinib and vemurafenib arm compared with no such events in the 
placebo plus vemurafenib arm.  All events required hospitalization and treatment with 
steroids. 
Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction.
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as IRRs and immune-related hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, meningoencephalitis, myocarditis, and hypophysitis.  In addition, systemic 
immune activation is a potential risk associated with atezolizumab.  Refer to Section 6 of
the Atezolizumab Investigator's Brochure for a detailed description of anticipated safety 
risks for atezolizumab and Appendix 9.
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is a potential risk when administered in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)

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If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.
5.1.3
Risks Associated with Regorafenib
The overall safety profile of regorafenib is based on data from more than 1200 treated 
patients in clinical trials including placebo-controlled Phase III data for 500 patients with 
metastatic colorectal cancer and 132 patients with gastrointestinal stromal tumors. 
The most serious adverse drug reactions in patients who receive regorafenib are severe 
liver injury, hemorrhage, hypertension, dermatologic toxicity, cardiac ischemia and 
infarction, reversible posterior leukoencephalopathy, and gastrointestinal perforation. 
The most frequently observed adverse drug reactions (30%) in patients who receive
regorafenib are asthenia/fatigue, hand foot skin reaction, diarrhea, decreased appetite 
and food intake, hypertension, dysphonia and infection.  
Please refer to the Stivarga (regorafenib) Prescribing Information for complete 
information regarding clinical safety.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
5.1.4.1
Cobimetinib and Regorafenib Dose Modifications
Cobimetinib and regorafenib dose modifications are provided in Table 3.
Table 3
Recommended Cobimetinib and Regorafenib Dose Modifications 
Grade (CTCAE) a
Recommended Cobimetinib 
Dose
Recommended Regorafenib 
Dose
Grade 1 or Grade 2 
(tolerable)
No dose reduction. Maintain 
cobimetinib at the same dose 
of 60 mg QD (3 tablets)
No dose reduction. Maintain 
regorafenib at the same
dose of 160 mg QD 
(4 tablets)
Grade 2 (intolerable) or 
Grade 3 or 4 (any)
First appearance
Interrupt treatment until 
Grade1, restart treatment 
at40 mg QD (2 tablets)
Interrupt treatment until 
Grade1, restart treatment 
at 120 mg QD (3 tablets)
Second appearance
Interrupt treatment until 
Grade1, restart treatment at
20 mg QD (1 tablet)
Interrupt treatment until 
Grade1, restart treatment 
at 80 mg QD (2 tablets)

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Grade (CTCAE) a
Recommended Cobimetinib 
Dose
Recommended Regorafenib 
Dose
Third appearance
Consider permanent 
discontinuation
Consider permanent 
discontinuation
CTCAECommon Terminology Criteria for Adverse Events; NCINational Cancer Institute; 
QDonce daily.
a   The intensity of clinical adverse events graded by NCI CTCAE v4.0.
5.1.4.2
Atezolizumab Dose Modifications
There will be no dose reduction for atezolizumab in this study.  
Guidelines for management of general adverse events are outlined in Table 4.
Table 4
Guidelines for Management of Patients Who Experience Adverse 
Events in Arm A and Arm B
Event
Action to Be Taken
Other toxicities:  Grade 1
No action required. 
Other toxicities:  Grade 2
No action required
Other toxicities:  Grade 3 or 4
Interrupt dosing of atezolizumab (or cobimetinib if in Arm A)
depending on the attribution of the toxicity, at the discretion 
of the investigator. During this time, treatment may continue 
with the other non-attributable treatment agent (i.e., either 
the atezolizumab in arm A or B or cobimetinib if in Arm A). 
If AE resolves to Grade1 within 1 cycle, then restart dosing 
of the attributable drug (atezolizumab at fixed dose and 
cobimetinib decreased by 1 dose level). 
If the AE does not resolve to Grade1 within 1 cycle, 
permanently discontinue the attributable drug. If one drug is 
discontinued dosing of the other drug may continue at the 
discretion of the investigator.
If the Grade 4 AE recurs (a second time), the attributable 
drug should be discontinued. If one drug is discontinued 
dosing of the other drug may continue at the discretion of the 
investigator.
For Grade3 toxicities associated primarily with laboratory 
abnormalities only, study treatment may continue without 
interruption and/or dose reduction at the discretion of the 
investigator per institutional practice.
AEadverse event. 
Additional guidelines for specific adverse events delineated by the different study arms 
are provided in the subsections below and the specific management guidelines are 
highlighted in Appendix 3 for cobimetinib plus atezolizumab.  For information regarding 

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management of atezolizumab-associated adverse events, please refer to the 
Appendix 9.
5.1.4.3
Management of Cobimetinib- and Atezolizumab-Specific 
Adverse Events (Arm A)
Toxicities associated or possibly associated with cobimetinib plus atezolizumab 
treatment should be managed according to standard medical practice.  
Refer to Appendix 3 for management of cobimetinib plus atezolizumab specific toxicities,
including gastrointestinal toxicity, hepatotoxicity, dermatologic toxicity, pulmonary toxicity, 
potential eye toxicity, left ventricular ejection fraction, rhabdomyolysis and elevated CPK, 
hemorrhage, and systemic immune activation.
Guidelines for management of patients who experience atezolizumab-associated 
adverse events, including infusion-related reactions and immune-related events (e.g., 
endocrine, ocular, pancreatic, and neurologic events), are provided in Appendix 9.
5.1.4.4
Management of Adverse Events in the Atezolizumab 
Monotherapy Arm (Arm B)
Guidelines for management of patients who experience specific adverse events 
associated with atezolizumab, including infusion-related reactions and immune-related 
events (e.g., pulmonary, hepatic, gastrointestinal, endocrine, ocular, pancreatic, 
dermatologic, and neurologic events), are provided in Appendix 9.
5.1.4.5
Management of RegorafenibAssociated Adverse Events 
(Arm C)
Toxicities associated or possibly associated with regorafenib treatment should be 
managed according to standard medical practice.  Highlighted below are the dose 
modifications for selected adverse events outlined in the Stivarga (regorafenib) 
prescribing information. Please refer to the Stivarga (regorafenib) prescribing 
information for further guidance.
For symptomatic Grade 2 hypertension interrupt regorafenib and reduce the dose of 
regorafenib by a dose level.
Recommended dose modifications for hand-foot skin reaction and palmar-plantar 
erythrodysesthesia syndrome are provided in Table 5, and recommended dose 
modifications for liver function abnormalities are provided in Table 6. 

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Table 5
Recommended Dose Modification and Measure for HandFoot 
Skin Reaction/Palmar-Plantar Erythrodysesthesia Syndrome
Skin Toxicity Grade
Occurrence
Recommended Dose Modification and 
Measures
Grade 1
Any
Maintain dose level and immediately institute 
supportive measures for symptomatic relief
Grade 2
First occurrence
Decrease dose by 40 mg and immediately 
institute supportive measures.
If no improvement occurs despite dose 
reduction, interrupt therapy for a minimum of 
7 days, until toxicity resolves to Grade 01.
A dose re-escalation is permitted at the 
discretion of the physician.
No improvement 
within 7 days or 
second occurrence
Interrupt therapy until toxicity resolves to 
Grade 01.
When restarting treatment, decrease dose by 
40 mg.
A dose re-escalation is permitted at the 
discretion of the physician
Third occurrence
Interrupt therapy until toxicity resolves to 
Grade 01.
When restarting treatment, decrease dose by 
40 mg.
A dose re-escalation is permitted at the 
discretion of the physician.
Fourth occurrence
Discontinue treatment with regorafenib 
permanently.
Grade 3
First occurrence
Institute supportive measure immediately.
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 01.
When restarting treatment, decrease dose by 
40 mg.
A dose re-escalation is permitted at the 
discretion of the physician.
Second occurrence
Institute supportive measures immediately.
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 01.
When restarting treatment, decrease dose by 
40 mg.
Third occurrence
Discontinue treatment with regorafenib 
permanently.

