A Phase II, Open-Label, Multicenter, Randomized Study of the Efficacy and Safety of RO7198457 in Combination With Pembrolizumab Versus Pembrolizumab in Patients With Previously Untreated Advanced Melanoma
Phase: PHASE2
Conditions: Advanced Melanoma
Sponsor: Genentech, Inc.

 
Official Title: 
A Phase II, Open-Label, Multicenter, Randomized Study of the 
Efficacy and Safety of RO7198457 in Combination with 
Pembrolizumab Versus Pembrolizumab in Patients with Previously 
Untreated Advanced Melanoma 
NCT Number: 
NCT03815058 
Document Date: 
Protocol Amendment Version 5: 14-Nov-2023 
 
 
 

CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
RO7198457—Genentech, Inc. 
Protocol GO40558, Version 5  
PROTOCOL 
TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY OF THE EFFICACY AND SAFETY 
OF RO7198457 IN COMBINATION WITH 
PEMBROLIZUMAB VERSUS PEMBROLIZUMAB IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
ADVANCED MELANOMA 
PROTOCOL NUMBER: 
GO40558 
STUDY NAME: 
IMCODE001 
VERSION NUMBER: 
5 
REGULATORY AGENCY 
IDENTIFIER NUMBERS  
IND Number:  18374 
EU CT Number:  2023-507389-15-00 
EUDRACT Number:  2018-001773-24 
TEST PRODUCT: 
RO7198457 
SPONSOR NAME AND 
ADDRESS: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080 
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 

RO7198457—Genentech, Inc. 
2/Protocol GO40558, Version 5 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
5 
See electronic date stamp 
on final page. 
4 
11 October 2023 
3 (Germany) 
21 October 2019 
2 
27 April 2019 
1 
14 August 2018 
 

RO7198457—Genentech, Inc. 
3/Protocol GO40558, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol GO40558 has been amended to correct minor errors introduced in 
Protocol GO40558, Version 4.  Protocol GO40558, Version 4 was amended to align with 
the harmonized multinational Clinical Trials Regulation (CTR) guidelines and to add 
clarity on study conduct.  This amendment supersedes Protocol GO40558 Version 3 
(Germany) and Version 4.  Due to the administrative nature of this amendment, 
cumulative changes to the protocol from Version 3 (Germany) and Version 4 along with 
changes specific to this amendment are included. 
Changes specific to Version 5, along with a rationale for each change, are summarized 
below: 
 
Minor deletions have been made to correct errors from Protocol GO40558, 
Version 4 (Section 4.3.1, Appendices 2, 3, and 13). 
 
The email address to which the paper Clinical Trial Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form is sent has been updated from 
“SAEIntake@covance.com” to “SAEIntake@Fortrea.com” (Section 5.4.2.1). 
 
Changes specific to Version 4, along with a rationale for each change, are summarized 
below: 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitor has been removed from the protocol (front matter and Section 5.4.1).  
Medical Monitor contact information in Section 5.4.1 has been replaced with a 
sentence indicating that this information will be provided separately to sites. 
 
The synopsis has been simplified to align with CTR and other guidelines. 
 
Language has been updated to clarify the responsibilities of the investigator and the 
role of the Medical Monitor and Sponsor to ensure the appropriate execution of the 
study (Sections 3.3.13, 4.1.1, 4.1.2, 4.2, 4.3.2.1, 4.4.14.4.3, 4.5.7, 5.1.1.1, 
5.1.4.15.1.4.3; Appendices 1, 2, and 7). 
 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products has been added to align with CTR requirements (Section 4.3 and 
Appendix 13). 
 
 
 
 
Updated the frequency of tumor assessments during follow-up to better align with 
standard of care (Section 4.5.5, Appendix 1, and Appendix 2). 
 
Language describing procedures for patient withdrawal from the study and the 
Research Biosample Repository has been updated to clarify that patients may 
withdraw verbally or in writing (Sections 4.5.13.6 and 4.6.2). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.13.6). 

RO7198457—Genentech, Inc. 
4/Protocol GO40558, Version 5 
 
Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12). 
 
Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1). 
 
Language regarding investigator reporting of pregnancies has been clarified 
(Section 5.4.3.2). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 8.4). 
 
To align with CTR requirements, text has been modified to clarify that summaries of 
clinical study results may be available for public access in health authority 
databases.  And language has been modified to clarify that Roche's global policy on 
data sharing does not have requirements that must be met before study results can 
be made available (Sections 8.4 and 9.5). 
 
The URL for the Roche Global Policy on Sharing of Clinical Study Information has 
been updated (Section 9.5). 
 
Blood biomarker collection (PBMC-I) has been removed for patients in the 
Follow-Up period (Appendix 1 and Appendix 2). 
 
Language has been added to clarify that questionnaires can be performed at earlier 
timepoints in the event that other assessments associated with Day 1 are done in 
advance of study treatment within protocol-specified time windows (Appendix 1 and 
Appendix 2). 
 
Language has been added to allow patients who cross over from Arm A to Arm B to 
skip screening assessments (Parts A and B) and the Cycle 1, Day 1 (C1D1) visit  
 
 
 
 
 
Changes specific to Version 3 (Germany), along with a rationale for each change, are 
summarized below: 
 
Sections 3.1.3 and 3.1.4 have been updated to specify that informed consent to 
treatment beyond disease progression or to cross over from treatment Arm A to B 
includes understanding and actively declining other treatment options available. 
 
Section 5.1.4.2 has been amended to align treatment interruption and modification 
guidelines for pembrolizumab (Keytruda) with the Keytruda Summary of Product 
Characteristics. 
 

RO7198457—Genentech, Inc. 
5/Protocol GO40558, 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. 

RO7198457—Genentech, Inc. 
6/Protocol GO40558, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on Melanoma ....................................................... 21 
1.2 
Background on RO7198457 .................................................... 21 
1.2.1 
Summary of Nonclinical Studies Supporting RO7198457 ........ 24 
1.2.2 
Summary of RO7198457 Phase I Clinical Data ....................... 24 
1.2.2.1 
Clinical Safety .......................................................................... 24 
1.2.2.2 
Clinical Efficacy ........................................................................ 25 
1.2.2.3 
Pharmacodynamic Activity of RO719845 ................................ 25 
1.3 
Combination of a Therapeutic Cancer Vaccine and 
Inhibition of PD-L1/PD-1 Pathways as Potential 
Anti-Cancer Therapy ................................................................ 26 
1.4 
Study Rationale and Benefit-Risk Assessment ........................ 27 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 29 
2.1 
Efficacy Objectives .................................................................. 29 
2.1.1 
Primary Efficacy Objective ....................................................... 29 
2.1.2 
Secondary Efficacy Objectives ................................................ 29 
2.1.3 
Exploratory Efficacy Objective ................................................. 30 
2.2 
Safety Objective ....................................................................... 30 
2.3 
Pharmacokinetic Objectives..................................................... 31 
2.4 
Biomarker Objective ................................................................ 31 
3. 
STUDY DESIGN ........................................................................... 31 
3.1 
Description of the Study ........................................................... 31 
3.1.1 
Overview of Study Design........................................................ 31 
3.1.2 
Safety Run-In Stage ................................................................ 36 
3.1.3 
Treatment after Disease Progression ...................................... 37 
3.1.4 
Crossover from Control Arm A to Experimental Treatment ...... 39 
3.1.5 
Internal Monitoring Committee Reviews .................................. 41 
3.2 
End of Study and Length of Study ........................................... 41 
3.3 
Rationale for Study Design ...................................................... 42 

RO7198457—Genentech, Inc. 
8/Protocol GO40558, Version 5 
4.3.1.1 
RO7198457 ............................................................................. 60 
4.3.1.2 
Pembrolizumab ........................................................................ 61 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 61 
 
 ............................................................................. 61 
4.3.2.2 
Pembrolizumab ........................................................................ 64 
4.3.3 
Investigational Medicinal Product Accountability ..................... 64 
4.3.4 
Continued Access to RO7198457 and/or Pembrolizumab ....... 65 
 
 .............................................................. 66 
 
 ................................................................... 66 
 
 ................................................................. 67 
 
 ......................................................... 67 
 
 ...................................... 67 
 
 .................................................................. 68 
4.5 
Study Assessments ................................................................. 69 
4.5.1 
Informed Consent Forms and Screening Log .......................... 69 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 70 
4.5.3 
Physical Examinations ............................................................. 71 
4.5.4 
Vital Signs ................................................................................ 71 
4.5.5 
Tumor and Response Evaluations ........................................... 72 
4.5.6 
Photography of Cutaneous Lesions ......................................... 74 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 74 
4.5.7.1 
Local Laboratory Tests ............................................................ 74 
4.5.7.2 
Central Laboratory Tests ......................................................... 75 
4.5.8 
Electrocardiograms .................................................................. 79 
4.5.9 
Cancer-Related Procedures .................................................... 80 
4.5.10 
Patient-Reported Outcomes .................................................... 80 
4.5.10.1 
EORTC Library ........................................................................ 80 
4.5.10.2 
Patient-Reported Outcomes Common Terminology Criteria 
for Adverse Events .................................................................. 81 
4.5.10.3 
Work Productivity and Activity Impairment: Melanoma, 
Version 2.0............................................................................... 81 
4.5.11 
Samples for Optional Whole Genome Sequencing .................. 82 
4.5.12 
Tumor Biopsies ........................................................................ 82 

RO7198457—Genentech, Inc. 
10/Protocol GO40558, Version 5 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 107 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 108 
5.3.1 
Adverse Event Reporting Period ............................................ 108 
5.3.2 
Eliciting Adverse Event Information ....................................... 109 
5.3.3 
Assessment of Severity of Adverse Events ........................... 109 
5.3.4 
Assessment of Causality of Adverse Events.......................... 110 
5.3.5 
Procedures for Recording Adverse Events ............................ 111 
5.3.5.1 
Systemic Infusion Reactions During or After Study Drug 
Infusion .................................................................................. 111 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 112 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 112 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 113 
5.3.5.5 
Abnormal Laboratory Values ................................................. 113 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 114 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 114 
5.3.5.8 
Deaths ................................................................................... 115 
5.3.5.9 
Preexisting Medical Conditions .............................................. 115 
5.3.5.10 
Lack of Efficacy or Worsening of Incurable, Advanced 
Malignancy............................................................................. 116 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 116 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ............... 116 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 117 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 118 
5.4.1 
Emergency Medical Contacts ................................................ 118 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 118 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 118 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 119 
5.4.3 
Reporting Requirements for Pregnancies .............................. 119 
5.4.3.1 
Pregnancies in Female Patients ............................................ 119 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 120 
5.4.3.3 
Abortions................................................................................ 120 

RO7198457—Genentech, Inc. 
11/Protocol GO40558, Version 5 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 120 
5.5 
Follow-Up of Patients after Adverse Events........................... 121 
5.5.1 
Investigator Follow-Up ........................................................... 121 
5.5.2 
Sponsor Follow-Up ................................................................ 121 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 121 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 121 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 122 
6.1 
Determination of Sample Size ............................................... 122 
6.2 
Summaries of Conduct of Study ............................................ 124 
6.3 
Summaries of Demographic and Baseline Characteristics .... 124 
6.4 
Efficacy Analyses ................................................................... 124 
6.4.1 
Primary Efficacy Endpoint of PFS .......................................... 124 
6.4.2 
Secondary Efficacy Endpoints ............................................... 125 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 126 
6.5 
Safety Analyses ..................................................................... 126 
6.6 
Pharmacokinetic Analyses ..................................................... 127 
6.7 
Biomarker Analyses ............................................................... 127 
6.8 
Interim Analyses .................................................................... 128 
6.8.1 
Planned Interim Analyses ...................................................... 128 
6.8.2 
Optional Interim Analyses ...................................................... 128 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 128 
7.1 
Data Quality Assurance ......................................................... 128 
7.2 
Electronic Case Report Forms ............................................... 129 
7.3 
Source Data Documentation .................................................. 129 
7.4 
Use of Computerized Systems .............................................. 130 
7.5 
Retention of Records ............................................................. 130 
8. 
ETHICAL CONSIDERATIONS .................................................... 130 
8.1 
Compliance with Laws and Regulations ................................ 130 
8.2 
Informed Consent .................................................................. 131 
8.3 
Institutional Review Board or Ethics Committee .................... 132 
8.4 
Confidentiality ........................................................................ 132 

 
RO7198457—Genentech, Inc. 
14/Protocol GO40558, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY OF THE EFFICACY AND SAFETY 
OF RO7198457 IN COMBINATION WITH 
PEMBROLIZUMAB VERSUS PEMBROLIZUMAB IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
ADVANCED MELANOMA 
PROTOCOL NUMBER: 
GO40558 
VERSION NUMBER: 
5 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  18374 
EU CT Number:  2023-507389-15-00 
EUDRACT Number:  2018-001773-24 
TEST PRODUCT: 
RO7198457 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the Sponsor. 
 

 
RO7198457—Genentech, Inc. 
15/Protocol GO40558, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY OF THE EFFICACY AND SAFETY OF RO7198457 IN 
COMBINATION WITH PEMBROLIZUMAB VERSUS 
PEMBROLIZUMAB IN PATIENTS WITH PREVIOUSLY 
UNTREATED ADVANCED MELANOMA  
PROTOCOL NUMBER: 
GO40558 
VERSION NUMBER: 
5 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  18374 
EU CT Number:  2023-507389-15-00 
EUDRACT Number:  2018-001773-24 
SPONSOR: 
Genentech, Inc. 
 
PRIMARY AND SECONDARY OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and patient-reported outcomes 
(PROs) of RO7198457 plus pembrolizumab compared with pembrolizumab alone in patients 
with previously untreated advanced melanoma.  Specific objectives and corresponding 
endpoints for the study are outlined below. 

 
RO7198457—Genentech, Inc. 
16/Protocol GO40558, Version 5 
Primary Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
RO7198457 plus pembrolizumab 
compared with pembrolizumab alone 
 Progression-free survival (PFS) after 
randomization, defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever 
occurs first), as determined by the investigator 
according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of 
RO7198457 plus pembrolizumab 
compared with pembrolizumab alone 
 Objective response rate (ORR), defined as the 
proportion of patients with a complete response 
(CR) or partial response (PR) on two consecutive 
occasions   4 weeks apart, as determined by the 
investigator according to RECIST v1.1 
 Overall survival (OS) after randomization, defined 
as the time from randomization to death from any 
cause 
 Duration of response (DOR), defined as the time 
from the first occurrence of a documented objective 
response to disease progression or death from any 
cause, as determined by the investigator according 
to RECIST v1.1 
 Mean change from baseline in health-related quality 
of life (HRQoL) scores as assessed through use of 
the two-item global health status (GHS)/HRQoL 
subscale (Questions 29 and 30) of the European 
Organisation for Research and Treatment of Cancer 
Quality of Life-Core 30 (EORTC QLQ-C30) at 
specified timepoints 
Secondary Objectives (cont.) 
Corresponding Endpoints (cont.) 
 To evaluate the efficacy of 
RO7198457 plus pembrolizumab in 
patients who have progressed 
following pembrolizumab 
monotherapy 
 ORR, defined as the proportion of patients with a 
CR or PR on two consecutive occasions ³ 4 weeks 
apart, as determined by the investigator according 
to RECIST v1.1, at the time of crossover 
 To evaluate the safety of RO7198457 
plus pembrolizumab compared with 
pembrolizumab alone 
 Incidence and severity of adverse events, with 
severity determined according to National Cancer 
Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 (NCI CTCAE v5.0) 
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical laboratory 
test results 
 
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase II, randomized, open-label, multicenter study designed to evaluate the efficacy 
and safety of RO7198457 plus pembrolizumab compared with pembrolizumab alone in patients 
with previously untreated advanced melanoma.   
The study has an initial safety run-in stage and a randomized stage.   
Several key aspects of the study design and study population are summarized below.  

 
RO7198457—Genentech, Inc. 
17/Protocol GO40558, Version 5 
Phase: 
II 
Population Type: 
Adult patients 
Control Method: 
Active comparator 
Population Diagnosis 
or Condition: 
Advanced melanoma 
Interventional 
Model: 
Parallel group 
Population Age: 
Age  18 years 
Test Compound: 
RO7198457 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator: Pembrolizumab 
Study Intervention 
Assignment Method: 
Randomized 
Number of Arms:  
2 
Number of 
Participants to Be 
Enrolled: 
Approximately 120 
STUDY TREATMENT 
Patients in the safety run-in will receive at least 1 cycle (21 days) of 200 mg pembrolizumab 
monotherapy administered by IV infusion.  Once RO7198457 is manufactured and availabl e, 
patients will receive 200 mg pembrolizumab by IV infusion every 3 weeks (Q3W) and 
 
RO7198457 by IV infusion. 
DURATION OF PARTICIPATION 
The study consists of two stages:  an initial safety run-in stage and a randomized stage.  
Each stage will have a two-part screening period (Part A and Part B), a treatment period of 
24 months, and post-treatment follow-up period. 
COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee 
 

 
RO7198457—Genentech, Inc. 
18/Protocol GO40558, Version 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AJCC v8.0 
American Joint Committee on Cancer 8th Edition 
anti-HBc 
antibody to hepatitis B core antigen 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration–time curve 
CIT 
cancer immunotherapy 
CL 
clearance 
Cmax 
maximum serum concentration observed 
Cmin 
minimum serum concentration observed 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyteassociated protein 4 
CV 
coefficient of variation 
DC 
dendritic cell 
 
 
DOR 
duration of response 
 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of LifeCore 30 
ESMO 
European Society for Medical Oncology 
FACS 
fluorescence-activated cell sorting 
FPI 
first patient in 
G-CSF 
granulocyte colony-stimulating factor 
GHS 
global health status 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 

 
RO7198457—Genentech, Inc. 
19/Protocol GO40558, Version 5 
Abbreviation 
Definition 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
human leukocyte antigen 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IFN(-,-) 
interferon(-,-) 
IHC 
immunohistochemistry 
IL(-2,-6,-12) 
interleukin(-2,-6,-12)  
IMC 
Internal Monitoring Committee 
iRECIST  
immune-based therapeutics Response Evaluation 
Criteria in Solid Tumors 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITT 
intent-to-treat (population) 
IWRS 
interactive web-based response system 
LC 
liquid chromatography 
LDH 
lactate dehydrogenase 
MAOI 
monoamine oxidase inhibitor 
MHC 
major histocompatibility complex 
MRI 
magnetic resonance imaging 
MS 
mass spectrometry 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 
NGS 
next-generation sequencing 
NK 
natural killer (cell) 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PCV 
personalized cancer vaccine 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic 

 
RO7198457—Genentech, Inc. 
20/Protocol GO40558, Version 5 
Abbreviation 
Definition 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events 
Q3W 
every 3 weeks 
qRT-PCR 
quantitative reverse transcription polymerase chain 
reaction 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
RO7198457 
investigational medicinal product 
SCID 
severe combined immunodeficiency 
SJS 
Stevens-Johnson syndrome 
TCR 
T-cell receptor 
TEN 
toxic epidermal necrolysis 
TIL 
tumor-infiltrating lymphocyte 
TNF- 
tumor necrosis factor 
ULN 
upper limit of normal 
Vss 
volume of distribution under steady-state conditions 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
WPAI 
Work Productivity and Activity Impairment 
WPAI:Melanoma 
Work Productivity and Activity Impairment:  Melanoma, 
Version 2.0 
 

 
RO7198457—Genentech, Inc. 
21/Protocol GO40558, Version 5 
1. 
BACKGROUND 
1.1 
BACKGROUND ON MELANOMA 
Melanoma is a potentially deadly form of skin cancer originating from melanocytes.  
In 2012, there were approximately 232,000 new cases and 55,000 deaths from 
melanoma worldwide, with more than 100,000 new cases and 22,000 deaths in Europe 
(Ferlay et al. 2013).  In the United States in 2018, an estimated 91,270 new diagnoses of 
melanoma are projected and approximately 9,320 patients are expected to die of the 
disease (American Cancer Society 2018).  Additionally, estimates suggest a doubling of 
the incidence of melanoma every 10−20 years (Garbe and Leiter 2009). 
The clinical outcome of patients with melanoma is highly dependent on the stage at 
presentation.  Until recently, treatment options for metastatic melanoma were limited.  
Dacarbazine was considered to be the standard first-line treatment; however, outcomes 
were poor, with response rates of 5%–12%, median progression-free survival (PFS) of 
less than 2 months, and median overall survival (OS) of 6.4 to 9.1 months (Middleton et 
al. 2000; Bedikian et al. 2006; Chapman et al. 2011; Robert et al. 2011).  Combination 
chemotherapy and chemotherapy combined with interferon- (IFN)- or interleukin-2 
(IL-2), although showing improved response rates, have not resulted in improved OS 
(Chapman et al. 1999; Ives et al. 2007).  
Immunotherapeutic agents that target co-inhibitory receptors or "immune checkpoints" 
that suppress T-cell activation have improved the outcomes of patients with advanced 
melanoma.  In the Phase I KEYNOTE-001 study of pembrolizumab monotherapy in 
advanced melanoma, 3-year OS was 40% in all patients and 45% in treatment-naive 
patients (Robert et al. 2016), and 5-year OS was 34% in all patients and 41% in 
treatment-naive patients (Hamid et al. 2018).  In the Phase III KEYNOTE-006 study 
(pembrolizumab vs. ipilimumab) in advanced melanoma, the 1-year OS rates ranged 
from 74%–58% for pembrolizumab and ipilimumab, respectively (Robert et al. 2015b).  
Two-year OS rates were 55%43% (Schachter et al. 2017), and 4-year OS rates were 
41%34% (Long et al. 2018).  In the CheckMate 067 trial, the median OS in the 
nivolumab group was 37.6 months (95% CI: 29.1, not reached), with 52% of the patients 
in the nivolumab group alive at 3 years, as compared with 34% of those in the 
ipilimumab group.  At a minimum follow-up of 36 months, the median OS had not been 
reached in the nivolumab-plus-ipilimumab group.  The survival rate at 3 years was 58% 
among patients in the nivolumab plus-ipilimumab group (Wolchok et al. 2017). 
Despite these advances, many patients do not respond to current therapies or later 
succumb to their disease, highlighting the continuing unmet medical need for more 
efficacious treatment options. 
1.2 
BACKGROUND ON RO7198457 
Human cancers carry numerous non-synonymous mutations, many of which are 
immunogenic and, therefore, targetable by cancer vaccines.  Some cancers, like 

 
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melanoma, can harbor in excess of 500 non-synonymous mutations on average.  
Although some non-synonymous mutations may act as drivers for maintaining the 
oncogenic phenotype, every patient's cancer bears a highly individual mutation 
repertoire. 
Several recent studies have shown that neoantigens may have an important role in 
anti-tumor immunity.  High mutational burden correlates with higher tumor-infiltrating 
CD8+ T cells (Brown et al. 2014) and cytolytic activity of natural killer (NK) and CD8+ 
T cells (Rooney et al. 2015).  Multiple studies have suggested that mutational burden 
and neoantigen frequency in melanoma, bladder cancer, and lung cancer correlate with 
improved survival in response to checkpoint inhibitors, such as antiCTLA-4 and 
antiPD-1 (van Rooij et al. 2013; Snyder et al. 2014; Rizvi et al. 2015; Van Allen et al. 
2015; Rosenberg et al. 2016; Ramalingam et al. 2018).  Furthermore, a comparison of the 
effects of PD-1 blockade in patients with mismatch repair proficient and deficient cancer 
shows a strong association between clinical response and mismatch repair deficiency 
(Le et al. 2015).  Neoantigen-specific CD4+ and CD8+ T cells can be detected in cancer 
patients (Snyder et al. 2014; Linnemann et al. 2015; Rizvi et al. 2015) and the frequency 
of CD8+ T cells against neoantigens in the tumor or the blood increases after checkpoint 
inhibitor treatment (Snyder et al. 2014; Rizvi et al. 2015), indicating that these T cells are 
the targets of checkpoint blockade.  The neoantigen-specific immune-stimulating effects 
of a therapeutic vaccine may improve the efficacy of checkpoint blockade by expanding 
the tumor-specific T-cell repertoire through the priming of de novo immune response and 
by further expanding the preexisting immune response, which may significantly improve 
the response rate and durability of responses compared to either agent alone. 
Most mutations are randomly induced by carcinogens, ultraviolet radiation, or DNA 
repair defects.  As the resulting neoantigens are unique to each patient, targeting them 
through vaccination requires a personalized approach (Hartmaier et al. 2017).  
RO7198457 is a personalized cancer vaccine (PCV) classified as an iNeST 
(Individualized Neoantigen Specific Therapy) that is based on the immunotherapeutic 
targeting of the unique mutations in a given patient's tumor.  Multiple key technologies 
have been combined to generate a controlled process that covers all steps from 
identification of mutations in individual clinical tumor specimens to the supply of an 
individually tailored RNA vaccine for use in a specific patient. 
 
