A Phase Ib Study Evaluating Cobimetinib Plus Atezolizumab in Patients With Advanced BRAF V600 Wild-Type Melanoma Who Have Progressed During or After Treatment With Anti-PD-1 Therapy and Atezolizumab Monotherapy in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
Phase: PHASE1
Conditions: Malignant Melanoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
A Phase Ib Study Evaluating Cobimetinib Plus Atezolizumab in 
Patients With Advanced BRAF V600 Wild-Type Melanoma Who Have 
Progressed During or After Treatment With Anti−PD-1 Therapy and 
Atezolizumab Monotherapy in Patients With Previously Untreated 
Advanced BRAF V600 Wild-Type Melanoma  
NCT Number: 
NCT03178851 
Document Date: 
Protocol Version 5: 26-October-2018 
 
 
 

PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Cobimetinib and Atezolizumab —F. Hoffmann-La Roche Ltd 
Protocol CO39721, Version 5 
PROTOCOL 
TITLE: 
A PHASE IB STUDY EVALUATING COBIMETINIB
PLUS ATEZOLIZUMAB IN PATIENTS WITH
ADVANCED BRAFV600 WILD-TYPE MELANOMA
WHO HAVE PROGRESSED DURING OR AFTER
TREATMENT WITH ANTI−PD-1 THERAPY AND
ATEZOLIZUMAB MONOTHERAPY IN PATIENTS
WITH PREVIOUSLY UNTREATED ADVANCED
BRAFV600 WILD-TYPE MELANOMA 
PROTOCOL NUMBER: CO39721 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2016-004402-34 
IND NUMBER: 
135,717 
TEST PRODUCTS: 
Cobimetinib (RO5514041) 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
14 December 2016 
DATES AMENDED: 
Version 2:  23 June 2017 
Version 3:  19 September 2017 
Version 4:  3 February 2018 
Version 5:  See electronic date stamp below. 
 
26-Oct-2018 10:19:14
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol CO39721, Version 5 
PROTOCOL AMENDMENT, VERSION 5 
RATIONALE  
Protocol CO39721 has been amended primarily to update the primary analysis timelines 
and to align with current atezolizumab risk language.  
•
The primary analysis will be conducted in Cohorts A and B approximately 24 weeks
after the last patient is enrolled in Cohort A.  At this time, Cohorts A and B will have
a minimum follow up of approximately 24 weeks.  The primary analysis for Cohort C
may be analysed independently, with a minimum of 24 weeks follow up for patients
in Cohort C (Section 6).
•
The list of risks associated with atezolizumab has been revised to align with current
atezolizumab risk language (Section 5.1.2).
•
Guidelines for managing patients who experience atezolizumab-associated adverse
events have been revised to include nephritis (Appendix 8).
Additional changes to the protocol are summarized below: 
•
Independent review committee (IRC)-assessed objective response rate (ORR),
duration of response (DOR), disease control rate (DCR), and progression-free
survival (PFS) have been added as secondary efficacy endpoints for Cohort C
(Table 1 in Section 2 and Sections 3.1 and 6.4.2).
•
Text has been added to clarify that the patient numbers for each cohort are
approximate (Sections 3.1, 3.3.2.2, and 6.1).
•
The inclusion criterion that addresses female contraception has been modified to
specify when women must refrain from donating eggs (Section 4.1.1.4).
•
The exclusion criterion related to treatment with immunosuppressive medication for
patients who have received acute, low-dose systemic immunosuppressant
medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of
systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a
contrast allergy) has been revised, specifying that such patients are eligible for the
study after Medical Monitor approval has been obtained (Section 4.1.2.6).
•
Denosumab has been removed from the list of prohibited therapies (Section 4.3.2).
•
Text stating that ophthalmologic examinations should be performed prior to dosing
has been added, and the frequency of the examinations has been clarified (Table 3
in Section 4.4.7).
•
Text stating recurrent Grade 1 pneumonitis should be treated as a Grade 3 or 4
event has been removed (Table 6 in Section 5.1.3.3).
•
The Medical Monitor has been changed and updated contact information has been
provided (Section 5.4.1).
•
Language has been added for consistency with Roche's current data retention
policy and to accommodate more stringent local requirements (if applicable)
(Section 7.5).

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol CO39721, Version 5 
 
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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol CO39721, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. BACKGROUND ........................................................................................... 26 
1.1  
Background on Melanoma ..................................................... 26 
1.1.1  
Incidence and Pathogenesis .................................................. 26 
1.1.2  
Treatment Options for Melanoma .......................................... 26 
1.2  
Background on the Study Treatments ................................... 28 
1.2.1  
Cobimetinib ............................................................................ 28 
1.2.2  
Atezolizumab ......................................................................... 28 
1.3  
Study Rationale and Benefit-Risk Assessment ...................... 29 
1.3.1  
Rationale for Combining Cobimetinib and 
Atezolizumab for Advanced BRAFV600 Wild-Type 
Melanoma after Progression on Anti-PD-1 
Therapy ................................................................................. 29 
1.3.1.1 
Rationale for Atezolizumab Monotherapy for 
Previously Untreated Patients with Advanced 
BRAFV600-Wild-Type Melanoma ............................................ 29 
1.3.2  
Activity of Atezolizumab in Advanced Melanoma .................. 30 
1.3.2.1 
Study PCD4989g:  Atezolizumab Monotherapy ..................... 30 
1.3.3  
Activity of MEK Inhibitors in BRAFV600 Wild-Type 
Melanoma .............................................................................. 31 
1.3.4  
Effect of MAPK Inhibition on Tumor-Immune 
Contexture ............................................................................. 31 
1.3.5  
Clinical Data for Combination Treatment with 
Cobimetinib and Atezolizumab in Advanced 
Melanoma .............................................................................. 32 
1.3.5.1 
Study GP28363 ..................................................................... 32 
1.3.6  
Risk-Benefit Statement .......................................................... 36 
2. OBJECTIVES AND ENDPOINTS ................................................................ 36 
3. STUDY DESIGN .......................................................................................... 39 
3.1  
Description of the Study......................................................... 39 
3.1.1  
Biopsies and Archival Tissue ................................................. 42 
3.1.1.1 
Optional Biopsies (Cohort A) ................................................. 43 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol CO39721, Version 5 
3.1.1.2 
Mandatory Biopsies (Cohort B) .............................................. 43 
3.1.1.3 
Optional Biopsies (Cohort C) ................................................. 44 
3.1.2  
Dosing of Study Treatment beyond Disease 
Progression ........................................................................... 44 
3.2  
End of Study and Length of Study ......................................... 45 
3.3  
Rationale for Study Design .................................................... 45 
3.3.1  
Rationale for Cobimetinib plus Atezolizumab 
Dose and Schedule ............................................................... 45 
3.3.1.1 
Cohort A (Cobimetinib plus Atezolizumab with 
Concurrent Start) ................................................................... 45 
3.3.1.2 
Cohort B (Biopsy Cohort) ....................................................... 46 
3.3.1.3 
Cohort C (Atezolizumab Monotherapy Cohort) ...................... 46 
3.3.2  
Rationale for Patient Population and Cohorts ........................ 46 
3.3.2.1 
Cohort A (Cobimetinib plus Atezolizumab with 
Concurrent Start) ................................................................... 46 
3.3.2.2 
Cohort B (Biopsy Cohort) ....................................................... 46 
3.3.2.3 
Cohort C (Atezolizumab Monotherapy).................................. 47 
3.3.3  
Rationale for Primary Endpoint Selection .............................. 47 
3.3.4  
Rationale for Confirmation of Progressive 
Disease per RECIST v1.1 ...................................................... 48 
3.3.5  
Rationale for Biomarker Assessments ................................... 49 
3.3.6  
Rationale for Blood Sampling for Biomarker 
Assessments ......................................................................... 49 
3.3.7  
Rationale for Ophthalmologic Assessments 
(Cohorts A and B) .................................................................. 49 
3.3.7.1 
Rationale for Optional Whole Genome 
Sequencing ............................................................................ 50 
3.3.8  
Rationale for Pharmacokinetic Assessments ......................... 51 
4. MATERIALS AND METHODS ..................................................................... 51 
4.1  
Patients .................................................................................. 51 
4.1.1  
Inclusion Criteria .................................................................... 52 
4.1.1.1 
Disease-Specific Inclusion Criteria: Cohorts A 
and B ..................................................................................... 52 
4.1.1.2 
Additional Disease-Specific Inclusion Criteria in 
Cohort B (Biopsy Cohort) ....................................................... 52 
4.1.1.3 
Disease-Specific Inclusion Criteria:  Cohort C ....................... 52 

 
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6/Protocol CO39721, Version 5 
4.1.1.4 
General Inclusion Criteria ...................................................... 53 
4.1.2  
Exclusion Criteria ................................................................... 55 
4.1.2.1 
Cancer-Related Exclusion Criteria ......................................... 55 
4.1.2.2 
Ocular Exclusion Criteria (Cohorts A and B) .......................... 56 
4.1.2.3 
Cardiac Exclusion Criteria (Cohorts A and B) ........................ 56 
4.1.2.4 
Central Nervous System Exclusion Criteria ........................... 56 
4.1.2.5 
Exclusions Related to Infections ............................................ 57 
4.1.2.6 
Exclusion Criteria Related to Autoimmune 
Conditions and Immunomodulatory Drugs............................. 57 
4.1.2.7 
Additional Exclusion Criteria .................................................. 58 
4.2  
Study Treatment .................................................................... 59 
4.2.1  
Formulation, Packaging, and Handling .................................. 59 
4.2.1.1 
Cobimetinib ............................................................................ 59 
4.2.1.2 
Atezolizumab ......................................................................... 59 
4.2.2  
Dosage, Administration, and Compliance .............................. 60 
4.2.2.1 
Cobimetinib ............................................................................ 60 
4.2.2.2 
Atezolizumab ......................................................................... 60 
4.2.3  
Investigational Medicinal Product Accountability ................... 62 
4.2.4  
Post-Trial Access to Cobimetinib and 
Atezolizumab ......................................................................... 62 
4.3  
Concomitant Therapy ............................................................ 63 
4.3.1  
Permitted Therapy ................................................................. 63 
4.3.2  
Prohibited Therapy ................................................................ 64 
4.3.3  
Cautionary Therapy for Atezolizumab-Treated 
Patients .................................................................................. 65 
4.3.3.1 
Corticosteroids and Tumor Necrosis Factor-α 
Inhibitors ................................................................................ 65 
4.4  
Study Assessments ............................................................... 65 
4.4.1  
Informed Consent Forms and Screening Log ........................ 66 
4.4.2  
Medical History and Demographic Data ................................ 66 
4.4.3  
Physical Examinations ........................................................... 66 
4.4.4  
Vital Signs .............................................................................. 67 
4.4.5  
Tumor and Response Evaluations ......................................... 67 
4.4.6  
Left Ventricular Ejection Fraction ........................................... 68 

 
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4.4.7  
Ophthalmologic Examination (Cohorts A and B) ................... 69 
4.5  
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 70 
4.5.1  
Patient Discontinuation .......................................................... 70 
4.5.2  
Laboratory, Biomarker, and Other Biologic 
Samples ................................................................................. 71 
4.5.2.1 
Local Laboratory Assessments .............................................. 71 
4.5.2.2 
Central Laboratory Assessments ........................................... 72 
4.5.3  
Study Treatment Discontinuation ........................................... 75 
4.5.4  
Study and Site Discontinuation .............................................. 76 
5. ASSESSMENT OF SAFETY ........................................................................ 76 
5.1  
Safety Plan ............................................................................ 76 
5.1.1  
Risks Associated with Cobimetinib ........................................ 77 
5.1.1.1 
Important Identified Risks Associated with 
Cobimetinib ............................................................................ 77 
5.1.1.2 
Potential Risks Associated with Cobimetinib ......................... 79 
5.1.1.3 
Other Risks with Cobimetinib ................................................. 80 
5.1.2  
Risks Associated with Atezolizumab ..................................... 82 
5.1.3  
Management of Patients Who Experience 
Specific Adverse Events ........................................................ 82 
5.1.3.1 
Cobimetinib Dose Modifications ............................................ 82 
5.1.3.2 
Atezolizumab Dose Modifications .......................................... 83 
5.1.3.3 
Management of Cobimetinib- and 
Atezolizumab-Specific Adverse Events ................................. 83 
5.2  
Safety Parameters and Definitions ........................................ 97 
5.2.1  
Adverse Events ..................................................................... 97 
5.2.2  
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 98 
5.2.3  
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 99 
5.3  
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 100 
5.3.1  
Adverse Event Reporting Period ......................................... 100 
5.3.2  
Eliciting Adverse Event Information ..................................... 100 
5.3.3  
Assessment of Severity of Adverse Events ......................... 101 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Protocol CO39721, Version 5 
5.3.4  
Assessment of Causality of Adverse Events ....................... 101 
5.3.5  
Procedures for Recording Adverse Events .......................... 102 
5.3.5.1 
Infusion-Related Reactions .................................................. 102 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 102 
5.3.5.3 
Adverse Events That are Secondary to Other 
Events.................................................................................. 102 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 103 
5.3.5.5 
Abnormal Laboratory Values ............................................... 103 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 104 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 105 
5.3.5.8 
Deaths ................................................................................. 105 
5.3.5.9 
Preexisting Medical Conditions ............................................ 105 
5.3.5.10 
Lack of Efficacy or Worsening of Melanoma ........................ 106 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 106 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 106 
5.4  
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 107 
5.4.1  
Emergency Medical Contacts .............................................. 108 
5.4.2  
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 108 
5.4.2.1 
Events That Occur before Study Drug Initiation ................... 108 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 108 
5.4.3  
Reporting Requirements for Pregnancies ............................ 109 
5.4.3.1 
Pregnancies in Female Patients .......................................... 109 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 109 
5.4.3.3 
Abortions ............................................................................. 109 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 110 
5.5  
Follow-Up of Patients after Adverse Events ........................ 110 
5.5.1  
Investigator Follow-Up ......................................................... 110 
5.5.2  
Sponsor Follow-Up .............................................................. 110 
5.6  
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 110 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
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5.7  
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 110 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...................... 111 
6.1  
Determination of Sample Size ............................................. 111 
6.2  
Summaries of Conduct of Study .......................................... 112 
6.3  
Summaries of Demographic and Baseline 
Characteristics ..................................................................... 112 
6.4  
Efficacy Analyses ................................................................ 112 
6.4.1  
Primary Efficacy Endpoint .................................................... 112 
6.4.2  
Secondary Efficacy Endpoints ............................................. 112 
6.4.3  
Exploratory Efficacy Endpoints ............................................ 113 
6.5  
Safety Analyses ................................................................... 113 
6.6  
Pharmacokinetic Analyses ................................................... 113 
6.7  
Immunogenicity Analyses .................................................... 114 
6.8  
Biomarker Analyses ............................................................. 114 
6.9  
Optional interim Analyses .................................................... 114 
7. DATA COLLECTION AND MANAGEMENT .............................................. 115 
7.1  
Data Quality Assurance ....................................................... 115 
7.2  
Electronic Case Report Forms ............................................. 115 
7.3  
Source Data Documentation ................................................ 115 
7.4  
Use of Computerized Systems ............................................ 116 
7.5  
Retention of Records ........................................................... 116 
8. ETHICAL CONSIDERATIONS ................................................................... 117 
8.1  
Compliance with Laws and Regulations .............................. 117 
8.2  
Informed Consent ................................................................ 117 
8.3  
Institutional Review Board or Ethics Committee .................. 118 
8.4  
Confidentiality ...................................................................... 118 
8.5  
Financial Disclosure ............................................................ 119 
9. STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119 
9.1  
Study Documentation .......................................................... 119 
9.2  
Protocol Deviations .............................................................. 119 

 
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10/Protocol CO39721, Version 5 
9.3  
Site Inspections ................................................................... 120 
9.4  
Administrative Structure....................................................... 120 
9.5  
Publication of Data and Protection of Trade 
Secrets ................................................................................ 120 
9.6  
Protocol Amendments ......................................................... 121 
10. REFERENCES ......................................................................................... 122 
 
LIST OF TABLES 
Table 1  
Objectives and Corresponding Endpoints ................................... 37 
Table 2  
Administration of First and Subsequent Infusions of 
Atezolizumab .............................................................................. 61 
Table 3  
Ophthalmologic Examination Schedule ...................................... 69 
Table 4  
Proposed Biomarkers for Exploratory Research ......................... 74 
Table 5  
Recommended Cobimetinib Dose Modifications ......................... 83 
Table 6  
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) .......... 84 
Table 7  
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 101 
 
 
LIST OF FIGURES 
Figure 1  
Phase I Study of Atezolizumab Monotherapy in Cutaneous 
Melanoma ................................................................................... 30 
Figure 2  
Tumor Burden Over Time by Investigator-Confirmed 
Response per RECIST v1.1 in All Melanoma Patients:  Study 
GP28363 ..................................................................................... 33 
Figure 3  
Tumor Burden Over Time by Investigator-Confirmed 
Response per RECIST v1.1 in Patients with BRAFV600-Wild-
Type Melanoma: Study GP28363 ............................................... 34 
Figure 4  
Study Schema ............................................................................. 40 
Figure 5  
Treatment and Biopsy Schedule (Cohort A)................................ 40 
Figure 6  
Treatment and Biopsy Schedule (Cohort B)................................ 41 
Figure 7  
Treatment and Biopsy Schedule (Cohort C) ............................... 41 
 
 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol CO39721, Version 5 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Activities ................................................................ 127 
Appendix 2  Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 142 
Appendix 3  Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication .............................................. 145 
Appendix 4  Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) .. 157 
Appendix 5  Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 167 
Appendix 6  Preexisting Autoimmune Diseases and Immune Deficiencies .. 168 
Appendix 7  Anaphylaxis Precautions ........................................................... 169 
Appendix 8  Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 170 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol CO39721, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IB STUDY EVALUATING COBIMETINIB PLUS 
ATEZOLIZUMAB IN PATIENTS WITH ADVANCED 
BRAFV600 WILD-TYPE MELANOMA WHO HAVE 
PROGRESSED DURING OR AFTER TREATMENT WITH 
ANTI−PD-1 THERAPY AND ATEZOLIZUMAB 
MONOTHERAPY IN PATIENTS WITH PREVIOUSLY 
UNTREATED ADVANCED BRAFV600 WILD-TYPE 
MELANOMA 
PROTOCOL NUMBER: CO39721 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2016-004402-34 
IND NUMBER: 
135,717 
TEST PRODUCTS: 
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 the contract research organization. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
16/Protocol CO39721, Version 5 
• 
Cohort B (biopsy cohort):  Approximately 12 patients will be enrolled in a mandatory biopsy 
cohort  
  
Approximately 50 patients who have not received any prior anti-cancer treatment in the 
metastatic setting will be enrolled in Cohort C. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Disease-Specific Inclusion Criteria:  Cohorts A and B 
• 
Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAFV600 WT 
(locally advanced) melanoma  
• 
Documentation of BRAFV600 mutation−negative status in melanoma tumor tissue (archival 
[< 5 years old] or newly obtained) through use of a clinical mutation test approved by the 
local health authority (e.g., U.S. Food and Drug Administration [FDA]-approved test, CE-
marked [European conformity] in vitro diagnostic in E.U. countries, CLIA-certified NGS test, 
or equivalent) 
• 
Measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1)  
• 
Disease progression during or after treatment with a PD-1 inhibitor either as monotherapy 
or in combination with other agent(s) 
 
Additional Disease-Specific Inclusion Criteria in Cohort B (Biopsy Cohort) 
• 
Patients in this cohort must have progressed during or after anti−PD-1 therapy within 
12 weeks before study start. 
• 
Patients in this cohort must have received a minimum of two cycles of anti−PD-1 therapy. 
• 
Patients in this cohort must meet criteria for primary (n = 6) or secondary (n = 6) resistance 
to an anti−PD-1 agent as outlined below: 
Primary resistance is defined as progressive disease, according to RECIST v1.1, as best 
response. 
Secondary resistance is defined as progressive disease after initial confirmed response 
according to RECIST v1.1, 
• 
Patients in this cohort must consent to undergo tumor biopsies of accessible lesions before 
and during treatment and at radiographic progression for biomarker analyses. 
• 
Patients in this cohort must have at least two accessible lesions that are amenable to 
excisional or core-needle (minimum three cores and minimum diameter 18 gauge; however, 
16 gauge is desirable) biopsy with acceptable risk of a major procedural complication.  
Exceptions may be made if patient has only one lesion that allows multiple biopsies 
following discussion with Medical Monitor. 
 
Disease-Specific Inclusion Criteria:  Cohort C 
• 
Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAFV600 WT 
(locally advanced) melanoma  
• 
Naive to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal 
therapy, targeted therapy, immunotherapy, or other biologic therapies), with the following 
exceptions: 
Adjuvant treatment with interferon-α (IFN-α), interleukin-2 (IL-2), or vaccine therapies, 
if discontinued at least 28 days prior to initiation of study treatment 
Adjuvant treatment with ipilimumab, if discontinued at least 90 days prior to initiation of 
study treatment 
Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to 
initiation of study treatment 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
17/Protocol CO39721, Version 5 
• 
Documentation of BRAFV600 mutation−negative status in melanoma tumor tissue (archival 
[< 5 years old] or newly obtained) through use of a clinical mutation test approved by the 
local health authority (e.g., U.S. Food and Drug Administration [FDA]-approved test, 
CE-marked [European conformity] in vitro diagnostic in E.U. countries, CLIA-certified next-
generation sequencing [NGS] test or equivalent) 
• 
A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin 
block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study entry.  If 20 slides are not 
available or the tissue block is not of sufficient size, the patient may still be eligible for the 
study, after discussion with and approval by the Medical Monitor. 
If archival tissue is unavailable or is determined to be inadequate, tumor tissue must 
be obtained from a biopsy performed at screening. 
• 
Measureable disease according to RECIST v1.1 
 
General Inclusion Criteria 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
Eastern Cooperative Oncology Group Performance Status of 0 or 1  
• 
Available and adequate baseline tumor tissue sample (archival  [< 5 years old] or newly 
obtained biopsy) 
• 
Life expectancy ≥ 18 weeks 
• 
Adequate hematologic and end-organ function, defined using the following laboratory test 
results, obtained within 14 days before initiation of study treatment: 
Neutrophils (ANC ≥ 1500 cells/µL without granulocyte-colony stimulating factor support 
within 2 weeks before Cycle 1, Day 1) 
WBC counts > 2500 cells /µL and < 15,000 cells /µL 
Lymphocyte count ≥ 500 cells/µL 
Platelet count ≥ 100,000 cells /µL (without transfusion within 2 weeks before Cycle 1, 
Day 1) 
Hemoglobin ≥ 9.0 g/dL (without transfusion) 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min on the basis of 
measured CrCl from a 24-hour urine collection or Cockcroft-Gault glomerular filtration 
rate estimation: 
CrCl = 
(140 − age) × (weight in kg) 
( × 0.85 if female) 
72 × (serum creatinine in mg/dL) 
 
AST, ALT, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the 
following exceptions.   
Patients with documented liver metastases:  AST and/or ALT ≤ 5 × ULN.  Patients 
with documented liver or bone metastases:  alkaline phosphatase ≤ 5 × ULN 
Serum albumin ≥ 25 g/L 
Total bilirubin ≤ 1.5 × ULN; patients with known Gilbert’s disease may have a 
bilirubin ≤ 3.0 × ULN 
For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤ 1.5 × ULN within 
28 days before initiation of study treatment 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR during the 28 days immediately preceding initiation of study treatment 

 
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• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year 
during the treatment period and for 5 months after the last dose of atezolizumab within 
3 months after the last dose of cobimetinib.  Women must refrain from donating eggs 
during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 3 months 
after the last dose of cobimetinib to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Related Exclusion Criteria 
• 
Prior treatment with a MAPK inhibitor  
• 
Ocular melanoma 
• 
Major surgical procedure other than for diagnosis within 4 weeks before initiation of study 
treatment, or anticipation of need for a major surgical procedure during the course of the 
study 
• 
Traumatic injury within 2 weeks before initiation of study treatment 
• 
Palliative radiotherapy within 14 days before initiation of study treatment 
• 
Active malignancy (other than BRAFV600 mutation−negative melanoma) or malignancy 
within 3 years before screening, with the exception of resected melanoma, resected basal 
cell carcinoma, resected cutaneous squamous cell carcinoma, resected carcinoma in situ of 
the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage 
bladder cancer, or other curatively treated malignancies from which the patient has been 
disease-free for at least 3 years  
Patients with a history of isolated elevation in prostate-specific antigen in the absence of 
radiographic evidence of metastatic prostate cancer are eligible for the study. 
• 
Treatment with any anti-cancer agent 14 days prior to Cycle, Day 1 other than aPD-1 based 
therapy 
• 
Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1  
Clinically stable patients with manageable immune-related adverse events resulting from 
prior cancer immunotherapy may be eligible for the study after discussion with and 
approval by the Medical Monitor. 