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Table 6
Recommended Measures and Dose Modifications in Case of 
DrugRelated Liver Function Test Abnormalities
Observed elevations of ALT 
and/or AST
Occurrence
Recommended measures and dose 
modification
5ULN (maximum Grade 2)
Any 
occurrence
Continue regorafenib treatment.
Monitor liver function weekly until 
transaminases return to3ULN (Grade 1) or 
baseline
5ULN
20ULN (Grade 3)
First
occurrence
Interrupt regorafenib treatment.
Monitor transaminases weekly until return to 
3ULN or baseline.
Restart: If the potential benefit outweighs the 
risk of hepatotoxicity, restart regorafenib
treatment, reduce dose by 40 mg, and monitor 
liver function weekly for at least 4 weeks.
Re-
occurrence
Discontinue treatment with regorafenib 
permanently.
20ULN (Grade 4)
Any 
occurrence
Discontinue treatment with regorafenib 
permanently.
3ULN (Grade 2 or higher) 
with concurrent 
bilirubin2ULN
Any 
occurrence
Discontinue treatment with regorafenib 
permanently.
Monitor liver function weekly until resolution or 
return to baseline.
Exception: patients with Gilbert’s syndrome 
who develop elevated transaminases should 
be managed as per the above outlined 
recommendations for the respective observed 
elevation of ALT and/or AST.
ULNupper limit of normal.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocolspecified safety laboratory assessments, measuring protocolspecified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe form 
or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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; 

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see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 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 for reporting instructions). Adverse events of special interest for this study 
include the following:

Suspected transmission of an infectious agent by the study drug, 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 the study drug is suspected.

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, or thyroid 
disease

Systemic lupus erythematosus

Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis

Nephritis

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system, or infusion-reaction syndromes

Retinal vein occlusion

Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment, and central serous 
chorioretinopathy

Rhabdomyolysis or Grade 3 CPK elevation

Grade3 hemorrhage or any grade cerebral hemorrhage

Grade3 rash

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
Grade3 diarrhea

Significant liver toxicity
o
AST and/or ALT10ULN
o
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): 

Treatment emergent ALT or AST3ULN in combination with 
either an elevated total bilirubin (2ULN) or clinical jaundice, 
without initial findings of cholestasis (elevated serum alkaline 
phosphatase)

No other reason can be found to explain the combination of 
increased ALT/AST and total bilirubin, such as: liver metastasis; 
viral hepatitis A, B, or C; alcoholic and autoimmune hepatitis; 
other liver diseases; or exposure to other drugs known to cause 
liver injury 

Symptomatic heart failure or Grade3 left ventricular ejection fraction reduction 
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), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all serious adverse events and Adverse Events of Special 
Interest, regardless of relationship to study drug, will be reported until 90 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs 
first.  All other adverse events, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug or initiation of new anti-cancer 

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therapy, whichever occurs first. Instructions for reporting adverse events that occur 
after the adverse event reporting period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 7 Adverse Event Severity Grading Scale for Events Not Specifically
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE v4.0 which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htmhttp://ctep.cancer.g
ov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 

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adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured 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 drug, 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 vs. 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.

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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
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 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation 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)

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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.5 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.

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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 5.5 for details 
on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) 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ULN in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
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 colorectal cancer should be recorded on the 
Death Attributed to Progressive Disease eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.

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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Colorectal Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer

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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
There is no clinical experience with an overdose of cobimetinib and thus no safety data 
related to overdosing are available.  Please see the cobimetinib Investigator’s Brochure
for more details.
There is no clinical experience with an overdose of atezolizumab and thus no safety data 
related to overdosing are available. Please see the atezolizumab Investigator’s 
Brochure for more details.
The highest dose of regorafenib studied clinically was 220 mg/day. The most frequently 
observed adverse drug reactions at this dose were dermatological events, dysphonia, 
diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and 
fatigue. Please see the Stivarga (regorafenib) Prescribing Information for more details.
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.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.

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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, an Emergency Medical Call Center 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 Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.
For all other non-emergency medical questions, please contact your clinical study 
monitor the following Medical Monitor:

, M.D.:  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  

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The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug or initiation of 
another anti-cancer drug, whichever comes first.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study, within 5 months after the last dose 
of atezolizumab, or within 3 months after the last dose of cobimetinib or regorafenib.  
A Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  

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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 
90 days after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
Any 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).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.

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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, 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
POST-STUDY ADVERSE EVENTS
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the last dose of study drug or initiation of a 
new anti-cancer treatment whichever comes first), 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 a serious adverse event that is believed to be 
related to prior study drug treatment, the event should be reported through use of the 
Adverse Event eCRF.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Cobimetinib Investigator's Brochure

Atezolizumab Investigator’s Brochure

Summary of Product Characteristics (SPC) for regorafenib (StivargaSPC 2017)
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of cobimetinib plus atezolizumab and atezolizumab 
monotherapy as compared to treatment with regorafenib in approximately 360 patients 
with unresectable locally advanced or metastatic colorectal adenocarcinoma.

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The efficacy analyses of OS, PFS, and ORR will be performed on all randomized 
patients (i.e., intent to treat [ITT]) irrespective of whether the assigned treatment was 
actually received.  DOR will be assessed in patients who have an objective response.  
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization.
The safety population will include all randomized patients who received any amount of 
study drug.  Patients who are randomized into the study but do not receive any amount 
of study drug will not be included in the safety population.  For safety analyses, patients 
will be grouped according to whether any amount of cobimetinib and/or atezolizumab 
was received, including the case when study drug (cobimetinib and/or atezolizumab) 
was received in error.
Statistical details for all the analyses will be documented in the Statistical Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
The study will randomize approximately 360 patients, including a minimum of 
180 patients with extended RAS-mutant mCRC (assuming a prevalence of at least 50%),
to cobimetinib plus atezolizumab (Arm A), atezolizumab monotherapy (Arm B), and 
regorafenib (Arm C) with the randomization ratio of 2:1:1, respectively.
The type 1 error () for the analysis of the primary endpoint of OS in the comparison of 
cobimetinib plus atezolizumab (Arm A) against the control arm of regorafenib (Arm C) is 
0.05 (2-sided).  If OS in the comparison of Arm A against Arm C is statistically significant, 
then the OS in the comparison of Arm B against Arm C will be tested at a 2-sided level
of 0.05. 
The sample size of this study is determined on the basis of the number of events 
required to demonstrate efficacy with regard to OS in both comparisons (Arm A vs. 
Arm C and Arm B vs. Arm C).
The overview of the Type I error (α) control is shown in Figure 3.

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Figure 3
Overview of Hierarchical Testing Sequence for Type I Error a
Control (2-Sided)
OSoverall survival.
a OS will be tested at a 2-sided significance level 0.05 only if the result of previous testing 
is positive (i.e., statistically significant).  
The estimate of the number of events required to demonstrate efficacy with regard to OS 
is based on the following assumptions:

Two-sided significance level of 0.05

Arm A versus Arm C: 87% power to detect an HR of 0.61, corresponding to an 
improvement in median OS from 6.4 months in Arm C to 10.5 months in Arm A

Arm B versus Arm C: 80% power to detect an HR of 0.61, corresponding to an
improvement in median OS from 6.4 months in Arm C to 10.5 months in Arm B 

No interim analysis for OS

Dropout rate of 10% in 24 months

Hierarchical testing of Arm A versus Arm C followed by Arm B versus Arm C to 
control the overall level of 5%
With these assumptions, approximately 360 patients in total will be randomized into this 
study, with approximately 270 patients for the comparison of Arm A versus Arm C and 
approximately 180 patients for the comparison of Arm B versus Arm C.  The OS final 
analysis will be conducted when there are approximately 235 deaths in the study.  This 
is expected to occur approximately 23 months after the first patient is randomized.  At 
that time, it is expected that approximately 178 deaths for the comparison of Arm A 
versus Arm C and approximately 127 deaths for the comparison of Arm B versus 
Arm C will have occurred.
This number of events corresponds to a minimum detectable difference in HR of 
approximately 0.73 for the Arm A versus Arm C comparison and approximately 0.71 for 
the Arm B versus Arm C comparison.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The incidence of study drug discontinuation for reasons 
other than disease progression will similarly be tabulated.  Protocol violations, including 

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major violations of inclusion/exclusion criteria, will be summarized in a similar manner by 
treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics will be summarized by treatment arms for the ITT populations.  
Descriptive statistics (mean, median, standard deviation, and range) will be presented 
for continuous data, and frequencies and percentages will be presented for categorical 
data.  Study treatment administration will be summarized by treatment arm for all treated 
patients.
6.4
EFFICACY ANALYSES
Unless otherwise noted, all efficacy analyses will include all randomized patients
(ITT analysis), and patients will be grouped according to the treatment assigned at 
randomization.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is OS, which is defined as the time (in months) between 
the date of randomization and the date of death due to any cause.  Patients who have 
not died at the time of analysis will be censored at the date when they were last known 
to be alive.  
Comparisons with respect to OS between two treatment arms (i.e., Arm A vs. Arm C, 
Arm B vs. Arm C) will be tested based on a stratified log-rank test. The stratification 
factors will be extended RAS mutation status of the tumor and time since diagnosis of 
first metastasis (18 months and 18 months).
Each comparison will be tested at a 2-sided significance level of 0.05 within the ITT 
population:

Test to reject the null hypothesis of no difference in OS between either experimental 
arm (i.e., Arm A or Arm B) and the control arm (Arm C) in the ITT population. If the 
2sided p-value corresponding to the stratified log-rank test is less than 0.05, the 
null hypothesis will be rejected.
The HR for OS will be estimated using a stratified Cox model.  Two-sided 95% CIs for 
the HR will be provided. The stratified analyses will incorporate extended RAS mutation 
status and time since diagnosis of first metastasis as stratification factors.  Results from 
an unstratified log-rank test and the unstratified HR will also be presented.  Kaplan-Meier 
methodology will be used to estimate median OS for each treatment arm, and the 
Kaplan-Meier curves will be provided.  The Brookmeyer-Crowley methodology will be 
used to construct the 95% CI for the median OS for each treatment arm 
(Brookmeyer and Crowley 1982).