 
  
 
 
 
 

 
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Enrollment and analyses are ongoing in Study GO39733, and all clinical data presented 
in this document are preliminary.  Refer to the RO7198457 Investigator's Brochure for 
details on clinical safety. 
1.2.2.2 
Clinical Efficacy 
Preliminary clinical data are available on similar vaccine platforms (Kranz et al. 2016; 
Sahin et al. 2017).  
 
  The first in human study of RO7198457 is ongoing in patients with 
advanced solid tumors. 
For further details, refer to the RO7198457 Investigator's Brochure for details on clinical 
efficacy. 
1.2.2.3 
Pharmacodynamic Activity of RO719845 
As of 05 October 2018, preliminary PD data measuring cytokine response in peripheral 
blood are available for patients treated in Phase Ia portion of Study GO39733 at

 
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transient returns to baseline levels by 24 hours.  Similar cytokine induction is observed 
after repeated RO719845 infusions in individual patients.  These cytokine data 
demonstrate PD effects of RO7198457 mediated through TLR7/8 stimulation.  
For further details, refer to the RO7198457 Investigator's Brochure. 
1.3 
COMBINATION OF A THERAPEUTIC CANCER VACCINE AND 
INHIBITION OF PD-L1/PD-1 PATHWAYS AS POTENTIAL 
ANTI-CANCER THERAPY 
Clinical and nonclinical data on currently available immunotherapeutics suggest that 
single-agent immunotherapy is unlikely to induce complete and durable anti-tumor 
responses in the majority of patients.  Host immunosuppression by malignant cells is 
mediated by multiple pathways; therefore, combination therapy regimens employing two 
or more targeted cancer immunotherapy (CIT) agents may be required to fully engage 
the anti-tumor potential of the host immune system.  Therapeutic vaccines, while 
promising, have historically fallen short of expectations.  One of the potential reasons is 
that cancer-specific T cells become functionally exhausted during chronic exposure to 
cancer cells.  Conversely, no objective responses are observed in the majority of 
patients treated with antiPD-L1/PD-1 antibodies.  A possible explanation for this is the 
lack of natural infiltration of effector immune cells into the tumor microenvironment 
(Herbst et al. 2014). 
Nonclinical studies indicate that the combination of checkpoint inhibitors and vaccines 
has the potential for combined effects.  Experimental animal models of chronic infection 
and cancer demonstrate that the PD-L1/PD-1 pathway plays a critical role in shaping 
CD8+T cells and may cooperate with therapeutic vaccination to enhance anti-tumor 
T-cell responses and elicit tumor regression (Ha et al. 2008).  PD-1 blockade combined 
with therapeutic vaccination results in an increased influx of IFN- producing activated 
T cells to the tumor compared to single treatment (Allie et al. 2011; Soares et al. 2015) 
and resulted in increased tumor regression (Fu et al. 2014; Soares et al. 2015).  In 
mouse models of glioblastoma multiforme, the combination of tumor-lysate−loaded DC 
vaccine and antiPD-1 also resulted in longer survival benefit dependent on CD8+T cells 
(Antonios et al. 2016) and was more effective than monotherapy with antiPD-1 alone 
(Li et al. 2009). 
Early data from clinical studies suggest that the combination of checkpoint inhibitors and 
vaccines is well tolerated and has potential synergy.  The initial combination of 
anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor (GM-CSF) 
secreting cancer vaccine (GVAX) demonstrated objective clinical responses in patients 
with pancreatic ductal adenocarcinoma while neither single agent was able to induce 
responses (Le et al. 2013).  As another example, recently, a PD-1 inhibitor was 
combined with a peptide vaccine in resected high-risk metastatic melanoma with 
HMB-45, NY-ESO−1, and/or MART-1 positive resected tumors.  The combination was 
well tolerated, demonstrated increases in tumor antigen-specific CD8+T cells, and 

 
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showed an improved relapse-free survival rate compared to stage-matched historical 
controls (Gibney et al. 2015).  Multiple ongoing clinical trials are assessing vaccines in 
combination with antiPD-L1/PD-1 inhibitors (NCT02451982, NCT03406715, 
NCT03164772, NCT03169738). 
The combination of RO7198457 and antiPD-1 represents an attractive strategy for 
potentiating anti-tumor activity and is expected to enhance both the magnitude and 
quality of the tumor-specific T-cell responses, which may result in increased anti-tumor 
activity that might be observed with RO7198457 or pembrolizumab as a single agent. 
Refer to the RO7198457 Investigator's Brochure for details on nonclinical and 
clinical studies. 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Checkpoint inhibitors are currently the standard of care for metastatic melanoma.  
However, the durable clinical benefit observed with agents targeting PD-L1/PD-1 across 
diverse malignancies, including melanoma, appears limited to a subset of patients.   
Despite the advances in OS that have accompanied the development of now widely 
administered immunotherapies such as PD-1 therapies (nivolumab, pembrolizumab), or 
the combination of anti-PD1 with antiCTLA-4 therapy (nivolumab and ipilimumab), a 
significant fraction of patients do not respond to treatment with checkpoint inhibitors or 
experience only transient disease stabilization (Robert et al. 2015a; Rosenberg et al. 
2016), which demonstrates the persistent unmet need for patients with metastatic solid 
tumors.  Although objective responses in the approximately 10%30% of patients who 
respond to treatment with PD-1 inhibitors tend to be durable, these patients nonetheless 
remain at risk for progression.  In a recent study of melanoma patients treated with PD-1 
blockade, 53 out of 205 patients (26%) who had had an objective response to 
pembrolizumab had disease progression at a median follow-up of 21 months 
(Ribas et al. 2016). 
While anti-PD1 and anti-PD1 plus antiCTLA-4 combinations have significantly improved 
long-term outcomes in patients with melanoma the latter has come at the cost of 
increased treatment related toxicities.  Despite these improvements, a significant 
proportion of patients remain at risk of disease progression and succumb to their 
disease.  Combination therapies that address mechanisms of resistance checkpoint 
blockade with increasing toxicity are needed. 
Resistance may occur at the level of the effector T cell, whose activity may be limited 
due to poor T-cell stimulation.  In preclinical models, induction of antigen specific 
immunity combined with concomitant blockade of PD-L1/PD-1 pathways demonstrated 
superior efficacy over the respective single-agent inhibitors of these pathways, even in 
models in which single-agent vaccine had limited activity.  In these studies, 
tumor-infiltrating T cells demonstrated increased IFN- expression (a hallmark of 

 
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activation and anti-tumor activity of T cells) only when PD-L1 was blocked but not with 
single-agent vaccine (Duraiswamy et al. 2013; Fu et al. 2014).  On the basis of these 
studies, it is hypothesized that the combination of RO7198457 with antiPD-L1/PD-1 
may result in activation of anti-tumor immune responses leading to enhanced killing of 
tumor cells and improved clinical responses in cancer patients.  
Clinical efficacy data for RO7198457 in combination with antiPD-L1/PD-1 is limited.  
While no direct clinical benefits are known at this time, the role of neoantigen reactive 
T cells in endogenous therapeutic anti-tumor responses has been well characterized in 
patients.  In addition, the available nonclinical data provide a strong rationale for 
investigating the potential benefit of RO7198457 in combination with antiPD-L1/PD-1 in 
patients with advanced melanoma.  In addition, the postulated mechanism of action of 
RO7198457 in combination with antiPD-L1/PD-1 is predicted to complement and 
enhance immune-potentiating activity; hence, the combination of RO7198457 and 
antiPD-L1/PD-1 may be associated with a higher frequency and/or greater severity of 
immune-related adverse events than observed with either molecule as a single agent.  
The potential risks with RO7198457, 
 
 
may occur more 
frequently or in greater severity when RO7198457 is administered in combination with 
antiPD-L1/PD-1.  Conversely, in combination with antiPD-L1/PD-1, RO7198457 may 
exacerbate antiPD-L1/PD-1 related adverse events (see the pembrolizumab 
prescribing information) or may have non-overlapping toxicities with antiPD-L1/PD-1. 
This proof-of-concept Phase II study will determine clinical benefit of adding 
RO7198457 to a standard-of-care therapy for advanced melanoma.  Comparing novel 
immuno-oncology therapies to historical single-agent immunotherapy regimens with a 
baseline level of activity possesses many challenges.  Outcomes may be biased by 
baseline characteristics of patients leading to misinterpretation of efficacy or lack thereof.  
In addition, stable plateaus are more commonly seen at the tail of PFS and OS curves in 
patients receiving immunotherapy and may be challenging to evaluate in single-arm 
studies (Kirkwood et al. 2000; Maio et al. 2015; Rittmeyer et al. 2017).  These plateaus 
represent subsets of patients with long-term benefit.  Finally, there may be discordance 
between ORR, PFS and OS benefit when comparing immuno-oncology agents or other 
therapies making reliance on one single endpoint challenging.  A comparison of the DC 
vaccine Sipuleucel-T to placebo in patients with metastatic prostate cancer identified a 
22% survival benefit (hazard ratio [HR]  0.78; 95% CI: 0.61, 0.98) while the time to 
disease progression was similar in the two groups (Kantoff et al. 2010).  Similarly, 
there was no significant difference in PFS between patients with pretreated metastatic 
renal-cell carcinoma who received nivolumab compared to everolimus (median PFS 
approximately 4 months in both groups) despite an OS benefit with nivolumab over 
everolimus (HR for death  0.73; 98.5% CI: 0.57, 0.93; p  0.002) (Motzer et al. 2015).  
Since randomized studies with time dependent endpoints provide the most effective 

 
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approach to determining efficacy (Hoos et al. 2010; Anagnostou et al. 2017), this proof 
of concept study will utilize a randomized Phase II design to determine if the addition of 
RO7198457 to standard-of-care pembrolizumab in melanoma provides an efficacy 
signal.  Given the unmet need in advanced melanoma, the current data support 
development of RO7198457 in combination with PD-L1/PD-1 blockade in this indication. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and patient-reported 
outcomes (PROs) of RO7198457 plus pembrolizumab compared with pembrolizumab 
alone in patients with previously untreated advanced melanoma.  Specific objectives and 
corresponding endpoints for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of RO7198457 
plus pembrolizumab compared with pembrolizumab alone on the basis of the following 
endpoint: 
 
PFS after randomization, defined as the time from randomization to the first 
occurrence of disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) 
 
2.1.2 
Secondary Efficacy Objectives 
A secondary efficacy objective for this study is to evaluate the efficacy of RO7198457 
plus pembrolizumab compared with pembrolizumab alone on the basis of the following 
endpoints: 
 
Objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) on two consecutive occasions 
 4 weeks apart, as determined by the investigator according to RECIST v1.1 
 
OS after randomization, defined as the time from randomization to death from any 
cause  
 
Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause, as 
determined by the investigator according to RECIST v1.1 
 
Mean change from baseline in health-related quality of life (HRQoL) scores as 
assessed through use of the two-item global health status (GHS)/HRQoL subscale 
(Questions 29 and 30) of the European Organisation for Research and Treatment of 
Cancer Quality of LifeCore 30 (EORTC QLQ-C30) at specified timepoints 
 

 
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Another secondary objective is to evaluate the efficacy of RO7198457 plus 
pembrolizumab in patients who have progressed following pembrolizumab monotherapy 
on the basis of the following endpoint: 
 
ORR, defined as the proportion of patients with a CR or PR on two consecutive 
occasions  4 weeks apart, as determined by the investigator according to 
RECIST v1.1, at the time of crossover 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7198457 
plus pembrolizumab compared with pembrolizumab alone on the basis of the following 
endpoints: 
 
PFS rate at 12 months, defined as the proportion of patients in the intent-to-treat 
(ITT) population who have not experienced disease progression or death from any 
cause as determined by the investigator according to RECIST v1.1  
 
PFS after randomization, defined as the time from randomization to the first 
occurrence of disease progression or death from any cause (whichever occurs first), 
as determined according to immune-based therapeutics Response Evaluation 
Criteria in Solid Tumors (iRECIST)  
 
ORR, defined as a CR or PR on two consecutive occasions  4 weeks apart, as 
determined according to iRECIST  
 
Change from baseline in disease and treatment-related symptoms, as assessed 
through use of the Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) and an additional item regarding bother due to side 
effects  
 
Change from baseline on role, physical function, and on-work productivity as 
assessed through use of select scales of the EORTC QLQ-C30  
 
Change from baseline on role, physical function, and on-work productivity as 
assessed through use of select scales of the Work Productivity and Activity 
Impairment (WPAI) 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of RO7198457 plus 
pembrolizumab compared with pembrolizumab alone on the basis of the following 
endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
 

 
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2.3 
PHARMACOKINETIC OBJECTIVES 
The exploratory PK objectives for this study are as follows: 
 
To characterize the RO7198457 PK profile on the basis of the following endpoints:  
– 
Plasma concentrations 
 at specified timepoints 
– 
Plasma concentrations 
 at specified timepoints  
 
To characterize the PK of pembrolizumab when given in combination with 
RO719847 on the basis of the following endpoint: 
– 
Serum concentrations of pembrolizumab at specified timepoints 
 
To evaluate potential relationships between drug exposure and the efficacy and 
safety of RO7198457 and pembrolizumab on the basis of the following endpoints: 
– 
Relationship between plasma concentration or PK parameters 
 and 
efficacy endpoints 
– 
Relationship between plasma concentration or PK parameters 
 and 
efficacy endpoints 
– 
Relationship between plasma concentration or PK parameters 
 and 
safety endpoints 
– 
Relationship between plasma concentration or PK parameters 
 and 
safety endpoints 
 
2.4 
BIOMARKER OBJECTIVE 
The exploratory biomarker objectives for this study is to make a preliminary assessment 
of biomarkers that might act as predictors of response to RO7198457 in combination 
with pembrolizumab (i.e., predictive biomarkers) or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following 
endpoints: 
 
Immunogenicity of RO7198457 in combination with pembrolizumab as determined 
by antigen-specific T-cell responses relative to baseline 
 
Relationship between biomarkers in blood and tumor tissue (listed in Section 4.5.7) 
and efficacy, safety, and other biomarker endpoints. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase II, randomized, open-label, multicenter study designed to evaluate the 
efficacy and safety of RO7198457 plus pembrolizumab compared with pembrolizumab 
alone in patients with previously untreated advanced melanoma.  The patient population 
includes patients with unresectable locally advanced (Stages IIIC and IIID) and 
metastatic (recurrent or de novo Stage IV) melanoma.  This study will be conducted 
globally.   

 
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The study consists of two stages:  an initial safety run-in stage and a randomized stage.  
Each stage will have a two-part screening period (Part A and Part B), a treatment period, 
and post-treatment follow-up period.   
The safety run-in stage will consist of a single arm that will enroll approximately 
612 patients.  Patients in the safety run-in will receive at least 1 cycle (21 days) of 
200 mg pembrolizumab monotherapy administered by IV infusion.  Once RO7198457 is 
manufactured and available, patients will receive 200 mg pembrolizumab IV every 
3 weeks (Q3W) and
RO7198457 IV as detailed in Section 4.3.2.1.  Accrual in the 
randomized stage will not start until an Internal Monitoring Committee (IMC) has 
reviewed the safety data of the first 6 patients treated in the safety run-in stage 
(see Section 3.1.2).   
The randomized stage will enroll approximately 120 patients, randomized in a 2:1 ratio, 
to either the experimental or control arm: 
 
Arm A (control):  200 mg pembrolizumab administered by IV infusion Q3W  
 
Arm B (experimental):  at least 1 cycle of 200 mg pembrolizumab administered by 
IV infusion followed by 200 mg pembrolizumab IV Q3W and
RO7198457 IV 
as detailed in Section 4.3.2.1.  
 
A third arm (Arm C) may be added to the study at a later time via a protocol amendment, 
pending the results of dose escalation in an ongoing Genentech sponsored Phase Ib 
study (GO39733).  Patients in this arm would receive RO7198457 plus pembrolizumab 
with an alternative RO7198457 dose, alternative RO7198457 dosing paradigm 
(e.g., step-up dosing), and/or schedule of administration.  
Upon confirmed disease progression (as assessed by the investigator per 
RECIST v1.1), patients randomized to Arm A will be given the option to cross over and 
receive combination treatment with RO7198457 and pembrolizumab, provided they meet 
eligibility criteria described in Section 4.1.3.  
The study schema is presented in Figure 1.

 
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The duration of treatment on this study will be up to 24 months for all patients as long as 
they are experiencing clinical benefit as assessed by the investigator in the absence of 
unacceptable toxicity or symptomatic deterioration attributed to disease progression after 
an integrated assessment of radiographic data and clinical status.  Patients may be 
permitted to continue treatment after RECIST v1.1 criteria for progressive disease are 
met (see Section 3.1.3).  Patients in Arm A may have the option to cross over to 
combination treatment with RO7198457 plus pembrolizumab after confirmed disease 
progression, if crossover eligibility criteria are met (see Section 3.1.4).  In addition, if a 
patient in Arm A completes 24 months of pembrolizumab and experiences confirmed 
disease progression  6 months after discontinuing pembrolizumab, they may have 
the option to receive crossover treatment with RO7198457 plus pembrolizumab 
(see Section 3.1.4).  
Patients will undergo tumor assessments as detailed in Section 4.5.5, Appendix 1, and 
Appendix 2.  Digital photography of cutaneous lesions, if indicated, will be performed at 
screening, on the same day as tumor assessment visit or at the first clinic visit following 
each tumor assessment (see Section 4.5.6).   
Patients may be permitted to continue study treatment even if standard RECIST v1.1 
criteria for progressive disease are met, provided they meet the criteria for continued 
treatment (see Section 3.1.3). 
All patients who discontinue study treatment for reasons other than disease progression 
(e.g., adverse events) will continue tumor assessments per Section 4.5.5, Appendix 1 
and Appendix 2.  
Patients who discontinue study treatment will return to the clinic for a treatment 
discontinuation visit within 30 days after the last dose of study treatment.  All patients will 
be followed for survival and subsequent anti-cancer therapy information approximately 
every 3 months until death, loss to follow-up, or study termination by Genentech, unless 
the patient requests to be withdrawn from follow-up.  See Section 4.6 for details. 
Primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints if needed. 
In addition, patients will also be asked to complete PRO assessments at the beginning 
of each cycle until disease progression or treatment discontinuation, whichever occurs 
later (see Section 4.5.10, Appendix 1, and Appendix 2).  
3.1.2 
Safety Run-In Stage  
Dosing of the first 2 patients in the safety run-in stage (RO7198457 plus pembrolizumab) 
will be separated by at least 48 hours. 
Safety data from the first 6 patients in the safety run-in stage who are treated with at 
least 1 dose of RO7198457 will be formally reviewed by the IMC (see Section 3.1.5).  