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•
For Cohort C, specific exclusion criteria include any prior anti-cancer therapy for advanced
melanoma
Ocular Exclusion Criteria (Cohorts A and B) 
•
History of serous retinopathy
•
History of retinal vein occlusion (RVO)
•
Evidence of ongoing serous retinopathy or RVO at baseline
Cardiac Exclusion Criteria (Cohorts A and B) 
•
History of clinically significant cardiac dysfunction, including the following:
Unstable angina, or new-onset angina within 3 months before initiation of study 
treatment 
Symptomatic congestive heart failure, defined as New York Heart Association Class II or 
higher 
Myocardial infarction within 6 months before initiation of study treatment 
Unstable arrhythmia 
History or presence of an abnormal ECG that is clinically significant in the investigator’s 
opinion, including complete left bundle branch block, second- or third-degree heart block, 
or evidence of prior myocardial infarction 
Left ventricular ejection fraction below the institutional lower limit of normal or below 50%, 
whichever is lower 
Central Nervous System Exclusion Criteria 
•
Untreated or actively progressing central nervous system (CNS) lesions (carcinomatous
meningitis)
Patients with stable and asymptomatic CNS metastases are eligible, if they meet all of the
following:
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
All known CNS lesions are clinically stable. 
CNS lesions have not been treated with whole-brain radiotherapy, except in patients 
who underwent definitive resection of or stereotactic therapy for all radiologically 
detectable parenchymal brain lesions. 
Absence of interim progression must be confirmed by radiographic study within 4 weeks 
before initiation of study treatment.  If new CNS metastases are suspected during the 
screening period, a confirmatory radiographic study is required before initiation of study 
treatment. 
Any radiotherapy or surgery must be completed ≥ 4 weeks before initiation of study 
treatment. 
There is no ongoing requirement for corticosteroids, and any prior corticosteroid 
treatment must be discontinued ≥ 2 weeks before initiation of study treatment.  
Treatment with an anticonvulsant at a stable dose is allowed. 
•
History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the
optic apparatus (optic nerves and chiasm)
•
History of leptomeningeal metastatic disease
Exclusions Related to Infections 
•
HIV infection
•
Active tuberculosis infection
•
Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to,
hospitalization for complications of infection, bacteremia, or severe pneumonia

 
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• 
Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1 
• 
Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1 
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or 
chronic obstructive pulmonary disease) are eligible. 
• 
Active or chronic viral hepatitis B or C infection 
Patients with a past or resolved HBV infection, defined as having a negative HBsAg test 
and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for 
the study if quantitative HBV DNA < 500 IU/mL at screening. 
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain reaction 
test for HCV RNA is negative. 
 
Exclusion Criteria Related to Autoimmune Conditions and Immunomodulatory Drugs 
• 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, anti−phospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 
with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are 
eligible for the study. 
Patients with a history of manageable immune-related adverse events resulting from 
prior immunotherapy may be eligible for the study after discussion with and approval by 
the Medical Monitor. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the 
study provided all of following conditions are met: 
Rash must cover less than 10% of body surface area. 
Disease is well controlled at baseline and requires only low−potency topical 
corticosteroids  
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months. 
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor−alpha [TNF-α] agents) within 2 weeks before initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during the course of the 
study with the following exceptions: 
Patients who have received acute, low-dose systemic immunosuppressant medication 
(≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of systemic 
immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) 
are eligible for the study after Medical Monitor approval has been obtained. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 

 
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Additional Exclusion Criteria 
• 
Current severe, uncontrolled systemic disease (including, but not limited to, clinically 
significant cardiovascular, pulmonary, or renal disease) other than cancer 
• 
Any Grade ≥ 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 
• 
History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 
6 months prior to Day 1 
• 
Any psychological, familial, sociological, or geographic condition that may hamper 
compliance with the protocol and follow-up after treatment discontinuation 
• 
Inability or unwillingness to swallow pills 
• 
History of malabsorption or other clinically significant metabolic dysfunction that may 
interfere with absorption of oral study treatment 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days before initiation of study treatment. 
• 
Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and 
other inherited liver disease as well as active viral disease, including positive HIV test at 
screening 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications 
• 
Treatment with a live, attenuated vaccine within 4 weeks before initiation of study treatment 
or anticipation of need for such a vaccine during the course of the study 
• 
Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary 
cells 
• 
Known hypersensitivity to any component of the atezolizumab or cobimetinib formulations 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
• 
Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent 
• 
Requirement for concomitant therapy or food that is prohibited during the study 
 
End of Study 
The study will end when all patients enrolled have been followed until death, have withdrawn 
consent, have been lost to follow-up, or when the Sponsor decides to end the trial, whichever 
occurs first.   
Length of Study 
The total length of the study, from first patient in until the end of follow-up, is expected to be 
approximately 4 years. 
Investigational Medicinal Products 
Test Products (Investigational Drugs) 
Cobimetinib tablets will be supplied by the Sponsor.  The 20-mg cobimetinib drug product is a 
film-coated, white, round, immediate-release tablet.  Patients in Cohorts A and B will receive 
60 mg (three tablets of 20 mg each) orally QD for Days 1−21 of each 28-day cycle.  This 4-week 
period is considered a treatment cycle. 
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.  For Cohorts A and B, extraction of 
14 mL of atezolizumab solution from a 1200 mg vial contains an 840-mg dose.   
Cohort A:  Patients will initiate dosing with atezolizumab concurrently with cobimetinib and will 
receive atezolizumab 840 mg intravenously Q2W on Days 1 and 15 of all cycles. 

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Cohort B:  Patients will receive the first dose of atezolizumab at 840 mg intravenously on Day 
15 of Cycle 1.  Thereafter, they will receive atezolizumab 840 mg intravenously Q2W on Days 1 
and 15 of Cycle 2 and all subsequent cycles. 
Cohort C:  Patients will receive atezolizumab 1200 mg intravenously Q3W as monotherapy. 
Statistical Methods 
Primary Analysis 
The primary analysis will be conducted in Cohorts A and B approximately 24 weeks after the 
last patient is enrolled in Cohort A.  At this time, Cohorts A and B will have a minimum 
follow up of approximately 24 weeks.  The primary analysis for Cohort C may be analyzed 
independently, with a minimum of 24 weeks follow up for patients in Cohort C.  Both 
separate and pooled efficacy and safety analyses will be performed on Cohorts A and B given 
their similar patient populations.  Additional tumor immunology and biomarker analyses will also 
be conducted on Cohort B.  Study data will be described and summarized for Cohort C 
separately. 
Determination of Sample Size   
This study is designed for hypothesis generation with the intention to provide an informative 
evaluation on the selected efficacy endpoints.  No formal inferential testing is planned.  
Approximately 152 patients are anticipated to be enrolled, with approximately 90 patients in 
Cohort A, 12 patients in Cohort B, and 50 patients in Cohort C. 
A combined 102 patients in Cohorts A and B allows for a robust comparison against historical 
control of ipilumumab and chemotherapy in patients who have previously progressed on 
anti-PD1 therapy, which generally have response rates of less than 17%.  For example, with 
102 patients in Cohorts A and B, observing 26 patients with objective response corresponds to 
ORR (95% CI) of 25.5% (17.4%, 35.1%) and observing 60 patients with disease control 
corresponds to a DCR (95% CI) of 58.8% (48.6%, 68.5%). 
Enrolling 50 patients in Cohort C provides reasonably reliable estimates of the ORR and DCR in 
patients who have not been previously treated to allow for an accurate understanding of the 
achievable magnitude of efficacy in this population.   
For example, observing 17 patients with objective response corresponds to ORR (95% CI) of 
34.0% (21.1%, 48.8%) and observing 32 patients with disease control corresponds to DCR 
(95% CI) of 64% (49.2%, 77.1%).  Enrolling 50 patients in Cohort C also provides an 
opportunity to explore the preliminary efficacy in relevant patient subgroups including biomarker 
subgroups defined by PD-L1 expression. 
Interim Analyses  
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct 
interim efficacy analyses.  The decision to conduct an optional interim analysis and the timing 
of the analysis will be documented in the Sponsor's trial master file prior to the conduct of the 
interim analysis.  The interim analysis will be performed and interpreted by Sponsor study team 
personnel. 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody (anti-therapeutic antibody) 
anti−PD-1 
anti−programmed death-1 
anti−PD-L1 
anti−programmed death ligand-1 
CE 
European conformity 
CNS 
central nervous system 
CPK 
increased creatine phosphokinase 
CR 
complete response 
CRC 
colorectal cancer 
CT 
computed tomography 
DCR 
disease control rate 
DOR 
duration of response 
EC 
Ethics Committee 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte-colony stimulating factor 
GWAS 
genome-wide association studies 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
IC 
immune cell 
IFN 
interferon 
IL-2 
interleukin-2 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
 

 
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Abbreviation 
Definition 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
intravenous 
IxRS 
interactive voice- or web-based response system 
LVEF 
left ventricular ejection function 
MAPK 
mitogen activated−protein kinase 
MHC 
major histocompatibility complex 
MHCI 
major histocompatibility complex class I 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NGS 
next-generation sequencing 
NRAS 
neuroblastoma RAS 
NSCLC 
non−small cell lung cancer 
OCT 
optical coherence tomography 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed death−1 
PD-L1 
programmed death−ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
RECIST  
Response Evaluation Criteria in Solid Tumors 
RVO 
retinal vein occlusion 
QD 
once daily 
QW 
every week 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
SD 
stable disease 
 

 
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Abbreviation 
Definition 
T3 
triiodothyronine 
TCR 
T-cell receptor 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
VF 
visual field 
WT 
wild type 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON MELANOMA 
1.1.1 
Incidence and Pathogenesis 
Melanoma is a potentially deadly form of skin cancer that originates from melanocytes.  
The clinical outcome of patients with melanoma is highly dependent on the stage of 
disease at presentation.  Although the outcome for promptly diagnosed superficial 
tumors is good and despite recent therapeutic advances, melanoma is associated with 
high rates of mortality and disease-related morbidity in the metastatic setting (see 
Section 1.1.2).  
In 2012, there were about 232,000 new cases and 55,000 deaths from melanoma 
worldwide, with more than 100,000 new cases and 22,000 deaths in Europe 
(Ferlay et al. 2013).  In the United States, an estimated 76,380 new cases of melanoma 
will be diagnosed and approximately 10,130 patients are expected to die of the disease 
in 2016 (American Cancer Society 2016).  Moreover, the number of melanoma cases 
worldwide is increasing faster than any other cancer, especially in fair-skinned, 
Caucasian populations (Diepgen and Mahler 2002); estimates suggest a doubling of 
melanoma incidence every 10−20 years (Garbe and Leiter 2009).  The incidence is 
particularly high among Caucasian populations in Australia (42.4 per 100,000) and 
Western Europe (10.6 per 100,000) (American Cancer Society 2016). 
The mitogen−activated protein kinase (MAPK) signaling cascade is a key intracellular 
signaling network that transduces multiple proliferative and differentiating signals from 
the extracellular environment to the nucleus of cells to activate cellular growth and 
differentiation (Johnson and Lapadat 2002; Roberts and Der 2007).  This pathway is 
highly implicated in pathogenesis of melanoma.  Approximately 40%−50% of all 
melanomas harbor an activating mutation in BRAF, a major driver of MAPK signaling 
(Davies et al. 2002; Curtin et al. 2005; Jakob et al 2012), and an additional 15%−30% 
harbor an activating mutation of neuroblastoma RAS (NRAS) (Lee et al. 2011; CGAN 
2015).  Approximately 14% harbor mutations of NF1, an inhibitory protein of the MAPK 
pathway (CGAN 2015).  Thus, the MAPK pathway is an important driver of pathogenesis 
in BRAFV600 wild-type (WT) melanoma, as well as BRAFV600-mutated melanoma. 
1.1.2 
Treatment Options for Melanoma 
Until recently treatment options for metastatic melanoma were limited.  Dacarbazine was 
considered the standard first-line treatment with response rates of 5%–12%, median 
progression-free survival (PFS) of less than 2 months, and a median overall survival (OS) 
of 6.4−9.1 months (Middleton et al. 2000; Bedikian et al. 2006; Chapman et al. 2011; 
Robert et al. 2011).  Combination chemotherapy and chemotherapy combined with 
interferon (IFN)-alpha or interleukin-2 (IL-2), although showing improved response rates, 
have not resulted in improved OS (Chapman et al. 1999; Ives et al. 2007). 

 
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In recent years, targeting of the MAPK pathway has emerged as an effective treatment 
strategy in BRAFV600-mutated melanoma, and several targeted therapies are now 
approved globally for treatment of this indication (Richman et al. 2015).  
Treatment options for BRAFV600 WT melanoma have also improved dramatically with 
approvals of several immunotherapeutic agents.  Melanoma cells are highly 
immunogenic and thus an appropriate target for these agents (Zhu et al 2016).  T-cell 
activation is an essential component of cell-mediated immunity, which has led to the 
development of immunomodulation as a strategy for anti-cancer therapy.  The two-signal 
model of T-cell activation involves interaction of the T-cell receptor (TCR) with its antigen 
(signal one), followed by signal two, which is a co-stimulatory interaction between CD28 
on the T-cell surface and its ligand B7-1 on antigen-presenting cells (Chen and Flies 
2013).  Co-inhibitory receptors, or “immune checkpoints”, including CTLA-4 and 
programmed death−1 (PD-1) receptor can prevent T-cell overactivation and 
downregulate the immune system, protecting against autoimmunity (Freeman et al. 
2000).  Targeting of these checkpoints can render cancer cells susceptible to immune 
attack and has been applied in the treatment of melanoma.  
Immunotherapeutic agents currently available for advanced melanoma include the 
following: 
• 
The anti−CTLA-4 antibody, ipilimumab 
• 
Two anti−PD-1 antibodies, nivolumab and pembrolizumab 
• 
Nivolumab and ipilimumab combination therapy 
 
Although responses to anti−PD-1 agents can be prolonged, they are limited to 30%−40% 
of patients across several clinical trials.  Median PFS for these agents is 5−6 months 
(Robert et al. 2015a; Robert et al. 2015b; Weber et al. 2015), and OS is approximately 
20−24 months (Hodi et al 2016; Robert et al. 2016).  Reported response rates for 
ipilimumab monotherapy are 10%−15% and OS 10−11 months (Hodi et al. 2010; 
Robert et al. 2011).  In Phase III studies in previously untreated patients with advanced 
melanoma, the combination of ipilimumab and nivolumab showed an increased objective 
response rate (ORR) and improved PFS relative to either agent as monotherapy, but it 
resulted in challenging toxicity, with more than 50% of patients experiencing Grade ≥ 3 
adverse events.  The OS benefit for this combination is not yet known 
(Larkin et al. 2015). 
Thus, despite the therapeutic advance with the development of these agents, there still 
exists a high unmet need for all patients with advanced BRAFV600 WT melanoma. 
For BRAFV600 WT patients whose disease relapsed or is refractory to anti−PD-1 agents, 
treatment options are currently limited to ipilimumab (if they have not previously received 
this agent), chemotherapy, or rechallenge with anti−PD-1 therapy.  Consequently, there 
is an urgent need to develop new therapies for this population. 

 
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1.2 
BACKGROUND ON THE STUDY TREATMENTS 
1.2.1 
Cobimetinib 
Cobimetinib is a potent and highly selective inhibitor of MEK1 and MEK2, central 
components of the MAPK pathway.  Activated MEK triggers downstream signaling 
through ERK to promote growth.  Cancer cells transformed by BRAFV600 are 
exceptionally sensitive to MEK inhibition in vitro.  Allosteric MEK inhibitors can result in 
G1 phase growth arrest in melanoma cells (Solit et al. 2006; Haass et al. 2008).  In vitro, 
MEK inhibitors reduce cell proliferation, soft agar colony formation, and matrigel invasion 
of BRAFV600 mutation−positive melanoma cells and are also effective against BRAFV600 
mutation−positive melanoma xenografts, suggesting a potentially important role for MEK 
inhibitors in melanoma and other tumors that harbor the BRAFV600 mutation 
(Solit et al. 2006).   
Cobimetinib (Cotellic®) is approved for use with vemurafenib for the treatment of 
advanced BRAFV600-mutated melanoma in the European Union, United States, and 
Switzerland as well as a number of other countries across the world.  
Cobimetinib shows anti-tumor activity in both nonclinical models and cancer patients and 
is being investigated as a potential therapy in a wide variety of malignancies, in 
combination with chemotherapy, other targeted therapies, and cancer immunotherapy. 
Refer to the Cobimetinib Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.2.2 
Atezolizumab 
Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets 
programmed death−ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its 
receptors, PD-1 and B7-1 (also known as CD80), both of which function as inhibitory 
receptors expressed on T cells.  Therapeutic blockade of PD-L1 binding by atezolizumab 
has been shown to enhance the magnitude and quality of tumor-specific T-cell 
responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016).  Atezolizumab has minimal binding to fragment crystallizable 
(Fc) + receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 

 
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Atezolizumab (Tecentriq®) is approved in the United States for the treatment of patients 
with locally advanced or metastatic urothelial bladder carcinoma and metastatic 
non−small cell lung cancer (NSCLC) who have disease progression during or following 
platinum-containing chemotherapy and are currently in clinical development for other 
indications. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Rationale for Combining Cobimetinib and Atezolizumab for 
Advanced BRAFV600 Wild-Type Melanoma after Progression on 
Anti-PD-1 Therapy 
The rationale for combining cobimetinib, a MEK inhibitor, with atezolizumab, an 
anti−PD-L1 antibody, in treatment of patients with advanced BRAFV600 WT melanoma is 
based on the complementary mechanisms of action of these agents, as well as on 
observations that the effects of MAPK pathway inhibition on tumor microenvironment 
may enhance anti-tumor T cell−mediated immunity.  This rationale is supported by 
nonclinical and clinical data as summarized in this section.  
As detailed in Sections 1.1.2 and Section 1.3.2, only 30%–40% of patients with 
metastatic melanoma respond to anti−PD-1 monotherapies, and many of those who 
respond initially eventually progress.  Patients who do not respond or attain disease 
stabilization are defined as having refractory disease or primary resistance, whereas 
those whose tumors progress after initial response or stabilization are defined as having 
relapsed disease or secondary resistance.  The molecular mechanisms of primary and 
secondary resistance to immunotherapy are poorly understood.  However, the known 
effects of MAPK inhibitors, including cobimetinib, on tumor microenvironment (see 
Section 1.3.4) include effects that may enable conversion to an immuno-responsive 
phenotype, sensitize refractory tumors to anti−PD-1/PD-L1 agents, and/or resensitize 
relapsed tumors to these agents, leading researchers to the hypothesis that combining 
MEK inhibition with anti−PD-1/PD-L1 therapy may lead to improved efficacy.  This 
hypothesis is supported by clinical data from Study GP28363 (see Section 1.3.5), which 
has shown that combination therapy with cobimetinib and atezolizumab in advanced 
melanoma results in improved ORR and PFS relative to either PD-1/PD-L1 or MEK 
inhibitor monotherapy.  
1.3.1.1 
Rationale for Atezolizumab Monotherapy for Previously 
Untreated Patients with Advanced BRAFV600-Wild-Type 
Melanoma 
While evidence of efficacy of atezolizumab monotherapy in melanoma has also been 
demonstrated in Study PCD4989g, as described below, the patient population was 
heterogeneous with respect to line of therapy and BRAFV600 status.  Enrolling a cohort of 
previously untreated patients with advanced BRAFV600 WT melanoma in a separate 

 
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atezolizumab monotherapy cohort will allow a more accurate evaluation of the 
magnitude of efficacy achievable, pharmacokinetics, and safety profile in this patient 
population.  In addition, it will allow comparison of the potential molecular mechanisms of 
resistance to checkpoint inhibitor therapy between patients in Cohort C and those 
previously treated patients enrolled in Cohorts A and B.  
1.3.2 
Activity of Atezolizumab in Advanced Melanoma 
1.3.2.1 
Study PCD4989g:  Atezolizumab Monotherapy 
In the Phase Ia setting (Study PCD4989g), atezolizumab monotherapy has shown 
anti-tumor efficacy in melanoma efficacy parameters comparable to those documented 
reported for two PD-1 inhibitors that are currently approved for the treatment of 
melanoma (pembrolizumab and nivolumab; Hodi et al. 2014; see Figure 1).  In patients 
with metastatic non-ocular melanoma enrolled in Study PCD4989g who received doses 
of at least 10 mg/kg every 3 weeks (Q3W; N = 37), ORR by Response Evaluation Criteria 
in Solid Tumors Version 1.1 (RECIST v1.1) was 33% and median PFS was 5.5 months 
as of the 15 December 2015 data cut.  In addition, atezolizumab monotherapy was well 
tolerated by patients with metastatic melanoma. 
Figure 1 Phase I Study of Atezolizumab Monotherapy in Cutaneous 
Melanoma 
 
mPFS = median progression-free survival; ORR = objective response rate; SLD = sum longest 
diameter. 
Note:  n = 37. 
 
Please see the current Atezolizumab Investigator’s Brochure for the most current safety 
and efficacy data from atezolizumab studies.  

 
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1.3.3 
Activity of MEK Inhibitors in BRAFV600 Wild-Type Melanoma 
MEK inhibitors, as monotherapy and in combination with BRAF inhibitors, have proven 
efficacy in advanced BRAFV600-mutated melanoma (Chapman et al. 2011; Flaherty et al. 
2012; Larkin et al. 2014; Long et al. 2014; Robert et al. 2015a), and cobimetinib in 
combination with vemurafenib is approved in this indication. 
As described in Section 1.1.1, the MAPK pathway is also implicated in BRAFV600 WT 
melanoma.  Clinical evidence for modest anti-tumor activity of MEK inhibition in a subset 
of patients with BRAFV600 WT melanoma has recently been provided by the Phase III 
Study NCT01763164 (NEMO), which showed improved PFS for single-agent binimetinib, 
a small molecule MEK inhibitor, in patients with BRAFV600 WT, NRAS-mutated, 
advanced melanoma when compared with dacarbazine (hazard ratio = 0.62; 
Dummer et al. 2016). 
1.3.4 
Effect of MAPK Inhibition on Tumor-Immune Contexture 
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).  Further, in tumor biopsies from melanoma patients, 
BRAF and MEK inhibitors, alone or in combination, have been shown to increase 
melanoma antigen expression, major histocompatibility complex (MHC) expression, 
T-cell infiltration, and PD-L1 expression (Wilmott et al. 2012; Frederick et al. 2013; 
Kakavand et al. 2015; Liu et al. 2015; Hu-Lieskovan et al. 2015).  MEK inhibition has 
also been shown to increase tumor MHC expression and PD-L1 expression in 
triple-negative breast cancer cells in vivo and in vitro (Loi et al. 2016).  
Additional MAPK inhibition effects may further modulate the tumor microenvironment in 
ways that could enable an improved immune reaction against the tumor.  These effects 
include increased recruitment and activation status of CD8+ and CD4+ T cells and 
reduced secretion of granulocyte colony-stimulating factor (G-CSF) with reduced 
mobilization and activity of CD11-positive GRL+ myeloid−derived suppressor cells 
(Phan et al. 2013; Ebert et al. 2016), as well as reduced expression of angiogenesis 
factors with altered tumor vascular support (Ciuffreda et al. 2009; Chang et al. 2013; 
Mohan et al. 2015). 
In addition, the MEK inhibitor G-38963, which is mechanistically similar to cobimetinib, 
promotes the effector phenotype and longevity of tumor-infiltrating T cells in a CT26 
colon cancer mouse model and combines synergistically with anti−PD-L1 in inhibiting 
growth of CT26 tumors (Ebert et al. 2016).   
The nonclinical and clinical data described above show that inhibition of the MAPK 
pathway leads to an increase in immune effector cells in the tumor, thereby priming the 
microenvironment to enable the immune system to attack the tumor.   