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The comparison between the two experimental arms (Arm A vs. Arm B) will be 
conducted for descriptive purposes.
6.4.2
Secondary Efficacy Endpoints
The secondary endpoints include investigator-assessed PFS, ORR, and DOR per 
RECIST v1.1.  The analyses of PFS, ORR, and DOR will take place at the time of the 
OS analysis.
PFS is defined as the time between date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Disease progression 
will be determined based on investigator assessment using RECIST v1.1.  Data from 
patients who have not experienced disease progression or death will be censored at the 
last tumor assessment date and known to be free of disease progression.  Data from 
patients with no post-baseline tumor assessment will be censored at the randomization 
date plus 1 day.  Comparisons with respect to PFS between the two treatment arms will 
be tested based on a 2-sided stratified log-rank test.  The HR for PFS will be estimated 
using a stratified Cox model.  Two-sided 95% CIs for the HR will be provided.  Stratified 
analyses will incorporate the same stratification factors as for the analysis of OS. 
Results from an unstratified log-rank test and the unstratified HR will also be presented. 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm, 
and the Kaplan-Meier curves will be provided.
ORR is defined as the proportion of patients who had a confirmed objective response of 
CR or PR assessed by the investigator according to the RECIST v1.1.  An estimate of 
ORR and its 95% CI will be calculated using the Clopper-Pearson method for each 
treatment arm. 
Treatment difference in ORR will be tested using the stratified 
Cochrane-Mantel-Haenszel test, stratified by the same factors used in the OS analysis, 
and a 95% Hauck-Anderson CI will be calculated for the difference in ORR between 
treatment arms.
DOR is defined as the period measured from the date of the first occurrence of a CR or 
PR (whichever status is recorded first) until the first date that progressive disease or 
death is documented.  Disease progression will be determined on the basis of 
investigator assessment with use of RECIST v1.1.  DOR will be assessed in patients 
who have an objective response during the study as determined by the investigator with 
use of RECIST v1.1.  Patients who have not progressed and who have not died by the 
date of data cutoff for analysis will be censored at the time of last tumor assessment 
date.  If no tumor assessments were performed after the date of the first occurrence of a 
CR or PR, DOR will be censored at the date of the first occurrence of a CR or PR plus 
1 day.  Median DOR will be estimated using the Kaplan-Meier method, and the 95% CI 
will be calculated using the method of Brookmeyer and Crowley (1982).  DOR analysis is 

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performed on the basis of a non-randomized subset of patients (i.e., patients who 
achieve an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  
6.5
PATIENT-REPORTED OUTCOMES ANALYSES
For PROs, the EORTC QLQ-C30 questionnaire and two additional items will be scored 
according to the EORTC Scoring Manual.
The primary analysis population for evaluation of PRO assessments will include patients 
in the ITT population with a baseline PRO assessment and at least one post-baseline 
PRO assessment.
Data from the physical function scale and the global health status/quality of life will 
be analyzed as a time to deterioration, which will be compared as secondary efficacy 
endpoints among treatment groups with use of the log rank test (2-sided). Deterioration 
will be defined as 1) a decrease of 10 points on a transformed 0 to 100 score from 
baseline on the physical function score or the global status/quality of life scores, or 
2) death, or 3) progression. The HR will be estimated using a stratified Cox proportional 
hazards model and its 95% CI will be provided. 
For each assessment timepoint and for each treatment arm, the mean (and 95% CI) and 
median (and inter-quartile ranges) of the absolute scores for the EORTC QLQ-C30 and 
additional items and their changes from baseline (Cycle 1 Day 1), will be calculated.  
Exploratory descriptive analyses will be conducted using post-treatment data.
6.6
SAFETY ANALYSES
Safety analyses will be performed on the safety population and will include all 
randomized patients who received at least one dose of study drug.  Summaries will be 
presented for the safety-evaluable population by treatment arm.  For safety analyses, 
patients will be grouped according to whether any amount of atezolizumab or 
cobimetinib was received, including when atezolizumab or cobimetinib was received in 
error. For example, if a patient assigned to Arm C received either cobimetinib or 
atezolizumab in error, this patient will be grouped to Arm A or Arm B, respectively. If a 
patient assigned to Arm A received atezolizumab but no cobimetinib at all, then this 
patient will be grouped to Arm B. 
Study drug exposure, including treatment duration, number of doses, and dose intensity, 
will be summarized for each treatment arm using descriptive statistics.
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to NCI CTCAE v4.0.  All adverse events that occur during or after the 
first study drug dose will be summarized by treatment arm and NCI CTCAE grade.  
In addition, serious adverse events, severe adverse events (Grade 3, 4, and 5), adverse 

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events of special interest, and adverse events leading to study drug discontinuation or 
interruption will be summarized accordingly.  Multiple occurrences of the same event will 
be counted once at the maximum severity.  The proportion of patients who experience at 
least one adverse event will be reported by toxicity term and treatment arm.
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment discontinuation will be summarized by treatment arm.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data and vitals will be summarized by treatment arm.
6.7
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2.  Cobimetinib and 
atezolizumab maximum and minimum concentration data (Cmin and Cmax, respectively) 
will be tabulated and summarized (mean, standard deviation, median, range, coefficient 
of variation [CV%], geometric mean and geometric mean coefficient of variation [CVb%]), 
as appropriate.
Additional PK and pharmacodynamic analyses will be conducted, as appropriate, based 
on the availability of data.
6.8
IMMUNOGENICITY ANALYSES
Patients are considered to have treatment-induced ATA responses if they are ATA 
negative at baseline and then develop an ATA response following study drug 
administration.  Patients are considered to have treatment-enhanced ATA responses if 
they are ATA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater (i.e., 0.60 titer units) than the titer of the baseline sample.  
Patients are considered to be negative for ATAs if they are ATA negative at all 
timepoints.  Patients are considered to be treatment unaffected if they are ATA positive 
at baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample.
The immunogenicity analyses will include patients with at least one predose and one 
postdose ATA assessment, with patients grouped according to treatment received
(safety population).
The number and proportion of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment group.  
Patients are considered to be ATA positive if they have treatment-induced ATA 
responses or treatment-enhanced ATA responses. Patients are considered to be ATA 
negative if they are ATA negative or unaffected by treatment.
The relationship between ATA status and safety, efficacy, and pharmacokinetics will be 
analyzed and reported descriptively via subgroup analyses.  

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ATA sampling timepoints are provided in Appendix 2.
6.9
EXPLORATORY BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events.  The blood and tumor biomarkers include but are not limited to NGS, PD-L1, and 
CD8, as defined by IHC, qRT-PCR, or other methods.  Additional pharmacodynamic 
analyses will be conducted as appropriate.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory and other nonEDC 
system-captured data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
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.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
An electronic device will be used to capture PRO data.  The data will be transmitted to a 
centralized database maintained by the electronic device vendor.

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Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification 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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.

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7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO 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. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union (E.U.) 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 sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.

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

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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
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 

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
114/Protocol GO30182, Version 5
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities. As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  Approximately 75 study centers 
will participate in this study globally and enroll a total of approximately 360 patients.  
The Sponsor will provide clinical operations oversight, data management support, and 
medical monitoring. 
An IxRS will be used to manage site drug supply and to randomize patients to study 
drug.  For patients not previously tested for tumor mutational status, testing will be 
performed at screening.  Plasma and serum will be sent to a central laboratory for 
analysis and sample storage.  Routine sample analysis will be performed by an 
accredited external vendor; local laboratory ranges will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://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 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.