 
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The Sponsor may enroll up to 6 additional patients in the safety run-in stage to further 
assess safety of the combination treatment.   
Accrual in the randomized stage will not start until the IMC has reviewed the safety data 
of the first 6 patients treated in the safety run-in stage.  On the basis of these analyses, 
the IMC may recommend continued enrollment into the study or may recommend 
changes to the conduct of the study.  The Sponsor will communicate any changes to 
regulatory agencies and investigators for notification of the Institutional Review Boards 
and Ethics Committees (IRBs/ECs). 
Consistent with reporting requirements for serious adverse events and adverse events of 
special interest (see Sections 5.2.2 and 5.2.3), the Medical Monitor must be notified of 
these events within 24 hours of learning of the event.  This will allow for appropriate and 
timely communication of significant safety findings in patients in the safety run-in stage. 
The Sponsor will also organize regular teleconferences with the investigators to discuss 
adverse events and laboratory abnormalities observed in the first 612 patients treated 
with at least 1 cycle of combination therapy in the safety run-in stage.  
3.1.3 
Treatment after Disease Progression 
Because of the possibility of an initial increase in tumor burden caused by immune cell 
infiltration in the setting a T-cell response (termed pseudoprogression) with 
immunotherapy, patients may be permitted to continue treatment after RECIST v1.1 
criteria for progressive disease are met at the investigator's discretion, in the absence of 
unacceptable toxicity, after discussion with the Medical Monitor, and provided that the 
patients 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 worsening of laboratory values, 
e.g., new or worsening hyperkalemia) indicating unequivocal progression of disease 
 
Absence of decline in ECOG Performance Status 
 
Absence of tumor progression at critical anatomical sites that cannot be readily 
managed and stabilized by protocol-allowed medical interventions  
Critical anatomical sites include the CNS, central airway, the great vessels, and 
other organs or tissues where compromised function secondary to tumor 
progression would be expected to result acutely in severe and/or irreversible 
disability or death. 
 
Patient consent and acknowledgment of having discussed benefitrisk balance of 
treatment beyond radiographic progression, including options to pursue other 
treatments (if available) 
 

 
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Patients treated on any treatment arm in whom radiographic disease progression is 
confirmed at a subsequent tumor assessment may be considered for continued study 
treatment within the current treatment arm at the discretion of the investigator (regarding 
patients in Arm A, refer to Section 3.1.4 for rules regarding crossover), after discussion 
with the Medical Monitor, if they continue to meet the criteria above and have continued 
clinical benefit, as evidenced by at least one of the following: 
 
Tumor shrinkage (at least 30% decrease in diameter from baseline) of one or more 
evaluable lesions 
 
Improvement in one or more symptoms or signs attributable to the underlying 
cancer (e.g., decreased requirement for narcotics for pain, decreased dyspnea 
associated with pleural effusion, weight gain) as assessed by the investigator. 
 
If clinically feasible, collection of an optional tumor biopsy is requested at the time of first 
radiographic progression on treatment for patients being considered for treatment 
beyond progression to evaluate the utility of the biopsy in distinguishing 
pseudoprogression/tumor-immune infiltration from true disease progression and to 
identify possible markers of resistance or escape.  These data will be analyzed for the 
association between changes in tumor tissue and clinical outcome. 

 
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Figure 3 Conditions for Continuing Study Treatment beyond Progression 
 
ECOG  Eastern Cooperative Oncology Group; RECIST  Response Evaluation Criteria in Solid 
Tumors. 
Note:  “Arm B” refers to patients who are randomized into Arm B or cross over into 
Arm B. 
 
3.1.4 
Crossover from Control Arm A to Experimental Treatment 
Patients in Arm A (pembrolizumab only) with confirmed radiographic disease 
progression will be permitted to cross over to the experimental treatment (RO7198457 
plus pembrolizumab) at the investigator's discretion, after discussion with the Medical 
Monitor, and the patient meets all of the crossover eligibility criteria in Section 4.1.3.  In 
addition, if a patient in Arm A completes 24 months of pembrolizumab and experiences 

 
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confirmed disease progression  6 months after discontinuation of pembrolizumab, the 
patient may be permitted to receive crossover treatment (RO7198457 plus 
pembrolizumab) if crossover eligibility criteria are met (see Section 4.1.3).  For patients 
in Arm A who experience confirmed disease progression, an optional tumor biopsy will 
be collected for patients with a safely accessible site of disease (see Section 4.5.7.2).  
Patients must provide consent to acknowledge having had a discussion with the treating 
investigator of the benefit-risk balance, including other treatment options (if available), 
before beginning crossover treatment.  
 
 
 
 
 
  Refer to Appendix 2 for the schedule of assessments for 
crossover patients.   
A radiographic tumor assessment must also be performed, unless already done to 
document disease progression within 6 weeks prior to starting crossover treatment.  
The radiographic tumor assessment at the time of disease progression/recurrence will 
become the new baseline for future response assessments. 
Crossover treatment should begin no later than 
 after the last dose of prior 
study treatment on Study GO40558.  In patients with confirmed disease progression 
 6 months after discontinuation of pembrolizumab therapy, crossover treatment should 
begin within 
 of confirmed progression. 
Patients who cross over to the combination of RO7198457 plus pembrolizumab will 
continue treatment for up to 12 months as long as they are experiencing clinical benefit 
as assessed by the investigator.  Patients with confirmed disease progression after 
crossing over from Arm A to Arm B may be considered for treatment beyond disease 
progression provided that criteria for treatment beyond disease progression are met as 
specified in Section 3.1.3.  Patients will be evaluated for safety and efficacy according to 
the schedules of activity described in Appendix 2. 
Genentech has the right to restrict or suspend enrollment into crossover treatment at any 
time.  Reasons for this may include, but are not limited to, the following: 
 
The incidence or severity of adverse events during crossover treatment indicates a 
potential safety hazard to patients 
 
Data from ongoing studies suggest lack of equipoise 
 
Patient enrollment into crossover treatment is unsatisfactory 
 
Data recording is inaccurate or incomplete 
 

 
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3.1.5 
Internal Monitoring Committee Reviews 
The primary responsibility of the IMC is to review the available safety data and make 
recommendations on study conduct to ensure enhanced patient safety while patients 
receive study treatment.  The IMC will periodically evaluate the accumulating safety data 
from all patients treated in this study.  Following analysis of the primary endpoint of PFS, 
expected to occur approximately 24 months after enrollment of the first randomized 
patient, future safety analyses will be conducted.  The IMC Chair will be a medical 
oncologist who is not the Medical Monitor and is not associated with the study.  Other 
IMC members may include, but are not limited to, a safety scientist, biostatistician, and 
clinical pharmacologist.  The IMC will operate according to a pre-specified charter and 
make recommendations on study conduct related to patient safety (see Section 5).  
The IMC will review the safety data during the safety run-in stage as described in 
Section 3.1.2.  During the randomization stage, safety data from the first 20 patients in 
Arm B treated with at least 1 cycle of RO7198457 plus pembrolizumab will be formally 
reviewed by an IMC.  Following the initial data reviews in the safety run-in and 
randomization stages, the IMC will review the safety data approximately every 6 months, 
or more frequently if recommended by the IMC Chair or the Medical Monitor.  The safety 
data may include, but are not limited to, demographic data, adverse event data 
(including serious adverse events and adverse events of special interest), study conduct 
data, and relevant laboratory data. 
In addition, the Medical Monitor may request additional safety reports and may call for 
ad-hoc meetings of the IMC at any time during the study to review ongoing safety data 
for a benefit-risk balance. 
The IMC may make recommendations regarding study conduct, including, but not limited 
to, the following:  continuing the study as per the protocol, performing additional safety 
analyses, amending the study protocol, holding patient enrollment pending further safety 
evaluations, holding/discontinuing study treatment, or terminating the study.  
The IMC may share preliminary results from these safety and interim analyses with 
appropriate Sponsor employees and with the investigators, as the IMC Chair deems 
necessary.   
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last data required for all study 
analysis are collected.  
 
 
In addition, the Sponsor may decide to terminate the study at any time.  If the Sponsor 
decides to terminate the study, patients who are still receiving study treatment or 
undergoing survival follow-up may be enrolled in an extension study or a 
non-interventional study, if available. 

 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for RO7198457 Dose and Schedule 
The proposed starting dose of RO7198457 plus pembrolizumab is based on an 
integrated assessment of the proposed mechanism of action (i.e., generation of a T-cell 
response to a neoantigen), safety, and cytokine data in an ongoing study of RO7198457 
plus atezolizumab (GO39733), in vivo efficacy in murine tumor models, and in vivo 
safety in the Good Laboratory Practice toxicology study, which included evaluation of 
immune activation.  Refer to Section 1.2.2.1 regarding clinical safety profile of 
RO7198457. 
 
 
  See the RO7198457 
Investigator's Brochure for further details. 
3.3.2 
Rationale for Pembrolizumab Dose and Schedule 
Pembrolizumab will be administered at the approved dose and schedule of 200 mg IV 
Q3W.  Pembrolizumab is considered standard of care and is approved for the treatment 
of unresectable or metastatic melanoma (Dummer et al. 2015; NCCN 2018).  
Pembrolizumab (Keytruda) is approved in the United States and the European Union, 
as well as other countries, for the treatment of unresectable or metastatic melanoma, 
metastatic non−small cell lung cancer, the first-line treatment of metastatic non−small 
cell lung cancer, and recurrent or metastatic head and neck squamous cell carcinoma, 
refractory classical Hodgkin lymphoma, advanced or metastatic urothelial carcinoma, 
unresectable or metastatic microsatellite instability-high, or mismatch repair deficient in 
solid tumors or colorectal cancer, and recurrent locally advanced or metastatic gastric or 
gastroesophageal junction adenocarcinoma  Refer to the pembrolizumab prescribing 
information for a complete summary of safety information. 
 
  
 
 
 
 
  
3.3.4 
Rationale for Safety Run-In Stage 
The safety run-in stage is designed to confirm safety of the combination of 
RO7198457 plus pembrolizumab.  Pembrolizumab, a PD-1 inhibitor, has been approved 
for the treatment of melanoma patients with unresectable or metastatic melanoma.  

 
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As previously indicated, the selected starting dose of RO7198457 is currently being 
explored in patients with locally advanced or metastatic tumors in Study GO39733.  
The dose level of
has been considered safe in combination with atezolizumab, a 
PD-L1 inhibitor.  Pembrolizumab and atezolizumab both target the same PD-1/PD-L1 
pathway and have similar safety profiles.  The safety run-in cohort (612 patients) aims 
to evaluate if the starting dose can be expanded in the randomization phase of the 
study. 
3.3.5 
Rationale for Patient Population  
Study GO40558 will enroll patients with measurable advanced melanoma without a 
history of systemic therapy for locally advanced or metastatic disease.  All patients on 
this study will receive an approved standard of care (pembrolizumab) in either arm of the 
study.  Despite the recent advances in treatment options provided by immunotherapies, 
this patient population continues to have high unmet need.  Early data from clinical 
studies suggest that the combination of checkpoint inhibitors and vaccines is well 
tolerated and has potential synergy.  As an example, the combination of a PD-1 inhibitor 
and a peptide vaccine in resected high-risk metastatic melanoma with HMB-45, 
NY-ESO-1, and/or MART-1 positive resected tumors was well tolerated, demonstrated 
increases in tumor antigen-specific CD8+ T cells, and showed an improved relapse-free 
survival rate compared with stage-matched historical controls (Gibney et al. 2015).  
Combining the potential neoantigen-specific immune-stimulating effects of RO7198457 
with the release of immune suppression by pembrolizumab may significantly improve the 
response rate and durability of responses compared with that of either agent alone. 
In order to ensure that the primary endpoint of PFS as well as the secondary endpoints 
of ORR, OS and DOR can be adequately assessed, patients must have measurable 
disease (per RECIST v1.1) at baseline. 
Additional eligibility criteria have been incorporated that are pertinent to the safety 
profiles of RO7198457 and pembrolizumab (and anti−PD-L1 targeted therapies as a 
therapeutic class).  These have been informed by the known safety profiles of each drug 
and supplemented by experience in Study GO39733. 
3.3.6 
Rationale for Control Group (Arm A) 
The control arm (Arm A) will receive 200 mg of pembrolizumab monotherapy 
administered by IV infusion Q3W.  The intent of this study is to evaluate the magnitude 
of benefit achievable with the combination of RO7198457 and pembrolizumab, relative 
to current standard of care, in treatment-naive patients with advanced melanoma.  
Several therapies are currently available for this indication (refer to Section 1.1).  The 
current guidelines from the National Comprehensive Cancer Network (NCCN) and the 
European Society of Medical Oncology clinical practice guidelines (Dummer et al. 2015; 
NCCN 2018) recommend the anti−PD-1 monotherapies pembrolizumab and nivolumab 

 
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and the combination of nivolumab with ipilimumab.  The choice of treatment in clinical 
practice is based on evaluation of the individual patient by the treating physician. 
The anti−PD-1 monotherapies pembrolizumab and nivolumab have demonstrated 
comparable efficacy in patients with advanced melanoma across multiple clinical trials.  
Efficacy has been established for survival endpoints, as well as for the correlated 
surrogate endpoints of PFS and ORR (median PFS for these agents in advanced 
melanoma is 5–6 months, with an ORR of approximately 30% [Hodi et al. 2014; Robert 
et al. 2015a, 2015b; Weber et al. 2015a] and OS of approximately 32 months [Hodi et al. 
2016; Long et al. 2018]). 
On the basis of anti−PD-1 monotherapy being a currently approved, widely used 
standard of care, which affords the longest established survival benefit of currently 
available therapies and is recommended by advisory bodies for treatment of patients 
with advanced melanoma, pembrolizumab is considered an appropriate comparator arm 
for this study.   
3.3.7 
Rationale for Crossover to Experimental Treatment 
Patients treated with single-agent pembrolizumab (Arm A) may have the option of 
crossover to receive treatment with RO7198457 plus pembrolizumab.  
As failure to respond to PD-L1/PD-1 axis therapies is associated with a lack of 
preexisting immunity (Herbst et al. 2014), induction or enhancement of immune 
responses against tumor neoantigens via personalized cancer vaccination is a rational 
approach for patients that have become resistant or refractory to pembrolizumab 
monotherapy (Arm A).  The inclusion of study treatment crossover will address important 
questions regarding efficacy and tolerability of RO7198457 plus pembrolizumab 
following disease progression on pembrolizumab monotherapy.   
To be eligible for crossover treatment, patients will need to have met appropriate criteria 
(see Section 4.1.3). 
3.3.8 
Rationale for Primary and Secondary Endpoints 
PFS is established as a clinically relevant measure of treatment benefit and a correlate 
of OS in advanced melanoma, which in recent years has been an approvable endpoint 
in the setting of metastatic or unresectable melanoma for both targeted and 
immunotherapies (European Medicines Agency 2012).  In a meta-analysis of 
4416 patients with metastatic melanoma, PFS was found to be a robust surrogate for OS 
in dacarbazine-controlled randomized trials of metastatic melanoma.  Furthermore, PFS 
has also been demonstrated to be predictive of OS for pembrolizumab (Robert et al. 
2015a).  In addition, owing to the increased number of active treatment options 
available and under investigation resulting in patients receiving more lines of therapy 
than have previously been available, OS might be confounded by the use of effective 
subsequent-line therapies or by mortality unrelated to cancer (Flaherty et al. 2012).  

 
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As progression events provide reliable information on the treatment effect observed 
and generally are not confounded by subsequent lines of therapy, PFS provides a 
meaningful efficacy endpoint with earlier time to evaluation (Di Leo et al. 2003).  
In summary, multiple drugs, including both targeted therapy and immunotherapies, have 
been approved in metastatic melanoma in recent years on the basis of PFS, and 
extensive clinical experience validates PFS as a consistent strong correlate of survival 
across different treatment modalities.  
Metastatic melanoma is a deadly cancer that impacts patients' HRQoL (Cornish et al. 
2009).  Current treatment goals include improving survival, managing disease or 
treatment-related symptoms (insomnia, pain, and fatigue), and preserving HRQoL 
outcomes as feasible (Coit et al. 2016).  Studies have shown that patients with advanced 
melanoma tend to experience a decrease in GHS and physical functioning while 
undergoing treatment, which can vary by therapy and presence of disease progression 
(Schadendorf et al. 2015; Long et al. 2016).  In this study, impact of disease/treatment-
related symptoms on HRQoL will be assessed using the GHS/HRQoL scale of the 
EORTC QLQ-C30 in order to quantify patients' experience receiving treatments.  
Patients will complete selected items from the EORTC library including items from the 
EORTC QLQ C30 and IL 12. 
3.3.9 
Rationale for Choice of Stratification Factors 
In order to balance the distribution of prognostic factors between the treatment arms, the 
randomization will be stratified.  In Study GO40558, the stratification factors will be 
PD-L1 status and disease stage at baseline/LDH (see Section 4.2).  Tumor specimens  
will be assessed for PD-L1 expression by IHC in order to stratify patients in the 
treatment arms.  
PD-L1 expression ( 5% cutoff vs.  5% or unknown by SP263 PD-L1 IHC assay done in 
a central laboratory) has recently been recognized as a strong favorable prognostic 
factor in melanoma and is associated with improved outcomes for melanoma patients 
treated with pembrolizumab (Daud et al. 2016; Schachter et al. 2017). 
Disease stage as defined by the American Joint Committee on Cancer 8th Edition 
(AJCC v8.0) categorizes distant metastasis, M1 status, by both the anatomic site of 
distant metastatic disease as well as by the serum LDH levels (M0, M1a, or M1b vs. M1c 
or M1d or LDH  ULN).  Baseline LDH levels are recognized as strong prognostic factors 
in melanoma for long-term OS.  Elevated LDH level is associated with poorer outcomes 
across multiple therapies and is reflective of other factors associated with aggressive 
disease, such as tumor stage and burden (Balch et al. 2009; Chapman et al. 2011; 
Hauschild et al. 2012; Ascierto 2013; Kelderman et al. 2014; Long et al. 2014, 2015; 
McArthur et al. 2014; Diem et al. 2015; Hauschild and Garbe 2015; Robert et al. 2015b; 
Hauschild and Schadendorf 2016). 

 
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These stratification factors were chosen because of their known or suspected potential 
to affect prognosis in metastatic melanoma.  Prospective stratification by these factors 
will help to minimize potential underlying differences in the two treatment arms due to 
sources other than RO7198457. 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 

 
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3.3.12 
Rationale for Collection of Archival or Pretreatment Fresh 
Tumor Biopsy for Biomarker Analysis 
Tumor tissue will be analyzed for predictive biomarkers of RO7198457 plus 
pembrolizumab activity.  These exploratory analyses will include, but are not limited to, 
biomarkers such as immune infiltrates, presence of stromal compartment, or CD8 
expression.  In addition, methods such as NGS of tumor DNA and/or RNA may be 
applied to evaluate the relationship between clinical benefit and candidate predictive 
biomarkers, such as alterations in individual disease-related genes, aggregate 
mutational load, or gene expression profiles.  Further exploratory analyses of potential 
predictive and prognostic markers that are related to antiPD-1 activity, tumor 
immunology, or tumor type may also be analyzed as guided by accumulating nonclinical 
or clinical data. 
Patients who provide baseline biopsies for biomarker analysis during screening (see 
Section 4.5) should also provide an archival tumor specimen, if available.  Comparison 
between the archival specimen and the freshly obtained baseline specimen may provide 
additional information on the optimal sample specifications for evaluation of a potential 
predictive biomarker for RO7198457 plus pembrolizumab. 
3.3.13 
Rationale for Collection of Fresh Tumor Specimens at Baseline 
and On-Treatment for Biomarker Analysis 
One of the biomarker objectives of the study is to assess the biological activity of 
RO7198457 on the immune cell infiltration in the tumor.  Hence, during the randomized 
stage of the study, a minimum of approximately 20 patients in the RO7198457 plus 
pembrolizumab arm (Arm B) will be required to provide a mandatory on-treatment 
biopsy if these can be obtained with minimal risk and discomfort and are deemed safe 
and on-treatment biopsies will be optional for all other patients in Arm B.  To understand 
contribution of RO7198457 in Arm B, tumor data from the combination arm will be 
compared with tumor data from the pembrolizumab monotherapy Arm A.  To enable this 
analysis, a minimum of approximately 10 patients in the pembrolizumab arm will be 
required to provide a mandatory on-treatment biopsy, if these can be obtained with 
minimal risk and discomfort and deemed safe.  In addition, all patients will be asked via 
separate Informed Consent Forms to undergo optional on treatment biopsies, as well as 
biopsies at the time of progressive disease.  All may undergo additional on-treatment 
biopsies at any other time (including progression or response) at the investigator's 
discretion (if deemed clinically feasible by the investigator).  If the treating physician 
suspects that a patient will not have measurable disease at the designated time of 
collection due to clinical response (approximately 89 weeks after the first infusion of 
pembrolizumab in Arm A and 56 weeks after the first administration of RO7198457 in 

 
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Arm B, see Appendix 1 and Appendix 2), biopsy collection may be moved to an earlier 
time point as indicated.  The Medical Monitor is available to advise as needed. 
Based on the postulated mechanisms of action of RO7198457 plus pembrolizumab, 
several characteristics of the tumor microenvironment will be evaluated as candidate 
predictive biomarkers in paraffin-embedded tumor tissue including, but not limited to, the 
expression of PD-L1, CD8+ and other biomarkers on specific cell types, and the 
prevalence and/or activation of immune cells.  Fresh tumor tissue may also be used for 
antigen-specific immune monitoring using tumor-infiltrating lymphocytes (TILs).  In 
addition, WES from tumor DNA and gene-expression profiling (RNA sequencing) may be 
carried out to further understand biological activity of RO7198457.   
Tumor tissue post-treatment will be analyzed for changes in the immune infiltrate, 
immune activation markers, and changes in tumor microenvironment to define PD 
biomarkers of RO7198457 activity.  This sample may also be used for isolating TILs and 
antigen-specific immune monitoring thereof.  To enable such an evaluation it is important 
to have matched pretreatment and on-treatment biopsies from patients.  
3.3.14 
Rationale for Collection of Blood Samples for Biomarker 
Analyses 
Changes in biomarkers in blood may provide evidence for biologic activity of 
RO7198457 and may allow for the development of a blood-based biomarker to help 
predict which patients may benefit from RO7198457.  The mode of action of RO7198457 
depends on the induction of antigen-specific T cells by antigen presenting cells that 
process and present RNA-encoded peptides in addition to Toll-like receptor mediated 
immune modulatory effects that lead to cellular activation and the induction of 
pro-inflammatory cytokines.  Cytokine measurements in blood at baseline and potential 
changes upon treatment, in addition to immune monitoring assays such as ELISPOT 
and MHC-multimer fluorescence-activated cell sorting (FACS) staining in blood will serve 
as indicators of the immunogenicity and biological activity of RO7198457 plus 
pembrolizumab. 
In addition, potential changes in number and functions of immune cells will be measured.  
These include, but are not limited to, the frequency of antigen-specific T cells (as 
measured by immune monitoring analysis) the number of T, B, and NK cells; the 
number, proportion, and functional status (as assessed by protein or nucleic acid 
analysis using methods such as FACS, T-cell receptor [TCR] sequencing, and NGS) of 
blood cells, including T-cell subsets, myeloid-derived suppressor cells, and other 
immune cells; concentrations of cytokines; and titers of antibodies against reference 
antigens as well as against other exploratory markers.  These PD markers will be used 
to find potential correlation with the safety, PK, and preliminary anti-tumor activity of 
RO7198457 plus pembrolizumab.  