 
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1.3.5 
Clinical Data for Combination Treatment with Cobimetinib and 
Atezolizumab in Advanced Melanoma 
1.3.5.1 
Study GP28363 
Study GP28363 is an ongoing Phase Ib, open-label, multicenter study designed to 
assess the safety, tolerability, and pharmacokinetics of cobimetinib plus atezolizumab in 
patients with advanced solid tumors who are naive to anti−PD-1 therapy and for whom 
no standard therapy is available. 
The study has two stages:  Stage 1 (dose escalation) and Stage 2 (expansion).  
Stage 1 is designed to establish the combination maximum tolerated dose or maximum 
administered dose for cobimetinib plus atezolizumab.  In Stage 2, the recommended 
Phase II dose and schedule were investigated in tumor-specific expansion cohorts:  
metastatic melanoma, KRAS-mutant and WT metastatic colorectal cancer (CRC), and 
NSCLC.   
In a separate mandatory biopsy cohort, patients with diverse solid tumors (n = 16), 
including CRC, received 60 mg of cobimetinib once daily (QD) as monotherapy before 
initiation of atezolizumab treatment and underwent mandatory fresh biopsy collection 
before initiation of cobimetinib dosing and at the end of the 14-day period of cobimetinib 
monotherapy. 
During the Stage 1 dose-escalation phase, there were no dose-limiting toxicities, and 
60 mg of cobimetinib on a 21 days on/7 days off schedule with 800 mg of atezolizumab 
every 2 weeks (Q2W) was determined to be the recommended Phase II dose 
(Miller et al. 2017). 
1.3.5.1.1 
Efficacy in Non-Ocular Melanoma 
As of the data cutoff (17 January 2017), 20 patients with non-ocular melanoma, including 
10 patients with BRAFV600-mutated disease and 10 patients with BRAFV600 WT disease 
who had received no prior anti−PD-1 or anti−PD-L1 therapy, were evaluable for efficacy.  
The data were comparable in both BRAFV600-mutant and BRAFV600 WT melanoma.  Of 
note, 3 of the patients with BRAFV600-mutated melanoma who progressed without any 
tumor shrinkage had received prior trametinib, a MEK inhibitor.  Figure 2 and Figure 3 
show the RECIST v1.1 responses for all melanoma patients and BRAFV600 WT 
melanoma patients, respectively. 
Among these patients (n = 20), the ORR was 45% (confirmed response per 
RECIST v1.1), disease control rate (DCR; defined as a complete response [CR], a 
partial response [PR], or stable disease [SD]) was 75%, and median PFS was 15.7 
months (95% CI: 2.8, not evaluable).  Patients with metastatic melanoma had durability 
of response, as shown over time in Figure 2 (Miller et al. 2017). 

 
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Figure 2 Tumor Burden over Time by Investigator-Confirmed Response 
per RECIST v1.1 in All Melanoma Patients:  Study GP28363 
 
CR = complete response; PD = progressive disease; PR = partial response; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1, SD = stable disease. 
Note:  n = 10. 
 
For patients with BRAFV600 WT melanoma, the ORR was 50% (confirmed response per 
RECIST v1.1), the DCR was 80%, and median PFS was 15.7 months (95% CI: 2.8, not 
evaluable).  Patients with BRAFV600 WT metastatic melanoma had durability of response 
(confirmed response per RECIST v1.1), as shown in Figure 3.  

 
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Figure 3 Tumor Burden over Time by Investigator-Confirmed Response 
per RECIST v1.1 in Patients with BRAFV600 Wild-Type Melanoma: 
Study GP28363 
 
CR = complete response; PD = progressive disease; PR = partial response; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1, SD = stable disease. 
Note:  n = 10 
 
Biomarker Data 
Biomarker evaluation from the serial tumor biopsy cohort showed a 4-fold increase in 
CD8-positive T-cell infiltration in 75% of tumors, as well as increases in PD-L1 and 
MHC-I (major histocompatibility complex class I) expression (Bendell et al. 2016).  The 
data support the hypothesis that cobimetinib has beneficial immunomodulatory effects at 
the tumor site that allow for immune anti-tumor activity. 
Safety in Patients with Non-Ocular Melanoma  
At the time of the data cutoff (17 January 2017), 22 patients with melanoma, including 
20 with non-ocular melanoma and 2 patients with ocular melanoma, were evaluated for 
safety.  The median safety follow-up in these patients (n = 22) was 19.4 months (range, 
1.4−26.3 months).  All grade adverse events occurred in 100% of patients; study 
treatment−related Grades 3 and 4 adverse events were reported for 59.1% of patients, 
with diarrhea and dermatitis acneiform being the most common (reported for 3 patients 
[13.6%] and 2 patients [9.1%], respectively).  All adverse events were manageable.  
Although no cobimetinib-related Grade 5 adverse events occurred, 14% of patients had 

 
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study treatment−related serious adverse events, 82% of patients had an adverse event 
leading to study treatment dose modification and/or interruption, and 27% of patients 
had discontinued at least one treatment because of adverse events. 
Safety in All Patients 
As of 17 January 2017, a total of 150 patients were enrolled in the study and evaluable 
for safety.  Fourteen patients had been accrued in the dose-escalation phase (Stage 1, 
Cohorts 1−3), and 136 patients had been accrued in the expansion phase (Stage 2).  
To be considered evaluable for safety, patients must have received at least one dose of 
atezolizumab.  All patients who received atezolizumab also received cobimetinib.  The 
mean duration of safety follow-up was 3.3 months (0.0−31.3 months).  Safety follow-up 
is defined as the number of days from date of first dose to the minimum of date of last 
dose + 30 days, discontinuation date, initiation date of anti-cancer therapy, cutoff date, or 
death date.   
Overall, 98.7% of patients experienced at least one adverse event regardless of 
attribution; 64.0% experienced a Grade ≥ 3 adverse event; and 44. 7 % experienced a 
serious adverse event.  There were 7 (4.0%) Grade 5 (fatal) adverse events in the study, 
of which 6 were unrelated to study drug.  The patient whose death was considered to be 
related to atezolizumab was being treated with chronic steroids for preexisting 
hypopituitarism and succumbed to sepsis.   
The most common adverse events (occurring in ≥ 20% of patients) were diarrhea 
(70.7%), fatigue (56.0%), rash (48.0%), vomiting (42.0%), nausea (36.0%), pruritus 
(35.3%), decreased appetite (34.7%), constipation (29.3%), peripheral edema (26.0%), 
pyrexia (23.3%), acneiform dermatitis (23.3%), increased creatine phosphokinase (CPK) 
(22.7%), dyspnea (20.0%), and anemia (20.0%).  The most common Grade ≥ 3 events 
(occurring in ≥ 5% of patients) were fatigue (10.0%), anemia 9.3%, and diarrhea (8.0%). 
In the 17 Jan 2017 data cut for melanoma, the safety data were generally similar.  
The mean duration of safety follow-up was 19.4 months (range: 1.4−26.3 months).  For 
treatment-related adverse events, 100% of patients experienced at least one adverse 
event; 59.0% of patients experienced a Grade ≥ 3 adverse event; and 14.0% of patients 
experienced a serious adverse event and included pulmonary embolism, bacterial 
infection, and pain management.  There was one (treatment-unrelated) Grade 5 (fatal) 
adverse event in the melanoma cohort. 
The most common treatment-related adverse events (occurring in ≥ 20% of melanoma 
patients), as of 17 Jan 2017, were diarrhea (86.0%), rash (68.0%), fatigue (45.0%), 
nausea (45.0%), pruritus (45.0%), blood creatine phosphokinase increased (32.0%), 
vomiting (32.0%), abdominal pain (23.0%), decreased appetite (23.0%), and dermatitis 
acneiform (23.0%).  In this cohort, the most common Grade ≥ 3 events (occurring in 
≥ 5% of patients) were diarrhea (14.0%), anemia (9.0%), dermatitis acneiform (9.0%), 

 
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amylase increased (5.0%), asthenia (5.0%), bacterial infection (5.0%), edema peripheral 
(5%), lipase increased (5.0%), maculopapular rash (5.0%), musculoskeletal pain (5.0%), 
myalgia (5.0%), rash (5.0%), pain management (5.0%), pulmonary embolism (5.0%), 
pruritus (5.0%), seizure (5.0%), and vomiting (5.0%). 
1.3.5.1.2 
Summary 
The improved ORR and DCR suggest that the combination of cobimetinib and 
atezolizumab may lead to longer PFS than either agent given as monotherapy in 
patients with metastatic melanoma.  Together with the biomarker data from the 
mandatory biopsy cohort, the data suggest that cobimetinib may alter tumor immune 
contexture, thereby enhancing atezolizumab activity.  The safety profile was consistent 
with other cobimetinib studies, and no new safety concerns were reported. 
1.3.6 
Risk-Benefit Statement 
This Phase Ib protocol includes eligibility criteria, baseline measurements, and 
recommendations for management of adverse events, including guidelines for dose 
modifications, delays, and discontinuation of one or more of the study drugs in order to 
enhance the safety of patients in this trial.  Oversight will be provided by the Medical 
Monitor and drug safety personnel.   
Treatment options are extremely limited for patients with advanced BRAFV600 WT 
melanoma whose disease has progressed on or after treatment with an anti−PD-1 
therapy.  Given 1) the observed efficacy and safety data for cobimetinib and 
atezolizumab as single agents and in combination in the Phase Ib study GP28363, 2) 
biomarker data from Study GP28363, suggesting that the effects of cobimetinib on tumor 
immune contexture may sensitize refractory tumors or re-sensitize relapsed tumors to 
anti−PD-1/PD-L1 agents, and 3) the extent of safety monitoring proposed, the potential 
benefits for patients receiving this combination treatment for advanced melanoma 
outweigh the potential risks. 
The observed efficacy data for atezolizumab as a single agent in Study PCD4989g 
suggests comparable efficacy to the currently available anti-PD-1 therapies.  Based on 
the known safety profile of atezolizumab, the potential benefit for patients outweigh the 
potential risks 
2. 
OBJECTIVES AND ENDPOINTS  
This study will evaluate the preliminary efficacy, safety, and pharmacokinetics of 
cobimetinib and atezolizumab in patients with advanced BRAFV600 WT, metastatic, or 
unresectable locally advanced melanoma who have progressed on prior anti−PD-1 
therapy and atezolizumab monotherapy in patients with previously untreated advanced 
BRAFV600 WT melanoma.  Specific objectives and corresponding endpoints are outlined 
in Table 1. 

 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study CO39721 is a Phase lb, open-label, multicenter, global study designed to evaluate 
the preliminary efficacy, safety, and pharmacokinetics of cobimetinib and atezolizumab 
when given to patients with BRAFV600 WT metastatic or unresectable locally advanced 
melanoma who have progressed on a prior anti−PD-1 therapy.  It is also designed to 
evaluate efficacy, safety, and pharmacokinetics of atezolizumab monotherapy in patients 
with BRAFV600 WT metastatic or unresectable locally advanced melanoma who have not 
been previously treated.  The co-primary endpoints of the study are ORR and DCR. 
Approximately 102 patients with BRAFV600 WT advanced melanoma who have 
progressed on a prior anti−PD-1 therapy will be enrolled in Cohorts A and B of this study 
(see Figure 4). 
• 
Cohort A:  Approximately 90 patients who have progressed on or after treatment 
with an anti-PD-1 agent will be enrolled. 
• 
Cohort B (biopsy cohort):  Approximately 12 patients will be enrolled in a mandatory 
biopsy cohort with inclusion according to the eligibility criteria specified in 
Section 4.1. 
 
Approximately 50 patients who have not received any prior anti-cancer treatment in the 
metastatic setting will be enrolled in Cohort C. 
Cohort A and B 
All cycles will be 28 days in length for Cohorts A and B.  Patients in Cohort A will begin 
dosing with cobimetinib and atezolizumab concurrently and will receive in all cycles 
840 mg atezolizumab intravenous (IV) Q2W and 60 mg cobimetinib QD 21/7 
(see Figure 5).   
Patients in Cohort B (biopsy cohort) will also receive 60 mg cobimetinib QD 21/7 in all 
cycles.  However, patients in this cohort will begin dosing with cobimetinib before 
atezolizumab and will receive 60 mg cobimetinib alone QD for the first 14 days of 
Cycle 1.  Atezolizumab dosing (840 mg IV) will begin on Day 15, Cycle 1, and will 
continue thereafter at 840 mg IV Q2W.  In Cycle 2 and all subsequent cycles, patients in 
this cohort will receive 60 mg cobimetinib QD 21/7 and 840 mg atezolizumab IV Q2W 
(see Figure 6).  
Cohort C 
All cycles in Cohort C will be 21 days in length.  Patients in Cohort C will receive 
atezolizumab (1200 mg) Q3W (see Figure 6). 

 
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Figure 4 Study Schema 
 
 
aPD-1 = anti−programmed cell death 1; ECOG = Eastern Cooperative Oncology Group; 
PD = progressive disease; PS = performance score; RECIST = Response Evaluation Criteria in 
Solid Tumors. 
 
Figure 5 Treatment and Biopsy Schedule (Cohort A) 
 
D = day; IV = intravenous; PO = by mouth. 
 

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All patients will be closely monitored for safety and tolerability throughout the study.  
The National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0) will be used to characterize the toxicity profile of the 
study treatments for all patients.  The protocol includes a detailed risk management plan 
for monitoring and managing molecule-specific and potential combination toxicities 
(see Section 5). 
For all cohorts, tumor response will be evaluated by the investigator according to 
RECIST v1.1 (see Appendix 3); immune-modified RECIST v1.1 (see Appendix 4) will 
also be assessed by the investigator.  For Cohort C, tumor response will also be 
determined by the independent review committee (IRC) according to RECIST v1.1.  All 
measurable and non-measurable lesions will be documented at screening.  Response 
will be assessed at 8-week intervals until investigator-determined disease progression 
(according to RECIST v1.1), death, or initiation of subsequent anti-cancer therapy, 
whichever occurs first.  Patients who experience disease progression must have scans 
repeated 4 weeks after initial documentation of progression to confirm disease 
progression.  Tumor assessments are to continue according to schedule in patients who 
discontinue treatment for reasons other than confirmed disease progression, unless 
subsequent anti-cancer therapy is initiated. 
Study treatment will continue for all patients until investigator-determined disease 
progression (confirmed 4 weeks later, for clinically stable patients with a favorable 
benefit-risk assessment), death, unacceptable toxicity, or pregnancy, whichever occurs 
first.  Patients in Cohorts A and B who discontinue one study drug may be able to 
continue the remaining study drug per guidelines for management of specific adverse 
events provided in Table 5.  
Clinically stable patients who have a favorable benefit-risk assessment may continue on 
study treatment following radiographic progression per RECIST v1.1.  Approval from 
study medical monitor must be obtained prior to continuing treatment.  Patients who 
continue treatment beyond radiographic disease progression will be closely monitored.   
After treatment discontinuation, patients will be followed for disease progression if 
applicable and followed for survival until death, withdrawal of consent, or loss to follow-
up, whichever occurs first. 
3.1.1 
Biopsies and Archival Tissue 
Biomarker assessments on tumor biopsy tissue are an important part of this study and 
will be used to elucidate mechanisms of resistance to anti−PD-1/anti−PDL-1 therapy as 
well as to evaluate the effects of atezolizumab monotherapy and cobimetinib-
atezolizumab combination therapy on tumor immune contexture.  All patients must 
provide archival (< 5 years old) tissue or a fresh biopsy before treatment start. 

 
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3.1.1.1 
Optional Biopsies (Cohort A) 
Patients in Cohort A will be requested, via separate optional consent, to provide biopsies 
(core needle [minimum three cores and minimum diameter 18 gauge; 16 gauge is 
preferable] or excisional biopsy) for the study of pharmacodynamic changes related to 
the activity of cobimetinib and atezolizumab.  For patients who consent to biopsies, a 
predose specimen will be obtained after eligibility criteria have been fulfilled before 
Cycle 1, Day 1, only if archival tissue (< 5 years old) was provided for the BRAF WT 
testing.  Predose specimens are not required for patients who provide a fresh biopsy 
before treatment start.  A subsequent biopsy will be performed 4−6 weeks after the first 
atezolizumab dose.  An additional biopsy may be collected per investigator discretion, 
preferably at the time of radiographic progression or response. 
3.1.1.2 
Mandatory Biopsies (Cohort B) 
Patients enrolled in Cohort B, the biopsy cohort, must have at least two (preferably three) 
accessible lesions that meet the requirements specified in the eligibility criteria.  
Exceptions may be made if patient has only one lesion that allows multiple biopsies 
following discussion with Medical Monitor.  One pretreatment, up to two on-treatment 
biopsies, and one post-progression biopsy will be performed.  If more than one biopsy 
will be obtained from one lesion, the lesion should be large enough to permit successive 
biopsies ≥ 1 cm apart.  Investigators are strongly encouraged to obtain two on-treatment 
biopsies as described below; at a minimum, the Day 10−14 biopsy should be obtained to 
test for possible immunologic effects of cobimetinib alone.  
Patients in the biopsy cohort will undergo biopsies according to the following schedule:  
• 
A predose biopsy will be taken before Day 1, Cycle 1.  (The predose biopsy is not 
required if a fresh biopsy was provided during screening). 
• 
On Day 1, Cycle 1, patients will start treatment with cobimetinib alone. 
• 
A mandatory on-treatment biopsy will be obtained between Days 10 and 14 of 
Cycle 1. 
• 
Patients will receive their first atezolizumab dose on Day 15 of Cycle 1.  
• 
A second, optional, on-treatment biopsy will be obtained during Cycle 2, 4−6 weeks 
after the first dose of atezolizumab to assess the combined effects of cobimetinib 
and atezolizumab. 
• 
A mandatory, post-treatment biopsy will be obtained at the time of radiographic 
progression. 
 
Patients in tumor biopsy cohorts whose tissue sample is not evaluable may receive 
study treatment, but these patients may be replaced for the purpose of serial biopsy 
assessment. 

 
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If a patient undergoes a medically indicated procedure at any time during the study that 
has the likelihood of yielding tumor tissue, any remaining samples or a portion of the 
tumor sample not necessary for medical diagnosis may be obtained for exploratory 
analysis.  Patients must have provided specific consent in order for discarded samples 
from routine care to be obtained. 
3.1.1.3 
Optional Biopsies (Cohort C) 
Patients in Cohort C are required to provide archival tissue or fresh biopsy during 
screening.  They will be requested to provide optional fresh biopsies (core needle 
[minimum three cores and minimum diameter 18 gauge; 16 gauge is preferable] or 
excisional biopsy) for the study of tumor immune contextures related to activity or 
resistance of atezolizumab.  For patients who consent to biopsies, a predose specimen 
will be obtained after eligibility criteria have been fulfilled before Cycle 1, Day 1, unless a 
fresh biopsy was provided during screening.  An additional biopsy is requested to be 
collected at the time of radiographic progression. 
A schedule of activities is provided in Appendix 1. 
3.1.2 
Dosing of Study Treatment beyond Disease Progression 
Dosing of study treatment beyond RECIST v1.1−defined disease progression is allowed 
for patients in all treatment arms. 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg Q2W 
(Cohorts A and B) and 1200 mg IV Q3W (Cohort C) until unacceptable toxicity or loss of 
clinical benefit, as determined by the investigator, after an integrated assessment of 
radiographic and biochemical data, local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease).  Due to the 
possibility of an initial increase in tumor burden caused by IC infiltration in the setting of 
a T-cell response (termed pseudoprogression) with atezolizumab treatment, 
radiographic progression per RECIST v1.1 may not be indicative of true disease 
progression.  In the absence of unacceptable toxicity, patients who meet criteria for 
disease progression per RECIST v1.1 while receiving atezolizumab will be permitted to 
continue atezolizumab if they meet all of the following criteria: 
• 
Evidence of clinical benefit, as determined by the investigator following a review of 
all available data 
• 
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• 
No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
that can be attributed to disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 

 
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• 
Patient's written consent to acknowledge deferring other treatment options in favor 
of continuing study treatment at the time of initial disease progression 
• 
Approval by the Medical Monitor 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The study will end when all patients enrolled have been followed until death, have 
withdrawn consent, have been lost to follow-up, or when the Sponsor decides to end the 
trial, whichever occurs first.  The total length of the study, from first patient in until end of 
follow-up, is expected to be approximately 4 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Cobimetinib plus Atezolizumab Dose and 
Schedule 
Concomitant administration of cobimetinib and atezolizumab was studied in Phase Ib 
Study GP28363 (Section 1.3.5).  Cobimetinib and atezolizumab in combination were 
found to be safe and tolerable with an atezolizumab dose of 800 mg IV Q2W (equivalent 
to the approved dose and schedule for treatment of bladder cancer of 1200 mg IV Q3W) 
and cobimetinib on the approved dose and schedule of 60 mg QD 21/7.  
Atezolizumab was administered as a single agent in Study PCD4989g with encouraging 
efficacy and safety outcomes at doses equivalent to the approved dose and schedule for 
treatment of bladder cancer of 1200 mg IV Q3W (Section 1.3.2).  Simulations using a 
population PK model for atezolizumab demonstrate that at the dose of 840 mg IV Q2W 
(atezolizumab dose schedule in Arm A and Arm B) provides an exposure within the 
range typically seen for the 1200 mg IV Q3W dose (Arm C atezolizumab dose schedule).  
Observed Phase 1 data after Q2W administration was consistent with popPK simulated 
profiles providing confidence in the predictability of the simulations.   Based on the data 
available, the two dose schedules are expected to be comparable in safety and efficacy.  
3.3.1.1 
Cohort A (Cobimetinib plus Atezolizumab with Concurrent 
Start)   
Cobimetinib will be given at the approved dose and schedule of 60 mg QD 21/7.  For 
administration with cobimetinib on this 28-day cycle, a dose of 840 mg atezolizumab will 
be given Q2W.  The 840-mg dose is expected to be similar to the 800-mg dose of 
atezolizumab and was selected in this study to simplify dose administration.  
Atezolizumab is formulated at a concentration of 60 mg/mL; thus, 800 mg corresponds 
to a volume of 13.33 mL.  To ensure consistent, precise, and clinically feasible 
administration in this study, the volume was rounded up to 14 mL, corresponding to a 
dose of 840 mg.  The 840-mg dose is not expected to result in meaningfully different 
exposures compared with an 800-mg dose.  