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115/Protocol GO30182, Version 5
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
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10.
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Appendix 1
Schedule of Assessments
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (28-Day Cycle)
Screeninga
Cycle
1
Cycle 
2
Cycle
3 
Treatment 
Discontinuationb
ATA Visit
Survival 
FUc
Day
-35 to 1
1
15
1
15
1
15
30 d after last dose
120 d after last 
dose
q3m
Informed consentd
x
Demographics
x
Medical and CRC history
x
Vital signse,f
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
Weight 
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination
xg
x
x
Hematologyh
x
x
x
x
Coagulation (INR and aPTT)
x
PK sample for cobimetinib
See Appendix 2
PK and ATA sample for atezolizumab
See Appendix 2
x
Serum samples for auto antibody tests
x
Optional WGS
x
Chemistryi
x
x
x
x
CEA
x
x
x
x
ECHO/MUGA
x
x
xj

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
123/Protocol GO30182, Version 5
Tumor assessmentsk
x
Scans will be done every 8 weeks
Serologyl
x
Arm A:  Cobimetinib Plus Atezolizumab Schedule of Assessments (cont.)
Screeninga
Cycle
1
Cycle 
2
Cycle
3 
Treatment 
Discontinuationb
ATA Visit
Survival 
FUc
Day
-35 to 1
1
15
1
15
1
15
30 d after last dose
120 d after last 
dose
q3m
Thyroid function
x
x
x
xm
Ophthalmologic examn
x
x
xn
x
Pregnancy testo
x
x
x
x
Adverse events
xp
x
x
x
x
x
x
xq
x
Tumor biopsyr
x
x
x
Concomitant medications
x
x
x
x
x
EORTC 
QLQ-C30 
EQ-5D-5Ls
x
x
x
x
xs
Survival and anti-cancer therapy 
follow-up
x
Biomarker blood samples
x
x
x
x
Atezolizumab administrationt
x
x
x
x
x
x
Cobimetinib administrationu
x
x
x
ATAanti-therapeutic antibody; C3Cycle 3; C4Cycle 4; CEAcarcinoembryonic antigen; CRCcolorectal cancer; dday; 
ECHOechocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30European Organization for 
Research and Treatment of Cancer Quality of Life-C30 questionnaire; EQ-5D-5LEuroQoL 5 Dimensions; FU follow-up; MUGAmultigated 
acquisition scan; PKpharmacokinetic; q3m every 3 months; WGSwhole genome sequencing.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
124/Protocol GO30182, Version 5
a Results of standard of care tests or examinations performed prior to obtaining informed consent and within 35 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit.
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, withdrawal of consent, the 
patient is lost to follow-up, or study termination by the Sponsor, whichever occurs first.  
d Informed consent must be documented before and study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment.
e Includes respiratory rate, heart rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  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
f
Vital signs will be measured and recorded at the following timepoints:  within 60 minutes prior to infusion and during and after infusion if clinically 
indicated.
g If physical examinations are assessed within 7 days of the Cycle 1 Day 1 visit, they do not have to be repeated at Day 1.
h Hematology (CBC, hemoglobin, hematocrit, WBC count with differential [neutrophils, eosinophils, lymphocytes], and platelet count) 3 days. 
i   Serum chemistry (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, CPK, 
lipase, amylase [albumin and LDH at screening only]) 3 days.
j
All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA, screening. Evaluation of LVEF by ECHO or MUGA
must be performed at the following timepoints only for patients taking cobimetinib: 
Cycle 2, Day 1 1 week 

Day 1 of every three treatment cycles thereafter starting at cycle 5 2 weeks 

The treatment discontinuation visit evaluation of LVEF does not need to be performed at the treatment discontinuation visit if an evaluation 
has been performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline. 

All patients restarting treatment with a dose reduction of Cotellic because of a decrease in LVEF should have LVEF measurements taken 
after approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then resume monitoring LVEF every three treatment cycles.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
125/Protocol GO30182, Version 5
k Tumor assessments will continue until disease progression per RECIST v1.1, loss of clinical benefit (patients who continue treatment after 
disease progression according to RECIST v1.1), consent withdrawal, study termination by the Sponsor, or death, whichever occurs first.  
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until 
disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
l
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.

HBV serology will include HBsAg, antibodies against HBsAg, total HBcAg antibody (anti-HBcAb). HBV DNA should be obtained prior to 
randomization if patient has a negative serology for HBsAg and a positive serology for anti-HBcAb.  

HCV serology will include HCV antibody (anti-HCV). HCV RNA should be obtained prior to randomization if patient tests positive for 
anti-HCV
m Thyroid function testing (TSH, free T3, free T4) collected at Day 1 of every cycle thereafter for patients on atezolizumab only 3 days.
n   All patients will undergo ophthalmologic examination (see Section 4.5.9 for exam requirements) at screening. Ophthalmologic examination must 
be performed at the following timepoints only for patients taking cobimetinib:

Cycle 2 Day 1 1 week

Day 1 of Cycles 5, 8, and 11 (every three treatment cycles) 2 weeks

Day 1 of Cycles 15, 19, and 23 (every four treatment cycles) 2 weeks

On Day 1 of Cycles 29, 35, 41, 47, etc. (every six treatment cycles) 2 weeks

Treatment discontinuation visit. The treatment discontinuation visit evaluation does not need to be performed if an evaluation has been 
performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline.
o All women of childbearing potential will have a serum pregnancy test within 14 days before Cycle 1 Day 1. Urine pregnancy tests will be 
performed at specific subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Refer to 
Section 5.4.3 for details.
p Only serious adverse events caused by protocol-mandated intervention should be reported.
q All serious adverse events and Adverse Events of Special Interest, regardless of relationship to study drug, will be reported until 90 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After 
this period the investigator should report any serious adverse events or adverse events of special interest that are believed to be related to prior 
study drug.
r
Archival or fresh baseline tumor tissue collected during screening; Optional on treatment biopsy at Cycle 1 Day 155 days; Mandatory biopsy at 
progression if clinically feasible.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
126/Protocol GO30182, Version 5
s PRO instruments EORTC QLQ-C30 and EQ-5D-5L will be completed in this order using an electronic device on Day 1 of each cycle during a 
visit and prior to any assessments. Data will be collected at end of study and at survival follow-up at 3 and 6 months only.  In the event a study 
visit is conducted by telephone, the PRO data for that visit will be collected via telephone interview and recorded by the investigative staff on the 
ePRO tablet.  To maintain validity and minimize patient burden, the PRO instruments administered via telephone interview will consist of a 
reduced version of the EORTC QLQ items (Items 17, 10, 12, 13, 16, 17, 18, 29, and 30 from the C30 and the two additional items from the item 
bank) and the telephone interview version of the EQ-5D-5L.
t
The initial dose will be delivered over 60 (± 10) minutes.  If the first infusion is well tolerated all subsequent infusions will be delivered over 30 (± 
10) minutes until loss of clinical benefit.  Dose can be given7 days from scheduled Day 1 of each cycle.
u Cobimetinib 60 mg/day PO will be given in a 21/7 dosing schedule.  Dose can be given7 days from scheduled Day 1 of each cycle, but the 
scheduled 7 -day break must be5 days.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol GO30182, Version 5
Arm B:  Atezolizumab Monotherapy Schedule of Assessments (21-Day Cycle)
Screening a
Cycle 1
Cycle 2
Cycle 3 
Treatment Discb
ATA Visit
Survival FUc
Day
-35 to 1
1
15
1
1
30 d after last dose
120 d after last dose
q3m
Informed consentd
x
Demographics
x
Medical and CRC history
x
Vital signse,f
x
x
x
x
ECOG PS
x
x
x
x
Weight 
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examinationg
x
x
x
Hematologyh
x
x
x
x
Coagulation (INR and aPTT)
x
Serum sample for autoantibody tests
x
x
Chemistryi
x
x
x
x
CEA
x
x
x
x
WGS (optional)
x
PK and ATA sample
See Appendix 2
x
ECHO/MUGA
x
Tumor assessmentsj
x
Scan assessments every 8 weeks
Serologyk
x