 
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3.3.15 
Rationale for Optional Stool Sample Collection 
Checkpoint inhibitors targeting the PD-L1/PD-1 axis have shown activity and efficacy in 
melanoma, but not all patients respond to treatment, suggesting that host factors, 
including genetics and tumor microenvironment, may play a role in determining 
responsiveness.  The gut microbiome has been shown to be a key determinant in 
immune regulation in cancer, in part by influencing T-cell driven anti-tumor responses 
(Routy et al. 2018).  For example, antibiotic treatment is associated with poor survival 
outcomes to antiPD-1 therapy in preclinical melanoma models (Routy et al. 2018).  
Conversely, the risk of colitis with checkpoint inhibitors may be predicted based on a 
patient's pretreatment microbiome (Chaput et al. 2017).  Thus, heterogeneity in 
microbiome composition across patients may be a key driver of safety events in addition 
to efficacy. 
This study will examine whether a patient's microbiome can determine response to 
RO7198457 plus pembrolizumab versus pembrolizumab alone, and conversely, 
whether RO7198457 plus pembrolizumab can alter the microbiome to such an extent 
that on-treatment changes to the microbiome could be early predictors of adverse 
events, including colitis.  Analyzing the microbiome in melanoma may provide the 
opportunity to discover systemic effects on distal cancers. 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.17 
Rationale for Allowing Patients to Continue Study Treatment 
beyond Progression per RECIST v1.1 
Checkpoint inhibitors may result in early radiographic progression (including the 
appearance of new lesions) that is followed by delayed tumor shrinkage consistent 

 
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with the time required to mobilize an effective antitumor immune response 
(Wolchok et al. 2009).  Additionally, responding tumors may appear to initially increase 
in size because of the influx of immune cells (Hoos et al. 2010; Pennock et al. 2012; 
Hodi et al. 2018).  Such unconventional "pseudoprogression" response patterns have 
been described in patients treated with an anti-CTLA-4 agent (Wolchok et al. 2009) and 
with antiPD-L1/antiPD-1 agents (Brahmer et al. 2012; Hamid et al. 2013; Hodi et al. 
2016).  Therefore, iRECIST criteria (see Appendix 5) will be used in this study to 
accommodate and to better characterize these different patterns of response to help 
understand the activity profile of RO7198457 plus pembrolizumab compared to 
pembrolizumab alone.  The key change in iRECIST criteria, as compared to 
conventional RECIST criteria (see Appendix 4), is that new lesions may be incorporated 
in the total measurement of tumor burden rather than categorically signifying progressive 
disease.  This study will also attempt to collect correlative clinical data at the time of 
apparent radiographic progression through on-treatment biopsies. 
iRECIST is intended to supplement, not supplant, standard RECIST v1.1 in the 
investigator's integrated assessment of benefit and risk for individual patients, as 
depicted in Figure 3.  Refer to Section 4.5.5 for tumor and response evaluations.   
3.3.18 
Rationale for Patient-Reported Outcome Assessments 
In this study, patients will rate their symptoms associated with the disease or treatment, 
their functional impact and HRQoL to inform patients' experience receiving treatments.  
To reduce patient and site burden while maintaining scales construct validity, selected 
scales from the European Organisation for Research and Treatment of Cancer (EORTC) 
library and selected items from the PRO-CTCAE library, and a single-item assessing 
bother due to side effects of treatment will be collected.  The WPAI will also be collected 
to measure impairments in work and activities due to disease/treatment-related 
symptoms. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 132 patients with previously untreated unresectable locally advanced or 
metastatic melanoma (AJCC v8.0) will be enrolled in this study at approximately 40 sites 
globally. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing the Informed Consent Form 
 
Able to comply with the study protocol, in the investigator's judgment 

 
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 
Histologically confirmed metastatic (recurrent or de novo Stage IV) or unresectable 
locally advanced (Stage IIIC or IIID) cutaneous, acral, or mucosal melanoma, as 
defined by the AJCC v8.0 (Amin et al. 2017).   
The enrollment of mucosal and acral melanoma patients will be limited to 
approximately 10 patients total.  
 
ECOG Performance Status of 0 or 1 (see Appendix 6) 
 
Life expectancy  12 weeks  
 
Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): 
– 
ANC  1,500 cells/L (without granulocyte colony-stimulating factor [G-CSF] 
support within 2 weeks prior to Cycle 1, Day 1) 
– 
WBC count  2,500/L 
– 
Lymphocyte count  500/L 
– 
Platelet count  100,000/L (without transfusion within 14 days prior to Cycle 1, 
Day 1) 
– 
Hemoglobin  9 g/dL 
Patients may be transfused or may receive erythropoietic treatment as per 
local standard of care. 
– 
Total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  serum bilirubin level  3  ULN 
– 
AST and ALT  3  ULN  
– 
ALP  2.5  ULN with the following exception: 
Patients with documented liver or bone metastases may have ALP  5  ULN. 
– 
Serum albumin  2.5 g/dL 
 
Measured or calculated creatinine CL  50 mL/min on the basis of the 
Cockcroft-Gault glomerular filtration rate estimation: 
(140  age)  (weight in kilograms)  (0.85 if female) 
72  (serum creatinine in mg/dL) 
 
Measurable disease per RECIST v1.1 (see Appendix 4) 
Previously irradiated lesions should not be counted as target lesions unless 
there has been demonstrated progression in the lesion and no other target 
lesions are available. 
Lesions that are intended to be biopsied should not be counted as target 
lesions. 

 
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 
Naive to prior systemic anti-cancer therapy for advanced melanoma 
(e.g., chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other 
biologic therapies), with the following exceptions for adjuvant therapies:  
– 
Adjuvant treatment with antiPD1/PD-L1 or anti-CTLA-4, if discontinued at least 
6 months prior to Cycle 1, Day 1 and not meeting any of the following criteria: 
 
Any history of an immune-related Grade 4 adverse event attributed to 
prior CIT (other than endocrinopathy managed with replacement therapy 
or asymptomatic elevation of serum amylase or lipase)  
 
Any history of an immune-related Grade 3 adverse event attributed to 
prior CIT that required permanent discontinuation of the prior 
immunotherapeutic agent per local prescribing information, European 
Society for Medical Oncology (ESMO) guidelines (Haanen et al. 2017), 
or American Society of Clinical Oncology (ASCO) guidelines (Brahmer 
et al. 2018) 
 
Adverse events from prior anti-cancer therapy that have not resolved to 
Grade  1 except for alopecia, vitiligo, or endocrinopathy managed with 
replacement therapy   
 
Immune-related adverse events related to prior CIT (other than 
endocrinopathy managed with replacement therapy or stable vitiligo) that 
have not resolved to baseline 
Patients treated with corticosteroids for immune-related adverse 
events must demonstrate absence of related symptoms or signs for 
 4 weeks following discontinuation of corticosteroids. 
– 
Adjuvant treatment with targeted therapies (e.g., BRAFi/MEKi), if 
discontinued at least 2 months prior to initiation of study treatment  
 
Confirmed availability of representative tumor specimens in formalin-fixed, 
paraffin-embedded blocks (preferred), or sectioned tissue (as described in the 
laboratory manual) with an associated pathology report.  Archival tumor tissue or 
fresh biopsy tissue are acceptable; it must be submitted and assessed for 
evaluation of mutations prior to enrollment.   
– 
Acceptable samples may also include core-needle biopsies for deep tumor 
tissue (recommend a minimum of five cores), excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  
Fine-needle aspiration samples, brushings, cell pellets from effusions or 
ascites, and lavage samples are not acceptable. 

 
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Tumor tissue from bone metastases is difficult to evaluate for PD-L1 expression 
and should be avoided.  However, if a bony metastatic site is the only viable 
source of tissue, it may be an acceptable tumor specimen.  The Medical Monitor 
is available to advise as needed.  Submitted tissue from bone metastases must 
not be exposed to decalcification agents that can render tissue not usable for 
RO7198457 manufacturing and PD-L1 testing. 
If adequate tissue from distinct timepoints (such as time of initial diagnosis and 
time of disease recurrence) and/or multiple metastatic tumors are available, 
priority should be given to the tissue with the highest tumor content and lowest 
necrotic area (if feasible).  Multiple samples may be collected for a given 
patient, on the basis of availability; however, the requirement for a block or 
sectioned tissue should be satisfied by a single biopsy or resection specimen.   
Prior to signing the main study ICF, patients may sign a prescreening ICF to 
specifically allow the collection and testing of archival or fresh tumor 
specimens. 
A patient with insufficient or unavailable archival tissue will not be eligible due to 
the need for evaluable tumor tissue to create RO7198457 unless the patient is 
willing to undergo a pretreatment biopsy sample collection of the tumor (refer to 
above for acceptable samples). 
 
 
  
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods that result in a 
failure rate of   1% per year during the treatment period and for at least 90 days 
after the final dose of RO7198457 and at least 4 months after the final dose of 
pembrolizumab, whichever occurs later.  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 is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of   1% per year include 
bilateral tubal ligation, male sterilization, and established proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
Hormonal contraceptive methods must be supplemented by a barrier method 
plus spermicide. 

 
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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
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 a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for at 
least 28 days after the final dose of study treatment 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 preventing drug 
exposure. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Ocular/uveal melanoma 
 
Inability to comply with study and follow-up procedures 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 90 days after the final dose of RO7198457 or 4 months after the final dose of 
pembrolizumab, whichever occurs later 
Women of childbearing potential (including women who have had a tubal 
ligation) must have a negative serum pregnancy test result within 14 days prior 
to initiation of study drug (i.e., Cycle 1, Day 1). 
 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater, see Appendix 12), myocardial infarction within the 
previous 3 months, unstable arrhythmias, and/or unstable angina  
 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse 
 
Major surgical procedure within 28 days prior to Cycle 1, Day 1, or anticipation of 
need for a major surgical procedure during the course of the study 
 
Any other diseases, metabolic dysfunction, physical examination finding, 
and/or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that may affect 
the interpretation of the results or may render the patient at high risk from treatment 
complications 

 
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 
Corticosteroids at dosages higher than 10 mg prednisolone (if not for physiologic 
substitution) 
 
Previous splenectomy 
 
Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, 
T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell 
immunodeficiencies (e.g., T- and B-negative SCID, Wiskott-Aldrich syndrome, 
ataxia telangiectasia, common variable immunodeficiency)  
 
Any medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study 
 
Symptomatic, untreated, or actively progressing CNS metastases   
Patients with a history of CNS lesions are eligible, provided that all of the 
following criteria are met: 
– 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
– 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases 
to midbrain, pons, medulla or spinal cord) 
– 
No history of metastases within 10 mm of the optic apparatus (optic nerves 
and chiasm) 
– 
No ongoing requirement for corticosteroids as therapy for CNS disease 
– 
No stereotactic radiation within 7 days 
– 
No prior whole-brain radiation 
– 
No clinical evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study 
– 
Patients with new asymptomatic CNS metastases detected at the 
screening scan must receive radiation therapy and/or surgery for CNS 
metastases.  Following treatment, these patients may then be eligible 
without the need for an additional brain scan prior to Cycle 1 Day 1, if all 
other criteria are met. 
– 
Treatment with an anticonvulsant at a stable dose is allowed. 
– 
No intracranial hemorrhage from CNS lesions 
 
History of leptomeningeal metastatic disease 
 
Uncontrolled tumor-related pain  
Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.  
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated >2 
weeks prior to Cycle 1, Day 1.  Patients should be recovered from the effects of 
radiation.    

 
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Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to Cycle 1, Day 1. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated 
drainage more than once every 28 days  
Indwelling drainage catheters (e.g., PleurX®) are allowed. 
 
Any anti-cancer therapy, in the metastatic setting whether investigational or 
approved, including chemotherapy, hormonal therapy, and/or radiotherapy, prior to 
initiation of study treatment, with the following exceptions: 
– 
Herbal therapy > 1 week before Cycle 1, Day 1  
– 
Palliative radiotherapy for painful metastases or metastases in potentially 
sensitive locations (e.g., epidural space)  2 weeks prior to Cycle 1, Day 1 
– 
Prior cancer vaccines (e.g., T-vec) are not allowed. 
 
Malignancies other than disease under study within 5 years prior to Cycle 1, Day 1, 
with the exception of those with a negligible risk of metastasis or death (such as 
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin 
cancer, localized prostate cancer, or ductal carcinoma in situ) 
 
Uncontrolled hypercalcemia ( 1.5 mmol/L ionized calcium or Ca+2  12 mg/dL or 
corrected serum calcium  ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy  
Patients who are receiving bisphosphonate therapy or denosumab specifically 
to prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.   
 
Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for  2 weeks prior to screening. 
 
History of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular thrombosis associated with antiphospholipid syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis (see Appendix 7 for a more 
comprehensive list of autoimmune diseases) with the following exceptions: 
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible. 
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen 
may be eligible. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., no psoriatic arthritis) may be eligible 
provided that they meet the following conditions: 

 
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– 
Rash must cover less than 10% of the body surface area. 
– 
Disease is well controlled at baseline and only requires low potency topical 
steroids. 
– 
There are no acute exacerbations of underlying condition within the last 
12 months (e.g., not requiring psoralen plus ultraviolet A radiation, 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high 
potency, or oral steroids). 
 
Treatment with monoamine oxidase inhibitors (MAOIs) within 3 weeks prior to 
Cycle 1, Day 1 
 
Treatment with systemic immunosuppressive medications (including, but not limited 
to, prednisone   10 mg/day, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and TNF- antagonists) within 2 weeks prior to Cycle 1, Day 1 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled in the study. 
The use of inhaled corticosteroids (e.g., fluticasone for chronic obstructive 
pulmonary disease) is allowed. 
The use of oral mineralocorticoids (e.g., fludrocortisone for patients with 
orthostatic hypotension) is allowed. 
Physiologic doses of corticosteroids for adrenal insufficiency are allowed. 
 
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed 
tomography (CT) scan  
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Positive test for HIV infection 
 
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) 
Patients with past or resolved hepatitis B infection (defined as having a 
negative HBsAg test and a positive IgG antibody to hepatitis B core antigen 
[anti-HBc]) are eligible.  HBV DNA must be obtained in these patients prior to 
Cycle 1, Day 1 and must demonstrate no active infection. 
 
Active hepatitis C 
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA.   
 
Known active or latent tuberculosis infection 
If the investigator considers a potential patient to be at an increased risk for 
infection with Mycobacterium tuberculosis, latent tuberculosis diagnostic 
procedures must be followed according to local practice standards during the 
screening period. 

 
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 
Severe infections within 4 weeks prior to Cycle 1, Day 1 including, but not limited 
to, hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
Recent infections not meeting the criteria for severe infections, including the 
following: 
– 
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
– 
Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 
– 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
 
Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
 
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
or anticipation that such a live, attenuated vaccine will be required during the study 
Influenza vaccination should be given during influenza season only.  Patients 
must not receive live, attenuated influenza vaccine (e.g., FluMist) within 
4 weeks prior to Cycle 1, Day 1 or at any time during the study, and for 
5 months following the last study treatment. 
 
Known hypersensitivity to the active substance or to any of the excipients in the 
vaccine 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary-cell products 
 
Allergy or hypersensitivity to components of the pembrolizumab formulation 
 
4.1.3 
Inclusion and Exclusion Criteria for Crossover Treatment 
Patients in Arm A (pembrolizumab alone) must meet all of the following eligibility criteria 
to be eligible to enter the crossover treatment (RO7198457 plus pembrolizumab). 
4.1.3.1 
Inclusion Criteria for Crossover Treatment 
 
Confirmed progression of disease as assessed by investigator per RECIST v1.1 
after at least one dose of pembrolizumab in Arm A   
Disease progression must be confirmed by a consecutive assessment 
 4 weeks from the date first documented. 
Patients who complete 24 months of pembrolizumab and experience disease 
progression < 6 months after discontinuing pembrolizumab may also be eligible 
to cross over.  
 
ECOG Performance Status of 0 or 1 (see Appendix 6) 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods that result in a 
failure rate of  1% per year during the treatment period and for at least 90 days 

 
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after the final dose of RO7198457 and at least 4 months after the final dose of 
pembrolizumab, whichever occurs later.  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 is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, and established proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
Hormonal contraceptive methods must be supplemented by a barrier method 
plus spermicide. 
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.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
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 a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for at 
least 28 days after the final dose of study treatment 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 preventing drug 
exposure. 
 
4.1.3.2 
Exclusion Criteria for Crossover Treatment 
 
Toxicity experienced while on study treatment in the control arm that would require 
permanent discontinuation of pembrolizumab or preclude treatment with the 
combination of RO7198457 and pembrolizumab in the Arm B portion of the study. 

 
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 
Tumor progression at critical anatomical sites that cannot be readily managed and 
stabilized by protocol-allowed medical interventions prior to repeat dosing   
Critical anatomical sites include the CNS, central airway, the great vessels, and 
other organs or tissues where compromised function secondary to tumor 
progression would be expected to result acutely in severe and/or irreversible 
disability or death. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label trial.  For the safety run-in stage, after written informed consent has 
been obtained and eligibility has been established, patients will be assigned to 
combination treatment with RO7198457 plus pembrolizumab.  For the randomization 
phase, after written informed consent has been obtained and eligibility has been 
established, each patient will be randomized to one of the two treatment arms through 
an interactive web-based response system (IWRS).  A stratified, permuted block 
randomization scheme will be used to obtain approximately a 2:1 ratio between the two 
treatment arms.  Patients should receive their first dose of study treatment as soon as 
possible and within approximately 1 week of randomization. 
Randomization will be stratified by the following criteria. 
 
PD-L1 status by SP263 IHC ( 5% vs.  5% or unknown)  
 
Disease stage (AJCC v8.0, based on screening Part B tumor assessment) combined 
with baseline LDH level (M0, M1a, or M1b vs. M1c or M1d or LDH  ULN) 
 
These stratification factors were chosen because of their known or suspected potential 
to affect prognosis in metastatic melanoma.  Prospective stratification by these factors 
will minimize differences in the two treatment arms due to sources other than 
RO7198457. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The IMPs for this study are RO7198457 and pembrolizumab.  Appendix 13 identifies all 
investigational and auxiliary medicinal products for this study. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
RO7198457 
RO7198457 will be supplied by the Sponsor 
 
   
 
 
 
For information on the formulation, packaging, and handling of RO7198457 see the 
RO7198457 pharmacy manual and/or the RO7198457 Investigator's Brochure. 

 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4.3.2.2 
Pembrolizumab 
Pembrolizumab will be administered at a dose of 200 mg as an IV infusion over 
30 ( 10) minutes.   
If pembrolizumab is administered in combination with RO7198457 (safety run-in stage 
and Arm B), refer to 
 for prophylactic treatment and RO7198457 administration 
information.  
 
Vital signs (pulse rate, respiratory rate, blood pressure and temperature) should be 
recorded within 60 minutes prior to the infusion.  If clinically indicated, vital signs should 
be recorded during the infusion at 15, 30, 45, and 60 minutes ( 5 minutes for all 
timepoints) during the infusion and at 30 ( 10) minutes after the infusion.  If the patient 
experienced an IRR with the previous infusion or if clinically indicated, vital signs should 
be recorded during the infusion and at 30 ( 5) minutes after the infusion. 
Patients should be observed for 30 minutes after the infusion.  Patients may be 
hospitalized overnight if required by institutional guidelines.  If infusion-related adverse 
events (e.g., fever, chills) are not resolved to  Grade 1 following the outpatient 
observation period, patients should be admitted for overnight observation. 
Patients should be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.  Guidance on study drug administration in the context of 
management of specific adverse events is provided in Section 5.1.4.3.  
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (RO7198457 and pembrolizumab) will be 
provided by the Sponsor where required by local health authority regulations.  