 
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In addition, the atezolizumab dose of 840 mg Q2W is equivalent to an average body 
weight−based dose of 15 mg/kg Q3W, the Phase II dose for atezolizumab derived from 
nonclinical and clinical studies.  It has been used in multiple atezolizumab Phase III 
studies in other indications. 
3.3.1.2 
Cohort B (Biopsy Cohort) 
Cohort B is designed to allow assessment of the effects of cobimetinib on immune 
therapy.  In this cohort, in Cycle 1 only, cobimetinib will be given for 14 days before 
initiation of atezolizumab treatment as described in Section 3.1.  Biopsies obtained 
before treatment start and at the end of the 14-day cobimetinib monotherapy period will 
allow elucidation of the effects of cobimetinib on tumor immune contexture.  Additional 
biopsies taken during the combination treatment period and at radiographic progression 
will support evaluation of the effects of combination treatment on the tumor 
micro-environment and the identification of potential mechanisms of resistance to 
combination therapy. 
During Cycle 2 and all subsequent cycles, patients in Cohort B will receive cobimetinib 
60 mg QD 21/7 and atezolizumab 840 mg IV Q2W, the same dose and schedule as in 
Cohort A. 
3.3.1.3 
Cohort C (Atezolizumab Monotherapy Cohort) 
Atezolizumab will be administered at a dose of 1200 mg IV Q3W.  As detailed in 
Section 3.3.1, this approved dose schedule based on average body weight results in 
similar atezolizumab exposure after the 840 mg Q2W dose schedule.  
3.3.2 
Rationale for Patient Population and Cohorts 
3.3.2.1 
Cohort A (Cobimetinib plus Atezolizumab with Concurrent Start) 
Cohort A will enroll patients with advanced BRAFV600 WT melanoma whose disease has 
progressed on or after treatment with an anti−PD-1 agent.  This patient population has 
limited treatment options and high unmet need.  The known effects of MAPK inhibitors, 
including cobimetinib, on tumor microenvironment (see Section 1.3.4), include effects 
that may enable conversion to an immunoresponsive phenotype, sensitize refractory 
tumors to anti−PD-1/PD-L1 agents, and/or re-sensitize relapsed tumors to these agents, 
and suggest that combination therapy with cobimetinib and atezolizumab may be 
efficacious in this population.  This hypothesis is supported by clinical data from 
Study GP28363 (see Section 1.3.5) which indicate that combination therapy with 
cobimetinib and atezolizumab in advanced melanoma results in improved ORR and PFS 
relative to either PD-1/PD-L1 or MEK inhibitor monotherapy.  
3.3.2.2 
Cohort B (Biopsy Cohort) 
The molecular mechanisms of primary and secondary resistance to anti−PD-1/PD-L1 
therapies and effects of cobimetinib on the tumor microenvironment in patients with 
post−PD-1 progression require further elucidation to inform optimal development of 
combination therapy.  In order to ensure that biomarker data collected from biopsies are 

 
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optimally informative, patients enrolled in Cohort B are required to fulfill additional 
eligibility criteria that define their disease as true primary or secondary resistant. 
In order to ensure that patients have received sufficient anti−PD-1 therapy to adequately 
assess the tumor’s sensitivity, and that the tumor’s current molecular profile represents 
the molecular profile at progression, all patients in this cohort must have received a 
minimum of two cycles of the anti−PD-1 agent and must have progressed on or after this 
therapy within 12 weeks before study start.   
The cohort will enroll approximately 6 patients with primary resistance, defined as 
progressive disease (PD) as best response, according to RECIST v1.1, and 
approximately 6 patients with secondary resistance, defined as PD following initial 
confirmed response according to RECIST v1.1.  
3.3.2.3 
Cohort C (Atezolizumab Monotherapy) 
Cohort C will enroll approximately 50 patients with advanced BRAFV600 WT melanoma, 
who have not received previous treatment, to receive atezolizumab monotherapy. 
Data from Study PCD4989g indicate that atezolizumab monotherapy provides efficacy 
benefit in advanced melanoma comparable with that reported for approved aPD-1 
monotherapies and has a comparable safety profile (Section 1.1.2).  However, since the 
patient population in this study was heterogeneous with respect to line of therapy and 
BRAF V600 status, evaluation of atezolizumab monotherapy in previously untreated, 
BRAF WT melanoma, will allow more accurate understanding of the achievable 
magnitude of efficacy in this population.  In addition, this cohort will allow comparison of 
the potential molecular mechanisms of resistance between the 3 cohorts. 
In all Cohorts A, B and C, inclusion criteria require that BRAFV600 WT status has been 
confirmed using an approved clinical test. 
In order to ensure that the ORR, DCR, duration of response (DOR), and PFS can be 
adequately assessed, patients must have measureable disease (per RECIST v1.1.) and 
locally advanced, unresectable or metastatic melanoma, as defined by the American 
Joint Committee on Cancer classification, Version 7 (Balch et al. 2009). 
Additional eligibility criteria have been incorporated that are pertinent to the safety 
profiles for cobimetinib and atezolizumab (and PD−L1-targeted therapies as a 
therapeutic class).  These criteria have been informed by clinical experience in 
Study GP28363, the Phase Ib study, which evaluates the combination of cobimetinib 
and atezolizumab in patients with diverse solid tumors, including advanced melanoma. 
3.3.3 
Rationale for Primary Endpoint Selection 
This study is designed to gain preliminary information on the potential for efficacy of 
atezolizumab in combination with cobimetinib in BRAFV600 WT melanoma that has 

 
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progressed on or after treatment with an anti−PD-1 therapy and will initially enroll a 
limited number of patients (n = 42).  Compelling evidence of anti-tumor activity in these 
patients will result in further evaluation of the combination’s activity in this indication 
The study will also enroll an additional cohort of patients with BRAFV600 WT melanoma 
who have not been previously treated to obtain additional efficacy and safety data for 
atezolizumab as monotherapy.  This will extend the efficacy data seen in melanoma in 
Study PCD4989g and clarify the magnitude of benefit achievable in previously untreated 
BRAFV600 WT patients. 
The co-primary endpoints for this study are ORR and DCR at 16 weeks. 
ORR is recognized as a correlate of survival in advanced melanoma and has been used 
as a primary endpoint in a pivotal study in this indication (Weber et al. 2015).  DCR at 
16 weeks is included as a co-primary efficacy endpoint because clinical experience in 
Study GP28363 indicates that early evaluations of ORR may underestimate the 
percentage of patients who benefit from the combination.  In Study GP28363, of the 
9 melanoma patients with a PR, 3 patients had prolonged SD and converted from SD to 
a PR after > 12 months of therapy.  Further, in a recent retrospective study that included 
172 metastatic melanoma patients treated with high-dose IL-2, SD and DCR were found 
to correlate well with survival (Hughes et al. 2015).  Early compelling evidence of 
anti-tumor activity, based on a high DCR rate, will allow timely initiation of further 
evaluation of the combination. 
3.3.4 
Rationale for Confirmation of Progressive Disease per 
RECIST v1.1  
In this study, all patients will have confirmatory scans performed 4 weeks after initial 
documentation of progression per RECIST v1.1.  Studies with immunotherapeutic 
agents indicate that conventional response criteria may not adequately assess the 
activity of immunotherapeutic agents because progressive disease (by initial 
radiographic evaluation) does not necessarily reflect therapeutic failure.  Initial increase 
in tumor burden caused by IC infiltration in the setting of a TCR can occur with 
immunotherapy and has been termed pseudoprogression (Hales et al. 2010).  However, 
the implications of atypical anti-tumor responses in the setting of immunotherapy 
combined with targeted therapy are currently unknown.  
Clinically stable patients who have a favorable benefit-risk assessment may continue on 
study treatment following radiographic progression per RECIST v1.1.  Approval from the 
study medical monitor must be obtained prior to continuing treatment.   Patients who 
continue treatment beyond radiographic disease progression will be closely monitored.  
Treatment may be discontinued if clinical deterioration occurs due to disease 
progression. 

 
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3.3.5 
Rationale for Biomarker Assessments  
Tumor tissue samples will be collected at baseline for genetic and histopathologic 
assessments at DNA, RNA, protein, and cellular levels to add to researchers' 
understanding of disease pathobiology.  Genetic alterations, immune contextures, and 
microenvironment of BRAFV600 WT melanoma may have profound effects on the efficacy 
of this combination.  Biomarker data from archival/baseline tumor will be analyzed 
together with the treatment outcomes to explore potential factors associated with 
favorable response or treatment escape.  Because these biomarkers may also have 
prognostic value, their potential association with disease progression will also be 
explored.   
Tumor biopsies are scheduled during treatment and at progression to further elucidate 
the possible mechanism of action or mechanisms of treatment escape (innate or 
acquired) of this regimen and may include evaluation of CD8+ T-cell or other IC infiltrate, 
PD-L1 expression, TCR repertoires, MAPK activation, and others involved in apoptosis 
or inflammation. 
3.3.6 
Rationale for Blood Sampling for Biomarker Assessments 
An exploratory objective of this study is to evaluate biomarkers (including, but not limited 
to, whole genome sequencing (WGS), mutations in circulating-tumor DNA), and TCR 
repertoires in blood samples.  The evaluation of blood biomarkers may provide evidence 
for biologic activity of atezolizumab plus cobimetinib in patients who have been 
previously treated with anti−PD-1 and of atezolizumab monotherapy in patients who 
have not been treated with anti-PD-1, respectively, and may allow for exploration of a 
relationship of these biomarkers with the activity of cobimetinib and atezolizumab. 
3.3.7 
Rationale for Ophthalmologic Assessments (Cohorts A and B) 
Serous retinopathy has been observed in patients treated with MEK-inhibitors, including 
cobimetinib (Flaherty et al. 2012).  Manifestations of serous retinopathy include retinal 
detachment (i.e., fluid accumulation between the neurosensory retina and the retinal 
pigment epithelium) and retinopathy. Although serous retinopathy can lead to visual 
disturbances, in some circumstances it may also be asymptomatic. 
Serous retinopathy was prospectively monitored in Study GO28141 in all patients.  
Serous retinopathy was reported more frequently in patients treated with cobimetinib 
plus vemurafenib than placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half the events were asymptomatic Grade 1 events.  Few patients treated 
with cobimetinib plus vemurafenib experienced Grade ≥ 3 ocular events (2.8%); the 
majority of these events were managed with dose modification of both cobimetinib and 
vemurafenib. Most events of serous retinopathy occurred early in treatment with a 
median onset of 1 month (De la Cruz-Merino et al. 2015). 

 
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In order to further characterize the nature and time course of this adverse event, and its 
impact to patients, additional ophthalmologic investigations have been incorporated in 
this study. All patients are required to undergo a baseline ophthalmologic examination to 
assess for history or evidence of retinal abnormalities. Thereafter, patients will have 
comprehensive ophthalmologic testing every 2 weeks during the first two cycles of 
treatment, and then every 4 weeks until Day 1 of Cycle 7 (Cohorts A and B).  If serous 
retinopathy is detected at any of these visits, monitoring will be continued at increased 
frequency (see Section 4.4.7) until the adverse event resolves or 6 months have elapsed, 
whichever occurs first. 
3.3.7.1 
Rationale for 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, 
7 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.  One example is the role of 
autophagy in Crohn 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 
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 and Ostrov 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). 

 
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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 Institutional Review 
Board/Ethics Committee (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. 
3.3.8 
Rationale for Pharmacokinetic Assessments 
The proposed PK sampling scheme for assessment of cobimetinib and atezolizumab 
concentration, together with available data from other clinical studies, will be used to 
investigate any potential drug interactions between the two molecules by comparing the 
PK data from this study with single-agent data from previous studies.  In addition, single-
agent atezolizumab data from Cohort C will be compared to atezolizumab PK collected 
in the combination cohorts (Cohort A and Cohort B). 
Atezolizumab is primarily eliminated by catabolism to inactive metabolites and, therefore, 
it has a low potential for drug interactions.  Cobimetinib is metabolized primarily by 
CYP3A, and to a lesser extent by UGT2B7, based on in vitro studies.  Because of the 
differences in metabolism, no drug−drug interaction is anticipated between cobimetinib 
and atezolizumab. 
A sparse sampling strategy will be applied in this study.  Samples for pharmacokinetic 
(PK) characterization of cobimetinib and atezolizumab will be collected as outlined in 
Appendix 2.  The pharmacokinetics of each compound each drug will be compared with 
single-agent data for each molecule from previous studies or previously developed 
population PK models. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 102 patients with advanced melanoma who have progressed on or after 
prior treatment with an anti−PD-1 therapy will be enrolled in Cohorts A and B. 
An additional 50 patients with advanced melanoma who have not received previous 
treatment will be enrolled in Cohort C. 

 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry. 
4.1.1.1 
Disease-Specific Inclusion Criteria: Cohorts A and B 
• 
Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAFV600 
WT (locally advanced) melanoma  
• 
Documentation of BRAFV600 mutation−negative status in melanoma tumor tissue 
(archival [< 5 years old] or newly obtained) through use of a clinical mutation test 
approved by the local health authority (e.g., U.S. Food and Drug Administration 
[FDA]-approved test, CE-marked [European conformity] in vitro diagnostic in E.U. 
countries, CLIA-certified next-generation sequencing (NGS) test or equivalent) 
• 
Measurable disease according to RECIST v1.1 (see Appendix 3) 
• 
Disease progression on or after treatment with a PD-1 inhibitor either as 
monotherapy or in combination with other agent(s) 
 
4.1.1.2 
Additional Disease-Specific Inclusion Criteria in Cohort B 
(Biopsy Cohort) 
• 
Patients in this cohort must have progressed on or after anti−PD-1 therapy within 
12 weeks before study start. 
• 
Patients in this cohort must have received a minimum of two cycles of anti−PD-1 
therapy. 
• 
Patients in this cohort must meet criteria for primary (n = 6) or secondary (n = 6) 
resistance to an anti-PD-1 agent as outlined below: 
Primary resistance is defined as PD as best response according to RECIST v1.1. 
Secondary resistance is defined as PD after initial response according to 
RECIST v1.1. 
• 
Patients in this cohort must consent to undergo tumor biopsies of accessible lesions, 
before and during treatment and at radiographic progression, for biomarker 
analyses. 
• 
Patients in this cohort must have at least two accessible lesions that are amenable 
to excisional or core-needle (minimum three cores and minimum diameter 18 gauge; 
however, 16 gauge is desirable) biopsy with acceptable risk of a major procedural 
complication.  Exceptions may be made if patient has only one lesion that allows 
multiple biopsies following discussion with Medical Monitor. 
 
4.1.1.3 
Disease-Specific Inclusion Criteria:  Cohort C 
 
• 
Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc 
BRAFV600 WT (locally advanced) melanoma  
• Naive to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, 
hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies), 
with the following exceptions: 
– Adjuvant treatment with interferon-α (IFN-α), interleukin-2 (IL-2), or vaccine 
therapies, if discontinued at least 28 days prior to initiation of study treatment 

 
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– Adjuvant treatment with ipilimumab, if discontinued at least 90 days prior to 
initiation of study treatment 
– Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to 
initiation of study treatment 
• 
Documentation of BRAFV600 mutation−negative status in melanoma tumor tissue 
(archival [< 5 years old] or newly obtained) through use of a clinical mutation test 
approved by the local health authority (e.g., U.S. Food and Drug Administration 
[FDA]-approved test, CE-marked [European conformity] in vitro diagnostic in E.U. 
countries, CLIA-certified next-generation sequencing [NGS] test or equivalent) 
• 
A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a 
paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial 
sections must be submitted along with an associated pathology report prior to 
study entry.  If 20 slides are not available or the tissue block is not of sufficient size, 
the patient may still be eligible for the study, after discussion with and approval by 
the Medical Monitor. 
If archival tissue is unavailable or is determined to be inadequate, tumor tissue 
must be obtained from a biopsy performed at screening.  
• 
Measurable disease according to RECIST v1.1 (See Appendix 3) 
 
4.1.1.4 
General Inclusion Criteria 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
ECOG performance status of 0 or 1 (see Appendix 5) 
• 
Available and adequate baseline tumor tissue sample (archival [< 5 years old] or 
newly obtained biopsy; see Section 3.1.1) 
• 
Life expectancy ≥ 18 weeks 
• 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days before initiation of study treatment: 
Neutrophils (ANC ≥ 1500 cells/µL without G-CSF support within 2 weeks before 
Cycle 1, Day 1) 
WBC counts > 2500 cells /µL and < 15,000 cells /µL 
Lymphocyte count ≥ 500 cells/µL 
Platelet count ≥ 100,000 cells /µL (without transfusion within 2 weeks 
before Cycle 1, Day 1) 
Hemoglobin ≥ 9.0 g/dL (without transfusion) 

 
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Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min on the 
basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault 
glomerular filtration rate estimation: 
CrCl  =  
(140  −  age) × (weight in kg) 
( × 0.85 if female) 
72 × (serum creatinine in mg/dL) 
 
AST, ALT, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the 
following exceptions:   
– 
Patients with documented liver metastases:  AST and/or ALT ≤ 5 × ULN   
– 
Patients with documented liver or bone metastases:  alkaline 
phosphatase ≤ 5 × ULN 
Serum albumin ≥ 25 g/L 
Total bilirubin ≤ 1.5 × ULN; patients with known Gilbert’s disease may have a 
bilirubin ≤ 3.0 × ULN 
For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤ 1.5 × ULN 
within 28 days before initiation of study treatment 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
and stable INR during the 28 days immediately preceding initiation of study 
treatment 
For women of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraceptive methods with a 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.  
Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 

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•
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or
use a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 3 months after the last dose of cobimetinib to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the criteria in the following sections will be excluded from 
study entry. 
4.1.2.1 
Cancer-Related Exclusion Criteria 
•
Prior treatment with a MAPK inhibitor
•
Ocular melanoma
•
Major surgical procedure other than for diagnosis within 4 weeks before initiation of
study treatment, or anticipation of need for a major surgical procedure during the
course of the study
•
Traumatic injury within 2 weeks before initiation of study treatment
•
Palliative radiotherapy within 14 days before initiation of study treatment
•
Active malignancy (other than BRAFV600 mutation−negative melanoma) or
malignancy within 3 years before screening, with the exception of resected
melanoma, resected basal cell carcinoma, resected cutaneous squamous cell
carcinoma, resected carcinoma in situ of the cervix, resected carcinoma in situ of
the breast, in situ prostate cancer, limited-stage bladder cancer, or other curatively
treated malignancies from which the patient has been disease-free for at least
3 years
Patients with a history of isolated elevation in prostate-specific antigen in the 
absence of radiographic evidence of metastatic prostate cancer are eligible for 
the study. 
•
Treatment with any anti-cancer agent 14 days prior to Cycle, Day 1 other than a
PD-1 based therapy
•
Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1
Clinically stable patients with manageable immune-related adverse events 
resulting from prior cancer immunotherapy may be eligible for the study after 
discussion with and approval by the Medical Monitor. 
•
For Cohort C, specific exclusion criteria include any prior anti-cancer therapy for
advanced melanoma

 
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4.1.2.2 
Ocular Exclusion Criteria (Cohorts A and B) 
• 
History of serous retinopathy 
• 
History of retinal vein occlusion (RVO) 
• 
Evidence of ongoing serous retinopathy or RVO at baseline 
 
4.1.2.3 
Cardiac Exclusion Criteria (Cohorts A and B) 
• 
History of clinically significant cardiac dysfunction, including the following: 
Unstable angina, or new-onset angina within 3 months before initiation of study 
treatment 
Symptomatic congestive heart failure, defined as New York Heart Association 
Class II or higher 
Myocardial infarction within 6 months before initiation of study treatment 
Unstable arrhythmia 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction 
LVEF below the institutional lower limit of normal or below 50%, whichever is 
lower 
 
4.1.2.4 
Central Nervous System Exclusion Criteria 
• 
Untreated or actively progressing central nervous system (CNS) lesions 
(carcinomatous meningitis) 
Patients with stable and asymptomatic CNS metastases are eligible, if they 
meet all of the following: 
– 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
– 
All known CNS lesions are clinically stable. 
– 
CNS lesions have not been treated with whole-brain radiotherapy, except 
in patients who underwent definitive resection of or stereotactic therapy for 
all radiologically detectable parenchymal brain lesions. 
– 
Absence of interim progression must be confirmed by radiographic study 
within 4 weeks before initiation of study treatment.  If new CNS metastases 
are suspected during the screening period, a confirmatory radiographic 
study is required before initiation of study treatment. 
– 
Any radiotherapy or surgery must be completed ≥ 4 weeks before initiation 
of study treatment. 
– 
There is no ongoing requirement for corticosteroids, and any prior 
corticosteroid treatment must be discontinued ≥ 2 weeks before initiation of 
study treatment.  Treatment with an anticonvulsant at a stable dose is 
allowed. 

 
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• 
History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of 
the optic apparatus (optic nerves and chiasm) 
• 
History of leptomeningeal metastatic disease 
 
4.1.2.5 
Exclusions Related to Infections 
• 
HIV infection 
• 
Active tuberculosis infection 
• 
Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited 
to, hospitalization for complications of infection, bacteremia, or severe pneumonia 
• 
Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of 
Cycle 1 
• 
Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1 
Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
• 
Active or chronic viral hepatitis B or C infection 
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening, are eligible for the study if quantitative HBV DNA <  500 IU/mL at 
screening. 
Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain 
reaction test for HCV RNA is negative. 
 
4.1.2.6 
Exclusion Criteria Related to Autoimmune Conditions and 
Immunomodulatory Drugs 
• 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti−phospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 6 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study. 
Patients with a history of manageable immune-related adverse events resulting 
from prior immunotherapy may be eligible for the study after discussion with 
and approval by the Medical Monitor 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
– 
Rash must cover <10% of body surface area. 

 
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– 
Disease is well controlled at baseline and requires only low−potency 
topical corticosteroids. 
– 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months. 
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti−tumor necrosis factor alpha [TNF-α] agents) within 2 weeks before initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during the course of the study with the following exceptions: 
Patients who have received acute, low-dose systemic immunosuppressant 
medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse 
dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical 
Monitor approval has been obtained. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
 
4.1.2.7 
Additional Exclusion Criteria 
• 
Current severe, uncontrolled systemic disease (including, but not limited to, clinically 
significant cardiovascular, pulmonary, or renal disease) other than cancer 
• 
Any Grade ≥ 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 
• 
History of stroke, reversible ischemic neurological defect, or transient ischemic 
attack within 6 months prior to Day 1 
• 
Any psychological, familial, sociological, or geographic condition that may hamper 
compliance with the protocol and follow-up after treatment discontinuation 
• 
Inability or unwillingness to swallow pills 
• 
History of malabsorption or other clinically significant metabolic dysfunction that may 
interfere with absorption of oral study treatment 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days before initiation of study treatment. 

 
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• 
Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, 
and other inherited liver disease as well as active viral disease, including positive 
HIV test at screening. 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
• 
Treatment with a live, attenuated vaccine within 4 weeks before initiation of study 
treatment, or anticipation of need for such a vaccine during the course of the study 
• 
Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster 
ovary cells 
• 
Known hypersensitivity to any component of the atezolizumab or cobimetinib 
formulations 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
• 
Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent 
• 
Requirement for concomitant therapy or food that is prohibited during the study, as 
described in Section 4.3, respectively 
 
4.2 
STUDY TREATMENT  
The investigational medicinal products (IMPs) for this study are cobimetinib and 
atezolizumab.   
4.2.1 
Formulation, Packaging, and Handling 
4.2.1.1 
Cobimetinib 
Cobimetinib tablets will be supplied by the Sponsor.  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. 
4.2.1.2 
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.  For 
Cohorts A and B, extraction of 14 mL of atezolizumab solution from a 1200 mg vial 
contains an 840-mg dose. 

 
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For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Investigator's Brochure and Pharmacy Manual. 
4.2.2 
Dosage, Administration, and Compliance 
4.2.2.1 
Cobimetinib 
Patients in Cohorts A and B will receive 60 mg (3 tablets of 20 mg each) orally QD for 
Days 1−21 of each 28-day cycle.  This 4-week period is considered a treatment cycle. 
Cobimetinib should be taken at the same time every day.  It can be taken with or without 
food.  If a 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 5.1.3. 
Any overdose or incorrect administration of cobimetinib should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of cobimetinib should be 
recorded on the Adverse Event eCRF (see Section 5.3.5.12). 
4.2.2.2 
Atezolizumab 
Cohort A:  Patients will initiate dosing with atezolizumab concurrently with cobimetinib 
and will receive atezolizumab 840 mg IV Q2W on Days 1 and 15 of all cycles. 
Cohort B:  Patients will receive the first dose of atezolizumab at 840 mg IV on Day 15 of 
Cycle 1.  Thereafter, they will receive atezolizumab 840 mg IV Q2W on Days 1 and 15 of 
Cycle 2 and all subsequent cycles. 
Cohort C:  Patients will receive atezolizumab 1200 mg IV Q3W as monotherapy. 
All dosing schedules will be given 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 Atezolizumab Investigator’s Brochure and Pharmacy Manual. 
Atezolizumab infusions will be given per the instructions outlined in Table 2. 

 
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Table 2 
Administration of First and Subsequent Infusions of 
Atezolizumab 
First Infusion 
Subsequent Infusions 
Premedication is allowed. 
If patient experienced IRR during any previous 
infusion, premedication 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 minutes before starting infusion.  
Record vital signs (HR, RR, BP, and T) within 
60 minutes before starting infusion. 
Infuse atezolizumab (one vial in 250 mL NaCl) 
over 60 (± 15) minutes 
If the patient tolerated the first infusion without 
infusion-associated AEs, the second infusion 
may be delivered over 30 (± 10) minutes. 
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) minutes. 
 
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. 
Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed 
to contact their study physician if they develop 
such symptoms. 
 
 
If no reaction occurs, continue subsequent 
infusions over 30 (± 10) minutes 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 reductions of atezolizumab are not permitted.  Guidelines for treatment interruption 
or discontinuation and the management of specific adverse events related to the 
combination of cobimetinib and atezolizumab are provided in Sections 5.1.3 (see 
Table 6).  Guidelines for treatment interruption or discontinuation and the management 
of atezolizumab-specific adverse events are provided in Section 5.1.2 and Appendix 8, 
as well as the Atezolizumab Investigator’s Brochure.  For anaphylaxis precautions, see 
Appendix 7.  
See the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
Any overdose or incorrect administration of atezolizumab should be noted on the 
atezolizumab administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of atezolizumab should be recorded on the Adverse Event eCRF 
(see Section 5.3.5.12). 

 
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4.2.3 
Investigational Medicinal Product Accountability 
Both IMPs required for completion of this study, cobimetinib and atezolizumab, will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs, using an interactive voice- or Web-based 
response system (IxRS) to confirm the shipment condition and content.  Any damaged 
shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
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. 
4.2.4 
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. 
A patient will be eligible to receive study drug 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 would not 
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 advanced melanoma that has progressed on or 
after treatment with an anti−PD-1 therapy. 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for advanced melanoma that has progressed on or after treatment with an 
anti−PD-1 therapy. 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country. 
 

 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.3 
CONCOMITANT THERAPY 
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 before initiation of study drug to treatment discontinuation visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.   
4.3.1 
Permitted Therapy  
The following therapies are permitted in the study: 
• 
Hormonal therapy with gonadotropin−releasing hormone agonists or antagonists for 
prostate cancer 
• 
Oral contraceptives 
• 
Hormone-replacement therapy 
• 
Prophylactic or therapeutic anticoagulation therapy (such as low-molecular weight 
heparin or warfarin at a stable dose level)  
Although allowable, caution should be used when using concomitant medications 
that increase the risk of bleeding, including antiplatelet or anticoagulant therapy, 
because of the risk of hemorrhage with cobimetinib. 
• 
Palliative radiotherapy (e.g., treatment of known bone metastases) provided it does 
not interfere with assessment of tumor target lesions 
It is not required to withhold atezolizumab during palliative radiotherapy.   
• 
Inactive influenza vaccinations during influenza season only 
• 
Megestrol given as an appetite stimulant 
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease 
• 
Mineralocorticoids (e.g., fludrocortisone) 
 
Anti-emetic and anti-diarrheal medications should not be given 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 
given prophylactically before initial treatment with study drugs.  Hematopoietic growth 
factors may be given according to local guidelines if indicated during the study.  
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist as per standard 

 
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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 β2-adrenergic agonists). 
All medications must be recorded on the Concomitant Medications eCRF. 
4.3.2 
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.   
Use of the following concomitant therapies is prohibited as described below: 
• 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority−approved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent, and 
during study treatment until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy and local 
therapy under certain circumstances.  
• 
Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks before study start or at 
any time during the study or within 5 months following the last infusion of 
atezolizumab. 
• 
Prohibited therapies applicable to patients receiving atezolizumab: 
Immunomodulatory agents, including, but not limited to, IFNs 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-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations 
where systemic corticosteroids or TNF-α inhibitors would be routinely given, 
alternatives, including antihistamines, should be considered first by the treating 
physician.  If the alternatives are not feasible, systemic corticosteroids and 
TNF-α inhibitors may be administered at the discretion of the treating physician 
(see Section 4.3.2). 