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol GO30182, Version 5
Thyroid functionl
x
x
x
x
Ophthalmologic exam
x
Pregnancy testm
x 
x
x
x
Arm B:  Atezolizumab Monotherapy Schedule of Assessments (cont.)
Screeninga
Cycle1
Cycle 
2
Cycle 
3 
Treatment Discb
ATA Visit
Survival 
FUc
Day
-35 to 1
1
15
1
1
30 d after last 
dose
120 d after last 
dose
q3m
Adverse events
xn
x
x
x
x
x
xo
Tumor biopsyp
x
x
x
Concomitant medications
x
x
x
x
x
x
EORTC QLQ-C30 and EQ-5D-5Lq
x
x
x
x
xq
Survival and anti-cancer therapy 
follow-up
xr
Biomarker blood samples
x
x
x
x
Atezolizumab administrations
x
x
x
ATAanti-therapeutic antibody; C3Cycle 3; C4Cycle 4; CEAcarcinoembryonic antigen; CRCcolorectal cancer; dday; disc discontinuation; 
ECHOechocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30European Organization for 
Research and Treatment of Cancer Quality of Life-C30 questionnaire; EQ-5D-5LEuroQoL 5 Dimensions; FU follow-up; MUGAmultigated 
acquisition scan; PKpharmacokinetic; q3m every 3 months; WGSwhole genome sequencing.
a Results of standard of care tests or examinations performed prior to obtaining informed consent and within 35 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, withdrawal of consent, the 
patient is lost to follow-up, or study termination by the Sponsor, whichever occurs first.  .

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol GO30182, Version 5
d Informed consent must be documented before and study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment
e Includes respiratory rate, heart rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  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
f
Vital signs will be measured and recorded at the following timepoints: within 60 minutes prior to infusion and during and after infusion if clinically 
indicated.
g If physical examinations are assessed within 7 days of the Cycle 1 Day 1 visit, they do not have to be repeated at Day 1.
h Hematology (CBC, hemoglobin, hematocrit, WBC count with differential [neutrophils, eosinophils, lymphocytes], and platelet count) 3 days
i
Serum chemistry (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, LDH, 
CPK, lipase, amylase, [albumin and LDH at screening only])3 days.
j
Tumor assessments will continue until disease progression per RECIST v1.1, loss of clinical benefit (patients who continue treatment after 
disease progression according to RECIST v1.1), consent withdrawal, study termination by the Sponsor, or death, whichever occurs first.  
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until 
disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.
k   All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.
HBV serology will include HBsAg, antibodies against HBsAg, total HBcAg antibody (anti-HBcAb). HBV DNA should be obtained prior to 
randomization if patient has a negative serology for HBsAg and a positive serology for anti-HBcAb.  
HCV serology will include HCV antibody (anti-HCV). HCV RNA should be obtained prior to randomization if patient tests positive for anti-HCV
l
Thyroid function testing (TSH, free T3, free T4) collected at Day 1 of every cycle thereafter for patients on atezolizumab only3 days.
m All women of childbearing potential will have a serum pregnancy test within 14 days before Cycle 1 Day 1. Urine pregnancy tests will be 
performed at specific subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. Refer to 
Section 5.4.3 for details.
n Only serious adverse events caused by protocol-mandated intervention should be reported
o All serious adverse events and Adverse Events of Special Interest, regardless of relationship to study drug, will be reported until 90 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After 
this period the investigator should report any serious adverse events or adverse events of special interest that are believed to be related to prior 
study drug.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol GO30182, Version 5
p   Archival or fresh baseline tumor tissue collected during screening; Optional on treatment biopsy at Cycle 1 Day 155 days; Mandatory biopsy at 
progression if clinically feasible.
q PRO instruments EORTC QLQ-C30 and EQ-5D-5L will be completed in this order using an electronic device on Day 1 of each cycle during a 
visit and prior to any assessments. Data will be collected at end of study treatment and at survival follow-up at 3 and 6 months only.  In the event 
a study visit is conducted by telephone, the PRO data for that visit will be collected via telephone interview and recorded by the investigative staff 
on the ePRO tablet.  To maintain validity and minimize patient burden, the PRO instruments administered via telephone interview will consist of a 
reduced version of the EORTC QLQ (Items 17, 10, 12, 13, 16, 17, 18, 29, and 30 from the C30 and the two additional items from the item bank) 
and the telephone interview version of the EQ-5D-5L.
r
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until 
disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
s The initial dose will be delivered over 60 (± 10) minutes.  If the first infusion is well tolerated all subsequent infusions will be delivered over 30 (± 
10) minutes until loss of clinical benefit. Dose can be given7 days from Day 1.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol GO30182, Version 5
Arm C:  Regorafenib Schedule of Assessments
Screeninga
Cycle 1
Cycle 2
Cycle 3 
Treatment 
Discontinuationb
Survival FUc
Day
-35 to 1
1
8
15
22
1
8
15
1
30 d after last dose
q3m
Informed consentd
x
Demographics
x
Medical and CRC history
x
Vital signse,f
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
Weight 
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination
xg
x
x
Hematologyh
x
x
x
x
Coagulation (INR and aPTT)
x
Chemistryi
x
x
x
x
x
x
CEA
x
x
x
x
WGS (Optional)
x
ECHO/MUGA
x
Tumor assessments
x
Scan assessments every 8 weeksj
Serologyk
x
Thyroid function
x

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol GO30182, Version 5
Ophthalmologic exam
x
Pregnancy testl
x
x
x
x
Adverse events
xm
x
x
x
x
x
x
x
x
xn
x
Arm C:  Regorafenib Schedule of Assessments (cont.)
Screeninga
Cycle 1
Cycle 2
Cycle 3 
Treatment Discontinuationb
Survival FUc
Day
-35 to 1
1
8
15
22
1
8
15
1
30 d after last dose
q3m
Tumor biopsyo
x
x
x
Concomitant medications
x
x
x
x
x
EORTC QLQ-C30, EQ-5D-5Lp
x
x
x
x
x
Survival and anti-cancer therapy follow-up
xq
Biomarker blood samples
x
x
x
x
Regorafenib administrationr
x
x
x
ATAanti-therapeutic antibody; C3Cycle 3; C4Cycle 4; CEAcarcinoembryonic antigen; CRCcolorectal cancer; dday; 
ECHOechocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30European Organization for 
Research and Treatment of Cancer Quality of Life-C30 questionnaire; EQ-5D-5LEuroQoL 5 Dimensions; FU follow-up; MUGAmultigated 
acquisition scan; PKpharmacokinetic; q3m every 3 months; WGSwhole genome sequencing.
a Results of standard of care tests or examinations performed prior to obtaining informed consent and within 35 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening.
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, withdrawal of consent, the 
patient is lost to follow-up, or study termination by the Sponsor, whichever occurs first.  .

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol GO30182, Version 5
d Informed consent must be documented before and study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment
e Includes respiratory rate, heart rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  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
f
Monitor vital signs weekly for the first 6 weeks and then with every cycle, especially systolic and diastolic blood pressure.
g If physical examinations are assessed within 7 days of the Cycle 1 Day 1 visit, they do not have to be repeated at Day 1.
h Hematology (CBC, hemoglobin, hematocrit, WBC count with differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)
i
Serum chemistry (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, LDH, 
CPK, lipase, amylase, [albumin and LDH at screening only]).  LFTs are tested every 2 weeks for the first 2 months of treatment and then at every 
cycle thereafter.  All other labs are tested at the beginning of each cycle.
j
Tumor assessments will continue until disease progression per RECIST v1.1, loss of clinical benefit (patients who continue treatment after 
disease progression according to RECIST v1.1), consent withdrawal, study termination by the Sponsor, or death, whichever occurs first.  
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until 
disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
k All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.
HBV serology will include HBsAg, antibodies against HBsAg, total HBcAg antibody (anti-HBcAb). HBV DNA should be obtained prior to 
randomization if patient has a negative serology for HBsAg and a positive serology for anti-HBcAb.  
HCV serology will include HCV antibody (anti-HCV). HCV RNA should be obtained prior to randomization if patient tests positive for anti-HCV
l
All women of childbearing potential will have a serum pregnancy test within 14 days before Cycle 1 Day 1. Urine pregnancy tests will be 
performed at specific subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. Refer to 
Section 5.4.3 for details.
m Only serious adverse events caused by protocol-mandated intervention should be reported
n All serious adverse events and Adverse Events of Special Interest, regardless of relationship to study drug, will be reported until 90 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After
this period the investigator should report any serious adverse events or adverse events of special interest that are believed to be related to prior 
study drug.