 
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The study site will acknowledge receipt of IMPs supplied by the Sponsor using the IWRS 
to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to RO7198457 and/or Pembrolizumab 
The Sponsor (Genentech, a member of the Roche Group) will offer continued access to 
IMPs RO7198457 and/or pembrolizumab (in countries where applicable) 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 IMPs RO7198457 and/or pembrolizumab 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 Genentech IMP 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 IMPs RO7198457 and/or pembrolizumab 
(in countries where applicable) after completing the study if any of the following 
conditions are met: 
 
The IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for advanced melanoma 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
advanced melanoma 
 
Provision of the Genentech IMP 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 web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
 
 
 
 
  
 
   
 
 
   

 
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 
 
 
  
 
 
 
   
. 
 
4.5 
STUDY ASSESSMENTS  
The schedules of activities to be performed during the study are provided in Appendix 1 
and Appendix 2.  All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability and will be assessed for 
toxicity prior to each dose of RO7198457 and/or pembrolizumab.  Dosing will occur only 
if the clinical assessment and select local laboratory test results are acceptable.  Results 
from local lab tests with longer turn-around times (e.g., thyroid function test, 
amylase/lipase) may not be required prior to dosing. 
All assessments will be performed on the day of the scheduled visit date unless a time 
window is specified.  Assessments scheduled on the days of study treatment should be 
performed before the infusion of study drug(s) unless otherwise noted.  If the timing of a 
study visit coincides with a holiday, weekend, or other administrative disruption that 
precludes the visit, the visit should be scheduled on the nearest following feasible date, 
with subsequent visits rescheduled accordingly. 
Patient care kits, which consist of a thermometer and memory aid log, will be provided to 
patients.  These are provided to help patients monitor and recall signs and symptoms 
that occur after leaving the clinic to relay to the study staff at their next study visit. 
Collection of any nonsafety-related data or patient samples may be suspended or 
terminated by the Sponsor at any time if further collection of such data or samples is 
also not related to the study's primary objective(s).  The decision to suspend or 
discontinue any data collection will be communicated to sites' IRBs\ECs by means of a 
memorandum and will not require a protocol amendment. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 

 
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This study requires documentation of consent for the following components of study 
participation, as applicable: 
 
Participation in Study GO40558 
Written informed consent for participation in the study must be documented by 
signing the relevant page before any study-specific screening tests or 
evaluations are performed. 
 
Acknowledgement of Treatment Continuation after Possible Disease Worsening 
This applies only to patients who continue study treatment beyond radiographic 
progression in the study (see Section 3.1.3). 
 
Acknowledgement of Treatment Crossover  
This applies only to patients randomized to Arm A who elect to cross-over to 
RO7198457 plus pembrolizumab (see Section 3.3.7).  
 
In addition, a separate, specific signature will be required to document consent for either 
of the following:  
 
Screening Part A (i.e., collection and testing of archival or fresh tumor specimens 
and blood prior to signing of the main study Informed Consent Form).  This applies 
to all patients in the study. 
 
Optional research, including the conduct of optional tumor biopsies, the collection of 
optional stool samples, and the storage of remaining biological samples up to 
15 years or until depleted 
 
The investigator or authorized designee will explain to each patient in the study the 
objectives of screening Part A or optional research.  Patients will be told that they are 
free to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period.  Patients who decline to participate will not sign the 
applicable Informed Consent Forms. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment in the study.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history includes cancer history (including, but not limited to, prior cancer 
therapies and/or prior CITs and procedures and tumor characteristics such as hormone 
receptor status or mutation status), other clinically significant diseases, surgeries, 
smoking history, use of alcohol and/or drugs of abuse, reproductive status, and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, and nutritional supplements) used by the patient within 7 days prior to the 
screening visit. 

 
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Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment. 
4.5.3 
Physical Examinations 
A complete physical examination performed at screening should include an evaluation of 
the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
ECOG Performance Status (see Appendix 6) should be assessed per the schedules of 
activities in Appendix 1 and Appendix 2. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in the patient's medical record.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
As part of tumor assessments, the physical examination should also include evaluation 
for lymphadenopathy, splenomegaly, hepatomegaly, and cutaneous neoplasms or 
metastases.  All patients should be monitored for symptoms of CNS metastases and 
such reported symptoms should be followed by a full neurological examination.  A brain 
magnetic resonance imaging (MRI) scan or contrast-enhanced head CT scan should be 
conducted as clinically indicated to confirm or refute new or worsening brain 
involvement. 
4.5.4 
Vital Signs  
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressures while the patient is in a seated position.  Blood 
oxygen saturation will be measured at baseline by pulse oximetry. 
Vital signs should be measured during the infusion of pembrolizumab and during the 
observation period (see 
 and Section 4.3.2.2 for frequency of vital sign 
assessments) or if clinically indicated (see schedules of activities in Appendix 1 and 
Appendix 2). 
All vital signs collected per protocol should be documented in the patient's medical 
record and recorded in the appropriate eCRF.  For other measurements, only those vital 
signs that constitute an adverse event (e.g., temperature for event of fever) or a primary 
manifestation of an adverse event (e.g., blood pressure associated with an IRR or heart 
rate associated with an arrhythmia) should be recorded in the eCRF. 

 
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4.5.5 
Tumor and Response Evaluations  
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation. 
Screening and subsequent tumor assessments must include CT scans of the chest, 
abdomen, and pelvis (with IV contrast unless contraindicated and oral contrast as 
appropriate per institutional standards).  Patients who have a contraindication to IV 
contrast may have MRI scans of the abdomen and pelvis performed in lieu of CTs and a 
non-contrast CT of the chest.  If a CT scan for tumor assessment is performed in a 
positron emission tomography-CT scanner, the CT acquisition must be of full diagnostic 
quality and include CT contrast. 
A CT or MRI scan (with IV contrast unless contraindicated) 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 CT scan.  Patients with untreated or actively progressing CNS metastases are 
not eligible for the study (see Section 4.1.2).  Stable brain metastases 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 (in addition to radiographic 
assessments).  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. 
Further investigations, such as bone scans and CT scans of the neck or extremities, 
should also be performed as indicated by the underlying disease and if there is any 
clinical suspicion of disease at any site that may not be demonstrated by the minimum 
schedule of assessments listed above.  As the investigator's discretion, other methods of 
assessment of measurable disease as per RECIST v1.1 may be used. 
Results of standard of care tests or examinations performed prior to obtaining Informed 
Consent and  28 days prior to Day 1 of Cycle 1 may be used for the purposes of 
screening rather than repeating such tests.  All measurable and evaluable lesions should 
be re-assessed at each subsequent tumor evaluation.  The same radiographic 
procedures used to assess disease sites at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans).   
Response will be assessed on the basis of the Investigator’s physical examinations and 
the imaging modalities detailed above, using both RECIST v1.1 and iRECIST criteria 
(see Appendix 4 and Appendix 5, respectively).  The investigator's assessment of overall 
tumor response at all timepoints should only be based on RECIST v1.1.  Assessments 
should be performed by the same evaluator if possible to ensure internal consistency 
across visits.  Results must be reviewed by the investigator before dosing the next cycle. 

 
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The timing of tumor assessments will be determined based on weeks from first study 
treatment (C1D1; pembrolizumab monotherapy) and will not be tied to cycle-specific 
visits.  The purpose of having the tumor assessments independent of cycle-specific visits 
is so that they occur at the same interval for all patients, regardless of delays in dosing. 
Tumor assessments must be obtained and documented during Screening Part B 
(to establish a baseline assessment prior to Cycle 1, Day 1), during Week 12, and then 
every 6 weeks thereafter for the first 48 weeks (i.e., during Weeks 12, 18, 24, 30, 36, 42, 
and 48).  "During week" is defined as the first day/Day 1 of each targeted week 
(e.g., 12, 18, or 24 weeks from C1D1 date) plus 6 calendar days.  After Week 48, tumor 
assessments will occur every 12 ( 1) weeks through Week 96 (i.e., during Weeks 60, 
72, 84, and 96).  After Week 96, follow-up tumor assessments will occur approximately 
every 12 weeks through Week 156 (i.e., Weeks 108, 120, 132, 144, and 156).  After 
Week 156, follow-up tumor assessments will occur approximately every 24 weeks 
(i.e., Weeks 180, 204, 228, and 252); see also Appendix 1 and Appendix 2.  
Per investigator discretion, tumor assessments may also occur as clinically indicated.   
If applicable, cutaneous lesions are to be obtained by digital photography and 
documented at each tumor assessment as described in Section 4.5.6.   
After initial study treatment discontinuation (if discontinuation were for reasons other 
than disease progression), follow-up tumor assessments will be performed until death, 
disease progression, initiation of another systemic anti-cancer therapy, loss to follow-up, 
withdrawal of consent, or study termination, whichever occurs first.   
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 will be monitored with a follow-up scan in 6 ( 1) weeks (i.e., at the next 
scheduled tumor assessment when the protocol-defined scan frequency is every 
6 weeks or as an unscheduled tumor assessment when the protocol-defined scan 
frequency is every 12 [±1] weeks), or earlier if clinically indicated.  Tumor assessments 
should be continued every 6 weeks thereafter until two consecutive scans demonstrate 
stability or improvement with respect to the first scan that showed radiographic disease 
progression, at which point the scan frequency should revert or transition to every 
12 weeks if applicable.  For patients who consented to treatment beyond radiographic 
disease progression (see Section 3.1.3), new lesions will also be assessed according to 
the iRECIST criteria, and applicable measurements should be entered into the eCRF.  
While the Sponsor will derive overall tumor assessment as per iRECIST, investigator 
assessment of overall tumor response at all timepoints should be only based on 
RECIST v1.1. 
Patients who fulfill the criteria to receive crossover treatment (see Section 3.1.4) will 
have tumor assessments during the crossover treatment period as described in 
Appendix 2, footnote k.  Refer to Section 3.1.4 for guidance on duration of treatment on 

 
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Arm B after crossing over from Arm A.  Patients who discontinue from crossover 
treatment will be asked to return to the clinic within 30 days after the final dose of 
RO7198457 or pembrolizumab, whichever is later, for a crossover treatment 
discontinuation visit.  The visit at which response assessment shows disease 
progression on crossover treatment may be used as the early termination visit.  Refer 
to Appendix 1 and Appendix 2 for assessments to be performed at the treatment 
discontinuation visit. 
An independent review of the responses of all patients may be conducted, including a 
central review of CT and/or MRI scans, at an independent review facility.  All primary 
imaging data used for tumor assessment may be collected by the Sponsor to enable a 
centralized, independent review of response endpoints.  If available, a scan prior to the 
baseline (up to 3 months) may also be obtained to evaluate changes in tumor 
growth rate. 
4.5.6 
Photography of Cutaneous Lesions 
Cutaneous lesions not evaluable by CT or MRI will be documented by color digital 
photography, including a ruler to estimate lesion size.  Cutaneous lesions may be 
considered target lesions if they meet RECIST v1.1 criteria (see Appendix 4), otherwise 
they may be considered non-target lesions. 
Photographs of cutaneous lesions will be taken at screening and on the same day as a 
tumor assessment visit, or at the first clinic visit following each tumor assessment 
(see Appendix 1 and Appendix 2).  Copies of the de-identified photographs should be 
forwarded to for potential retrospective analysis.   
4.5.7 
Laboratory, Biomarker, and Other Biological Samples  
4.5.7.1 
Local Laboratory Tests 
The following laboratory tests will be performed at the study site's local laboratory: 
 
Hematology:  CBC including RBC count, hemoglobin, hematocrit, platelet count, and 
WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, and other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, BUN or 
urea, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, 
AST, ALP, LDH, total protein, albumin, amylase, and lipase 
 
Serum ferritin 
 
C-reactive protein 
 
Coagulation:  PT, aPTT, and INR 

 
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 
Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) 
If a urine pregnancy test result is positive, dosing will be delayed until the 
patient's status is determined by a serum pregnancy test.   
 
Urinalysis:  dipstick (pH, specific gravity, glucose, protein, ketones, blood) and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
and bacteria) if warranted by dipstick results 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine, and free 
thyroxine 
 
Serology: 
– 
HBsAg, antibodies against HBsAg and hepatitis B core antigen 
HBV DNA test is to be obtained prior to Cycle 1, Day 1 if the patient has 
positive serology for anti-HBc. 
– 
Anti-HCV 
HCV RNA test is required prior to Cycle 1, Day 1 for consideration of 
eligibility if the patient has positive serology for anti-HCV. 
– 
HIV antibodies 
 
Tuberculosis testing (only if patient is considered at increased risk for infection with 
Mycobacterium tuberculosis):  IFN- release assays or tuberculin skin test (according 
to local standard practice) 
 
4.5.7.2 
Central Laboratory Tests 
The tests listed below will be performed at the central laboratory, a specialty laboratory, 
BioNTech, or at Genentech.  Instruction manuals and supply kits will be provided by the 
central laboratory for these central assessments.  Please refer to the central laboratory 
manual for additional details on biosample collection and handling instructions.   
Assessments Performed on Blood Samples 
 
PK assays 
– 
EDTA-plasma samples will be obtained for measurement of RO7198457 
component concentration 
 using liquid 
chromatography/mass spectrometry (LC/MS) and appropriate mRNA 
measurement assay 
– 
Serum samples will be obtained for measurement of pembrolizumab 
concentration using a validated assay. 
 
Auto-antibody testing 
Serum samples will be obtained for auto-antibody testing including, but not 
necessarily limited to, anti-nuclear antibody, antidouble-stranded DNA, 
anti-neutrophil cytoplasmic antibodies, and thyroid peroxidase antibody, to be 
performed based on clinical events during the study, either in individual patients or 
across the study population. 

 
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 
Immune monitoring assays 
The following analysis will be applied on PBMCs or plasma samples for immune 
monitoring:  
– 
– 
 
 
– 
 
– 
 
 
Exploratory biomarker assays in blood 
– 
Samples will be obtained for cytokine biomarker and circulating tumor DNA 
evaluation as detailed in the schedule of assessments (see Appendix 3). 
 
NGS analysis 
Blood sample will be collected for NGS (WES, RNA sequencing, circulating tumor 
DNA analysis or TCR sequencing) and may be sent to one or more laboratories for 
analysis.  NGS data and associated clinical data may be shared with researchers 
who are not participating in the study or may be submitted to government or other 
health research databases for broad sharing with other researchers to perform 
research on human health and disease.  Study participants will not be identified by 
name or any other personally identifying information. 
NGS data will be analyzed in the context of this study for the identification of 
mutations in the tumor and explored in aggregate with other studies to better 
understand disease pathobiology and guide the development of new therapeutic 
approaches.  Given the complexity and exploratory nature of these analyses, NGS 
data and analyses are for research purposes only and will not be shared with 
investigators or study participants unless required by law. 
 
 
 
Assessments Performed on Tumor Samples 
The status of immune-related and tumor type-related biomarkers (including, but not 
limited to, the expression of PD-L1 on specific cell types and the prevalence and/or 
activation of infiltrating T cells) will be evaluated using methods including, but not limited 
to, IHC, immunofluorescence, and NGS assays in both archival and fresh tumor 
samples.  Fresh tumor samples may also be used to generate TIL cultures for antigen-
specific immune monitoring in tumors.  In addition, tumor RNA and/or DNA may be 
purified and subject to characterization by NGS.  Additional exploratory biomarkers may 
also be assessed if guided by clinical and nonclinical data.  

 
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 
Archival tumor tissue:  for all patients enrolled in the study 
If available, archival tumor tissue samples obtained outside of this study for other 
purposes will be collected from all patients (paraffin blocks are preferred; see 
laboratory manual for further details) to enable RO7198457 manufacturing and 
determine PD-L1 expression for stratification.  Fine-needle aspirates, cell pellets 
from effusions or ascites, lavage samples, and bone biopsies do not satisfy the 
requirement for archival tissue. 
If adequate tissue from different timepoints (such as time of initial diagnosis and 
time of disease recurrence) and/or multiple metastatic tumors is available, priority 
should be given to the tissue with highest tumor content and lowest necrotic area 
(when feasible). 
Archival or fresh tumor tissue will be used for RO7198457 manufacturing and for 
testing PD-L1 expression, leftover material, if sufficient, will be used for the 
evaluation of potential predictive biomarkers using characterized assays for analysis 
of proteins, RNA and DNA. 
 
Fresh tumor biopsy at baseline:  For patients who do not have sufficient archival 
tumor tissue sample, a fresh biopsy is required to enable vaccine manufacturing. 
 
An optional tumor tissue biopsy after investigator-assessed radiographic disease 
progression for patients being considered for either continuation of current treatment 
beyond progression or crossover from pembrolizumab monotherapy to RO7198457 
plus pembrolizumab: 
An optional biopsy at time of progression will be collected if the sample collection is 
deemed safe and clinically feasible by the investigator and also if the scheduling can 
be accommodated.  Tumor tissue samples consisting of core-needle biopsies for 
deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions will be obtained.  
The biopsy at progression will be used for evaluation of tumor PD biomarkers and 
potential predictive biomarkers using characterized assays for analysis of proteins, 
RNA, and DNA. 
 
On-treatment tumor biopsies to assess tumor pharmacodynamic effects 
(randomized stage only):  
On treatment biopsy is mandatory for a minimum of 20 patients enrolled in Arm B 
and for 10 patients in Arm A.  Once the required numbers of interpretable biopsies 
are collected, patients may provide an optional biopsy in both arms.  The 
on-treatment biopsy should be obtained approximately 89 weeks after the first 
infusion of pembrolizumab in Arm A and 56 weeks after the first administration of 
RO7198457 in Arm B or an earlier time point as indicated.  The Medical Monitor is 
available to advise as needed. 
Tumor tissue samples can be collected using core-needle, punch, excisional (as 
specified above), or forceps biopsy.  Please refer to the sample specifications 
described below for mandatory tumor biopsies for further guidance pertinent to the 
chosen biopsy technique.  

 
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The mandatory and optional tumor biopsies will be used for evaluation of tumor PD 
biomarkers and potential predictive biomarkers using characterized assays for 
analysis of proteins, and NGS assays using RNA, and DNA.  NGS data will be 
analyzed in the context of this study for the identification of mutations in the tumor 
and explored in aggregate with other studies to better understand disease 
pathobiology and guide the development of new therapeutic approaches.  Given the 
complexity and exploratory nature of these analyses, NGS data and analyses are 
for research purposes only and will not be shared with investigators or study 
participants unless required by law. 
Sample specifications:  The mandatory and optional biopsies should meet the 
following sample requirements: 
Tumor tissue samples consisting of core-needle biopsies of deep tumor tissue or 
lymph nodes or excisional, incisional, punch, or forceps biopsies of cutaneous, 
subcutaneous, or mucosal lesions will be obtained.  Fine-needle aspirates, cell 
pellets from effusions or ascites, lavage samples, and bone biopsies are not 
permitted.  Lesions considered for core needle biopsies should be deemed suitable 
for retrieval of at minimum three cores (but recommend five cores) at a given 
timepoint (refer to the Laboratory Manual for more details regarding biopsy 
requirements).  The quality and quantity of tissue provided is critical for RO7198457 
manufacturing and biomarker analysis.  If possible, successive passes through the 
same lesion should be  1 cm apart.   
If multiple lesions are available, it is preferable to obtain the on-treatment biopsy 
from the same lesion (or organ) as the pretreatment biopsy, if feasible, to avoid 
introduction of heterogeneity related to site of metastasis. 
RECIST target lesions are not to be biopsied. 
 
Sample Storage 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions: 
 
Serum/plasma samples collected for PK analysis may be needed for additional 
method development, assay validation, and characterization; therefore, these 
samples will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed. 
 
Blood samples collected for NGS will be stored no later than 5 years after the final 
Clinical Study Report has been completed.  
 
Blood and plasma samples collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after final closure of the study database, whichever 

 
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occurs first.  For patients who are not enrolled, remaining archival tissue blocks will 
be returned to the site upon request or within 3 months of eligibility determination, 
whichever occurs first. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, 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.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.8 
Electrocardiograms 
Single ECG recordings will be obtained at screening and end of treatment visits, as 
outlined in the schedules of activities (see Appendix 1 and Appendix 2), and may be 
obtained at unscheduled timepoints as clinically indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
Blood draws and other procedures should be avoided, if possible, during the period 
immediately before ECG measurement, and activity should be controlled as much as 
possible to minimize variability due to the effects of physiologic stress. 
ECGs will be reviewed by the investigator to determine patient eligibility at screening.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. 
If at a particular postdose timepoint the mean QT interval corrected through use of 
Fridericia's formula (QTcF) is  500 ms and/or  60 ms longer than the baseline value, 
another ECG must be recorded, ideally within the next 5 minutes, and ECG monitoring 
should continue until QTcF has stabilized on two successive ECGs.  The Medical 
Monitor should be notified.  Standard-of-care treatment may be instituted per the 
discretion of the investigator.  If a PK sample is not scheduled at that timepoint, an 
unscheduled PK sample should be obtained.  A decision on study drug discontinuation 
should be made, as described in Section 4.6.1.  The investigator should also evaluate 

 
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the patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.9 
Cancer-Related Procedures 
Collection of cancer-related medical, surgical, and radiation procedures will begin on 
Day 1 and be performed throughout the treatment period and during the survival 
follow-up period. 
4.5.10 
Patient-Reported Outcomes 
To more fully characterize the clinical profile of RO7198457 plus pembrolizumab 
compared with pembrolizumab, PRO data will be obtained through use of select scales 
of the EORTC library, select items of the PRO-CTCAE library, an item capturing "bother" 
of treatment-related symptoms, and the full WPAI.  The questionnaires will be translated 
as appropriate into the local language.  
A total of 31 items from these 3 measures will be administered.  Using selected 
scales/items from an item library instead of static questionnaires, minimize patient 
response burden (response fatigue), avoid concept redundancy (e.g., two scales 
assessing fatigue) and improve patients' compliance in rating the burden associated with 
their disease and treatment.  
Paper PRO questionnaires scheduled for administration during a clinic visit must be 
completed by the patient at the investigational site at the start of the clinic visit prior to 
other study assessments that might bias patients' ratings of symptoms, function, and 
HRQoL and before administration of study treatment.  Interviewer-administered 
assessment is allowed but can only be conducted by a member of the clinic staff for 
patients who are unable to complete the measures on their own.  Study personnel 
should only review all questionnaires for completeness before the patient leaves the 
investigational site.   
4.5.10.1 
EORTC Library 
The EORTC library (see Appendix 9) includes single-item or multi-item symptom scales 
as well as GHS/HRQoL scale and five functional scales  (Aaronson et al. 1993; 
Sprangers et al. 1996; Fitzsimmons et al. 1999).  The Global GHS/HRQoL, Physical 
Function and Role Function scales will be collected from patients at baseline, while 
receiving treatment, and at time of treatment discontinuation. 
The EORTC scales will be scored according to EORTC scoring manual (Fayers et al. 
2001).  Scale scores vary from 0 to 100 with 100 indicating a better functioning or 
HRQoL; a 10-point change from baseline within a treatment arm is considered clinically 
meaningful (Osoba et al. 1998). 
PRO completion, compliance rates, and reasons for missing data will be summarized 
at each timepoint by treatment arm for each measure in the ITT population.  