 
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• 
For patients receiving 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. 
 
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication is metabolized by or strongly inhibits or 
induces CYP3A.  In addition, the investigator should contact the Medical Monitor if 
questions arise regarding medications not listed above. 
4.3.3 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.3.3.1 
Corticosteroids and Tumor Necrosis Factor-α Inhibitors 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-α inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered.  If the alternatives are not feasible, 
systemic corticosteroids and TNF-α inhibitors may be administered at the discretion of 
the investigator (see Section 4.3.2). 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to Appendix 8 for details). 
4.4 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities to be performed during the study.  
All activities must be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study.  Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment 
and local laboratory test values are acceptable.  Safety assessments specified in this 
section are for the purposes of monitoring and management of toxicities known to be 
associated with study drugs included in this study (see Section 5 for further information). 

 
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4.4.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  Informed Consent Forms for enrolled patients 
will be maintained at the study site. 
BRAFV600 WT status must be known before beginning the remaining screening 
evaluations.  All screening evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before study start.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Screening Window Extension and Re-screening 
The screening window may be extended for an agreed upon and acceptable period to 
allow re-evaluation of assessments after discussion and agreement with the 
Medical Monitor. 
Patients may be eligible for re-screening up to two additional times, with all inclusion and 
exclusion criteria being re-assessed. 
4.4.2 
Medical History and Demographic Data 
Medical history, including clinically significant diseases and surgeries within 5 years 
before initiation of study treatment, cancer history (including prior cancer therapies, 
surgeries, and procedures), and use of alcohol, will be recorded at baseline.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days before initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity (where 
permissible). 
4.4.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat (HEENT), neck, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  HEENT examination should include visual 
inspection and/or palpation of the oral cavity and oropharynx, and palpation of the 
draining lymph nodes of the neck.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations, consisting of an evaluation of the oral 
cavity, oropharynx, head and neck (including lymph nodes), lungs, heart, abdomen, and 
skin, should be performed at specified post-baseline visits and as clinically indicated.  

 
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Patients should be asked specifically about skin and vision changes as part of each 
physical examination.  Changes from baseline abnormalities should be recorded at each 
subsequent physical examination.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.   
Patients should be asked specifically about skin and vision changes as part of each 
physical examination. 
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.4.4 
Vital Signs  
Vital signs include measurements of heart rate, respiratory rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, as well as oral or 
tympanic temperature.  Blood pressure and heart rate measurements will be recorded 
after a 5-minute rest while the patient is in a seated position.  Resting oxygen saturation 
will be measured during screening. 
Vital signs should be measured within 60 minutes before each atezolizumab infusion 
and, if clinically indicated, during or after the infusion.  In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1). 
For patients in the atezolizumab arm who experienced an infusion-related reaction (IRR) 
during the previous atezolizumab infusion, refer to Section 5.3.5.1). 
4.4.5 
Tumor and Response Evaluations  
All measurable and non-measurable lesions must be documented at screening (within 
28 days before initiation of study treatment).  Evaluation of tumor response conforming 
to RECIST v1.1 must then be documented every 8 weeks (± 1 week); from the date of 
first study drug administration until investigator-determined disease progression 
(according to RECIST v1.1 that is confirmed 4 weeks after initial documentation of 
progression) or death, whichever occurs first.  Thus, tumor assessments are to continue 
according to schedule for patients who discontinue treatment for reasons other than 
disease progression.  At the investigator’s discretion, tumor assessments may be 
repeated at any time if disease progression is suspected.   
Tumor assessments must be performed independently of changes to the study 
treatment administration schedule (i.e., when treatment is withheld).  If a tumor 
assessment has to be performed early or late, subsequent assessments should be 
conducted according to the original schedule based on the date of first study treatment.  
Tumor assessments will include contrast-enhanced CT or MRI scans of the chest, 
abdomen, and pelvis.  Imaging of the neck should be included if clinically indicated.  In 

 
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the event a positron emission tomography (PET)/CT scanner is used for tumor 
assessments, the CT portion of the PET/CT scanner must meet criteria for diagnostic 
quality.   
A CT or MRI scan of the head must be performed at screening to assess CNS 
metastasis.  An MRI scan of the brain is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal scan.  Patients with untreated 
or actively progressing CNS metastases are not eligible for the study (see 
Section 4.1.2).  Stable brain metastases (as defined in Appendix 1) must be evaluated at 
each tumor assessment with the same radiographic procedure as the baseline study.  
Patients without brain metastases do not need brain scans for tumor assessment unless 
clinically warranted.  Clinical disease assessments by physical examination should be 
performed for patients with palpable/superficial lesions.  Tumor measurements for each 
patient should be made by the same investigator or radiologist, if feasible, using the 
same assessment technique or procedure throughout the study. 
Tumor response and progression will be evaluated according to RECIST v1.1 (see 
Appendix 3) and immune-modified RECIST (see Appendix 4).  Objective response 
(a CR or PR) must be confirmed by repeat assessments ≥ 4 weeks after initial 
documentation.  In the case of SD, tumor measurements must meet criteria for 
SD ≥ 6 weeks after initiation of study treatment.   
4.4.6 
Left Ventricular Ejection Fraction  
All patients will require evaluation of LVEF at screening and Cohorts A and B will require 
subsequent evaluations of LVEF. 
Evaluation of LVEF by ECHO or MUGA scan 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)  
• 
The treatment discontinuation visit evaluation of LVEF does not need to be 
performed at the treatment discontinuation visit if an evaluation has been performed 
within the last 12 weeks, and there are no clinically significant findings and/or 
changes from baseline.  
• 
All patients restarting treatment with a dose reduction of cobimetinib because of a 
decrease in LVEF should have LVEF measurements taken after approximately 2, 4, 
10, and 16 weeks, and then resume monitoring LVEF every three treatment cycles. 
 
Any patient who develops clinical signs or symptoms suspicious of cardiac failure should 
undergo an LVEF assessment.  Evaluation of LVEF must be performed by the same 
method (ECHO or MUGA scan) for each patient.  It is strongly encouraged that the same 
laboratory and operator perform ECHO/MUGA scans for each patient.  Investigators 

 
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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. 
4.4.7 
Ophthalmologic Examination (Cohorts A and B) 
All patients in Cohorts A and B will require an ophthalmologic examination at screening 
and subsequent ophthalmologic examinations.  The objective of a baseline 
ophthalmologic examination is to evaluate for evidence of retinal abnormalities.  An 
ophthalmologic examination must be performed by a qualified ophthalmologist.   
Baseline and serial surveillance ophthalmologic examinations will include visual acuity 
testing using a standard Snellen chart, intraocular pressure measurement by tonometry, 
slit-lamp biomicroscopy, indirect ophthalmoscopy, spectral−domain optical coherence 
tomography (OCT), and automatic visual field testing.  Spectral-domain OCT, if not 
available, may be substituted with time-domain OCT.  Ophthalmologic examinations 
must be performed according to the schedule in Table 3. 
Table 3 
Ophthalmologic Examination Schedule 
 
Frequency 
Assessments 
Screening 
One time 
Visual acuity test, VF 24-2, slit-lamp 
biomicroscopy, IOP measurement, OCT, 
indirect ophthalmoscopy 
Cycles 1 and 2 
Q2W (± 1) day of the 
scheduled visit, if serous 
retinopathy is not detected 
Visual acuity test, OCT, indirect 
ophthalmoscopy a 
Increase to QW (± 1) day, if 
serous retinopathy is 
detected, until resolution or 
until Cycle 2, Day 28, 
whichever occurs first 
Visual acuity test, VF b, OCT, indirect 
ophthalmoscopy 
Cycles 3 to 6 
Q4W ± 1 day of the 
scheduled visit, if serous 
retinopathy is not diagnosed 
Visual acuity test, OCT, indirect 
ophthalmoscopy a 
Increase to Q2W ± 1 day, if 
serous retinopathy is 
detected, until resolution or 
until Cycle 6, Day 28, 
whichever occurs first 
Visual acuity test, VF b, OCT, indirect 
ophthalmoscopy 
 

 
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Table 3 
Ophthalmologic Examination Schedule (cont.)  
From Cycle 7  
Every 3 cycles (± 2 weeks) 
Visual acuity test, indirect ophthalmoscopy c 
Treatment 
discontinuation d 
One time 
Visual acuity test, VF b, slit-lamp 
biomicroscopy, IOP measurement, OCT, 
indirect ophthalmoscopy 
IOP = intraocular pressure; OCT = optical coherence tomography; Q2W = every two weeks; 
Q4W = every 4 weeks; VF = visual field.  
Note:  Examinations should be performed prior to dosing. 
a If serous retinopathy is diagnosed at any visit, patients must also have visual field testing if not 
already performed at this visit.   
b Perform Swedish Interactive Threshold Algorithm Fast strategy (or equivalent):  
• 
10-2 threshold test if serous retinopathy is detected only within the macula 
• 
24-2 threshold test if serous retinopathy is extramacular or if extends beyond the macula  
c Per ophthalmologist discretion, may perform other clinically indicated tests.  Also refer to 
management guidelines in Table 6. 
d Does not need to be performed if an evaluation has been performed within the last 12 weeks 
and no signs of serous retinopathy were detected. 
 
4.5 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
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 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
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. 

 
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4.5.2 
Laboratory, Biomarker, and Other Biologic Samples 
4.5.2.1 
Local Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
reticulocyte count, and differential count (neutrophils, bands, eosinophils, basophils, 
monocytes, and lymphocytes) 
• 
Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
bicarbonate (or total carbon dioxide), BUN or urea, creatinine, albumin, phosphorus, 
calcium, direct and total bilirubin, ALP, ALT, AST, LDH, CPK, and glucose (non-
fasting), total protein, and uric acid  
• 
Fasting blood glucose (after a minimum 8-hour fast), at screening only 
• 
Fasting lipids:  total cholesterol, LDL cholesterol, and triglycerides (after a minimum 
8-hour fast), at screening only 
• 
Coagulation:  INR, aPTT 
• 
Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3; or 
total T3 for sites where free T3 is not performed), and free thyroxine 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, blood and microscopic 
examination) 
• 
HIV serology 
• 
HBV serology:  HBsAg, and total HBcAb and (if HBsAg test is negative and total 
HBcAb test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
• 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test must 
also be performed to determine if the patient has an active HCV infection. 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening, within 7 days before initiation of study treatment.  Urine pregnancy 
tests will be performed at specified subsequent visits.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).   
 

 
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4.5.2.2 
Central Laboratory Assessments 
The following samples will be sent to one or several central laboratories or to the 
Sponsor for analysis: 
• 
Serum samples for atezolizumab PK analysis through use of a validated assay 
• 
PBMC and plasma samples for cobimetinib PK analysis through use of a validated 
assay 
• 
Serum samples for assessment of anti-drug antibodies (ADAs) to atezolizumab 
through use of a validated assay 
• 
Plasma and blood samples for exploratory research on biomarkers 
• 
Archival (most recently obtained [< 5 years old]) or fresh tumor tissue sample 
consistent with the patient's diagnosis, collected at baseline for determination of 
BRAFV600-mutation status and for exploratory research on biomarkers 
A representative formalin-fixed paraffin-embedded tumor specimen in a paraffin 
block (preferred) or 20 slides containing unstained, freshly cut, serial sections 
must be submitted along with an associated pathology report prior to study start. 
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Tumor tissue should be of good quality based on total and viable tumor content.  
Acceptable samples include those from resections, core-needle biopsies (at 
least three cores, embedded in a single paraffin block), or excisional, incisional, 
or forceps biopsies.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), brushing, 
cell pellets from pleural effusion, and lavage samples are not acceptable.  
Tumor tissue from bone metastases that have been decalcified is not 
acceptable. 
If 20 slides are not available or the tissue block is not of sufficient size, the 
patient may still be eligible for the study after discussion with and approval by 
the Medical Monitor.  If archival tissue is unavailable or unacceptable, a 
pretreatment tumor biopsy is required.   
For archival samples (< 5 years old), remaining tumor tissue blocks for enrolled 
patients will be returned to the site upon request or 18 months after final closure 
of the study database, whichever occurs first.  Remaining tumor tissue blocks 
for patients who are not enrolled in the study will be returned to the site no later 
than 3 months after eligibility determination.  Slides will not be returned. 
• 
For patients in Cohorts A and C, optional tumor tissue samples collected at the time 
of progression, if deemed clinically feasible by the investigator, for exploratory 
research on biomarkers 
Biopsies should be performed at the time of progression, preferably within 
3 days after the last does of study treatment.  Acceptable samples include 
those from resections, core-needle biopsies (three cores preferred), or 
excisional, incisional, or forceps biopsies. 

 
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• 
For Cohort A patients, an optional biopsy can also be collected 4−6 weeks after the 
first atezolizumab dose.   
• 
For patients enrolled in Cohort B, the biopsy cohort will undergo biopsies according 
to the following schedule:  
A mandatory predose biopsy will be obtained before Cycle 1, Day 1. 
A mandatory on-treatment biopsy will be obtained between Days 10 and 14 of 
Cycle 1. 
A second, optional, on-treatment biopsy will be obtained during Cycle 2, after 
the second dose of atezolizumab, to assess the combined effects of 
cobimetinib and atezolizumab. 
A mandatory biopsy at the time of progression 
 
Biomarker research may include, but will not be limited to, analysis of S100, ctDNA, 
genes or gene signatures associated with tumor immunobiology, tumor immune profiles 
(e.g., CD8, MHC, and PD-L1), lymphocytes, or TCR repertoire and may involve DNA or 
RNA extraction, analysis of somatic mutations, and use of NGS (see Table 4).  An 
optional blood sample for WGS may also be obtained. 

 
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Table 4 
Proposed Biomarkers for Exploratory Research 
Sample Type  
Timing  
Proposed Biomarker(s) 
Plasma 
Predose on Day 1 of Cycles 
1, 2, at time of subsequent 
radiologic tumor 
assessments, and at 
disease progression 
• S100 
• ctDNA 
PBMC 
Predose on Day 1 of Cycles 
1, 2, and at time of 
subsequent radiologic 
tumor assessments, and at 
disease progression 
• TCR repertoires 
Tumor tissues  
Prior to study: archival (< 5 
years old) or at baseline 
(required) 
• Tumor mutations 
• Tumor-immune contexture, 
such as PD-L1, MHCI, and 
CD8+ T cells  
Tumor biopsy 
On-treatment (optional) and 
time of disease progression 
(required if clinically 
feasible) 
• Tumor-immune contexture, 
such as PD-L1, MHCI, and 
CD8+ T cells 
DNA and RNA extracted 
from tumor tissues, 
plasma and PBMC 
Same as tumor tissue and 
biopsy 
• Mutation load/profiles in DNA 
• TCR profiles in DNA 
• Immuno-signatures by RNA 
expression 
ctDNA = circulating tumor DNA; MHCI = major histocompatibility complex class I; 
PBMC = peripheral blood mononuclear cell; PD-L1 = programmed death−ligand 1; 
TCR = T-cell receptor. 
 
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from these analyses in the form of an NGS report, 
which is available upon request directly from Foundation Medicine.  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. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 

 
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Biologic samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 
• 
Plasma and serum samples collected for PK analysis or immunogenicity analysis 
may be needed for additional immunogenicity characterization and PK and 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed. 
• 
Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted. 
• 
Blood and tissue samples collected for biomarker analyses will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed, or earlier, 
depending on local regulations. 
 
When a patient withdraws from the study, samples collected before the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.3 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Clinical deterioration due to disease progression 
• 
Any adverse event that requires study treatment discontinuation per the guidelines 
in Appendix 7. 
• 
Use of a non−protocol-specified anti-cancer therapy  
• 
Intolerance of study treatment despite undergoing protocol-defined dose reduction 
• 
Pregnancy 
• 
Withdrawal of consent 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment 

 
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• 
Investigator or Sponsor determines it is in the best interest of the patient 
(e.g., unwillingness to comply with study assessments that compromise their safety) 
 
Patients who discontinue study drug for any reason will be asked to return to the clinic 
for a treatment discontinuation visit 30 (± 3) days after the last dose of study drug.  The 
visit at which response assessment shows disease progression may be used as the 
treatment discontinuation visit, provided all required assessments have been performed 
and it is 30 (± 3) days after the last dose of study drug.  The primary reason for study 
treatment discontinuation should be documented on the appropriate eCRF.  Patients 
who discontinue study treatment will not be replaced. 
After treatment discontinuation, information on survival follow-up and subsequent 
anti-cancer therapy will be collected via telephone calls, patient medical records, and/or 
clinic visits approximately every 12 weeks until death (unless the Sponsor terminates the 
study).  If the patient withdraws from the study, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only 
as is permissible per local laws and regulations. 
4.5.4 
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 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with cobimetinib 
and atezolizumab in completed and ongoing studies and on published data from similar 
molecules.  The anticipated important safety risks for cobimetinib and atezolizumab are 

 
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outlined below.  Refer to the Cobimetinib Investigator's Brochure and Atezolizumab 
Investigator’s Brochure for a complete summary of safety information.  
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study. Eligibility criteria have been designed to exclude patients at 
higher risk for toxicities.  Administration of atezolizumab will be performed in a monitored 
setting in which there is immediate access to trained personnel and adequate equipment 
and medicine to manage potentially serious reactions.   
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.  Refer to the 
specific guidelines for each arm individually. 
The risks associated with cobimetinib and atezolizumab are detailed in Section 5.1.1 and 
5.1.2, respectively.  Additional information on the risks of atezolizumab and management 
of atezolizumab-related adverse events are outlined in Appendix 8 
Adverse events will be reported as described in Sections 5.2−5.4. Oversight will be 
provided by the Medical Monitor and drug safety personnel. 
5.1.1 
Risks Associated with Cobimetinib 
The information related to the risks attributed to cobimetinib is based on safety data from 
Studies GO28141, NO25395, and MEK4592g.  Additional clinical experience has been 
obtained through postmarketing experience and clinical studies with cobimetinib in 
combination with other agents.  The safety data are also based on postmarketing 
experience.  For further information regarding clinical safety, refer to the current 
Cobimetinib Investigator’s Brochure. 
5.1.1.1 
Important Identified Risks Associated with Cobimetinib 
5.1.1.1.1 
Hemorrhage 
Hemorrhage, including major hemorrhages, defined as symptomatic bleeding in a critical 
area or organ, can occur with cobimetinib.  In clinical studies with cobimetinib, events of 
cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract hemorrhage, 
and hematuria, have been reported. 
In Study GO28141, Grade 1−4 hemorrhagic events were reported in 13.0% of patients 
treated with cobimetinib plus vemurafenib and in 7.3% of patients treated with placebo 
plus vemurafenib.  The majority of hemorrhagic events were Grade 1 or 2 and 
non-serious.  Grade 3 and 4 hemorrhage events were reported in 1.2% of patients 

 
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receiving cobimetinib plus vemurafenib and in 0.8% of patients receiving placebo plus 
vemurafenib.  
Caution should be used in patients with additional risk factors for bleeding, such as brain 
metastases, and/or in patients that use concomitant medications that increase the risk of 
bleeding (including antiplatelet or anticoagulant therapy). 
Instructions for dose modification for hemorrhagic events are included in Section 5.1.3.3. 
5.1.1.1.2 
Serous Retinopathy 
Serous retinopathy is a known adverse effect of cobimetinib and has also been observed 
with other MEK inhibitors (refer to Section 3.3.7 for details). 
To address serous retinopathy with cobimetinib treatment, all patients are required to 
undergo ophthalmologic examination at baseline and at specified timepoints throughout 
the study.  Details regarding baseline and subsequent ophthalmologic examinations are 
provided in Section 4.4.7. 
Guidelines for management of patients who develop Grade ≥ 2 visual disorders or 
retinopathy are provided in Section 5.1.3.3. 
5.1.1.1.3 
Left Ventricular Dysfunction 
Decreases in LVEF from baseline have been reported in patients receiving cobimetinib.  
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF events may be asymptomatic. 
Left ventricular dysfunction has been characterized in Study GO28141.  The study 
incorporated prospective serial LVEF evaluations in all patients.  With active surveillance, 
measured Grade 2 or 3 reductions in LVEF were observed more frequently in patients 
treated with cobimetinib plus vemurafenib than placebo plus vemurafenib (8.5% vs. 
3.7%, respectively).  Of the patients treated with cobimetinib plus vemurafenib, 
2 patients (0.8%) had symptomatic reduction in LVEF and the remaining patients were 
asymptomatic.  Most LVEF reduction events in patients on cobimetinib plus vemurafenib 
(62%) improved or resolved with management according to dose modification guidelines 
(see in Section 5.1.3.3).  

 
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5.1.1.1.4 
Rhabdomyolysis and CPK Elevations 
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 
elevations reported was asymptomatic, non-serious, and resolved with or without study 
drug interruption.  One event of rhabdomyolysis was reported in the Phase III study 
GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported in the 
postmarketing experience. 
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade ≥ 3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade ≥ 3 events). 
CPK will be monitored at baseline and monthly during treatment or as clinically indicated. 
5.1.1.1.5 
Liver Laboratory Abnormalities 
Liver laboratory abnormalities can occur when cobimetinib is used with vemurafenib. 
Liver laboratory abnormalities, specifically increases in ALT, AST, and ALP, have been 
observed in patients treated with cobimetinib and vemurafenib. 
Liver laboratory tests should be monitored before initiation of treatment and monthly 
during treatment, or more frequently as clinically indicated. 
Grade 3 and 4 liver laboratory abnormalities should be managed with dose interruption, 
reduction, or discontinuation of cobimetinib. 
5.1.1.1.6 
Pneumonitis 
Events of pneumonitis have been reported in cobimetinib clinical studies.  Most reported 
events were considered to be non-serious and of low severity grade.  In Study GO28141, 
pneumonitis events were reported more frequently in patients treated with cobimetinib 
plus vemurafenib than placebo plus vemurafenib (1.6% vs. 0.4%; all grades).  
There were no reported Grade ≥ 3 events in either study arm.  Serious events were 
reported for 2 patients (0.8%) treated with cobimetinib plus vemurafenib. 
5.1.1.2 
Potential Risks Associated with Cobimetinib 
5.1.1.2.1 
Severe Hepatotoxicity (Grade ≥ 3) 
Liver laboratory test abnormalities, including increases in ALT, AST, and ALP, have 
been reported as adverse events and serious adverse events in patients treated with 
cobimetinib. 
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines and the majority of Grade ≥ 3 liver laboratory test abnormalities 
resolved. 

 
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One case of drug-induced liver injury and one case of concurrent elevations of AST/ALT 
and total bilirubin in Study GO28141 were reported.  However, the causality assessment 
for cobimetinib was confounded by the known liver toxicity of vemurafenib and/or the 
presence of liver metastases.  Therefore, severe hepatotoxicity is a potential risk for 
cobimetinib. 
5.1.1.2.2 
Impaired Female Fertility and Developmental Toxicity 
There is a potential for effects on fertility and embryofetal toxicity based on results from 
nonclinical studies.  
Although no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased 
apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal 
epithelial cells in rats, and epididymal epithelial cells in dogs.  These changes were 
reversible upon discontinuation of cobimetinib administration. 
5.1.1.2.3 
Teratogenicity and Developmental Toxicity 
In a dedicated embryofetal toxicity study, cobimetinib produced fetal toxicity (resorptions 
and reductions in fetal weight) and teratogenicity (malformations of the great vessels and 
skull) at similar systemic exposures to those observed in patients administered the 
60-mg dose. 
5.1.1.3 
Other Risks with Cobimetinib 
5.1.1.3.1 
Rash 
In Study GO28141, combined rash events of all types and grades were reported more 
frequently in patients treated with cobimetinib plus vemurafenib than placebo plus 
vemurafenib (71.7% vs. 66.7%, respectively), although Grade ≥ 3 events (approximately 
16% of patients) and types of rash reported were similar between study arms.  Specific 
events in patients treated with cobimetinib plus vemurafenib included rash (39% all 
grades, 5.9% Grade ≥ 3, and 1.6% serious adverse events) and maculopapular rash 
(14.6% all grades, 6.3% Grade ≥ 3, and 1.2% serious adverse events). 
Generally, Grade ≥ 3 rash events were effectively managed with dose modification 
guidelines.  In Study GO28141, approximately 90% of Grade ≥ 3 rash events resolved in 
both arms. 