Appendix 1
Schedule of Assessments (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GO30182, Version 5
o Archival or fresh baseline tumor tissue collected during screening; Optional on treatment biopsy at Cycle 1 Day 155 days; Mandatory biopsy at 
progression.
p PRO instruments EORTC QLQ-C30 and EQ-5D-5L will be completed in this order using an electronic device on Day 1 of each cycle during a 
visit and prior to any assessments. Data will be collected at end of study treatment and at survival follow-up at 3 and 6 months only.  In the event 
a study visit is conducted by telephone, the PRO data for that visit will be collected via telephone interview and recorded by the investigative staff 
on the ePRO tablet.  To maintain validity and minimize patient burden, the PRO instruments administered via telephone interview will consist of a 
subset of the EORTC QLQ items (Items 1-7, 10, 12, 13, 16, 17, 18, 29 and 30 from the C30 and the two additional items from the item bank) and 
the telephone interview version of the EQ-5D-5L.
q Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until 
disease progression, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
r
Regorafenib 160 mg/day PO will be given in a 21/7 dosing schedule. Dose can be given7 days from Day 1 but the scheduled 7-day break must 
be5 days.

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol GO30182, Version 5 
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
Visit
Timepoint
Sample Type 
Drug
aCycle 1 Day 15
aCycle 4 Day 15
Predose and 3 to 
6 hours after dose
Plasma PK
Cobimetinib
Day 1 of Cycles 1–4
Predose (prior to 
infusion)
Serum PK
Atezolizumab
Serum ATA
Atezolizumab
Day 1 of Cycles 1 and 
4
30 minutes (± 10) 
after infusion
Serum PK
Atezolizumab
Day 1 of Cycle 8 and 
every 8 cycles after 
Cycle 8
Predose (prior to 
infusion)
Serum PK
Atezolizumab
Serum ATA
Atezolizumab
Treatment 
discontinuation b
At visit
Serum PK
Atezolizumab
Serum ATA
Atezolizumab
120 days ± 30 days 
after treatment 
discontinuation b
At visit
Serum PK
Atezolizumab
Serum ATA
Atezolizumab
ATAanti-therapeutic antibody; PKpharmacokinetic.
a Arm A (cobimetinib with atezolizumab) only.
b These samples will be collected provided that the blood draws are clinically feasible and do not 
cause the patient undue hardship (e.g., the patient is in hospice care and not able to come in 
for a visit).

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GO30182, Version 5 
Appendix 3
Management of Cobimetinib plus AtezolizumabAssociated
Adverse Events (Arm A)
Note:  For information regarding management of atezolizumab-associated adverse 
events, including infusion-related reactions and immune-related events (e.g., endocrine, 
ocular, pancreatic, and neurologic events), please refer Appendix 9.
GASTROINTESTINAL TOXICITY
Diarrhea and colitis have been associated with the administration of cobimetinib plus 
atezolizumab.
Diarrhea 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 diarrhea.  Investigators 
should treat diarrhea and intervene promptly for patients who appear to be at increased 
risk of developing significant dehydration, electrolyte imbalances, and/or multi-organ 
failure.  Patients should receive maximum supportive care per institutional guidelines.
See Table 1 for guidelines on how to manage gastrointestinal toxicity in patients treated 
with cobimetinib plus atezolizumab.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GO30182, Version 5
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity
Event
Action to be Taken
Gastrointestinal
events:  general 
guidance
All events of diarrhea or colitis should be thoroughly evaluated for 
more common etiologies other than drug induced effects.
For events of significant duration or severity or associated with signs 
of systemic inflammation or acute phase reactants, check for immune-
related colitis. 
Administer anti-diarrheal agents and other maximal supportive care 
per institutional guidelines such as: at the first report of watery 
diarrhea or loose stool, initiate maximal anti-diarrheal supportive care 
(Lomotil and loperamide).
Suggested regimen: 
o
Loperamide: Initiate dose with 4 mg, then 4 mg/6 hr around the 
clock, alternating with Lomotil. 
o
Lomotil (diphenoxylate and atropine): 2 tablets (diphenoxylate 
5 mg, atropine 0.05 mg) every 6 hr around the clock 
o
Continue Lomotil and loperamide until no loose stools for 24 
hours. 
o
If Grade2 diarrhea persists after 48 hr 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 
diarrhea or vomiting. 
Dietary modifications: 
o
Stop all lactose-containing products and eat small meals. 
o
The BRAT (banana, rice, apples, toast) diet, without fiber (other 
vegetables and fruits), may be helpful. 
o
Encourage adequate hydration with salt-containing liquids, such 
as broth or Gatorade.
Diarrhea, Grade 1 or 
Grade 2 (tolerable))
Continue atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely
Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis if appropriate.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GO30182, Version 5
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity (cont.)
Event
Management
Diarrhea, Grade 2 
(intolerable) or 
Grade 3
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDS) 
while investigating etiology.
Investigate etiology, 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 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.
Diarrhea, Grade 4
Permanently discontinue atezolizumab and cobimetinib, and contact 
Medical Monitor. c
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDS) 
while investigating etiology.
Rule out bowel perforation.
Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis, including biopsy if appropriate.
Colitis, Grade 1
Continue atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely. 
Discontinue medications that may exacerbate colitis (e.g., NSAIDS).
Refer patient to gastrointestinal 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 gastrointestinal 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 dose reduced by one level.  If not, permanently
discontinue cobimetinib.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol GO30182, Version 5
Table 1
Guidelines for Managing Atezolizumab- and 
Cobimetinib-Associated Gastrointestinal Toxicity (cont.)
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 gastrointestinal 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 gastrointestinal 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; 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 agreed upon by the investigator and the 
Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol GO30182, Version 5
HEPATOTOXICITY
Hepatoxicity has been associated with the administration of atezolizumab and 
cobimetinib.  Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminase, and liver function will be 
monitored throughout study treatment. 
While in this study, patients presenting 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.
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies 
should be considered and addressed, as appropriate.  Imaging of the liver, gall bladder, 
and biliary tree should be performed to rule out neoplastic or other causes for the 
increased LFTs.  Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, 
anti-liver kidney microsomal antibodies, and anti-smooth muscle antibody tests should 
be considered.
Patients with LFT abnormalities should be managed according to the guidelines in 
Table 2.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol GO30182, Version 5
Table 2
Guidelines for Managing Atezolizumab and 
CobimetinibAssociated Hepatotoxicity
LFT Abnormalities
Management
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baseline values 
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 related 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baseline values 
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 related 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