 
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The questionnaire is considered completed if at least one question was completed.  
The compliance rate will be based on the total number of patients expected to complete 
the questionnaire at a particular timepoint. 
4.5.10.2 
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events 
The PRO-CTCAE (see Appendix 10) is an item bank reflecting to date, 78 symptomatic 
adverse events rated according to their severity, interference with daily function, 
frequency, and/or occurrence (Basch et al. 2014).   
Symptomatic adverse events that are patient self-reportable were selected based on the 
side effects associated with CRS and immunotherapy (Weber et al. 2015b).  Adverse 
events of which assessments rely on laboratory testing (e.g., neutropenia) that are 
presented as being primarily asymptomatic or with nonspecific signs and symptoms 
were disregarded.  Adverse events that do not have an identifiable symptom equivalent 
in the PRO-CTCAE were also excluded.  Based on the above criteria, 8 symptomatic 
adverse events were selected from the PRO-CTCAE item bank (i.e., chills, nausea, 
rash, fatigue, headache, shortness of breath, heart palpitations, injection site reaction); 
a total of 16 items.  An additional item providing an overall assessment of the burden of 
side effects will be collected in addition to the 15 selected items of the PRO-CTCAE.  
PRO-CTCAE will be completed per the schedules of activities (see Appendix 1 and 
Appendix 2), only when available in the local language of the investigational site. 
4.5.10.3 
Work Productivity and Activity Impairment: Melanoma, 
Version 2.0  
The Work Productivity and Activity Impairment:  Melanoma, Version 2.0 
(WPAI:Melanoma) (see Appendix 11) evaluates effects on employment status, hours 
missed due to health problems, hours worked, and the degree to which health problems 
affect productivity and regular daily activities (Schadendorf et al. 2015).  Patients who 
are employed will answer all the questions, while those not employed will only answer 
questions about their ability to do daily activities.  For employed patients, work 
productivity impairment is expressed as percent work time missed, percent impairment 
while working, and percent overall work impairment.  For employed and unemployed 
patients, the ability to perform daily activities is expressed as percent activity impairment.  
Higher scores indicate greater impairment and less productivity.  The WPAI:Melanoma 
will be scored according to the WPAI scoring instructions (Reilly et al. 1993). 
The WPAI will be administered specifically at Day 1 of Cycles 1, 4, and 13 and at the 
discontinuation visit to capture responses at patient's transition through induction to 
maintenance therapy. 

 
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4.5.11 
Samples for Optional Whole Genome Sequencing 
At participating sites, blood samples will be collected for DNA extraction to enable whole 
genome sequencing (WGS) to identify mutations that are predictive of response to study 
drug, are associated with progression to a more severe disease state, are associated 
with susceptibility to developing adverse events, can lead to improved adverse event 
monitoring or investigation, or can increase the knowledge and understanding of disease 
biology and drug safety.  The samples may be sent to one or more laboratories 
for analysis. 
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's IRB/EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS sampling, this section 
of the protocol (Section 4.5.11) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS are to be stored no later than 5 years after the final 
Clinical Study Report has been completed.  
Patient medical information associated with WGS samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.12 
Tumor Biopsies 
Consenting patients will undergo tumor biopsies at baseline and may undergo additional 
on-treatment biopsies at any other time (including progression or response) at the 
investigator's discretion (if deemed clinically feasible by the investigator).  During the 
randomized stage, on treatment biopsy is mandatory for a minimum of 20 patients 
enrolled in Arm B and for 10 patients in Arm A.  Once the required numbers of 
interpretable biopsies are collected, patients may provide an optional biopsy in both 

 
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arms.  Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF. 
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
Refer to Section 4.5.13 for details on sample storage, use of samples after patient 
withdrawal, confidentiality standards for data, and availability of data from biomarker 
analyses. 
4.5.13 
Optional Samples for Research Biosample Repository  
4.5.13.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of 
facilities used for the long-term storage of human biological specimens, including body 
fluids, solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  
The collection, storage, and analysis of RBR samples will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives: 
 
To study the association of biomarkers with efficacy, or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.13.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 

 
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been granted approval for RBR sampling, this section of the protocol (Section 4.5.13) 
will not be applicable at that site. 
4.5.13.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7198457, diseases, or 
drug safety: 
 
Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover 
tissue samples from medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion during the course of the study 
 
Optional stool sample performed during screening and, if collected at screening, 
between C3D15 and C4D1 and C8D15 and C9D1 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.     
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.13.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 

 
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Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.13.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.13.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent (verbally or in writing) at any time for any reason.  After withdrawal of consent, 
any remaining samples will be destroyed or will no longer be linked to the patient.  
However, if RBR samples have been tested prior to withdrawal of consent, results from 
those tests will remain as part of the overall research data.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples during the study, the 
investigator must inform the Medical Monitor in writing of the patient's wishes through 
use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the RBR Research Sample Withdrawal of Informed Consent eCRF.  If a 

 
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patient wishes to withdraw consent to the testing of his or her RBR samples after closure 
of the site, the investigator must inform the Sponsor by emailing the study number and 
patient number to the following email address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.13.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
Use of an anti-cancer therapy not required per protocol 
 
Symptomatic deterioration (e.g., uncontrollable pain secondary to disease, 
unmanageable ascites) attributed to disease progression as determined by the 
investigator after an integrated assessment of all the radiographic data, biopsy 
results, and clinical status 
 
Intolerable toxicity related to study treatment, including development of an 
immune-related adverse event (see Section 5.1.1.2), determined by the investigator 
to be unacceptable given the individual patient's potential response to therapy and 
the severity of the event 
 
The primary reason for study treatment discontinuation should be documented on the 
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Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study drug (see Appendix 1 and Appendix 2 for additional details). 
The visit at which a response assessment shows disease progression that results in 
discontinuation of pembrolizumab and RO7198457 (if applicable) may be used as the 
treatment discontinuation visit as applicable, in which case all assessments associated 
with the treatment discontinuation visit should be performed at that time. 
See the schedules of activities provided in Appendix 1 and Appendix 2 for the respective 
assessments to be performed at the treatment discontinuation visit. 
Patients who discontinue study treatment primarily for reasons other than disease 
progression will continue tumor assessments (see Section 4.5.5) if feasible, until disease 
progression, initiation of another systemic anti-cancer therapy, death, loss to follow-up, 
withdrawal of consent, or study termination, whichever occurs first.  After treatment 
discontinuation, information on survival follow-up and new anti-cancer therapy will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 3 months until death (unless the patient withdraws consent or the Sponsor 
terminates the study).   
4.6.2 
Patient Discontinuation from Study 
Patient discontinuation from the study is distinguished from study treatment 
discontinuation (see Section 4.6.1) and occurs when the patient dies, is lost to follow-up, 
or withdraws consent to be followed.   
Patients have the right to voluntarily withdraw from the study (verbally or in writing) 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 
 
Study termination or site closure 
 
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 a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 

 
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4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
Data recording are inaccurate or incomplete 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
RO7198457 is not approved, and clinical development is ongoing.  The anticipated 
important safety risks for RO7198457 are outlined below.  Please refer to the 
RO7198457 Investigator's Brochure for a complete summary of safety information.  
Pembrolizumab is approved for several indications, including melanoma (see 
Section 3.3.2), and clinical development is ongoing.  Please refer to the pembrolizumab 
local prescribing information for a complete summary of safety information. 
The following information is based on limited data from an ongoing Phase I study of 
RO7198457 alone or in combination with atezolizumab, anticipated mechanism of 
action, results from nonclinical studies, results from ongoing clinical studies with similar 
RNA based vaccines and published data on similar molecules, in addition to the 
individual clinical safety profile of pembrolizumab that has been established to date 
(refer to pembrolizumab local prescribing information). 
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Administration of study drug will be performed in a setting with available 

 
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emergency medical facilities with access to a critical care unit and staff who are trained 
to monitor for and respond to medical emergencies.  Patients will undergo safety 
monitoring during the study, including assessment of the nature, frequency, and severity 
of adverse events.  All adverse events and serious adverse events will be recorded 
during the trial and for up to 90 days after the final dose of study treatment or until the 
initiation of another systemic anti-cancer therapy, whichever occurs first.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below. 
The risks associated with RO7198457 and pembrolizumab are detailed in Sections 5.1.1 
and 5.1.2, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 

 
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5.1.1.2 
Immune-Related Adverse Events 
Clinical experience with checkpoint inhibitors intended to enhance prevalent anti-tumor 
T-cell responses has demonstrated that development of autoimmune inflammatory 

 
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conditions is a general risk.  Such immune-related adverse events have been described 
for virtually all organ systems and include, but are not limited to, colitis, hepatitis, 
pneumonitis, endocrinopathy, ocular toxicity, pancreatic toxicity, neurologic toxicity, 
myocarditis and rash. 
In melanoma patients treated with non-mutated tumor antigens, cases of vitiligo were 
reported and may indicate an immune-mediated reaction to melanocyte-specific 
antigens.  In contrast, such adverse events suggestive of an immune-mediated nature 
were not reported in trials with neoantigen vaccines which are directed against tumor 
mutations that arise during the process of tumorigenesis and are therefore not 
expressed by normal cells. 
Theoretically, T cells directed against tumor–derived mutations might be cross-reactive 
to the respective wild-type sequence and, therefore, RO7198457 may increase the risk 
of autoimmune inflammation (also described as immune-related adverse events).  Risk 
mitigation is implemented on the level of neoantigen selection.  The bioinformatics 
workflow for creating the vaccine includes a process for excluding peptides associated 
with a high risk of autoimmunity.  The mutation discovery, prioritization, and confirmation 
processes are complemented by a database that provides comprehensive information 
about expression levels of respective wild-type genes in healthy tissues.  This 
information enables a personalized risk mitigation strategy by removing target 
candidates with an unfavorable risk profile.  Mutations occurring in proteins with a 
possible higher auto-immunity risk in critical organs are filtered out and not considered 
for vaccine production. 
In addition, eligibility criteria for this study are designed to exclude patient who may be at 
higher risk to develop immune-related adverse events.   
Patients with a history of autoimmune disease (other than autoimmune thyroid disease 
managed with thyroid hormone replacement, controlled type 1 diabetes mellitus, certain 
cases of eczema, psoriasis, lichen simplex chronicus or vitiligo) and patients with a 
history of Grade  3 immune-related adverse events associated with prior CIT that 
resulted in permanent discontinuation of prior CIT or history of any Grade 4 immune-
related adverse events attributed to prior CIT (other than endocrinopathy managed with 
replacement therapy) will be excluded from this trial (see Section 4.1.2).  In addition, all 
immune-related adverse events related to prior CIT must have resolved completely.  
Patients treated with corticosteroids for immune-related adverse events from prior CIT 
(other than endocrinopathy managed with replacement therapy or stable vitiligo) must 
demonstrate the absence of related symptoms or signs for at least 4 weeks following 
discontinuation of corticosteroids prior to study entry (see Section 4.1.2). 
Suggested management guidelines for individual suspected immune-related adverse 
events are provided in Section 5.1.4.3. 

 
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5.1.2 
Risks Associated with Pembrolizumab 
The overall safety profile for pembrolizumab is based on data from patients treated with 
pembrolizumab in clinical trials, including approximately 1500 patients with melanoma.  
Adverse drug reactions in patients who received pembrolizumab include 
immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, 
immune-mediated endocrinopathies (hypophysitis, thyroid dysfunction, and type 1 
diabetes mellitus), immune-mediated nephritis and renal dysfunction, immune-mediated 
skin reactions (rashes, including Stevens-Johnson syndrome [SJS], and toxic epidermal 
necrolysis [TEN]), other immune-mediated adverse reactions (may involve any organ 
system), IRRs, complications of allogeneic hematopoietic stem cell transplantation after 
treatment with pembrolizumab, increased mortality in patients with multiple myeloma 
when pembrolizumab is added to a thalidomide analogue and dexamethasone, and 
embryo−fetal toxicity.  Immune-mediated adverse reactions that occurred in less 
than 1% (unless otherwise indicated) of patients treated with pembrolizumab include 
arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, 
pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis.  In addition, myelitis and 
myocarditis were reported in other clinical trials and postmarketing use.  Solid organ 
transplant rejection has been reported in the postmarketing setting in patients treated 
with pembrolizumab. 
The most frequently observed adverse drug reactions in patients with melanoma who 
received pembrolizumab in clinical trials were fatigue, diarrhea, nausea, and rash.  
Please refer to the pembrolizumab local prescribing information for complete information 
regarding clinical safety.  

 
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5.1.3 
Potential for Overlapping Toxicities with RO7198457 and 
Pembrolizumab 
Based on nonclinical and/or clinical studies with each molecule as a single agent and 
experience with molecules with similar mechanisms of action, there is a potential for 
overlapping toxicity in patients treated with the combination of RO7198457 and 
pembrolizumab.  Because the expected pharmacological activity of these two molecules 
is to increase adaptive T-cell immune responses via complementary mechanisms, the 
combination may be associated with heightened immune-related toxicity relative to either 
agent alone.  
The largest clinical experience to date with the combination of complementary 
modulators of adaptive immunity is derived from trials of ipilimumab combined with 
nivolumab (Wolchok et al. 2013; Antonia et al. 2014; Hammers et al. 2014; 
Larkin et al. 2015).  In a Phase III trial of this combination in patients with advanced 
melanoma, an increased frequency of treatment-related toxicities of all grades as well as 
Grade 34 events was observed for the regimen of nivolumab 1 mg/kg and ipilimumab 
3 mg/kg Q3W (for the initial four doses followed by ipilimumab 3 mg/kg every 2 weeks 
beyond Cycle 3), as compared with either single agent alone (Larkin et al. 2015).  
Nevertheless, most treatment-related events in this trial were qualitatively similar to 
those observed with ipilimumab or nivolumab as a single agent and were manageable 
and reversible with established treatment guidelines.  Another combination with the 
antiPDL1 antibody durvalumab and the antiCTLA4 antibody tremelimumab in 
patients with NSCLC in a Phase Ib study also showed a similar manageable safety 
profile (Antonia et al. 2016). 
On the basis of these data, it is anticipated that any potential immune-related adverse 
events following treatment with RO7198457 and pembrolizumab will likewise be 
amenable to monitoring and manageable in the setting of this combination study.  
The extensive experience with immune checkpoint inhibitors to date was incorporated 
into the design and safety management plan (see Section 5.1.4), with the goal of 
reducing the risks to participating patients.   
 
 
 

 
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. 
Please refer to the pembrolizumab local prescribing information for detailed guidance on 
management of specific immune-related adverse events. 
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. 

 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 

 
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see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows. 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
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. 
 
 
 
Grade  3 hypoxia or dyspnea within 24 hours of study treatment 
 
Grade  3 hypotension within 24 hours of study treatment 
 
Conditions (regardless of grade) suggestive of an immune-mediated disorder, 
including, but not limited to, the following: 
– 
Pneumonitis 
– 
Colitis 
– 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
– 
Hepatitis, including AST or ALT  10  ULN 
– 
Systemic lupus erythematosus 

 
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– 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
– 
Nephritis 
– 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
– 
Myositis 
– 
Myopathies, including rhabdomyolysis 
– 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
– 
Vasculitis 
– 
Autoimmune hemolytic anemia 
– 
Severe cutaneous reactions (e.g., SJS, dermatitis bullous, TEN) 
 
Grade  3 AST/ALT/total bilirubin elevationasymptomatic 
 
Grade  2 AST/ALT/total bilirubin elevationwith constitutional symptoms 
 
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 
final dose of study drug or until initiation of another anti-cancer therapy, whichever 
occurs first.  After this period, the investigator is not required to actively monitor 
patients for new events, but should report any serious adverse events that are believed 
to be related to treatment with RO7198457 and/or pembrolizumab in this study 
(see Section 5.6).  Deaths should be reported as described in Section 5.3.5.8. 

 
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Ongoing adverse events thought to be related to study treatment will be followed until 
the event has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anti-cancer treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, or it has been determined that study treatment or participation is not 
the cause of the adverse event. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity unless otherwise specified.  Table 4 will be used for 
assessing severity for adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 9 
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 (v5.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 10): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 

 
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Table 10 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
5.3.5.1 
Systemic Infusion Reactions During or After Study Drug 
Infusion 
Adverse events that occur during or within 24 hours after completion of study drug 
administration and are judged to be related to study drug infusion(s) should be captured 
as a diagnosis (e.g., "flu-like symptoms," "infusion-related reaction," "cytokine release 
syndrome" or other adverse event term denoting the overall diagnosis) on the Adverse 
Event eCRF based on the most clinically-significant individual adverse event, its timing, 
and any required interventions.   
For example, mild to moderate presentation that may include fever, chills or other 
constitutional symptoms, may be best described as flu-like symptoms, whereas more 
severe events, such as hypotension, hypoxia or signs of organ toxicity, may be signs of 
CRS.  Events that occur during or shortly after the infusion may be referred to as 
"infusion-related reaction."  Clinical symptoms that include dyspnea, bronchospasm, 
chest tightness, urticaria, angioedema, hypotension and other cardiovascular symptoms, 
and (pre-)syncope may be indicative of hypersensitivity, allergic reaction or anaphylaxis. 

 
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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.  
 
 
 
 
 Section 5.2.3 for details on adverse events of 
special interest, and Section 5.3 for reporting requirements.  
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than systemic reactions during or after study drug infusion (see 
Section 5.3.5.1), a diagnosis (if known) should be recorded on the Adverse Event eCRF 
rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 

 
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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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes 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. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 

 
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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). 
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) 

 
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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 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), 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).  
This includes death attributed to progression of melanoma. 
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"). 
If the death is attributed to progression of malignancy, "malignant neoplasm progression" 
should be recorded on the Adverse Event eCRF.  The term "disease progression" 
should be avoided since it is not clearly linked to a patient's underlying malignancy. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 

 
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5.3.5.10 
Lack of Efficacy or Worsening of Incurable, Advanced 
Malignancy 
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 criteria.  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 
 
Hospitalization solely for coordination of care, including hospice arrangements 
 
Planned hospitalization required by the protocol (e.g., for study drug administration, 
protocol mandated observation window, insertion of access device for study drug 
administration, etc.) 
 
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 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error  
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 

 
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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For RO7198457, adverse events associated with special 
situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with RO7198457, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF.  Special 
situations should be recorded as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data  
Adverse event reports will not be derived from PRO data (e.g., EORTC QLQ-C30, 
PRO-CTCAE, and WPAI) by the Sponsor, and safety analyses will not be performed 
using PRO data.  Sites are not expected to review the PRO data for adverse events. 

 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
Once the electronic data capture (EDC) system is available, all information will need to 
be entered and submitted via the EDC system  
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.  
In the event the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 

 
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the form using the fax number or email address provided to investigators by emailing the 
form using the following email address:  SAEIntake@Fortrea.com  
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study drug or until initiation of 
subsequent systemic anti-cancer therapy, whichever occurs first.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the EDC 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur  90 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 90 days after the final dose of RO7198457 or 4 months after the final 
dose of pembrolizumab, whichever occurs later.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   

 
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5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
28 days after the final dose of study treatment.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study 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 with additional 
information on the pregnant partner and the course and outcome of the pregnancy as it 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects  
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).   