 
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5.1.1.3.2 
Gastrointestinal Toxicity 
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, 
have been reported in all cobimetinib studies in adult cancer patients. 
In Study GO28141, diarrhea was the most common adverse event reported.  Diarrhea 
events of all severity grades were reported in 59.9% of patients and Grade 3 or 4 events 
were reported in 6.5% of patients treated with cobimetinib plus vemurafenib versus 
30.9% (Grade 3) and 0.8% (Grade 4) in the patients treated with placebo plus 
vemurafenib.  No Grade 5 events of diarrhea have been reported.  Serious adverse 
events of diarrhea were reported for 1.2% of patients treated with cobimetinib plus 
vemurafenib. 
Nausea and vomiting have been reported in association with cobimetinib.  Most nausea 
and vomiting events were considered to be non-serious and of low severity grade.  In 
Study GO28141, nausea and vomiting events were reported more frequently in the 
active cobimetinib arm than the control arm (nausea, 41.3% vs. 25.2%; vomiting, 24.3% 
vs. 12.6%).  However, of patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea, 0.8%; vomiting, 1.2%). 
In the Phase I single-agent study (MEK4592g), all grades of nausea and vomiting were 
both reported as 33.9%, with 0.9% reported for Grade ≥ 3 nausea and none reported for 
vomiting. 
The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake.  In the majority of cases, diarrhea has been effectively 
managed with anti-diarrheal agents and supportive care.  Routine anti-emetic 
prophylaxis is not recommended.  
5.1.1.3.3 
Hypersensitivity 
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib monotherapy or cobimetinib when used 
with other agents.  These have appeared to be isolated reports, and in some cases, 
occurred in patients with history of drug allergies.  Thus, the relationship of cobimetinib 
to these events is unclear. 
In Study GO28141, Grade 3 hypersensitivity events were reported for 3 patients in the 
cobimetinib plus vemurafenib arm compared with no such events in the placebo plus 
vemurafenib arm.  All events required hospitalization and treatment with steroids.  
Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction. 

 
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5.1.2 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, 
hypophysitis, and nephritis.  In addition, systemic immune activation is a potential risk 
associated when atezolizumab is given in combination with other immunomodulating 
agents.  Refer to Appendix 8 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab. 
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 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) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.  See Appendix 8 for additional 
information on the diagnosis and management of systemic immune activation. 
5.1.3 
Management of Patients Who Experience Specific 
Adverse Events 
5.1.3.1 
Cobimetinib Dose Modifications 
General dose modifications for cobimetinib are provided in Table 5.  Dose modifications 
for specific adverse events are provided in Table 6. 

 
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Table 5 
Recommended Cobimetinib Dose Modifications 
Grade  
(NCI CTCAE) 
Recommended 
Cobimetinib Dose 
Grade 1 or Grade 2 (tolerable) 
No dose reduction.  Maintain cobimetinib at the same dose 
of 60 mg QD (3 tablets) 
Grade 2 (intolerable) or Grade 3 
or 4 (any) 
 
First appearance 
Interrupt treatment until Grade ≤ 1, restart treatment at 
40 mg QD (2 tablets) 
Second appearance 
Interrupt treatment until Grade ≤ 1, restart treatment at 
20 mg QD (1 tablet) 
Third appearance 
Consider permanent discontinuation. 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
QD = once daily. 
 
5.1.3.2 
Atezolizumab Dose Modifications 
There will be no dose reduction for atezolizumab in this study. 
5.1.3.3 
Management of Cobimetinib- and Atezolizumab-Specific 
Adverse Events 
Toxicities associated or possibly associated with cobimetinib plus atezolizumab 
treatment should be managed according to standard medical practice.  See Appendix 8 
for management of adverse events related to atezolizumab. 
For management of cobimetinib- and atezolizumab-specific toxicities, including IRRs, 
gastrointestinal toxicity, dermatologic toxicity, hepatotoxicity, pulmonary toxicity, potential 
eye toxicity, reductions in LVEF from baseline, rhabdomyolysis, elevated CPK, and 
hemorrhage, see Table 6. 

 
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Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) 
Event 
Action to Be Taken 
General guidance for dose 
modifications and treatment 
delays and discontinuation 
• There will be no dose modifications for atezolizumab.   
• If atezolizumab is withheld and corticosteroids are initiated for 
an atezolizumab-related toxicity, corticosteroids must be 
tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. a, b, c 
The dose of cobimetinib can be reduced by 20 mg (one dose 
level) up to two times (i.e., from 60 mg to 40 mg and then from 
40 mg to 20 mg).  If further dose reduction is indicated after 
two dose reductions, the patient must discontinue cobimetinib 
but may continue treatment with atezolizumab at the 
investigator’s discretion. 
• If atezolizumab is discontinued, treatment with cobimetinib 
may be continued at the investigator’s discretion and after 
discussion with the Medical Monitor. 
• If cobimetinib is withheld for > 28 days because of toxicity, the 
patient should be discontinued from cobimetinib, unless 
resumption of treatment is approved by the Medical Monitor 
after discussion with the investigator.  
• If atezolizumab is withheld for > 105 days because of toxicity, 
the patient should be discontinued from atezolizumab, unless 
resumption of treatment is approved by the Medical Monitor 
after discussion with the investigator. 
IRRs, anaphylaxis, and 
hypersensitivity reaction 
• Guidelines for management of IRRs are provided in 
Appendix 8. 
• For anaphylaxis precautions, see Appendix 7. 
• For severe hypersensitivity reactions, permanently discontinue 
all study treatment. 
IRR = infusion-related reaction. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for 
corticosteroids to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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. 
 

 
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Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity 
 
Gastrointestinal events:  
general guidance 
• All events of diarrhea or colitis should be thoroughly evaluated for 
more common etiologies other than drug-induced effects. 
• For events of significant duration or severity or associated with 
signs of systemic inflammation or acute-phase reactants, check for 
immune-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:  
– Loperamide: Initiate dose with 4 mg and then 4 mg/6 hr around 
the clock, alternating with Lomotil. ® 
– Lomotil® (diphenoxylate and atropine):  2 tablets (diphenoxylate 
5 mg, atropine 0.05 mg) every 6 hours around the clock  
– Continue Lomotil® and loperamide until no loose stools for 
24 hours.  
– If Grade ≤ 2 diarrhea persists after 48 hours of total treatment 
with Lomotil® and loperamide, consider second-line agents 
(e.g., octreotide, budesonide, tincture of opium).  
• Oral supplementation:  
– Initiate oral supplementation of potassium and/or magnesium if 
serum levels are < LLN.  
– Consider oral rehydration therapy (e.g., Pedialyte®) for 
Grade ≥ 1 diarrhea or vomiting.  
• Dietary modifications:  
– Stop all lactose-containing products and encourage eating small 
meals.  
– The BRAT (banana, rice, apples, toast) diet, without fiber (other 
vegetables and fruits), may be helpful.  
– Encourage adequate hydration with salt-containing liquids, such 
as broth or Gatorade®. 
Diarrhea, Grade 1 or 
Grade 2 (tolerable) 
• Continue atezolizumab and cobimetinib.  
• Investigate etiology, referring patient to GI specialist for evaluation 
of possible colitis if appropriate. 
• Initiate supportive care and monitor patient closely.  
GI = gastrointestinal; LLN = lower limit of normal. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
86/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
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 105 days, 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 GI specialist for evaluation and confirmatory biopsy 
if symptoms persist for > 7 days. 
GI = gastrointestinal; NSAID = non-steroidal anti-inflammatory drug.  
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids 
to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
87/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 2 
• Withhold atezolizumab and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs). 
• Refer patient to GI specialist for evaluation and confirmatory 
biopsy. 
• For recurrent events or events that persist > 5 days, initiate 
treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• If event resolves to Grade 1 or better within 105 days, 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 3 
• Withhold atezolizumab and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs). 
• Refer patient to GI specialist for evaluation and confirmatory 
biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better within 105 days, 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. 
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 105 days to allow for corticosteroids 
to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
88/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 4 
• Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. a 
• 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. 
IV = intravenous; NSAID = non-steroidal anti-inflammatory drug. 
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 rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
89/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Dermatologic toxicity 
 
General guidance 
• A dermatologist should evaluate persistent and/or severe 
rash or pruritus.  A biopsy should be considered unless 
contraindicated. 
Dermatologic event,  
Grade 1 or 2 
• Continue atezolizumab and cobimetinib. 
• Initiate supportive care (e.g., antihistamines, topical 
corticosteroids).  If event does not improve, consider 
treatment with higher-potency topical corticosteroids. 
• For Grade 2 rash, consider referral to dermatologist. 
Acneiform rash: 
• Consider topical corticosteroids (e.g., hydrocortisone 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline, 
or antibiotics covering skin flora) as clinically indicated. 
Dermatologic event,  
Grade 3 
• Withhold atezolizumab and cobimetinib. 
• Refer patient to dermatologist.  A biopsy should be performed 
if appropriate. 
• Consider initiating treatment with 10 mg/day oral prednisone 
or equivalent, increasing dose to 1−2 mg/kg/day if event does 
not improve within 48−72 hours. 
• If event resolves to Grade 2 or better within 105 days, 
resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and cobimetinib. a, b 
• Permanently discontinue atezolizumab and cobimetinib and 
contact Medical Monitor if event does not resolve to Grade 1 
or better within 105 days. a, b, c  
• If event resolves to Grade 2 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib. 
Acneiform rash: 
• Consider continuation of topical corticosteroids (e.g., 2.5% 
alclometasone) and oral antibiotics (e.g., minocycline, 
doxycycline, or antibiotics covering skin flora) when restarting 
cobimetinib. 
Dermatologic event,  
Grade 4 
• Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. c 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be 
reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-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. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
90/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be take 
Elevations in ALT, AST, 
and/or bilirubin 
 
AST/ALT > ULN to ≤ 3 × ULN 
with total bilirubin < 2 × ULN 
(Grade 1) 
• 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  
(Grade 2) 
• 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 
– 
Consider withholding atezolizumab a 
– 
Consider administering 1−2 mg/kg/day oral prednisone or 
equivalent followed by ≥ 1 month taper  
– 
Restart atezolizumab if event resolves to Grade 1 or better 
within 105 days. b, c 
– 
Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 105 days. a, 
b, c 
AST/ALT > 5 × baseline values 
to < 10 × ULN with total 
bilirubin < 2 × ULN  
(Grade 3) 
• Continue all study treatment. 
• Monitor LFTs at least weekly.   
• Consider referral to a hepatologist and liver biopsy. 
• For suspected immune-related events: 
– Withhold atezolizumab  
– Consider administering 1−2 mg/kg/day oral prednisone or 
equivalent followed by ≥ 1 month taper  
– If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month.  
– Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within  
105 days. a, b, c 
LFT = liver function test; Q4W = every 4 weeks; ULN = upper limit of normal.  
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 rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
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 Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids 
to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
91/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be take 
Elevations in ALT, AST, 
and/or bilirubin (cont.) 
 
AST/ALT > 3 × ULN with 
bilirubin > 2  × ULN  
• Withhold atezolizumab and cobimetinib. 
• Consult hepatologist and consider liver biopsy. 
• Consider administering 1−2 mg/kg/day oral prednisone or 
equivalent followed by ≥ 1 month taper (for possible autoimmune 
hepatitis). 
• If LFTs do not decrease within 48 hours after initiation of 
systemic steroids, consider adding an immunosuppressive 
agent (e.g., mycophenolate mofetil or TNF-α antagonist). 
• Monitor LFTs every 48−72 hours until decreasing and then 
follow weekly. 
• Restart atezolizumab at fixed dose and cobimetinib at 1 dose 
reduction after 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 hours after initiation of 
systemic steroids, addition of an alternative immunosuppressive 
agent (e.g., mycophenolate mofetil or TNF-α antagonist) or dose 
escalation of corticosteroids may be considered. 
• Monitor LFTs every 48−72 hours until decreasing and then 
follow weekly. 
LFT = liver function test; TNF-α = tumor necrosis factor−alpha; ULN = upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids 
to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
92/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be take 
Pulmonary events 
General guidance 
Mild-to-moderate events of pneumonitis have been reported with 
atezolizumab and cobimetinib.  All pulmonary events should be 
thoroughly evaluated for other commonly reported etiologies such 
as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension. 
For events concerning for pneumonitis, consider comprehensive 
infectious evaluation including viral etiologies. 
Pneumonitis, Grade 1 
(asymptomatic) 
• Continue atezolizumab and cobimetinib. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
Pneumonitis, Grade 2 
• Withhold atezolizumab and cobimetinib. 
• Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL.  
• If bronchoscopy is consistent with immune-related 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 105 days. a, b 
• Permanently discontinue atezolizumab and cobimetinib and 
contact Medical Monitor if event does not resolve to Grade 1 or 
better within 105 days. a, b, c 
• For recurrent events, treat as a Grade 3 or 4 event. 
Pneumonitis, Grade 3 or 4 
• Permanently discontinue atezolizumab and cobimetinib. c 
• Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL.  
• If bronchoscopy is consistent with immune-related etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
• If pulmonary event does not improve within 48 hours or 
worsens, consider adding an immunosuppressive agent 
(e.g., infliximab, cyclophosphamide, IVIg, or mycophenolate). 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
BAL = bronchoscopic alveolar lavage; IVIg = intravenous immunoglobulin. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be 
reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
93/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Ocular toxicity 
 
General guidance 
• 
An ophthalmologist should evaluate visual complaints.  
• 
Uveitis or episcleritis and other immune−mediated ocular 
disease may be associated with atezolizumab and may be 
treated with topical corticosteroid eye drops.  Atezolizumab 
should be permanently discontinued for immune-related 
ocular event that is unresponsive to local 
immunosuppressive therapy. 
• 
Serous retinopathy is associated with cobimetinib.  In clinical 
trials, most events were Grade 1 (asymptomatic) or 2 
(symptomatic).  Most events in clinical trials resolved or 
improved to asymptomatic Grade 1 following dose 
interruption or reduction.  If serous retinopathy is diagnosed, 
cobimetinib should be withheld until visual symptoms 
improve to Grade ≤ 1.   Serous retinopathy can be managed 
with treatment interruption, dose reduction, or treatment 
discontinuation.  
• 
RVO has been reported in patients treated with MEK 
inhibitors other than cobimetinib. 
Serous retinopathy 
 
Severity grade assessment 
based on NCI CTCAE v4 0 
“Eye Disorders–Other” scale a, 
b, c, d 
Serous retinopathy, Grade 1 a or 2 b (tolerable):  
• Continue cobimetinib and atezolizumab without dose change. 
• Follow the monitoring schedule detailed in Section 4.4.7. 
Serous retinopathy, Grade 2 b (intolerable) or Grade 3 or 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. 
• Follow the monitoring schedule detailed in Section 4.4.7. 
• The dose of cobimetinib should be reduced by one dose level 
when restarting.  
• Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite two dose level reductions. 
ADL = activities of daily living; NCI CTCAE v4.0 = National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0; OCT = optical coherence tomography; RVO = retinal vein 
occlusion. 
a Grade 1:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
b Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL. 
c Grade 3:  Severe or medically significant but not immediately sight threatening; hospitalization or 
prolongation of existing hospitalization indicated; disabling; limiting self-care ADL. 
d Grade 4:  Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or 
worse) in the affected eye. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
94/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Ocular toxicity (cont.) 
 
Potential immune-related 
ocular toxicity (e.g., uveitis, 
iritis, episcleritis, or retinitis) 
• Follow guidelines provided in Appendix 8. 
• Continue cobimetinib as clinically indicated. 
RVO (any grade) 
• If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines. 
• Continue atezolizumab. 
RVO = retinal vein occlusion. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
95/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
LVEF Decrease from Baseline 
Patient 
LVEF 
Value 
Recommended 
Action with Cobimetinib 
and Atezolizumab 
LVEF Value 
following  
Treatment Break 
Recommended 
Cobimetinib 
Daily Dose 
Asymptomatic 
≥ 50% 
(or 
40%−49% 
and < 10% 
absolute 
decrease 
from 
baseline) 
Continue atezolizumab 
and cobimetinib at current 
dose. 
NA 
NA 
< 40% (or 
40%−49% 
and 
≥ 10% 
absolute 
decrease 
from 
baseline) 
Interrupt cobimetinib 
treatment for 2 weeks. 
 
Continue atezolizumab as 
clinically indicated. 
< 10% absolute 
decrease from  
baseline 
First 
occurrence: 
40 mg 
Second 
occurrence: 
20 mg 
Third 
occurrence:  
permanent 
discontinuation 
< 40% (or ≥ 10% 
absolute decrease 
from baseline) 
Permanent 
discontinuation 
Symptomatic 
 NA 
Interrupt cobimetinib 
treatment for 4 weeks. 
Asymptomatic and 
< 10% absolute 
decrease from 
baseline 
First 
occurrence: 
40 mg  
Second 
occurrence: 
20 mg 
Third 
occurrence:  
permanent 
discontinuation 
Consider withholding 
atezolizumab. 
Discuss with Medical 
Monitor regarding 
resumption of 
atezolizumab. 
Asymptomatic and 
< 40% (or ≥ 10% 
absolute decrease 
from baseline) 
Permanent 
discontinuation 
Cardiology consultation is 
strongly recommended. 
Symptomatic 
regardless of 
LVEF 
Permanent 
discontinuation 
LVEF = left ventricular ejection fraction; NA = not applicable. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
96/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Rhabdomyolysis or CPK elevation 
General guidance 
• Rule out cardiac cause (check electrocardiogram, serum 
cardiac troponin, and CPK-isoforms M and B fraction) and 
rule out rhabdomyolysis (clinical examination; serum 
creatinine, potassium, calcium, phosphorus, uric acid, and 
albumin; and urine myoglobin).  
• Assess patient for any history of strenuous physical activity, 
blunt trauma, or recent intramuscular injections.  
For Grade ≤ 3 CPK elevations 
that are asymptomatic and 
deemed not clinically significant 
• Cobimetinib and atezolizumab dosing does not need to be 
modified or interrupted to manage asymptomatic Grade ≤ 3 
CPK elevations. 
• Recheck CPK at least once a week.  
For Grade 4 CPK elevations that 
are asymptomatic and deemed 
not clinically significant  
• Interrupt cobimetinib and atezolizumab treatment.  
• If improved to Grade ≤ 3 within 4 weeks, restart cobimetinib 
at a dose reduced by 20 mg, if clinically indicated. 
• If CPK elevations do not improve to Grade ≤ 3 within 
4 weeks following dose interruption, permanently 
discontinue cobimetinib treatment.  
• Resumption of atezolizumab may be considered in patients 
who are deriving benefit. 
Rhabdomyolysis or symptomatic 
CPK elevations 
• Interrupt cobimetinib and atezolizumab treatment.   
• If severity is improved by at least one grade and symptoms 
resolve within 4 weeks, restart cobimetinib at a dose 
reduced by 20 mg, if clinically indicated.   
• If rhabdomyolysis or symptomatic CPK elevations do not 
improve within 4 weeks, permanently discontinue 
cobimetinib treatment   
• Resumption of atezolizumab may be considered in patients 
who are deriving benefit after discussion with the Medical 
Monitor.  
CPK = creatine phosphokinase. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
97/Protocol CO39721, Version 5 
Table 6 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.) 
Event 
Action to Be Taken 
Hemorrhage 
Grade 3 hemorrhage 
• Interrupt cobimetinib treatment.  There are no data on the 
effectiveness of cobimetinib dose modification for hemorrhage 
events.  Clinical judgment should be applied when 
considering restarting cobimetinib treatment. 
• Continue atezolizumab treatment. 
Grade 4 hemorrhage or any 
grade cerebral hemorrhage 
• Interrupt cobimetinib treatment.  Permanently discontinue 
cobimetinib for hemorrhage events attributed to cobimetinib. 
• Continue atezolizumab treatment. 
Grade 3 or 4 or intolerable 
Grade 2 treatment-related 
toxicities not described 
above and in Table 5 (dose 
modifications for 
cobimetinib) 
• Withhold all study treatment. 
• If event resolves to Grade 1 or better within 105 days, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab. a, b, c  
• If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 105 days to allow for corticosteroids to be 
reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-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. 
 
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 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
98/Protocol CO39721, Version 5 
• 
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 
v4.0; see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 

 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Significant liver toxicity 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law (see Section 5.3.5.7) and based on the following observations: 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
Treatment-emergent ALT or AST > 3 × baseline value in combination with 
clinical jaundice 
Hepatitis, including AST or ALT > 10 × ULN 
• 
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, 
hyperthyroidism, and hypophysitis 
• 
Systemic lupus erythematosus 
• 
Neurologic disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• 
Nephritis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response system 
• 
Ocular toxicities 
Uveitis  
RVO 
Serous retinopathy 
Myositis 

 
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• 
Cardiac disorders for the following events: 
Grade ≥ 2 cardiac disorders, including atrial fibrillation, myocarditis, 
and pericarditis 
Symptomatic heart failure or Grade ≥ 3 reduction in LVEF  
• 
Vasculitis 
• 
Myopathies, including rhabdomyolysis or Grade ≥ 3 CPK elevation 
• 
Grade ≥ 3 hemorrhage or any-grade cerebral hemorrhage  
• 
Grade ≥ 3 rash 
• 
Grade ≥ 3 diarrhea  
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events 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 
(see 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?"  

 
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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.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  In addition to Table 7, the following guidance should be taken into 
consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 

 
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• 
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 versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 

 
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• 
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 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for 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. 

 
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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 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 

 
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5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of metastatic melanoma should be recorded on the 
Death Attributed to Progressive Disease eCRF.  All other on-study deaths, regardless of 
relationship to study 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. 
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 

 
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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 Melanoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study 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 
 
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 

 
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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. 
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. 
 
 

 
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5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab or within 3 months after the last dose of cobimetinib.  A Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
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.  When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  If 
the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form 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).   

 
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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. 
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 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 90 days after the last 
dose of study drug), 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. 

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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
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 study evaluates the preliminary efficacy, safety, and pharmacokinetics of 
atezolizumab plus cobimetinib in patients with BRAFV600 WT metastatic or unresectable 
locally advanced melanoma who have progressed on prior anti-PD-1 therapy (Cohorts A 
and B), and atezolizumab monotherapy in patients with BRAF V600 WT metastatic or 
unresectable locally advanced melanoma who have not been previously treated 
(Cohort C). 
The primary analysis will be conducted in Cohorts A and B approximately 24 weeks 
after the last patient is enrolled in Cohort A.  At this time, Cohorts A and B will have a 
minimum follow up of approximately 24 weeks.  The primary analysis for Cohort C may 
be analyzed independently, with a minimum of 24 weeks follow up for patients in 
Cohort C.  Both separate and pooled efficacy and safety analyses will be performed on 
Cohorts A and B, given their similar patient populations.  Additional tumor immunology 
and biomarker analyses will also be conducted on Cohort B.  Study data will be 
described and summarized for Cohort C separately. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is designed for hypothesis generation with the intention to provide an 
informative evaluation on the selected efficacy endpoints.  No formal inferential testing is 
planned.  Approximately 152 patients are anticipated to be enrolled, with approximately 
90 patients in Cohort A, 12 patients in Cohort B, and 50 patients in Cohort C.   
A combined 102 patients in Cohorts A and B allows for a robust comparison against 
historical control of ipilumumab and chemotherapy in patients who have previously 
progressed on anti-PD1 therapy, which generally have response rates of less than 17%.  
For example, with 102 patients in Cohorts A and B, observing 26 patients with objective 
response corresponds to ORR (95% CI) of 25.5% (17.4%, 35.1%) and observing 
60 patients with disease control corresponds to a DCR (95% CI) of 58.8% (48.6%, 
68.52%).   