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol GO30182, Version 5
Table 2
Guidelines for Managing Atezolizumab and 
CobimetinibAssociated Hepatotoxicity (cont.)
LFT Abnormalities
Management
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 or TNF-antagonist).
Monitor LFTs every 4872 hr until decreasing and then follow 
weekly.
Restart atezolizumab at fixed dose and cobimetinib at 1 dose 
reduction after discussion with medical monitor if 
AST/ALT 3ULN with bilirubin2ULN and steroid 
dose10 mg oral prednisone equivalent per day. a, b, c
Permanently discontinue atezolizumab and cobimetinib for 
life-threatening hepatic events, and contact the Medical 
Monitor.
AST/ALT 10ULN
Permanently discontinue atezolizumab and cobimetinib. c
Consult hepatologist and consider liver biopsy.
Consider administering 12 mg/kg/day oral prednisone or 
equivalent (for possible autoimmune hepatitis).  If event 
resolves to Grade 1 or better, taper corticosteroids over 1 
month.
If LFTs do not decrease within 48 hr after initiation of systemic 
steroids, addition of an alternative immunosuppressive agent 
(e.g., mycophenolate or TNF-antagonist) or dose escalation 
of corticosteroids may be considered.
Monitor LFTs every 4872 hours until decreasing and then 
follow weekly.
IVintravenous; LFT liver function test; q4wevery 4 weeks; TNFtumor necrosis factor; 
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 agreed upon by the investigator and the 
Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol GO30182, Version 5
DERMATOLOGIC TOXICITY
Treatment-emergent rash has been associated with atezolizumab and cobimetinib.  
The majority of the cases of rash were mild in severity and self-limited, with or without 
pruritus.
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.
Dermatologic toxicity and rash should be managed according to the guidelines in 
Table 3.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol GO30182, Version 5
Table 3
Guidelines for Managing Atezolizumab and Cobimetinib Rash
Dermatologic Toxicity/Rash 
(e.g., maculo-papular or 
purpura)
Management
Dermatologic event, 
Grade 1/2
Continue atezolizumab and cobimetinib.
Initiate supportive care (e.g., antihistamines, topical 
corticosteroids).
For Grade 2 rash, consider referral to dermatologist.
Acneiform rash:
Consider topical corticosteroids (hydrocortisone 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline, 
or antibiotics covering skin flora) BID for at least 4 weeks.
Dermatologic event, Grade 3
Withhold atezolizumab and cobimetinib.
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.
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. a,b
Permanently discontinue atezolizumab 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 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline 
or antibiotics covering skin flora) when restarting cobimetinib.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol GO30182, Version 5
Table 3
Guidelines for Managing Atezolizumab and Cobimetinib Rash (cont.)
Dermatologic Toxicity/Rash 
(e.g., maculo-papular or 
purpura)
Management
Dermatologic event, Grade 4
Permanently discontinue all study treatment and contact 
Medical Monitor.
BIDtwice daily; BSAbody surface area; PRNas needed.
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 agreed upon by the investigator and the Medical 
Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
PULMONARY TOXICITY
Mild-to-moderate events of pneumonitis have been reported with atezolizumab and 
cobimetinib.  All pulmonary events should be thoroughly evaluated for other commonly 
reported etiologies such as pneumonia/infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  
Pulmonary toxicity should be managed per the guidelines in Table 4.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol GO30182, Version 5
Table 4
Guidelines for Managing Atezolizumaband 
CobimetinibAssociated Pulmonary Toxicity
Pulmonary Toxicity
Management
General Guidance
Mild-to-moderate events of pneumonitis have been reported with 
atezolizumab and cobimetinib.  All pulmonary events should be 
thoroughly evaluated for other commonly reported etiologies such 
as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.
For events concerning for pneumonitis, Consider comprehensive 
infectious evaluation including viral etiologies.
Pneumonitis, Grade 1 
(asymptomatic)
Continue atezolizumab and cobimetinib.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
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 etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
Resume atezolizumab and cobimetinib if event resolves to Grade 1 
or better within 12 weeks. a, b
Permanently discontinue atezolizumab and contact Medical 
Monitor if event does not resolve to Grade 1 or better within 
12 weeks. a, b, c
For recurrent events, treat as a Grade 3 or 4 event.

Appendix 3Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (ArmA)(cont.)
Table4
Guidelines for Managing Atezolizumaband 
CobimetinibAssociated Pulmonary Toxicity(cont.)
Pulmonary Toxicity
Management
Pneumonitis, Grade 3/4
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-related etiology, initiate 
treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
If pulmonary event does not improve within 48 hr or worsens, 
consider adding an immunosuppressive agent (e.g.,infliximab, 
cyclophosphamide, IV Ig, or mycophenolate mofetil).
If event resolves to Grade 1 or better, taper corticosteroids 
over1month.
IV intravenous; GGO ground glass opacity.
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 agreed upon by the investigator and the Medical Monitor.
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.
POTENTIAL EYE TOXICITY
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 disease 
that is unresponsive to local immunosuppressive therapy.
Atezolizumabassociated ocular toxicity should be managed according to the guidelines 
in Table 5. 
Serous retinopathy is associated with cobimetinib. In clinical trials, most events were 
Grade 1 (asymptomatic) or 2 (symptomatic).  Most events in clinical trials resolved or 
improved to asymptomatic grade 1 following dose interruption or
 reduction.  If serous 
retinopathy is diagnosed, cobimetinib should be withheld until visual symptoms improve 
to Grade ≤1.   Serous retinopathy can be managed with treatment interruption, dose 
reduction or with treatment discontinuation.
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol GO30182, Version 5

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol GO30182, Version 5
Retinal vein occlusion (RVO) has been reported in patients treated with MEK inhibitors 
other than cobimetinib.
Cobimetinibassociated ocular toxicity should be managed according to the guidelines in 
Table 6.
Table 5
Guidelines for Managing AtezolizumabAssociated Ocular 
Toxicity (ImmuneMediated Ocular Disease)
Description
Management
Potential immune-related 
ocular toxicity 
(e.g., uveitis, iritis, 
episcleritis, or retinal 
events)
Follow guidelines provided in the Appendix 9.
Continue cobimetinib as clinically indicated.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol GO30182, Version 5
Table 6
Guidelines for Managing Cobimetinib-Associated Serous 
Retinopathy and Retinal Vein Occlusion
Description
Management
Serous retinopathy
Severity grade 
assessment based on 
NCI CTCAE v4 “Eye 
Disorders – Other” 
scale a-d
Serous retinopathy, Grade 1 a or 2 b (tolerable): 
Continue cobimetinib and atezolizumab without dose change.
Continue ophthalmology follow-up as clinically indicated.
Serous retinopathy, Grade 2 b (intolerable) or 3/4 c/d:
Interrupt cobimetinib until Grade1. 
Continue atezolizumab as clinically indicated.
Consult ophthalmology and undergo complete ophthalmologic 
examination, which includes visual acuity testing, intra-ocular 
pressure measurements, slit lamp ophthalmoscopy, indirect 
ophthalmoscopy, visual field, and OCT.  Consider a fluorescein 
angiogram and/or indocyanine green angiogram, if clinically 
indicated.
Cobimetinib should be dose reduced by 1 dose level when 
restarting.
Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite 2 dose level reductions
Retinal vein occlusion
Any grade
If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines.
Continue atezolizumab.
ADLactivities of daily living; NCI CTCAENational Cancer Institute Common Terminology 
Criteria for Adverse Events; RVO retinal vein occlusion; OCT optical coherence 
tomography.
a Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
b Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL.
c Grade 3: Severe or medically significant but not immediately sight threatening; 
hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-
care ADL.
d Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 
or worse) in the affected eye.
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
DECREASED LEFT VENTRICULAR EJECTION FRACTION  
Decreased left ventricular ejection fraction (LVEF) has been seen with cobimetinib (see 
Section 5.1.1.1). Refer to Table 7 for guidelines for management of LVEF.  Permanent 
discontinuation of cobimetinib treatment should be considered if cardiac symptoms are 
attributed to cobimetinib and do not improve after temporary interruption.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol GO30182, Version 5
Table 7
Recommended Dose Modifications for Cobimetinib in Patients 
with 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 BL)
Continue at 
current dose
N/A
N/A
40% (or 
40%49% 
and10% 
absolute 
decrease 
from BL)
Interrupt 
treatment for 
2 weeks
Continue 
atezolizumab as 
clinically 
indicated
10% 
absolute 
decrease from 
BL
First occurrence: 40 mg
Second occurrence: 20 mg
Third occurrence:
permanent discontinuation
40%
(or10% 
absolute 
decrease from 
BL)
Permanent discontinuation
Symptomatic
N/A
Interrupt 
treatment for 
4 weeks.
Consider 
withholding 
atezolizumab
Discuss with 
Medical Monitor 
regarding 
resumption of 
atezolizumab. 
Cardiology 
consultation is 
strongly 
recommended.
Asymptomatic 
and10% 
absolute 
decrease from 
BL
First occurrence: 40 mg
Second occurrence: 20 mg
Third occurrence:
permanent discontinuation
Asymptomatic 
and40% 
(or10% 
absolute 
decrease from 
BL)
Permanent discontinuation
Symptomatic 
regardless of 
LVEF
Permanent discontinuation
BLbaseline; LVEFleft ventricular ejection fraction; N/Anot applicable.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol GO30182, Version 5
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
ELEVATED CPK AND RHABDOMYOLYSIS
Elevated CPK has been reported with cobimetinib (see Section 5.1.1.2).  See Table 8 for 
guidelines for management of elevated CPK and rhabdomyolysis.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol GO30182, Version 5
Table 8
Recommended Dose Modifications for Cobimetinib and 
Atezolizumab in Patients with CPK Elevations and 
Rhabdomyolysis
Description
Management
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 IM injections.
Asymptomatic CPK 
elevations Grade 13
Cobimetinib dosing and atezolizumab do not need to be modified or 
interrupted to manage asymptomatic Grade3 CPK elevations
Asymptomatic CPK 
elevations Grade 4
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.a,b,c
Rhabdomyolysis or 
symptomatic CPK 
elevations
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.a,b,c
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 agreed upon by the investigator and the 
Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol GO30182, Version 5
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
HEMORRHAGE
Hemorrhage has been reported with cobimetinib (see Section 5.1.1.2).  See Table 9.
Table 9
Recommended Dose Modifications for Cobimetinib in Patients
with Hemorrhage
Hemorrhage
Grade 3 events
Interrupt cobimetinib treatment. There are no data on the 
effectiveness of cobimetinib dose modification for hemorrhage 
events. Clinical judgment should be applied when considering 
restarting Cobimetinib treatment.
Continue atezolizumab treatment.
Grade 4 hemorrhage or any 
grade cerebral hemorrhage
Interrupt cobimetinib treatment. Permanently discontinue 
cobimetinib for hemorrhage events attributed to cobimetinib.
Continue atezolizumab treatment.
SYSTEMIC IMMUNE ACTIVATION
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.
Recommendations regarding early identification and management of systemic immune 
activation are provided below.  In the event of suspected systemic immune activation, 
atezolizumab should be withheld and the Medical Monitor should be contacted 
immediately for additional guidance.
Early disease recognition is critical, and systemic immune activation should be 
suspected if, in the absence of an alternative etiology, the patient meets two or more of 
the following criteria:

Hypotension that is refractory to aggressive IV fluid challenge
Vasopressor support may be required.