 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 90 days after the final 
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 exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 

 
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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: 
 
RO7198457 Investigator's Brochure  
 
Pembrolizumab Summary of Product Characteristics (SmPC) 
 
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 will include an initial safety run-in stage followed by a randomization stage.  
During the safety run-in stage, 612 patients with metastatic melanoma will be enrolled 
and treated with RO7198457 and pembrolizumab.  Following IMC review, enrollment will 
be opened for the randomization stage.  
The randomization stage will enroll approximately 120 patients that will represent the ITT 
population for the primary PFS and secondary activity endpoints.  Unless otherwise 
stated, summaries of study conduct, patient demographics, baseline characteristics, and 
secondary and exploratory endpoints will be assessed in all randomized patients and 
separately for patients in the safety run-in stage. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation and hypothesis generation regarding the safety 
and efficacy of RO7198457 plus pembrolizumab relative to pembrolizumab 
monotherapy. 
Enrollment of 120 randomized patients (approximately 80 patients in the RO7198457 
plus pembrolizumab arm and 40 patients in the standard-of-care arm) is expected to 
occur 18 months after first patient in (FPI).  
The null and alternative hypotheses with respect to PFS can be phrased in terms of the 
survival function 𝑆𝑃𝐹𝑆𝑎(𝑡) in Arm A (control) and  𝑆𝑃𝐹𝑆𝑏(𝑡) in Arm B (experimental):  
 
𝐻0: 𝑆𝑃𝐹𝑆𝑎(𝑡) = 𝑆𝑃𝐹𝑆𝑏(𝑡) vs. 𝐻𝑎:𝑆𝑃𝐹𝑆𝑎(𝑡) ≠𝑆𝑃𝐹𝑆𝑏(𝑡) 
 
 
 

 
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 in our PFS primary efficacy endpoint, the first efficacy endpoint tested in a 
hierarchical fashion.  However, the totality of data, including safety and sensitivity 
analyses while accounting for non-proportional hazards as stated in Section 6.4.1 will be 
important for evaluating clinical benefit. 
Point and interval estimates for the primary endpoint of PFS HR and key secondary 
endpoint of improvement in ORR (i.e.,  ORR) in the RO7198457 plus pembrolizumab 
arm relative to the pembrolizumab arm will be obtained. 
To control for Type 1 error, two pre-specified interim analyses and one primary analysis 
will be conducted with a Haybittle-Peto alpha spending approach (Haybittle 1971; 
Peto et al. 1976).  Testing will be performed in a hierarchical fashion testing PFS 
followed by secondary endpoints.  Each interim analysis will be conducted at the two-
sided significance level of 0.001.  The final analysis will be conducted at the two-sided 
significance level of 5%.  If PFS is significant at the two-sided significance level of 5%, 
alpha will be passed down to the secondary endpoints in order of presentation below. 
The study will not, however, have adequate power to detect other potentially clinically 
meaningful differences in PFS and  ORR. 
improvement in ORR in the RO7198457 plus pembrolizumab arm relative to the 
pembrolizumab arm (assuming a 33% ORR in the pembrolizumab arm).  Thus, a 
statistically negative outcome does not rule out a potentially clinically meaningful 
outcome.  
Table 11 and Table 12 show the power and CIs for several possible true underlying 
improvements in PFS and ORR in favor of the RO7198457 plus pembrolizumab arm.  
The study will not have adequate power to detect other potentially clinically meaningful 
differences in PFS or ORR.  See Table 11 below. 
Table 11 Power and Confidence Intervals for Study Design for Several 
Possible True Underlying PFS Hazard Ratio Values 
 
True Underlying PFS Hazard Ratio 
PFS  progression-free survival. 
Notes:  Results are based on 80 total events from 120 total patients in a 2:1 ratio 
a Two-sided   0.05 
 

 
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Table 12 Power and Confidence Intervals for Study Design for Several 
Possible True Underlying  ORR Values 
 
True Underlying  ORR 
ORR  objective response rate. 
Notes: Results are based on 120 total patients (80 and 40 patients in the treatment and control 
arm, respectively). 
a Two-sided   0.05 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study treatment discontinuation will also 
be tabulated.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be listed by treatment arm and evaluated for their 
potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics such as age, sex, race, weight, stage, and 
baseline ECOG Performance Status will be summarized by treatment arm for all 
randomized patients.  Descriptive summaries of continuous data will present the group 
mean, standard deviation, median, minimum, and maximum.  Descriptive summaries of 
discrete data will present the category counts as frequencies and percentages. 
6.4 
EFFICACY ANALYSES 
The primary analysis population includes all patients randomized ( i.e., the intent-to-treat 
[ITT] population).  Supportive per protocol analysis populations will include patients 
on-study at Cycle 2 receiving intended treatment (e.g., patients who received at least 
2 cycles of study treatment) as well as safety run-in stage patients.  The primary analysis 
will be PFS. 
6.4.1 
Primary Efficacy Endpoint of PFS 
PFS is defined as the time from randomization to the date of first documented disease 
progression or death, whichever occurs first.  Disease progression for PFS analysis will 
be determined on the basis of investigator assessment using RECIST v1.1.  The primary 
PFS analysis will occur after approximately 80 events have been observed in the 
primary population or approximately 24 months from FPI.  

 
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Data for a patient without disease progression or death as of the clinical data cutoff date 
will be censored at the time of the last tumor assessment (or at the date of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit).  
Data from a patient who is lost to follow-up will be included in the analysis and censored 
on the last date of tumor assessment that the patient was known to be progression free.  
Kaplan-Meier methodology will be used to estimate the PFS curve and median PFS for 
each treatment arm.  A stratified Cox proportional-hazards model will be used to 
estimate the HR and its 95% CI.  The two-sided stratified log-rank test will be used to 
compare PFS between the two treatment arms at the two-sided significance level of 5%.  
Unstratified modeling approaches may be used to assess the robustness of the PFS 
primary endpoint results.  To account for patients who may discontinue study treatment 
prior to first administration of RO7198457, a landmark analysis restricted to patients 
treated at Cycle 2 and beyond may be performed with PFS time calculated starting from 
Cycle 2, Day 1 on the ITT and modified subsets. 
6.4.2 
Secondary Efficacy Endpoints 
ORR Analysis 
ORR is defined as the proportion of patients who have experienced a CR or PR on two 
consecutive occasions  4 weeks apart, as determined by the investigator according to 
RECIST v1.1.  Objective response will be evaluated by treatment arm.  Patients without 
postbaseline overall response assessments will be counted as non-responders.  An 
estimate of the difference between the ORR in the two arms will be computed along with 
its 95% CI.  The Mantel-Haenszel test will be used to compare the ORR between the 
two treatment arms at the two-sided significance level of 5%, if PFS analysis is 
significant at the 5% threshold for type I error control, stratified by the protocol-defined 
stratification factors.  Final ORR analysis will occur at the time of primary PFS analysis. 
OS Analysis 
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are alive at the time of the analysis data cutoff will be censored at the last date they 
were known to be alive.  Data from patients without postbaseline information will be 
censored at the date of randomization plus 1 day.  A final OS analysis will be performed 
at approximately 40% event maturity at approximately 40 months.  Statistical analyses 
will be performed similarly to PFS as described in 6.4.1. 
Duration of Response Analysis 
DOR is defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause, whichever occurs first, as 
determined by the investigator according to RECIST v1.1.  The analysis of DOR will 
include only patients who achieved an objective response to study treatment.  DOR will 
be estimated using the Kaplan-Meier methodology. 

 
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Crossover Analysis 
The statistical analysis to evaluate the efficacy of patients who have progressed 
following pembrolizumab monotherapy and received the combination of RO7198457 
plus pembrolizumab as assessed by ORR per RECIST v1.1 will be performed as 
described in Section 6.4.2. 
Patient-Reported Outcomes Analysis 
Summary statistics and longitudinal analyses will inform change from baseline in 
GHS/HRQoL scores at each timepoint (including baseline, end of induction, crossover 
for Arm A, time to first PD per RECIST v1.1, end of treatment for any cause) by 
treatment arm during treatment will be analyzed for all randomized patients who had a 
baseline and one or more postbaseline assessments.  A score change of at least 
10 points is considered clinically meaningful and will be used to define deterioration and 
improvement.   
6.4.3 
Exploratory Efficacy Endpoints 
A 12-month PFS rate will be analyzed in the ITT.  The PFS rate will be estimated using 
Kaplan Meier methodology for each treatment arm, along with 95% CIs calculated using 
the standard error derived from the Greenwood formula.  The 95% CI for the difference 
in the PFS rate between the two treatment arms will be estimated using the normal 
approximation method. 
PFS, ORR, and DOR may be further evaluated using definitions of response per 
iRECIST criteria (see Appendix 5) in all randomized patients. 
Exploratory PRO endpoints may be evaluated to further characterize the patient 
experience when treated with RO7198457 plus pembrolizumab versus pembrolizumab 
alone.  PRO scales (EORTC scales, PRO-CTCAE scale, single-item bother, and WPAI) 
completion, compliance rates, and reasons for missing data will be summarized at each 
timepoint by treatment arm for each measure in the ITT population.  Summary statistics 
at each timepoint including proportion of patients with meaningful changes, time-to-event 
analyses, and longitudinal analyses as relevant will be generated to inform patients' 
experience in each treatment arm. 
6.5 
SAFETY ANALYSES 
Safety analyses will be conducted in all randomized patients who received at least one 
dose of RO7198457 and/or pembrolizumab.  Safety analyses will be performed by 
treatment arm and will be based on actual treatment received.  Specifically, a patient will 
be included in the RO7198457 plus pembrolizumab arm in the safety analyses if the 
patient receives any amount of RO7198457, regardless of the initial treatment 
assignment at randomization.  
Safety endpoints will include incidence and severity of adverse events (using 
NCI CTCAE v5.0), including serious adverse events and adverse events of special 

 
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interest, changes from baseline in clinically relevant vital signs, physical findings, 
and clinical laboratory results following the administration of RO7198457 plus 
pembrolizumab or solely pembrolizumab.  Drug exposure will be summarized, including 
duration, dosage, and dose intensity.  Verbatim description of adverse events will be 
mapped to the MedDRA thesaurus terms and graded according to the NCI CTCAE v5.0.  
All adverse events that occur during or after the first study treatment, until 90 days after 
the final dose of study drug or initiation of another systemic anti-cancer therapy, 
whichever occurs first, will be summarized by treatment arm and NCI CTCAE grade.  
In addition, serious adverse events and adverse events leading to study treatment 
discontinuation or interruption will be summarized accordingly.  Multiple occurrence of 
the same event will be counted once at the maximum severity.  Laboratory data with 
values outside of the normal ranges will be identified.  Additionally, selected laboratory 
data will be summarized by treatment arm and grade.  Vital signs will also be 
summarized by treatment arm and visit.  Deaths and causes of deaths will be 
summarized.  Analyses of safety endpoints will be conducted at the time of the primary 
efficacy analysis. 
6.6 
PHARMACOKINETIC ANALYSES  
The PK analysis population will consist of patients with any blood sample drawn 
according to Appendix 3 for the purpose of PK analysis.  Individual and mean plasma 
 concentrations (minimum serum concentration observed [Cmin] and 
maximum serum concentration observed [Cmax]) will be tabulated and summarized for 
each cycle for which pharmacokinetics are to be measured.  Data will be pooled with 
data from the Phase Ia/Ib study (GO39733) using an established population PK model to 
estimate total AUC, total CL, Vss, and terminal half-life (as appropriate for data collected).  
Estimates for these parameters will be tabulated and summarized (mean, standard 
deviation, coefficient of variation [%CV], median, range, geometric mean, and geometric 
mean CV [%CV]) by treatment arm, when appropriate and as data allow.  Inter-patient 
variability and drug accumulation will be evaluated. 
Serum pembrolizumab concentration data (Cmax and Cmin) will be tabulated and 
summarized for each cycle where collected.  Descriptive statistics will include geometric 
mean and geometric mean CV, as appropriate.  Pembrolizumab concentration data may 
be pooled with data from other studies using an established population PK model to 
estimate total AUC, as warranted by the data.  Data may be compared with historical 
data, as these results will provide preliminary information on whether 
 
pembrolizumab pharmacokinetics are altered by co-administration of the other agent.  
6.7 
BIOMARKER ANALYSES  
Exploratory biomarker analyses may be performed in order to inform the disease 
pathobiology and provide greater understanding of the mechanism of action with 
response.  In particular, we may perform prognostic, predictive, and PD biomarker 

 
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analyses from IHC or DNA/RNA-based assays, where applicable.  Cellular immune 
responses, cytokines, antibody responses, and further immunological parameters as 
represented in the schedules of activities (see Appendix 1 and Appendix 2) will be 
determined once or repeatedly in the course of the study.  In the latter case, changes 
from baseline will be tabulated.  
Exploratory analysis of WGS data may additionally be conducted 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.  WGS is not applicable for a site that has not been granted regulatory 
approval for WGS sampling. 
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Analyses 
Periodic analyses of cumulative safety data and two interim analyses of efficacy data are 
planned for this study.  Safety interim analyses will be conducted at regular intervals by 
the IMC (see Section 3.1.5). 
The first efficacy interim analysis will take place after either approximately 60 patients 
have had two scans or 25% PFS event maturity, both of which are expected to occur 
at approximately 16 months after FPI.  The second interim analysis will occur at 
approximately 50% event maturity, which is expected to be around 18 months. 
Outcomes from these reviews that may affect study conduct will be communicated in a 
timely manner to the investigators, and IRBs and/or ECs will be notified.  Any changes to 
the study design resulting from these analyses will be addressed through a protocol 
amendment. 
6.8.2 
Optional Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to one additional interim efficacy analyses beyond what is specified in 
Section 6.8.1.  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.   
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. 

 
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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff. 
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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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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 and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), 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. 
Genentech will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable 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 

 
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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC) or Clinical Trials Regulation (536/2014) and 
applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a 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 
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 

 
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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 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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 exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, data may be disseminated as 
described in Section 9.5. 
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 (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 

 
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9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and managed by Genentech and a contract 
research organization (CRO).  The CRO will provide clinical operations management 
support. 
For the safety run-in stage, approximately 8 sites in the United States and Australia will 
participate to enroll up to 12 patients.  Approximately 40 sites globally will participate to 
enroll approximately 120 patients in the randomized stage of the trial.  Enrollment will 
occur through an IWRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.  An independent radiologic review facility will be used to collect and 
retain copies of tumor assessment scans for potential centralized review. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes, and in peer-reviewed 
journals.  The Sponsor will comply with all requirements for publication of study results.  
Study data may be shared with others who are not participating in this study (see 
Section 8.4 for more details), and redacted Clinical Study Reports and/or other 
summaries of clinical study results may be available in health authority databases for 
public access, as required by local regulation, and will be made available upon request.  

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

 
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10. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576. 
Allie SR, Zhang W, Fuse S, et al. Programmed death 1 regulates development of central 
memory CD8 T cells after acute viral infection. J Immunol 2011;186:62806. 
American Cancer Society. Key statistics for melanoma skin cancer [resource on the 
Internet]. 2018 [cited 21 May 2018]. Available from: 
http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-
cancer-key-statistics. 
Amin MB, Edge SB, Greene FL, et al., editors. AJCC cancer staging manual. 8th rev ed. 
New York: Springer; 2017. 
Anagnostou V, Yarchoan M, Hansen AR, et a. Immuno-oncology trial endpoints: 
capturing clinically meaningful activity. Clin Cancer Res 2017;23:495969. 
Antonia SJ, Gettinger SN, Chow LQM, et al. Nivolumab (antiPD-1, BMS-936558, 
ONO-4538) and ipilimumab in first-line NSCLC: interim phase I results. 
J Clin Oncol 2014;32(15 Suppl):8023. 
Antonia SJ, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of 
durvalumab plus tremelimumab in non-small cell lung cancer:  a multicentre, 
phase Ib study. Lancet Oncol 2016;17:299308. 
Antonios JP, Soto H, Everson RG, et al. PD-1 blockade enhances the 
vaccination-induced immune response in glioma. JCI Insight 2016;1:e87059. 
Ascierto PA. Ipilimumab in the treatment of metastatic melanoma: a summary of recent 
studies. Tumori 2013;99:302e-5e. 
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma 
staging and classification. J Clin Oncol 2009;27:6199206. 
Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute's 
patient-reported outcomes version of the common terminology criteria for adverse 
events (PRO-CTCAE). J Natl Cancer Inst 2014;106:dju244. 
Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) 
plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma 
Study Group. J Clin Oncol 2006;24:473845. 
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse 
events in patients treated with immune checkpoint inhibitor therapy: American 
Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 
2018;36:171468. 
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of antiPD-L1 antibody in 
patients with advanced cancer. N Engl J Med 2012;366:245565. 

 
RO7198457—Genentech, Inc. 
137/Protocol GO40558, Version 5 
Brown SD, Warren RL, Gibb EA, et al. Neo-antigens predicted by tumor genome 
meta-analysis correlate with increased patient survival. Genome Res 
2014;24:74350. 
Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of 
the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. 
J Clin Oncol 1999;17:274551. 
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011;364:250716. 
Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response 
and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 
2017;28:136879. 
Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. 
Immunity 2010;33:492503. 
Coit DG, Thompson JA, Algazi A, et al. Melanoma, Version 2.2016, NCCN Clinical 
Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016;14:45073. 
Cornish D, Holterhues C, van de Poll-Franse LV, et al. A systematic review of 
health-related quality of life in cutaneous melanoma. Ann Oncol 
2009;20(Suppl 6):vi518. 
Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and 
response to the anti-programmed death 1 antibody pembrolizumab in melanoma. 
J Clin Oncol 2016;34:41029. 
Diem S, Kasenda B, Martin-Liberal J, et al. Prognostic score for patients with advanced 
melanoma treated with ipilimumab. Eur J Cancer 2015;51:278591. 
Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of antiCTLA-4 
antibodies across clinical indications. Semin Oncol 2010;37:499507. 
Di Leo A, Bleiberg H, Buyse M. Overall survival is not a realistic end point for clinical 
trials of new drugs in advanced solid tumors: a critical assessment based on 
recently reported phase III trials in colorectal and breast cancer. J Clin Oncol 
2003;21:20457. 
Dummer R, Hauschild A, Lindenblatt N, et al., on behalf of the ESMO Guidelines 
Committee. Cutaneous melanoma: ESMO clinical practice guidelines for 
diagnosis, treatment and follow-up. Ann Oncol 2015;26(Suppl 5):v12632. 
Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual blockade of PD-1 and CTLA-4 
combined with tumor vaccine effectively restores T-cell rejection function in 
tumors. Cancer Res 2013;73:3591603. 

 
RO7198457—Genentech, Inc. 
138/Protocol GO40558, Version 5 
European Medicines Agency. Oncology Working Party. Guideline on the evaluation of 
anticancer medicinal products in man [resource on the Internet]. 2012 [cited 
21 May 2018]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
3/01/WC500137128.pdf. 
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: European 
Organisation for Research and Treatment of Cancer, 2001. 
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality 
patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 
2013;49:1374403. 
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality 
of life (QoL) questionnaire module to supplement the EORTC core cancer QoL 
questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study 
Group on Quality of Life. Eur J Cancer 1999;35:93941. 
Flaherty KT, Robert C, Hersey P, et al. METRIC Study Group. Improved survival with 
MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:10714. 
Fu J, Malm IJ, Kadayakkara DK, et al. Preclinical evidence that PD1 blockade 
cooperates with cancer vaccine TEGVAX to elict regression of established tumors. 
Cancer Res 2014;74:404252. 
Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009;27:39. 
Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical 
results of adjuvant nivolumab in combination with vaccine in resected high-risk 
metastatic melanoma. Clin Cancer Res 2015;21:71220. 
Ha SJ, Mueller SN, Wherry EJ, et al. Enhancing therapeutic vaccination by blocking 
PD-1-mediated inhibitory signals during chronic infection. J Exp Med 
2008;205:54355. 
Hamid O, Robert C, Daud A, et al. 5-year survival outcomes in patients (pts) with 
advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001. J 
Clin Oncol 2018;36(Suppl):9516. 
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(antiPD-1) in melanoma. N Engl J Med 2013;369:13444. 
Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination 
with ipilimumab in metastatic renal cell carcinoma (mRCC). Ann Oncol 
2014;25(Suppl 4):iv3612.  
Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from 
immunotherapy: ESMO clinical practice guidelines for diagnosis treatment and 
follow-up. Ann Oncol 2017;28:iv119iv142. 

 
RO7198457—Genentech, Inc. 
139/Protocol GO40558, Version 5 
Hartmaier RJ, Charo J, Fabrizio D, et al. Genomic analysis of 63,220 tumors reveals 
insights into tumor uniqueness and targeted cancer immunotherapy strategies. 
Genome Med 2017;9:16. 
Hauschild A, Garbe C. Immunotherapy: combined immunotherapya new standard in 
metastatic melanoma? Nat Rev Clin Oncol 2015;12:43940. 
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 
2012;380:35865. 
Hauschild A, Schadendorf D. Checkpoint inhibitors: a new standard of care for advanced 
Merkel cell carcinoma? Lancet Oncol 2016;17:13379. 
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol1971;44:7937. 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the 
antiPD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:5637. 
Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and 
RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. 
J Clin Oncol 2016;34:15107. 
Hodi FS, Lawrence D, Hamid O, et al. Clinical activity of the PD-L1 inhibitor MPDL3280A 
in patients with metastatic melanoma: updated phase 1 data. Pigment Cell 
Melanoma Res 2014;27:11989. 
Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst 2010;102:138897. 
Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new 
paradigm for cancer immunotherapy. Semin Oncol 2010;37:53346. 
Ives NJ, Stowe RL, Lorigan P, et al. Chemotherapy compared with biochemotherapy for 
the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 
2,621 patients. J Clin Oncol 2007;25:542634. 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-
resistant prostate cancer. N Engl J Med 2010;363:41122. 
Kelderman S, Heemskerk B, van Tinteren H, et al. Lactate dehydrogenase as a 
selection criterion for ipilimumab treatment in metastatic melanoma. Cancer 
Immunol Immunother 2014;63:44958. 
Keytruda® (pembrolizumab) Summary of Product Characteristics, Merck Sharp & Dohme 
Limited. 
Keytruda (pembrolizumab) U.S. Package Insert, Merck & Co., Inc. 