 
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Enrolling 50 patients in Cohort C provides reasonably reliable estimates of the ORR and 
DCR in patients who have not been previously treated to allow for an accurate 
understanding of the achievable magnitude of efficacy in this population.   
For example, observing 17 patients with objective response corresponds to ORR 
(95% CI) of 34.0% (21.1%, 48.8%) and observing 32 patients with disease control 
corresponds to DCR (95% CI) of 64% (49.2%, 77.1%).  Enrolling 50 patients in Cohort C 
also provides an opportunity to explore the preliminary efficacy in relevant patient 
subgroups including biomarker subgroups defined by PD-L1 expression. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, eligibility violations, and patient disposition will be summarized.  Study 
treatment administration will be summarized for all treated patients.  
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic variables and other baseline and disease characteristics will be 
summarized using descriptive statistics. 
6.4 
EFFICACY ANALYSES 
Efficacy analyses will include all patients who receive at least one dose of study drug. 
6.4.1 
Primary Efficacy Endpoint 
ORR is defined as the proportion of patients whose objective response is a CR or a PR.  
Objective response is defined as a CR or PR on two consecutive occasions ≥ 4 weeks 
apart, as determined by the investigators using RECIST v1.1.  A 95% Clopper-Pearson 
CI will be calculated for the ORR. 
DCR is defined as the proportion of patients with a CR, PR, or SD at 16 weeks after the 
baseline tumor assessment.   
6.4.2 
Secondary Efficacy Endpoints 
For patients who achieve an objective response, DOR is defined as the time from the 
first occurrence of a documented objective response to disease progression, as 
determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first.  Data for patients who have not experienced disease progression 
or have not died will be censored at the last tumor assessment date.  Data for patients 
with no post-baseline tumor assessment will be censored at 1 day after the first 
treatment date.  Kaplan-Meier methodology will be used to estimate the median PFS, 
and the 95% CI of the median DOR arm will be constructed using the Brookmeyer and 
Crowley method (Brookmeyer and Crowley 1982). 
PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease 
progression, as determined by the investigator according to RECIST v1.1, or death from 

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any cause, whichever occurs first.  The censoring and analysis method for PFS will be 
the same as that for DOR.  
For Cohort C, ORR, DCR, DOR, and PFS will also be determined by the IRC according 
to RECIST v1.1 using the same methods as described above. 
OS is defined as the time from Cycle 1, Day 1 to death from any cause.  For patients 
who are alive at the time of analysis data cutoff, OS time will be censored at the date the 
patient was last known to be alive.  Survival time for patients with no post-baseline 
survival information will be censored at 1 day after the first treatment date.  OS will be 
analyzed in a manner similar to PFS. 
6.4.3 
Exploratory Efficacy Endpoints 
ORR, DOR, and PFS as determined by the investigator according to immune-modified 
RECIST (see Appendix 4) will be analyzed using the same methods as described above. 
6.5 
SAFETY ANALYSES 
The safety analyses will include all patients who receive at least one dose of study drug. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and study treatment exposure.  
Verbatim description of adverse events will be summarized by mapped terms and 
appropriate thesaurus levels and graded according to NCI CTCAE v4.0.  All adverse 
events that occur during or after the first study drug dose will be summarized by NCI 
CTCAE grade.  In addition, serious adverse events, severe adverse events (Grades ≥ 3), 
adverse events of special interest, and adverse events leading to study drug 
discontinuation or interruption will be summarized accordingly.  Multiple occurrences of 
the same event will be counted once at the maximum severity.  The proportion of 
patients who experience at least one adverse event will be reported by toxicity term.  
Study drug exposure, including treatment duration, number of doses, and dose intensity, 
will be summarized using descriptive statistics.  
All deaths and causes of death will be summarized. 
Laboratory data with values outside the normal ranges will be identified.  In addition, 
relevant laboratory data and vital signs will be summarized. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analyses will include patients who have received at least one dose of study drug 
and for whom at least one evaluable PK sample (actual dose and actual sampling time 
recorded for each sample) is collected.  Since only a few samples are collected from 
patients, data will be analyzed using the existing population PK model for post hoc 

 
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estimates of apparent clearance or systemic clearance for cobimetinib and atezolizumab 
respectively.  Maximum or minimum concentration (Cmax or Cmin) will be reported for 
individual patients and summarized by study day, as data permit.  In addition, the 
relationship between drug exposure (cobimetinib or atezolizumab) and safety and 
efficacy endpoints will be explored for exposure-response relationship.  
Additional PK analyses will be conducted as appropriate on the basis of the available 
data. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses for atezolizumab will include patients with any ADA result, 
with patients grouped by cohort. 
The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up periods will be summarized by cohort.  Patients 
are considered to be ADA positive if they are ADA negative or are missing data at 
baseline but develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer unit) than 
the titer of the baseline sample (treatment-enhanced ADA response).  Patients are 
considered to be ADA negative if they are ADA negative or are missing data at baseline 
and all post-baseline samples are negative, or if they are ADA positive at baseline but do 
not have any post-baseline samples with a titer that is at least 4-fold greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported descriptively in subgroup analyses. 
6.8 
BIOMARKER ANALYSES  
Descriptive statistics will be used to explore the biomarkers and their relations to 
response or escape of combined treatment in patients, these biomarkers include: 
PD-L1 expression, CD8 T-cell density, NRAS or NF-1 mutation status, and other 
significant biological markers warranted by emerging scientific evidence at the 
conclusion of this study. 
NGS data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researchers’ understanding of disease pathobiology 
and guide the development of new therapeutic approaches. 
6.9 
OPTIONAL INTERIM ANALYSES 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct interim efficacy analyses.  The decision to conduct an optional interim analysis 
and the timing of the analysis will be documented in the Sponsor’s trial master file prior 

 
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to the conduct of the interim analysis.  The interim analysis will be performed and 
interpreted by Sponsor study team personnel. 
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 data 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 
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 

 
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and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
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. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRF data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 

 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
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 

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

 
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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, 
last visit). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
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. 

 
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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 60 study centers 
will participate in this study globally and enroll a total of approximately 152 patients.  The 
Sponsor will provide clinical operations oversight, data management support, and 
medical monitoring. 
An IxRS will be used to manage site drug supply.  For patients not previously tested for 
tumor mutation status, testing will be performed at screening.  Plasma and serum will be 
sent to a central laboratory for analysis and sample storage.  Routine sample analysis 
will be performed by an accredited external vendor or the center’s local laboratory; 
central and local laboratory ranges will be collected. 
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 website: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pd
f 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 

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

 
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a n d w h at i s n e xt ? C urr O pi n I m m u n ol 2 0 1 2; 2 4 : 5 7 1−5. 
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m el a n o m a a n d r e n al c ell c ar ci n o m a. C a n c er I m m u n ol I m m u n ot h er 2 0 1 5; 6 4: 4 5 9 -6 5.  
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J N K a n d p 3 8 pr ot ei n ki n a s e s. S ci e n c e 2 0 0 2; 2 9 8: 1 9 1 1 −2.  
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m ut at e d m e l a n o m a. N E n gl J M e d 2 0 1 4; 3 7 1: 1 8 6 7 −7 6.  
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m o n ot h er a p y i n u ntr e at e d m el a n o m a. N E n gl J M e d  2 0 1 5; 3 7 3: 2 3 −3 4.  
L e e J -H, C h oi J -W, Ki m Y -S. Fr e q u e n ci e s of B R A F  a n d N R A S  m ut ati o n s ar e diff er e nt i n 
hi st ol o gi c al t y p e s a n d sit e s of ori gi n of c ut a n e o u s m el a n o m a: a m et a -a n al y si s. 
Briti s h J D er m 2 0 1 1; 1 6 4: 7 7 6 -8 4.  
L e c o mt e T, L a n di B, B e a u n e P, et al. Gl ut at hi o n e S -tr a n sf er a s e s P 1  p ol y m or p hi s m 
(ll 3 1 0 5 V al) pr e di ct s c u m ul ati v e n er u o p at h y i n p ati e nt s r e c ei v ei n g o x ali pl ati n-b a s e d 
c h e m ot h er a p y.  Cli n C a n c er R e s 2 0 0 6; 1 2: 3 0 5 0 .  

 
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Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol CO39721, Version 5 
Appendix 1  
Schedule of Activities 
Cohort A 
Day (window) 
Screening a Cycle 1 Cycle 2 Cycle 3+ Treatment Discontinuation b 
Unplanned Visit c 
Survival FU d 
–35 to –1 
1 
15 1 
15 
1 
15 
30 (± 3) d after last dose 
 
Q3M 
Informed consent e 
x  
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
Vital signs f, g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
x 
 
x 
 
 
x 
 
Weight 
x 
x 
 
x 
 
x 
 
x 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
 
 
x 
 
 
Limited physical examination 
 
x h 
 
x 
 
x 
 
 
 
 
Hematology i 
x 
x 
 
x 
 
x 
 
x 
x 
 
Coagulation (INR and aPTT) 
x 
 
 
 
 
 
 
 
 
 
BRAFV600 WT mutation status 
x 
 
 
 
 
 
 
 
 
 
PK/ADA sample for atezolizumab 
See Appendix 2 
x 
 
PK sample for cobimetinib 
See Appendix 2 
 
 
Serum samples for auto antibody 
tests j 
 
x 
 
 
 
 
 
 
 
 
Optional WGS 
 
x 
 
 
 
 
 
 
 
 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol CO39721, Version 5 
Cohort A 
Day (window) 
Screening a Cycle 1 Cycle 2 Cycle 3+ 
Treatment 
Discontinuation b 
Unplanned Visit c 
Survival FU d 
–35 to –1 
1 
15 
1 
15 
1 
15 
30 (± 3) days after last 
dose 
 
Q3M 
Chemistry k 
x 
x 
 
x 
 
x 
 
x 
x 
 
Tumor assessments l 
x 
Scans will be done every 8 weeks ± 7 days 
ECHO/MUGA scan 
x 
 
 
x 
 
x m 
 
x 
x 
 
ECG (average of triplicate measurements) 
x 
 
 
 
 
 
 
 
x 
 
Serology n 
x 
 
 
 
 
 
 
 
 
 
Thyroid function o 
x 
x 
 
x 
 
x o 
 
x 
 
 
Ophthalmologic exam  
x 
Perform ophthalmology investigations as per Section 4.4.7. 
Pregnancy test p 
x 
x 
 
x 
 
x p 
 
x 
x 
 
Urinalysis q 
x 
 
 
 
 
 
 
 
 
 
Concomitant medications r 
x r 
x r 
 
x 
 
x 
 
x r 
 
 
Adverse events s 
x s 
x s 
x 
x 
x 
x 
x 
x s 
 
x s 
Tumor biopsy t 
x 
 
 
x 
 
 
x 
 
 
Biomarker blood samples 
 
See Appendix 2 
 
 
Atezolizumab administration u 
 
x 
x 
x 
x 
x 
x 
 
 
 
Dispense cobimetinib v 
 
x 
 
x 
 
x 
 
 
 
 
Survival and anti-cancer therapy FU 
 
 
 
 
 
 
 
 
 
x 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol CO39721, Version 5 
ADA = anti-drug antibody; CPK = increased creatine phosphokinase; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; eCRF = electronic Case Report Form; FU = follow-up; HBcAb = hepatitis B core antibody; HBcAg = hepatitis B core antigen; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; LVEF = left ventricular ejection fraction; MUGA = multiple-gated 
acquisition; PD = progressive disease; PK = pharmacokinetic; Q3M = every 3 months; RECIST = Response Evaluation Criteria in Solid Tumors; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WGS = whole genome sequencing; WT = wild type. 
Notes:  All assessments should be performed within ± 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed before dosing, unless otherwise specified.  On treatment days, pre-infusion laboratory samples should be drawn 
up to 4 hours before the start of infusion, and post-infusion laboratory samples should be drawn up to 30 minutes after the end of infusion, unless 
otherwise specified. 
a Results of standard-of-care tests or examinations performed before obtaining informed consent and within 35 days before Day 1 may be used; 
such tests do not need to be repeated for screening.  BRAFV600 status must be known before performing study-specific screening assessments.  
The 35-day window begins at the time of the first standard-of-care screening assessment or the first study-specific screening assessment after 
the BRAFV600 mutation test result is available, whichever is earlier.  Test results should be reviewed before study treatment is given.   
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit at 30 (± 3) days.  The visit at which response 
assessment shows PD may be used as the study discontinuation visit. 
c Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated. 
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or study 
termination by the Sponsor. 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment. 
f Includes respiratory rate, heart rate, and systolic and diastolic blood pressure (after patient has been in a seated position for 5 minutes) and 
temperature (oral or tympanic); resting oxygen saturation may be measured at screening.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF. 
g Vital signs at the first atezolizumab infusion will be collected within 60 min before the infusion, every 15 (± 5) min during the atezolizumab 
infusion, and 30 (± 10) min after the infusion.  For subsequent infusions, vital signs will be collected within 60 min before infusion and during the 
infusion (if clinically indicated or if symptoms occurred in the prior infusion), and 30 (± 10) min after the infusion. 
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.  If physical examinations are assessed within 7 days of the Cycle 1, Day 1 visit, they do not have to 
be repeated at Day 1. 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol CO39721, Version 5 
i Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, reticulocyte count, differential count (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes). 
j Includes anti-nuclear antibody, anti−double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil 
cytoplasmic antibody. 
k Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (or total carbon dioxide), BUN or urea, creatinine, 
total protein, magnesium, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, CPK, LDH, uric acid; albumin, non-fasting glucose 
(fasting blood glucose after a minimum 8-hour fast, at screening only), lipids, (Fasting lipids:  total cholesterol, LDL cholesterol, and triglycerides 
after a minimum 8-hour fast, at screening only).  
l 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.  At the 
investigator's discretion, tumor assessments may be repeated at any time if disease progression is suspected.  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. 
m All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA scan, at screening.  Evaluation of LVEF by ECHO or 
MUGA scan must be performed at the following time points only for patients taking cobimetinib: 
• 
Cycle 2, Day 1 (± 1 week) 
• 
Day 1 of Cycles 5, 8, 11, 14, 17, etc. (every three treatment cycles) ± 2 weeks 
• 
Treatment discontinuation visit evaluation of LVEF does not need to be performed at treatment discontinuation visit if an evaluation has been 
performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline. 
• 
All patients restarting treatment with a dose reduction of cobimetinib because of a decrease in LVEF should have LVEF measurements 
taken after approximately 2, 4, 10, and 16 weeks, and then resume monitoring LVEF every three treatment cycles. 
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study. 
• 
HBV serology will include HBsAg, total HBcAg antibody (anti-HBcAb).  HBV DNA should be obtained prior to study start 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 study start if patient tests positive for anti-HCV. 
o Thyroid function testing (TSH, free T3 [or total T3 for sites where free T3 is not performed, free T4) collected at Day 1 of Cycles 1−5, and every 
second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.) for patients on atezolizumab only. 
p All women of childbearing potential will have a serum pregnancy test at screening within 14 days prior to Day 1 of Cycle 1.  Urine pregnancy 
tests will be performed on Day 1 of every cycle and at the treatment discontinuation visit.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol CO39721, Version 5 
q Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
r Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days before initiation of study drug until 30 days after the last dose of study drug. 
s After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study drug or 
initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  After this 
period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study 
drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events or adverse events of special interest considered to be related to study drug or trial-related procedures until a 
final outcome can be reported. 
t Archival (< 5 years old) or fresh baseline tumor tissue collected during screening.  If a patient provides a fresh biopsy for BRAFV600 testing, this 
sample will be used also as baseline for biomarker analysis. Therefore predose specimens are not required for patients who provide a fresh 
biopsy before treatment start.  If archival tissue is used availability of adequate tumor tissue must be confirmed prior to any screening procedures 
(paraffin-embedded tumor block or a minimum of 20 unstained slides).  Submit archival tissue and associated pathology report within 30 days 
after Cycle 1, Day 1.  If a predose fresh biopsy is collected this sample should be obtained after eligibility criteria have been fulfilled and prior to 
Cycle 1, Day 1.  For patients who have consented to optional biopsies a subsequent biopsy may be performed 4-6 weeks after the first 
atezolizumab administration; an additional optional biopsy may be collected at the time of radiographic progression if clinically feasible. See 
Section 3.1.1 and the laboratory manual for further details.  
u In Cohort A, atezolizumab will be given on Days 1 and 15 of all cycles.  The initial dose will be delivered over 60 (± 15) minutes.  If the first 
infusion is well tolerated, all subsequent infusions will be delivered over 30 (± 10) minutes until loss of clinical benefit.  Study drug administration 
may be ± 3 days from the scheduled Day 1 and 15 of each cycle. 
v Cobimetinib 60 mg/day by mouth will be given in a 21/7 dosing schedule. 
  

Appendix 1 
Schedule of Activities (cont.) 
 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol CO39721, Version 5 
Cohort B:  Biopsy Cohort 
 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3+ 
Treatment 
Discontinuation b 
Unplanned 
Visit c 
Survival 
FU d 
Day (window) 
–35 to –1 
1 
15 
1 
15 
1 
15 30 (±3) days after last 
dose 
 
Q3M 
Informed consent e 
x  
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
Vital signs f,g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
x 
 
x 
 
 
x 
 
Weight 
x 
x 
 
x 
 
x 
 
x 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
 
 
x 
 
 
Limited physical examination 
 
x h 
 
x 
 
x 
 
 
 
 
Hematology i 
x 
x 
 
x 
 
x 
 
x 
x 
 
Coagulation (INR and aPTT) 
x 
 
 
 
 
 
 
 
 
 
BRAFV600 WT mutation status 
x 
 
 
 
 
 
 
 
 
 
PK and ADA sample for atezolizumab 
See Appendix 2 
x 
x 
PK sample for cobimetinib 
See Appendix 2 
 
 
Serum samples for auto-antibody tests j 
 
x 
 
 
 
 
 
 
 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol CO39721, Version 5 
Cohort B:  Biopsy Cohort 
 Screening a Cycle 1 Cycle 2 Cycle 3+ Treatment Discontinuation b Unplanned Visit c Survival FU d 
Day (window) 
–35 to –1 
1 15 1 15 
1 
15 <30 (± 3) days after last dose 
 
Q3M 
Optional WGS 
 
x 
 
 
 
 
 
 
 
 
Chemistry k 
x 
x 
 
x 
 
x 
 
x 
x 
 
Tumor assessments l 
x 
Scans will be done every 8 weeks ± 7 days  
ECHO/MUGA scan 
x 
 
 
x 
 
x m 
 
x 
x 
 
ECG  (average of triplicate measurements) 
x 
 
 
 
 
 
 
 
x 
 
Serology n 
x 
 
 
 
 
 
 
 
 
 
Thyroid function o 
x 
x 
 
x 
 
x o 
 
x 
 
 
Ophthalmologic exam  
x 
Perform ophthalmology investigations as per Section 4.4.7. 
Pregnancy test p 
x 
x 
 
x 
 
x p 
 
x 
x 
 
Urinalysis q 
x 
 
 
 
 
 
 
 
 
 
Concomitant medications r 
x r 
x r 
 
x 
 
x 
 
x r 
 
 
Adverse events s 
x s 
x s 
x 
x 
x 
x 
x 
x s 
 
x s 
Tumor biopsy t 
x 
 
x u 
x 
 
 
x 
 
 
Biomarker blood samples 
 
See Appendix 2 
 
 
Atezolizumab administration v 
 
 
x 
x 
x 
x 
x 
 
 
 
Dispense cobimetinib w 
 
x 
 
x 
 
x 
 
 
 
 
Survival and anti-cancer therapy FU 
 
 
 
 
 
 
 
 
 
x 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol CO39721, Version 5 
ADA = anti-drug antibody; CPK = increased creatine phosphokinase; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; eCRF = electronic Case Report Form; FU = follow-up; HBcAb = hepatitis B core antibody; HBcAg = hepatitis B core 
antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; LVEF = left ventricular ejection fraction; 
MUGA = multiple-gated acquisition; PD = progressive disease; PK = pharmacokinetic; Q3M = every 3 months; RECIST = Response Evaluation 
Criteria in Solid Tumors; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WGS = whole genome sequencing; 
WT = wild type. 
Notes:  All assessments should be performed within ± 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. On treatment days, pre-infusion laboratory samples should be 
drawn up to 4 hours before the start of infusion, and post-infusion laboratory samples should be drawn up to 30 minutes after the end of 
infusion, unless otherwise specified. 
a Results of standard-of-care tests or examinations performed before obtaining informed consent and within 35 days before Day 1 may be 
used; such tests do not need to be repeated for screening.  BRAFV600 status must be known prior to performing study-specific screening 
assessments.  The 35-day window begins at the time of the first standard-of-care screening assessment or the first study-specific 
screening assessment after the BRAFV600 mutation test result is available, whichever is earlier.  Test results should be reviewed before 
study treatment is given. 
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit at 30 (± 3) days.  The visit at which 
response assessment shows PD may be used as the study discontinuation visit. 
c Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated. 
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or study 
termination by the Sponsor. 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 35 days 
before initiation of study treatment. 
f Includes respiratory rate, heart rate, and systolic and diastolic blood pressure (monitored after the patient has been in a seated position for 
5 min), and temperature (oral or tympanic).  Resting oxygen saturation may be measured at screening. Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
g Vital signs at the first atezolizumab infusion will be collected within 60 minutes before the infusion, every 15 (± 5) min during the 
atezolizumab infusion, and 30 (± 10) min after the infusion.  For subsequent infusions, vital signs will be collected within 60 min before the 
infusion and during the infusion (if clinically indicated or if symptoms occurred in the prior infusion), and 30 (± 10) min after the infusion. 
 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol CO39721, Version 5 
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.  If physical examinations are assessed within 7 days of the Cycle 1, Day 1 visit, they 
do not have to be repeated at Day 1. 
i Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, reticulocyte count, differential count (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes). 
j Includes: anti-nuclear antibody, anti−double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, perinuclear anti-neutrophil 
cytoplasmic antibody. 
k Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (or total carbon dioxide), BUN or urea, creatinine, 
total protein, magnesium, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, CPK, LDH, uric acid; albumin, non-fasting 
glucose (fasting blood glucose after a minimum 8-hour fast, at screening only), and lipids (fasting lipids:  total cholesterol, LDL cholesterol, 
and triglycerides after a minimum 8-hour fast, at screening only). 
l 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.  
At the investigator's discretion, tumor assessments may be repeated at any time if disease progression is suspected.  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. 
m All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA scan, at screening.  Evaluation of LVEF by 
ECHO or MUGA scan must be performed at the following time points only for patients receiving cobimetinib: 
• 
Cycle 2, Day 1 ± 1 week 
• 
Day 1 of Cycles 5, 8, 11, 14, 17, etc. (every three treatment cycles; ± 2 weeks) 
• 
Treatment discontinuation visit evaluation of LVEF does not need to be performed at treatment discontinuation visit if an evaluation 
has been performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline. 
• 
All patients restarting treatment with a dose reduction of cobimetinib because of a decrease in LVEF should have LVEF 
measurements taken after approximately 2, 4, 10, and 16 weeks, and then resume monitoring LVEF every three treatment cycles. 
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study. 
• 
HBV serology will include HBsAg, total HBcAg antibody (anti-HBcAb).  HBV DNA should be obtained before study start 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 study start if patient tests positive for 
anti-HCV. 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol CO39721, Version 5 
o Thyroid function testing (TSH, free T3 [or total T3 for sites where free T3 is not performed], free T4) collected at Day 1 of Cycles 1−5, and 
every second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.) for patients on atezolizumab only. 
p All women of childbearing potential will have a serum pregnancy test at screening within 14 days before Day 1 of Cycle 1.  Urine 
pregnancy tests will be performed on Day 1 of every cycle and at the treatment discontinuation visit. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
q Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria). 
r Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from 7 days before initiation of study drug until 30 days after the last dose of study drug. 
s After informed consent has been obtained but before initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study 
drug or initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events or adverse events of special interest considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. 
t 
In Cohort B. If a patient provides a fresh biopsy for BRAFV600 test, this sample will be used also as baseline for biomarker analysis.  
Therefore, predose specimens are not required for patients who provide a fresh biopsy before treatment start.. 
A subsequent mandatory biopsy will be performed between Days 10 and 14 of Cycle 1.  An additional optional biopsy may be collected 
during Cycle 2, approximately 4−6 weeks after the first atezolizumab administration.  A mandatory biopsy will be collected at the time of 
radiographic progression, if clinically feasible. 
u Days 10−14. 
v In Cohort B, atezolizumab will be given on Cycle 1, Day 15 and on Days 1 and 15 of all subsequent cycles.  The initial dose will be 
delivered over 60 (± 15) minutes.  If the first infusion is well tolerated all subsequent infusions will be delivered over 30 (± 10) minutes until 
a loss of clinical benefit.  Study drug administration may be ± 3 days from the scheduled Day 1 and 15 of each cycle. 
w Cobimetinib 60 mg/day by mouth will be given in a 21/7 dosing schedule.  Dosing will start on Cycle 1, Day 1, 14 days before the first 
atezolizumab administration. 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol CO39721, Version 5 
Cohort C:  Atezolizumab Monotherapy (21-Day Cycle) 
Day (window) 
Screening a 
Cycle 1 
Cycle 2 
Cycle 3+ 
Treatment 
Discontinuation b 
Unplanned Visit 
c 
Survival FU 
d 
–35 to –1 
1 
 
1 
 
1 
 
30 (± 3) d after last 
dose 
 
Q3M 
Informed consent e 
x  
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
Vital signs f, g 
x 
x 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
x 
x 
 
x 
 
Weight 
x 
x 
x 
x 
x 
 
 
Height 
x 
 
 
 
 
 
 
Complete physical examination 
x 
 
 
 
x 
 
 
Limited physical examination 
 
x h 
x 
x 
 
 
 