Respiratory distress that requires aggressive supportive care
Supplemental oxygen and intubation may be required.

Fever 38.5C

Acute renal or hepatic failure

Bleeding from coagulopathy

Appendix 3 Management of Cobimetinib plus AtezolizumabAssociated 
Adverse Events (Arm A) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol GO30182, Version 5

Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, and coagulopathy
For patients with suspected systemic immune activation, an initial evaluation should 
include the following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
Laboratory tests with normal results should be repeated frequently in patients for whom 
a high clinical suspicion of systemic immune activation exists.
If cytopenias are present (Grade 2 in two or more lineages) or ferritin is 3000 ng/mL, 
the following evaluations should also be performed:  

Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis)

Soluble interleukin 2 (IL-2) receptor (sCD25)

Natural killer cell activity

Cytomegalovirus, Epstein-Barr virus, and herpes-simplex virus evaluation (for 
reactivated or active disease)

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol GO30182, Version 5 
Appendix 4
Anaphylaxis Precautions
PRECAUTIONS
Equipment needed:

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous (IV), and/or endotracheal use in 
accordance with standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the 
following procedures should be performed:
1.
Stop the drug infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of 
study drug.  Do not obstruct arterial flow in the limb.
3.
Maintain adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by physician in charge.
5.
Continue to observed the patient and document observations.

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol GO30182, Version 5
Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:
Measurable Tumor 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 of: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 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 no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Nontarget Lesions” for information on lymph node 
measurement.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with 10 to 15 mm short axis), 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 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 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.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication (cont.)
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure 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 
noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of 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.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
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, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to 
whether a noncontrast 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 noncontrast CT or MRI (enhanced or nonenhanced) 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 on a different modality 
and interpretation of nontarget disease or new lesions since the same lesion may appear 
to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NONTARGET 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 in instances where 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 
recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, 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.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, 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 nontarget lesions.  Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple nontarget 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”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
Special Notes on the Assessment of Target Lesions
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 nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While in the study, all lesions 
(nodal and non-nodal) that are recorded at baseline should be recorded as actual 
measurements 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 the CT scan that the radiologist may not feel comfortable 
assigning an exact measure 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 below measurable limit (BML) 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 BML should also be ticked.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  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 maximal 
longest diameter for the coalesced lesion.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  While some nontarget lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all nontarget 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 nontarget lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing nontarget lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Nontarget Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the nontarget disease, there must be an overall 
level of substantial worsening in nontarget disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget 
disease in the face of SD or PR of target disease will therefore be extremely rare.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in
some Phase III studies when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here as noted above; however, in this 
instance, there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden.  Because worsening in nontarget 
disease cannot be easily quantified (by definition:  if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression is 
to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required 
to declare PD for measurable disease, that is, an increase in tumor burden representing 
an additional 73% increase in volume (which is equivalent to a 20% increase in diameter 
in a measurable lesion).  Examples include an increase in a pleural effusion from “trace” 
to “large” or an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  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, then progression should be declared using the date of 
the initial scan.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore nontarget) disease only, Table 2 is to be 
used.
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Nontarget Lesions)
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not 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.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
Table 2
Timepoint Response:  Patients with Nontarget Lesions Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for nontarget 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
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 only a subset of lesion measurements are made at an 
assessment, 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 lesion(s) 
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. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more nontarget lesions are not assessed, the response for 
nontarget lesions should be “unable to assess” except where there is clear progression.  
Overall response would be “unable to assess” if either the target response or the 
nontarget response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
PR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.

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Appendix 5
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)
Patients with a global deterioration of 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 nontarget disease as shown in Tables Table 1, Table 2, and Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or nontarget 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or nontarget lesion.

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

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Appendix 7
EuroQoL 5 Dimensions Health Questionnaire
EQ-5D-5L Health Questionnaire
English version for the USA

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170/Protocol GO30182, Version 5
Appendix 7
EuroQoL 5 Dimensions Health Questionnaire (cont.)
Under each heading, please check the ONE box that best describes your health 
TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family 
or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort


Appendix 7
EuroQoL 5 Dimensions Health Questionnaire (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol GO30182, Version 5
ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed


Appendix 7
EuroQoL 5 Dimensions Health Questionnaire (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol GO30182, Version 5 
The worst health 
you can imagine

We would like to know how good or bad your health is 
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is 
TODAY.

Now, please write the number you marked on the scale in the 
box above.
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95

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Appendix 8
European Organisation for Research and Treatment of Cancer 
30-Item Quality of Life Questionnaire (Version 3)
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential.
Not at
A
Quite
Very
All
Little
a Bit
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4 
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
6.
Were you limited in doing either your work or other daily activities? 1
2
3
4
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4

Appendix 8 European Organisation for Research and Treatment of Cancer 
30-Item Quality of Life Questionnaire (Version 3) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol GO30182, Version 5
Please go on to the next page
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent

Appendix 8 European Organisation for Research and Treatment of Cancer 
30-Item Quality of Life Questionnaire (Version 3) (cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol GO30182, Version 5
Additional items
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
.
Did you have abdominal pain?
1
2
3
4
Did you have a bloated feeling in your abdomen?
1
2
3
4

Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol GO30182, Version 5 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-related 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-related 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-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.  If atezolizumab is 
withheld for 105 days after event onset, the patient will be discontinued from 
atezolizumab.  However, atezolizumab may be withheld for 105 days to allow for 
patients to taper off corticosteroids prior to resuming treatment.  Atezolizumab can be 
resumed after being withheld for 105 days if the Medical Monitor agrees that the 
patient is likely to derive clinical benefit.  Atezolizumab treatment may be suspended 
for reasons other than toxicity (e.g., surgical procedures) with Medical Monitor 
approval.  The investigator and the Medical Monitor will determine the acceptable 
length of treatment interruption.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol GO30182, Version 5
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.  Management guidelines for pulmonary events are provided 
in Table 1.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol GO30182, Version 5
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL bronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol GO30182, Version 5
HEPATIC EVENTS
Immune-related hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored 
throughout study treatment.  Management guidelines for hepatic events are provided in 
Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
LFT liver function tests.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol GO30182, Version 5
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
LFT liver function tests.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-related colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol GO30182, Version 5
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol GO30182, Version 5
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist for evaluation and confirmation 
biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) 
and magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol GO30182, Version 5
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 weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-related 
hyperthyroidism. c
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol GO30182, Version 5
Table 4 Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol GO30182, Version 5
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol GO30182, Version 5
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol GO30182, Version 5
IMMUNE-RELATED MYOCARDITIS
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or 
syncope.  Immune-related myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g., in a patient who reports a recent history 
of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol GO30182, Version 5
Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.a

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-related 
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a,b

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
ECMO extracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol GO30182, Version 5
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  
For subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be increased 
to the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRR infusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol GO30182, Version 5
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.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider 
treatment with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset.
a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol GO30182, Version 5
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset.
a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c
Immune-related 
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol GO30182, Version 5
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases 
of rash were mild in severity and self limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  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.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids 
if event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

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
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol GO30182, Version 5
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 etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-related 
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Immune-related 
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 

Appendix 9:  Risks Associated with Atezolizumab and Guidelines 
for Management of Adverse Events Associated with Atezolizumab 
(cont.)
Cobimetinib plus Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol GO30182, Version 5
IMMUNE-RELATED MENINGOENCEPHALITIS
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-related 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 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, 
or edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Related 
Meningoencephalitis
Event
Management
Immune-related 
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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.