Hematology i 
x 
x 
x 
x 
x 
x 
 
Coagulation (INR and aPTT) 
x 
 
 
 
 
 
 
BRAFV600 WT mutation status 
x 
 
 
 
 
 
 
PK/ADA sample for 
atezolizumab  
See Appendix 2 
Serum samples for auto 
antibody tests j 
 
x 
 
 
 
 
 
 
Optional WGS 
 
x 
 
 
 
 
 
 

Appendix 1 
Schedule of Activities (cont.) 
 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol CO39721, Version 5 
Cohort C:  Atezolizumab Monotherapy (21-Day Cycle) 
Day (window) 
Screening a Cycle 1 Cycle 2 
Cycle 3+ 
Treatment 
Discontinuation b 
Unplanned Visit c Survival FU d 
–35 to –1 
1 
 
1 
 
1 
 
30 (± 3) days after last 
dose 
 
Q3M 
Chemistry k 
x 
x 
x 
x 
x 
x 
 
Tumor Assessments l 
x 
Scan assessments every 8 weeks± 7 days 
ECHO/MUGA scan m 
x 
 
 
 
 
 
 
ECG (average 
of triplicate measurements) 
x 
 
 
 
 
x 
 
Serology n 
x 
 
 
 
 
 
 
Thyroid function o 
x 
x 
x 
x o 
x 
 
 
Pregnancy test p 
x 
x 
x 
x p 
x 
x 
 
Urinalysis q 
x 
 
 
 
 
 
 
Concomitant medications r 
x r 
x r 
x 
x 
x r 
 
 
Adverse events s 
x s 
x s 
x 
x 
x s 
 
x s 
Collection of archival tissue or tumor 
biopsy t 
x 
 
 
 
x 
 
 
Biomarker blood samples 
 
See Appendix 2 
 
 
Atezolizumab administration u 
 
x 
x 
x 
 
 
 
Survival and anti-cancer therapy FU 
 
 
 
 
 
 
x 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol CO39721, Version 5 
ADA = anti-drug antibody; CPK = increased creatine phosphokinase; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; eCRF = electronic Case Report Form; FU = follow-up; HBcAb = hepatitis B core antibody; HBcAg = hepatitis B core antigen; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; LVEF = left ventricular ejection fraction; MUGA = multiple-gated 
acquisition; PD = progressive disease; PK = pharmacokinetic; Q3M = every 3 months; RECIST = Response Evaluation Criteria in Solid Tumors; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WGS = whole genome sequencing; WT = wild type. 
Notes:  All assessments should be performed within ± 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed before dosing, unless otherwise specified.  On treatment days, pre-infusion laboratory samples should be drawn 
up to 4 hours before the start of infusion, and post-infusion laboratory samples should be drawn up to 30 minutes after the end of infusion, unless 
otherwise specified. 
a Results of standard-of-care tests or examinations performed before obtaining informed consent and within 35 days before Day 1 may be used; 
such tests do not need to be repeated for screening.  BRAFV600 status must be known before performing study-specific screening assessments.  
The 35-day window begins at the time of the first standard-of-care screening assessment or the first study-specific screening assessment after 
the BRAFV600 mutation test result is available, whichever is earlier.  Test results should be reviewed before study treatment is given.   
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit at 30 (± 3) days.  The visit at which response 
assessment shows PD may be used as the study discontinuation visit. 
c Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated. 
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or study 
termination by the Sponsor.  PK/ADA sample is required 120 days +/- 30 days after last atezolizumab infusion 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 35 days before 
initiation of study treatment. 
f Includes respiratory rate, heart rate, and systolic and diastolic blood pressure (after patient has been in a seated position for 5 minutes) and 
temperature (oral or tympanic); resting oxygen saturation may be measured at screening.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF. 
g Vital signs at the first atezolizumab infusion will be collected within 60 min before the infusion, every 15 (± 5) min during the atezolizumab 
infusion, and 30 (± 10) min after the infusion.  For subsequent infusions, vital signs will be collected within 60 min before infusion and during the 
infusion (if clinically indicated or if symptoms occurred in the prior infusion), and 30 (± 10) min after the infusion. 
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.  If physical examinations are assessed within 7 days of the Cycle 1, Day 1 visit, they do not have to 
be repeated at Day 1. 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol CO39721, Version 5 
i Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, reticulocyte count, differential count (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes). 
j Includes anti-nuclear antibody, anti−double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil 
cytoplasmic antibody. 
k Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (or total carbon dioxide), BUN or urea, creatinine, 
total protein, magnesium, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, CPK, LDH, uric acid; albumin, non-fasting glucose 
(fasting blood glucose after a minimum 8-hour fast, at screening only), lipids, (Fasting lipids:  total cholesterol, LDL cholesterol, and triglycerides 
after a minimum 8-hour fast, at screening only).  
l 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.  At the 
investigator's discretion, tumor assessments may be repeated at any time if disease progression is suspected.  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. 
m All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA scan, at screening.  Treatment discontinuation visit 
evaluation of LVEF does not need to be performed at treatment discontinuation visit if an evaluation has been performed within the last 12 weeks 
and there are no clinically significant findings and/or changes from baseline. 
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study. 
• 
HBV serology will include HBsAg, total HBcAg antibody (anti-HBcAb).  HBV DNA should be obtained prior to study start 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 study start if patient tests positive for anti-HCV. 
o Thyroid function testing (TSH, free T3 [or total T3 for sites where free T3 is not performed, free T4) collected at Day 1 of Cycles 1−5, and every 
second cycle thereafter (e.g., Day 1 of Cycles 7, 9, 11, etc.) for patients on atezolizumab only. 
p All women of childbearing potential will have a serum pregnancy test at screening within 14 days prior to Day 1 of Cycle 1.  Urine pregnancy 
tests will be performed on Day 1 of every cycle and at the treatment discontinuation visit.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
q Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
r Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from   7 days before initiation of study drug until 30 days after the last dose of study drug. 
 

Appendix 1 
Schedule of Activities (cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol CO39721, Version 5 
s After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study drug or 
initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  After this 
period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study 
drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events or adverse events of special interest considered to be related to study drug or trial-related procedures until a 
final outcome can be reported. 
t 
Archival (<5 years) or fresh baseline tumor tissue collected during screening.  If a patient provides a fresh biopsy for BRAF test, this sample will 
be used also as baseline for biomarker analysis.  Therefore predose specimens are not required for patients who provide a fresh biopsy before 
treatment start. 
If archival tissue is used availability of adequate tumor tissue must be confirmed prior to any screening procedures (paraffin-embedded tumor 
block or a minimum of 20 unstained slides).  Submit archival tissue and associated pathology report within 30 days after Cycle 1, Day 1.  If a 
predose fresh biopsy is collected this sample should be obtained after eligibility criteria have been fulfilled and prior to Cycle 1, Day 1.  For 
patients who have consented to optional biopsies; an additional optional biopsy may be collected at the time of radiographic progression if 
clinically feasible. See Section 3.1.1 and the laboratory manual for further details.  
u In Cohort C, atezolizumab (1200 mg) will be given on Cycle 1, Day 1 IV Q3W.  The initial dose will be delivered over 60 (± 15) minutes.  If the 
first infusion is well tolerated, all subsequent infusions will be delivered over 30 (± 10) minutes until a loss of clinical benefit.  Study drug 
administration may be ± 3 days from the scheduled Day 1 of each cycle. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol CO39721, Version 5 
Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 
Cohort A 
Visit 
Timepoint 
Sample Type(s) 
Cycle 1, Day 1 
Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
30 (± 10) minutes following the 
end of atezolizumab infusion 
Atezolizumab PK (serum) 
2−4 hours after the cobimetinib 
dose 
Cobimetinib PK (plasma) 
Cycle 1, Day 15 
Prior to cobimetinib dose 
2−4 hours post cobimetinib 
dose 
Cobimetinib PK (plasma) 
Cycles 2, 3, 4, 8, 12, and 16 
Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
Cycles 1 and 2, Day 1 
At time of tumor assessments 
(preferably within 3 days) 
At disease progression  
Predose 
Biomarker (plasma, PBMC) 
Treatment discontinuation 
visit a 
At visit 
Atezolizumab PK and ADA 
(serum) 
 
Biomarker (plasma, PBMC) b 
120 days ± 30 days after last 
atezolizumab infusion 
At visit 
Atezolizumab PK and ADA 
(serum) 
ADA = anti-drug antibody; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetic. 
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within ± 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays. 
a Patients who discontinue study drug will return to the clinic for a treatment discontinuation 
visit 30 (± 3) days after the last dose of study drug.  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit. 
b At confirmed disease progression, lack of clinical benefit, or at treatment discontinuation. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
143/Protocol CO39721, Version 5 
Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (cont.) 
Cohort B 
Visit 
Timepoint 
Sample Type(s) 
Cycle 1, Day 15 
Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
 
30 (± 10) minutes following the 
end of atezolizumab infusion 
Atezolizumab PK (serum) 
 
Prior to cobimetinib dose 
2−4 hours post cobimetinib dose 
Cobimetinib PK (plasma) 
Cycles 2, 3, 4, 8, 12, and 16 Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
Cycles 1 and 2, Day 1 
At time of tumor 
assessments (preferably 
within 3 days) 
At disease progression  
Predose 
Biomarker (plasma, PBMC) 
Treatment discontinuation 
visit a 
At visit 
Atezolizumab PK and ADA 
(serum) 
 
Biomarker (plasma, PBMC) b 
120 days ± 30 days after 
last atezolizumab infusion 
At visit 
Atezolizumab PK and ADA 
(serum) 
ADA = anti-drug antibody; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetic; 
RECIST = Response Evaluation Criteria in Solid Tumors. 
Note:  Except for Day 15 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within ± 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays. 
a Patients who discontinue study drug will return to the clinic for a treatment discontinuation 
visit 30 (± 3) days after the last dose of study drug.  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit. 
b At confirmed disease progression, lack of clinical benefit, or at treatment discontinuation. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
144/Protocol CO39721, Version 5 
Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (cont.) 
Cohort C 
Visit 
Timepoint 
Sample Type(s) 
Cycle 1, Day 1 
Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
30 (± 10) minutes following the 
end of atezolizumab infusion 
Atezolizumab PK (serum) 
Cycles 2, 3, 4, 8, 12, and 16 
Prior to the first infusion 
Atezolizumab PK and ADA 
(serum) 
Cycles 1 and 2, Day 1 
At time of tumor assessments 
(preferably within 3 days) 
At disease progression  
Predose 
Biomarker (plasma, PBMC) 
Treatment discontinuation 
visit a 
At visit 
Atezolizumab PK and ADA 
(serum) 
 
Biomarker (plasma, PBMC) b 
120 days ± 30 days after last 
atezolizumab infusion 
At visit 
Atezolizumab PK and ADA 
(serum) 
ADA = anti-drug antibody; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetic. 
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within ± 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays. 
a Patients who discontinue study drug will return to the clinic for a treatment discontinuation 
visit 30 (± 3) days after the last dose of study drug.  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit. 
b At confirmed disease progression, lack of clinical benefit, or at treatment discontinuation. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
145/Protocol CO39721, Version 5 
Appendix 3  
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 Non-target 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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
146/Protocol CO39721, Version 5 
Appendix 3 
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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol CO39721, Version 5 
Appendix 3 
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 non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or 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 non-target 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. 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
148/Protocol CO39721, Version 5 
Appendix 3 
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 NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means 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 non-target lesions.  Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed. 

 
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Appendix 3 
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 non-target 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 non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
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 non-target) 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 3 
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 3 
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)  
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level) 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits 
• 
PD:  unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
Special Notes on Assessment of Progression of Non-target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target 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 non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore be extremely rare. 

 
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Appendix 3 
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 non-target 
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 3 
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 non-target) disease only, Table 2 is to 
be used. 
Table 1 
Timepoint Response:  Patients with Target Lesions 
(with or without Non-target Lesions) 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not 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 3 
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.)  
Table 2 
Timepoint Response:  Patients with Non-target Lesions Only 
Non-target 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 non-target 
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 non-target lesions are not assessed, the response 
for non-target 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 non-target 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 3 
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 3 
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 non-target disease as shown in 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 non-target 
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 non-target lesion. 

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

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

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
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Bone Lesions: 
• 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
• 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
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CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is ≤ 5 mm.  When CT scans 
have slice thickness of > 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation. 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
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161/Protocol CO39721, Version 5 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
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lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST 
(e.g., non−lymph node lesions must be ≥ 10 mm on the longest diameter; new lymph 
nodes must be ≥ 15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints.  
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden that is performed as part of 
the tumor response evaluation.  New lesion types that would not qualify as target lesions 
per RECIST cannot be included in the calculation of tumor burden and thus will not 
affect overall tumor response evaluation.  New lesions that are not measurable at first 
appearance but meet measurability criteria at a subsequent timepoint can be included in 
the tumor response evaluation from that point on, if the maximum number of measurable 
new lesions has not been reached. 
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is ≥ 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is ≥ 10 mm and < 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 
axis of a lymph node is < 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is ≥ 15 mm. 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline as a measure of 
tumor burden.  At each subsequent tumor assessment, a sum of the diameters (longest 
diameter for non-lymph node lesions, short axis for lymph node lesions) will be 
calculated for all target lesions plus measurable new lesions (up to five new lesions, with 
a maximum of two new lesions per organ) that have emerged after baseline.  Hence, 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol CO39721, Version 5 
each net percentage change in tumor burden per assessment accounts for the size and 
growth kinetics of both old lesions and new lesions as they appear. 
Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is ≥ 15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters.  
If the new lymph node lesion is included in the sum of diameters, it will continue to be 
measured and included in the sum of diameters at subsequent timepoints, even if the 
short axis decreases to < 15 mm (or even < 10 mm).  However, if it subsequently 
decreases to < 10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of < 10 mm (if lymph nodes), a response assessment of 
complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the node 
regresses to < 10 mm during the study.  Thus, when lymph nodes are included in the 
sum of diameters, the sum may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph node 
and non−lymph node) should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions or lymph nodes become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol CO39721, Version 5 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is < 5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE 
NEW LESIONS 
Measurements are not required for non-target lesions or non-measurable new lesions.  
Non-target lesions should be noted at baseline, and non-measurable new lesions should 
be noted at the time of identification.  At subsequent evaluations, non-target lesions and 
non-measurable new lesions will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or 
measurable new lesions in excess of five total or two per organ) will contribute only in 
the assessment of complete response (i.e., a complete response is attained only with 
the complete disappearance of all tumor lesions, including non-target lesions and 
non-measurable new lesions) and will not be used to assess progressive disease. 
RESPONSE CRITERIA 
Definitions of the criteria used to determine objective tumor response are provided below: 
• 
Complete response (CR):  Disappearance of all lesions 
Any pathological lymph nodes must have reduction in short axis to < 10 mm. 
• 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the baseline sum of diameters, in the absence of CR 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol CO39721, Version 5 
• 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of all 
target lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the smallest sum of diameters on study (including 
baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥ 5 mm. 
New lesions alone do not qualify as progressive disease.  However, their 
contribution to total tumor burden is factored into the sum of the diameters, 
which is used to determine the overall immune-modified RECIST tumor 
response. 
• 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 2 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 2 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions and 
Measurable New Lesions a 
Non-Target Lesions and 
Non-Measurable New Lesions b 
Overall Response 
CR 
Absent 
CR 
CR 
Present or not all evaluated 
PR 
PR 
Any 
PR 
SD 
Any 
SD 
Not all evaluated 
Any 
NE 
PD 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
a Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden, in addition to the target 
lesions identified at baseline. 
b Also includes measurable new lesions in excess of five total or two per organ. 
 

 
 
Appendix 4 
Response Evaluation Criteria in Solid Tumors:  
Modified-Immune Criteria (Excerpt from Original Publication) 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol CO39721, Version 5 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target or 
measurable new lesions at a timepoint, usually the case is also considered not evaluable 
at that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions, as well as new lesions, as shown in Table 1. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47.   
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Can 2014;2:17. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 
2009;15:7412−20. 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol CO39721, Version 5 
Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol CO39721, Version 5 
Appendix 6  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias for whom the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty about autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
• Acute disseminated 
encephalomyelitis 
• Addison disease 
• Ankylosing spondylitis 
• Antiphospholipid antibody 
syndrome 
• Aplastic anemia 
• Autoimmune hemolytic 
anemia 
• Autoimmune hepatitis 
• Autoimmune 
hypoparathyroidism 
• Autoimmune hypophysitis 
• Autoimmune myocarditis 
• Autoimmune oophoritis 
• Autoimmune orchitis 
• Autoimmune 
thrombocytopenic purpura 
• Behçet disease 
• Bullous pemphigoid 
• Chronic fatigue syndrome 
• Chronic inflammatory 
demyelinating 
polyneuropathy 
• Churg-Strauss syndrome 
• Crohn disease  
• Dermatomyositis 
• Diabetes mellitus type 1 
• Dysautonomia 
• Epidermolysis bullosa 
acquisita 
• Gestational pemphigoid 
• Giant cell arteritis 
• Goodpasture syndrome 
• Graves disease 
• Guillain-Barré syndrome 
• Hashimoto disease 
• IgA nephropathy 
• Inflammatory bowel disease 
• Interstitial cystitis 
• Kawasaki disease 
• Lambert-Eaton myasthenia 
syndrome 
• Lupus erythematosus 
• Lyme disease, chronic 
• Meniere syndrome 
• Mooren ulcer 
• Morphea 
• Multiple sclerosis 
• Myasthenia gravis 
• Neuromyotonia 
• Opsoclonus myoclonus 
syndrome 
• Optic neuritis 
• Ord thyroiditis 
• Pemphigus 
• Pernicious anemia 
• Polyarteritis nodosa 
• Polyarthritis 
• Polyglandular autoimmune 
syndrome 
• Primary biliary cirrhosis 
• Psoriasis 
• Reiter syndrome 
• Rheumatoid arthritis 
• Sarcoidosis 
• Scleroderma 
• Sjögren syndrome 
• Stiff-Person syndrome 
• Takayasu arteritis 
• Ulcerative colitis 
• Vitiligo 
• Vogt-Koyanagi-Harada 
disease 
• Wegener granulomatosis 
 

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol CO39721, Version 5 
Appendix 7  
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 observe the patient and document observations

 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol CO39721, Version 5 
Appendix 8  
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.  
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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol CO39721, 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.  

 
 
A p p e n di x 8  
Ri s k s A s s o ci at e d wit h At e z oli z u m a b a n d G ui d eli n e s f or 
M a n a g e m e nt of A d v er s e E v e nt s A s s o ci at e d wit h At e z oli z u m a b 
( c o nt.) 
C o bi m eti ni b a n d At e z oli z u m a b — F.  H off m a n n -L a R o c h e Lt d  
1 7 4 /Pr ot o c ol C O 3 9 7 2 1, V er si o n 5  
T a bl e  3 
M a n a g e m e nt G ui d eli n e s f or G a str oi nt e sti n al E v e nt s ( Di arr h e a or 
C oliti s)  
E v e nt  
M a n a g e m e nt  
Di arr h e a or 
c oliti s, Gr a d e 1  
•  C o nti n u e at e z oli z u m a b.  
•  I niti at e s y m pt o m ati c tr e at m e nt. 
•  E n d o s c o p y i s r e c o m m e n d e d if s y m pt o m s p er si st f or >  7 d a y s.  
•  M o nit or cl o s el y.  
Di arr h e a or 
c oliti s, Gr a d e 2  
•  Wit h h ol d at e z oli z u m a b f or u p t o 1 2 w e e k s aft er e v e nt o n s et.
 a  
•  I niti at e s y m pt o m ati c tr e at m e nt. 
•  P ati e nt r ef err al t o GI s p e ci ali st i s r e c o m m e n d e d.  
•  F or r e c urr e nt e v e nt s or e v e nt s t h at p er si st 
 5 d a y s, i niti at e tr e at m e nt 
wit h 1 −2 m g/ k g/ d a y or al pr e d ni s o n e or e q ui v al e nt.  
•  If e v e nt r e s ol v e s t o Gr a d e 1 or b ett er, r e s u m e at e z oli z u m a b. b 
•  If e v e nt d o e s n ot r e s ol v e t o Gr a d e 1 or b ett er w hil e wit h h ol di n g 
at e z oli z u m a b, p er m a n e ntl y di s c o nti n u e at e z oli z u m a b a n d c o nt a ct 
M e di c al M o nit or.
 c 
Di arr h e a or 
c oliti s, Gr a d e 3  
•  Wit h h ol d at e z oli z u m a b  f or u p t o 1 2 w e e k s aft er e v e nt o n s et. a 
•  R ef er p ati e nt t o GI s p e ci ali st f or e v al u ati o n a n d c o nfir m at or y bi o p s y.  
•  I niti at e tr e at m e nt wit h 1 −2 m g/ k g/ d a y I V m et h yl pr e d ni s ol o n e or 
e q ui v al e nt a n d c o n v ert t o 1 −2 m g/ k g/ d a y or al pr e d ni s o n e or e q ui v al e nt  
u p o n i m pr o v e m e nt.  
•  If e v e nt r e s ol v e s t o Gr a d e 1 or b ett er, r e s u m e at e z oli z u m a b. b 
•  If e v e nt d o e s n ot r e s ol v e t o Gr a d e 1 or b ett er w hil e wit h h ol di n g 
at e z oli z u m a b, p er m a n e ntl y di s c o nti n u e at e z oli z u m a b a n d c o nt a ct 
M e di c al M o nit or.
 c 
GI
 =  g a str oi nt e sti n al.  
a At e z oli z u m a b m a y b e wit h h el d f or a l o n g er p eri o d of ti m e (i. e., >  1 2 w e e k s aft er e v e nt 
o n s et) t o all o w f or c orti c o st er oi d s (if i niti at e d) t o b e r e d u c e d t o ≤ 1 0 m g/ d a y or al 
pr e d ni s o n e or e q ui v al e nt.  T h e a c c e pt a bl e l e n gt h of t h e e xt e n d e d p eri o d of ti m e m u st b e 
a gr e e d u p o n b y t h e i n v e sti g at or a n d t h e M e di c al M o nit or.  
b If c orti c o st er oi d s h a v e b e e n i niti at e d, t h e y m u st b e t a p er e d o v er ≥ 1 m o nt h t o ≤ 1 0 m g/ d a y 
or al pr e d ni s o n e or e q ui v al e nt b ef or e at e z oli z u m a b c a n b e r e s u m e d.  
c R e s u m pti o n of at e z oli z u m a b m a y b e c o n si d er e d i n p ati e nt s w h o ar e d eri vi n g b e n efit a n d 
h a v e f ull y r e c o v er e d fr o m t h e i m m u n e -r el at e d e v e nt.  P ati e nt s c a n b e r e-c h all e n g e d wit h 
at e z oli z u m a b o nl y aft er a p pr o v al h a s b e e n d o c u m e nt e d b y b ot h t h e i n v e sti g at or ( or a n 
a p pr o pri at e d el e g at e) a n d t h e M e di c al M o nit or.  

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol CO39721, 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) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol CO39721, Version 5 
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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
178/Protocol CO39721, 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.  
 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol CO39721, Version 5 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent.   
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to 
≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol CO39721, 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. 
• 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. 
• 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
182/Protocol CO39721, 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. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol CO39721, Version 5 
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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
184/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
185/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
186/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol CO39721, 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 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
188/Protocol CO39721, 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. 
 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol CO39721, Version 5 
RENAL EVENTS 
Immune-related nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function, and renal function, including 
serum creatinine, should be monitored throughout study treatment.  Patients with 
abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis 
and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
190/Protocol CO39721, Version 5 
Table 12 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact Medical 
Monitor.  
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-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.  
 
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 atezolizumab is given in combination with other 
immunomodulating agents. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
191/Protocol CO39721, Version 5 
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 clinical specialists (e.g., rheumatology, clinical 
immunology, or solid organ or hematopoietic stem cell transplant specialists) and the 
Medical Monitor should be consulted 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 
• 
Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, or 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 
• 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) 
• 
Triglycerides 
• 
AST, ALT, and direct 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 neurologic abnormalities are present, consider cerebrospinal fluid analysis and/or an 
MRI of the brain. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol CO39721, Version 5 
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) 
• 
Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes-simplex virus, and human 
herpesvirus 6, 7, and 8 evaluation (for reactivated or active disease) 
 
Diagnostic criteria and recommended management for systemic immune activation are 
provided in Table 13.  The diagnostic criteria apply only when alternative etiologies have 
been excluded. 
An adverse event of systemic immune activation should be reported on the Adverse 
Event eCRF if it meets the criteria for "consistent with systemic immune activation" or 
"probable systemic immune activation" as outlined in Table 13. 

 
 
Appendix 8 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
(cont.) 
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 
194/Protocol CO39721, Version 5 
REFERENCES 
Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful 
criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. 
PLoS ONE 2014;9(4):e94024. doi: 10.1371/journal.pone.0094024.