 
RO7198457—Genentech, Inc. 
140/Protocol GO40558, Version 5 
Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in 
high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin 
Oncol 2000;18:244458. 
Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery to dendritic cells exploits 
antiviral defence for cancer immunotherapy. Nature 2016;534:396401. 
Kreiter S, Selmi A, Diken M, et al. Increased antigen presentation efficiency by coupling 
antigens to MHC class I trafficking signals. J Immunol 2008;180:30918. 
Kreiter S, Selmi A, Diken M, et al. Intranodal vaccination with naked antigen-encoding 
RNA elicts potent prophylactic and therapeutic antitumoral immunity. Cancer Res 
2010;70:903140. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med 2015;373:2334. 
Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic 
pancreatic tumor cells transfected with a GM-CSF gene in previously treated 
pancreatic cancer. J Immunother 2013;36:3829. 
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Engl J Med 2015; 372:250920. 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and 
management of cytokine release syndromes. Blood 2014;124:18895. 
Li B, VanRoey M, Wang C, et al. Anti-programmed death-1 synergizes with granulocyte 
macrophage colony-stimulating factor—secreting tumor cell immunotherapy 
providing therapeutic benefit to mice with established tumors. Clin Cancer Res 
2009;15:162334. 
Linnemann C, van Buuren MM, Bies L, et al. High-throughput epitope discovery reveals 
frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat 
Med 2015;21:815. 
Long GV, Atkinson V, Ascierto PC, et al. Effect of nivolumab on health-related quality of 
life in patients with treatment-naive advanced melanoma: results from the phase III 
CheckMate 066 study. Ann Oncol 2016:27:19406. 
Long GV, Schachter J, Ribas A, et al. 4-year survival and outcomes after cessation of 
pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive 
advanced melanoma in KEYNOTE-006. J Clin Oncol 2018;36(Suppl):abstr 9503. 
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus 
BRAF inhibition alone in melanoma. N Engl J Med 2014;371:187788. 
Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib 
and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, 
phase 3 randomised controlled trial. Lancet. 2015;386:44451. 

 
RO7198457—Genentech, Inc. 
141/Protocol GO40558, Version 5 
Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients 
with advanced melanoma who received ipilimumab plus dacarbazine in a phase III 
trial. J Clin Oncol 2015;33:11916. 
McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in 
BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended 
follow-up of a phase 3, randomised, open-label study. Lancet Oncol 
2014;15:32332. 
Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide 
versus dacarbazine in the treatment of patients with advanced metastatic 
malignant melanoma. J Clin Oncol 2000;18:15866. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced 
renal-cell carcinoma. N Engl J Med 2015;373:180313. 
[NCCN] National Comprehensive Cancer Network. NCCN clinical practice guidelines 
in oncology. Melanoma, Version 3 [resource on the Internet]. 2016 [cited 
21 May 2018]. Available from: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944. 
Pennock GK, Waterfield W, Wolchok JD. Patient responses to ipilimumab, a novel 
immunopotentiator for metastatic melanoma: how different are these from 
conventional treatment responses? Am J Clin Oncol 2012;35:60611. 
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials 
requiring prolonged observation of each patient. I. Introduction and design. Br J 
Cancer 1976;34:585612. 
Ramalingam SS, Hellmann MD, Awad MM, et al. Abstract CT078: Tumor mutational 
burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint 
blockade with nivolumab (nivo)+ ipilimumab (ipi) in first-line (1L) non-small cell 
lung cancer (NSCLC): identification of TMB cutoff from CheckMate 
568.  Proceedings of the 109th Annual Meeting of the American Association for 
Cancer Research; 1418 April 2018 [cited date]; Chicago, Illinois. Abstract CT078. 
Available from: www.abstractsonline.com/pp8/#!/4562/presentation/11131. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics 1993;4:35365. 
Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response 
and survival among patients with advanced melanoma. JAMA 2016;315:16009. 
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, 
multicentre randomised controlled trial. Lancet. 2017;389:25565. 

 
RO7198457—Genentech, Inc. 
142/Protocol GO40558, Version 5 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
2015;348:1248. 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without 
BRAF mutation. N Engl J Med 2015a;372:32030. 
Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced 
melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol 
2016;34(15 Suppl):9503. 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med 2015b;372:252132. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 2011;364:251726. 
Rooney MS, Shukla SA, Wu CJ, et al. Molecular and genetic properties of tumors 
associated with local immune cytolytic activity. Cell 2015;160:4861. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920. 
Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-
based immunotherapy against epithelial tumors. Science 2018;359:917. 
Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines 
mobilize poly-specific therapeutic immunity against cancer. Nature 2017;547:222. 
Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced 
melanoma: final overall survival results of a multicentre, randomised, open-label 
phase 3 study (KEYNOTE-006). Lancet 2017;390:185362. 
Schadendorf D, Amonkar MM, Stroyakovskiy D, et al. Health-related quality of life impact 
in a randomised phase III study of the combination of dabrafenib and trametinib 
versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. 
Eur J Cancer 2015;51:83340. 
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. N Engl J Med 2014;371:218999. 
Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together with vaccine therapy 
facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 
2015;38:111. 
Solhpour A, Jafari A, Hashemi M, et al. A comparison of prophylactic use of meperidine, 
meperidine plus dexamethasone, and ketamine plus midazolam for preventing of 
shivering during spinal anesthesia: a randomized, double-blind, placebo-controlled 
study. J Clin Anesth 2016;34:12835. 

 
RO7198457—Genentech, Inc. 
143/Protocol GO40558, Version 5 
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol 
1996;14:275668. 
Tran E, Robbins PF, Lu YC, et al. T-cell transfer therapy targeting mutant KRAS in 
cancer. N Engl J Med 2016;375:225562. 
Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 
blockade in metastatic melanoma. Science 2015;350:20711. 
van Rooji N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals 
neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. 
J Clin Oncol 2013;31:e43942. 
Verdegaal EM, de Miranda NF, Visser M, et al. Neoantigen landscape dynamics during 
human melanoma-T cell interactions. Nature 2016;536:915. 
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after antiCTLA-4 treatment (CheckMate 
037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015a;16: 
37584. 
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and 
kinetics of response with ipilimumab. J Clin Oncol 2012;30:26917. 
Weber JS, Postow M, Lao CD, et al. Management of adverse events following treatment 
with anti-programmed death-1 agents. Oncologist 2016;21:123040. 
Weber JS, Yang JC, Atkins MB, et al. Toxicities of immunotherapy for the practitioner. J 
Clin Oncol 2015b;33:20929. 
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined 
nivolumab and ipilimumab in advanced melanoma. N Engl J Med 
2017;377:134556. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:741220. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:12233. 

 
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Appendix 1  
Schedule of Activities:  Arm A (Pembrolizumab) 
Arm AScreening Parts A and B and Cycles 112 
Screening Period  a 
Treatment Period (Initial) 
Part A 
Part B 
Cycle 1 
Cycle 2 
Cycles 
3, 5, 7 
Cycles 
4, 6 
Cycles 
9, 11 
Cycles 
8,10, 12 
UV b 
Day (Window) 
 
 
1 (2) 
1 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
Signed informed 
consent c 
x 
x 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria d 
x 
x 
 
 
 
 
 
 
 
 
Medical, surgical, 
cancer histories, 
demographic data e 
 
x 
 
 
 
 
 
 
 
 
Tumor assessments f, g 
 
x 
 
x h 
 
Digital photography, 
cutaneous lesions j 
 
x 
 
x 
 
Concomitant 
medications k 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
Adverse events l 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
Vital signs m 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance 
Status n 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
Weight 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
Height 
 
x 
 
 
 
 
 
 
 
 
Complete physical 
examination o 
 
x 
 
 
 
 
 
 
 
 
Limited physical 
examination o 
 
 
 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG p 
 
x 
 
 
 
 
 
 
 
 
Hematology q 
 
 
x 
x 
x 
x 
x 
x 
x 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
Screening Parts A and B and Cycles 112 
 
RO7198457—Genentech, Inc. 
145/Protocol GO40558, Version 5 
Screening Period  a 
Treatment Period (Initial) 
Part A 
Part B 
Cycle 1 
Cycle 2 
Cycles 
3, 5, 7 
Cycles 
4, 6 
Cycles 
9, 11 
Cycles 
8,10, 12 
UV b 
Day (Window) 
 
 
1 (2) 
1 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
Serum/plasma 
chemistry r 
x r 
 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation (PT, aPTT, 
INR) 
 
 
x 
 
 
 
 
 
 
 
Amylase, lipase 
 
 
x 
 
x 
 
x 
 
x 
 
Urinalysis s 
 
 
x 
 
x 
 
x  
(C6 only) 
 
x  
(C10 only) 
 
Pregnancy test t 
 
 
x 
 
x 
 
x 
 
x 
 
Serum ferritin and 
CRP u 
 
 
x 
 
x 
x 
 
x 
 
 
TSH, free T3, and free 
T4 v 
 
 
x 
 
 
 
x 
(C4 only) 
 
x 
(C8 and C12 
only) 
 
Autoantibody tests w 
 
 
x 
 
 
 
 
 
 
 
HBV, HCV, HIV, TB 
serology tests x 
x 
 
 
 
 
 
 
 
 
 
Cancer-related 
procedures y 
 
 
 
x 
x 
x 
x 
x 
x 
 
EORTC scales z 
 
 
 
x 
x 
x 
x 
x 
x 
 
PRO-CTCAE scales 
and single-item bother z 
 
 
 
x 
x 
x 
x 
x 
x 
 
WPAI aa 
 
 
 
x 
 
 
x 
(C4 only) 
 
 
 
Pembrolizumab 
infusion bb 
 
 
 
x 
x 
x 
x 
x 
x 
 
Serum 
(pembrolizumab) PK 
sample 
See Appendix 3 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
Screening Parts A and B and Cycles 112 
 
RO7198457—Genentech, Inc. 
146/Protocol GO40558, Version 5 
Screening Period  a 
Treatment Period (Initial) 
Part A 
Part B 
Cycle 1 
Cycle 2 
Cycles 
3, 5, 7 
Cycles 
4, 6 
Cycles 
9, 11 
Cycles 
8,10, 12 
UV b 
Day (Window) 
 
 
1 (2) 
1 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
Plasma sample for 
biomarkers 
See Appendix 3 
 
Blood sample for WGS 
(optional) ee 
 
 
 
x 
 
 
 
 
 
 
Stool sample for RBR 
(optional) ff 
 
 
x 
 
 
 
x 
(C4 only) 
x 
(C9 only) 
 
 
Baseline tumor tissue gg 
x 
 
 
 
 
 
 
 
 
 
On-treatment tumor 
biopsies hh 
x 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
Cycles 1334, Treatment Discontinuation, and Follow-Up 
 
RO7198457—Genentech, Inc. 
147/Protocol GO40558, Version 5 
Cycles 1334, Treatment Discontinuation, and Follow-Up 
Treatment Period (Maintenance) ii 
TX DC jj 
FU 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
13, 21, 29 
14, 20, 22, 
28, 30 
15, 23, 31 
16, 24, 32 
17, 25, 33 
18, 26, 34 
19, 27 
Days (Window) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
Tumor assessments f, g 
x h 
 
x i 
Digital photography, 
cutaneous lesions  j 
x 
 
x 
Concomitant 
medications k 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events l 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital signs m 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance 
Status n 
x 
x 
x 
x 
x 
x 
x 
x 
 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
 
Limited physical 
examination o 
x 
x 
x 
x 
x 
x 
x 
x 
 
12-lead ECG p 
 
 
 
 
 
 
 
x 
 
Hematology q 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum/plasma chemistry r 
x 
x 
x 
x 
x 
x 
x 
x 
 
Amylase, lipase 
 
x 
 
x 
 
x 
 
x 
 
Urinalysis s 
 
x 
(C14, C22, 
C30 only) 
 
 
 
x 
 
x 
 
Pregnancy test t  
 
x 
 
x 
 
x 
 
x 
 
Serum ferritin and CRP u 
x 
 
 
 
x 
 
 
x 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
Cycles 1334, Treatment Discontinuation, and Follow-Up 
 
RO7198457—Genentech, Inc. 
148/Protocol GO40558, Version 5 
Treatment Period (Maintenance) ii 
TX DC jj 
FU 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
Cycles 
13, 21, 29 
14, 20, 22, 
28, 30 
15, 23, 31 
16, 24, 32 
17, 25, 33 
18, 26, 34 
19, 27 
Days (Window) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
TSH, free T3, and free 
T4 v 
 
x  
C20, C28 
only 
 
x 
 
 
 
x 
 
Cancer-related 
procedures y 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EORTC scales z 
x 
x 
x 
x 
x 
x 
x 
x 
 
PRO-CTCAE scales and 
single-item bother z 
x 
x 
x 
x 
x 
x 
x 
x 
 
WPAI aa 
x 
C13 only 
 
 
 
 
 
 
x 
 
Survival, anticancer 
therapy, and -follow-up kk 
 
 
 
 
 
 
 
 
x 
Pembrolizumab 
infusion bb 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum (pembrolizumab) 
PK sample 
See Appendix 3 
Blood sample for 
biomarkers 
See Appendix 3 
Blood sample (PBMC-I) 
for biomarkers cc 
 
 
 
 
 
 
 
x 
 
On-treatment tumor 
biopsies hh 
x 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
 
RO7198457—Genentech, Inc. 
149/Protocol GO40558, Version 5 
C  cycle; CCP  cyclic citrullinated peptide; CIT  cancer immunotherapy; CRP  C-reactive protein; CT  computed tomography; D  day;
; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic Case Report Form; 
EORTC QLQ-C30 and IL12  European Organisation for Research and Treatment of Cancer, Quality of Life QuestionnaireCore 30 and IL12; 
FU  Follow-Up; HBc  hepatitis B core antigen; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus;  
HLA  human leukocyte antigen; iRECIST   immune-based therapeutics Response Evaluation Criteria in Solid Tumors; LDH  lactate dehydrogenase; 
MRI  magnetic resonance imaging; PBMC  peripheral blood mononuclear cell; PCR  polymerase chain reaction; PET  positron emission tomography; 
PRO  patient-reported outcome; PRO-CTCAE  Patient-Reported Outcomes Common Terminology Criteria for Adverse Events; RBR  Research 
Biosample Repository; RECIST  Response Evaluation Criteria in Solid Tumors; RF  rheumatoid factor; TB   Mycobacterium tuberculosis; 
T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone; TX DC  Treatment Discontinuation; UV  unscheduled visit; WGS  whole 
genome sequencing; WPAI  Work Productivity and Activity Impairment. 
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. 
a During screening period Part A and after informed consent has been obtained, patients will provide tumor tissue and blood samples to allow time for 
vaccine manufacturing.  Patients whose samples are of sufficient quality and quantity for vaccine manufacturing will sign the main consent 
(Participation in Study GO40558 ICF) and start the remaining procedures outlined for the screening Part B section.  Time window for screening 
equals the number of days to Cycle 1, Day 1 (see Section 3.1). 
b  Unscheduled visits may include the assessments indicated.  Additional assessments and/or procedures may be requested or performed as needed. 
c Written informed consent is required before performing any study-specific tests or procedures (including screening evaluations) and may be 
obtained at any time prior to such tests or procedures.  
d A limited review of the eligibility checklist (e.g., ECOG Performance Status, blood chemistry, serology for HIV, HBV, and HCV) may be performed 
during the first part of screening (Part A).  The rest of the eligibility checklist will be reviewed during the second part of screening (Part B). 
e Medical history includes cancer history (including, but not limited to, prior cancer therapies and/or prior CITs and procedures and tumor 
characteristics such as hormone receptor status or mutation status), other clinically significant diseases, surgeries, smoking history, use of alcohol 
and/or drugs of abuse, reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
and nutritional supplements) used by the patient within 7 days prior to the screening visit.  Demographic information includes sex, age, and 
self-reported race/ethnicity. 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
 
RO7198457—Genentech, Inc. 
150/Protocol GO40558, Version 5 
f All sites of disease should be assessed and documented.  If available, a scan prior to the baseline (up to 3 months) may also be obtained to 
evaluate changes in tumor growth rate.  Baseline CT assessments should be performed within 28 days prior to the start of study treatment (Cycle 1, 
Day 1).  Screening and subsequent tumor assessments should include CT scans (with IV contrast unless contraindicated and oral contrast per 
institutional standards) of the chest, abdomen, and pelvis.  Patients who have a contraindication to IV contrast may have MRI scans of the abdomen 
and pelvis performed in lieu of CTs and a non-contrast CT of the chest.  A CT or MRI scan (with IV contrast unless contraindicated) 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 CT scan (see Section 4.5.5).  Bone scans and CT scan of neck or extremities should also be performed if 
clinically indicated.  If a CT scan for tumor assessment is performed in a PET-CT scanner, the CT acquisition must be consistent with standards of a 
full-contrast CT scan.  The same radiographic procedure used to define measurable lesions at baseline should be used throughout the study for 
each patient.   
g Patients who continue treatment beyond radiographic disease progression (see Section 3.1.3) will be monitored with a follow-up scan in 
6 ( 1) weeks (i.e., at the next scheduled tumor assessment when the scan frequency is every 6 weeks or as an unscheduled tumor assessment 
when the scan frequency is every 12 (±1) weeks) or earlier if clinically indicated.  Tumor assessments should be continued until two consecutive 
scans demonstrate stability or improvement with respect to the first scan that showed radiographic disease progression, at which point the scan 
frequency should revert or transition to at least every 12 weeks), if applicable.  For patients who consented to treatment beyond progression, new 
lesions will also be assessed according to iRECIST (see Section 3.1.3) and applicable measurements entered into eCRF.  While the Sponsor will 
derive overall tumor assessment as per iRECIST, investigator assessment of overall tumor response at all timepoints should be only based on 
RECIST v1.1 (see Section 3.1.3). 
h The timing of tumor assessments will be based on weeks from first study treatment (C1D1; pembrolizumab monotherapy) and will not be tied to 
Cycle-specific visits.  Tumor assessments will occur during Week 12 (based from C1D1) and every 6 weeks thereafter until Week 48 (i.e., during 
Weeks 12, 18, 24, 30, 36, 42, and 48).  "During week" is defined as the first day/Day 1 of each targeted week (e.g., 12, 18, or 24 weeks from 
C1D1 date) plus 6 calendar days.  After Week 48, tumor assessments will occur every 12 ( 1) weeks through Week 96 (i.e., during Weeks 60, 72, 
84, and 96).  After Week 96, follow-up tumor assessments will occur approximately every 12 weeks through Week 156 (i.e., Weeks 108, 120, 132, 
144, and 156).  After Week 156, follow-up tumor assessments will occur approximately every 24 weeks (i.e., Weeks 180, 204, 228, and 252). 
i Patients who discontinue study treatment for reasons other than disease progression (e.g., toxicity) should continue to undergo scheduled tumor 
assessments approximately every 12 weeks until Week 156, then approximately every 24 weeks until disease progression, death, initiation of 
another systemic anticancer therapy, loss to follow-up, withdrawal of consent, or study termination, whichever occurs first.   
j Photographs of cutaneous lesions will be taken at screening and on the same day a tumor assessment is obtained or at the first clinic visit after 
each tumor assessment if timing is preferable to the patient and clinical site study team.  See Section 4.5.6 for more details. 
 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
 
RO7198457—Genentech, Inc. 
151/Protocol GO40558, Version 5 
k Concomitant medications any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment (including prophylactic treatment after RO7198457 administration and 
medications as a result of an adverse event) from 7 days prior to screening to the study completion/discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications eCRF. 
l After informed consent has been obtained but prior to initiation of study treatment, report only serious adverse events caused by a protocol-
mandated intervention.  After initiation of study treatment, report all adverse events until 90 days after the final dose of study treatment or until 
initiation of another systemic anti-cancer therapy, whichever occurs first.  Patients will be contacted at approximately 60 and 90 days after the final 
dose of study treatment to determine whether any new adverse events have occurred or if the patient has initiated another systemic anti-cancer 
therapy.  After this period, the investigator is not required to actively monitor patients for adverse events but should report any serious adverse 
events that are believed to be related to prior study treatment.  Deaths should be reported as described in Section 5.3.5.8.  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 treatment or trial-related procedures until a final outcome can be reported 
m Vital signs include measurements of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a 
seated position.  See Section 4.5.4 for more details. 
n ECOG Performance Status, weight, limited physical examination, and local hematology and serum/plasma chemistry panels may be obtained 
 96 hours before each scheduled treatment and the treatment discontinuation visit, as applicable.   
o Complete and limited physical examinations are defined in Section 4.5.3. 
p Digitized, single ECGs will be performed as part of the screening assessment and at the treatment discontinuation visit.  If sustained QTc 
prolongation ( 500 ms and/or 60 ms longer than baseline value; at two consecutive readings) is noted, repeat ECG, and notify the Medical Monitor 
(see Section 4.5.8).  Single ECG recordings may be obtained at unscheduled timepoints as clinically indicated. 
q Hematology consists of CBC including RBC count, hemoglobin, hematocrit, platelet count, and WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells).  A manual differential can be done if clinically indicated.  During screening, hematology results 
must be obtained within 14 days prior to Cycle 1, Day 1 (see Section 4.1.1). 
r Serum/plasma chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, 
BUN or urea, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, ALP, LDH, total protein, and albumin.  During first part 
of screening (Part A), results of standard–of–care tests or examinations performed prior to obtaining informed consent may be used for assessments 
rather than repeating such tests.  During second part of screening (Part B), serum/plasma chemistry results must be obtained within 14 days prior to 
Cycle 1, Day 1 (see Section 4.1.1). 
s Urinalysis/urine dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria) if warranted by dipstick results. 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
 
RO7198457—Genentech, Inc. 
152/Protocol GO40558, Version 5 
t Serum pregnancy test (for women of childbearing potential, as defined in Section 4.1.1) must be performed and documented as negative within 
14 days prior to Day 1.  Urine or serum pregnancy tests (for women of childbearing potential only) will be performed at the specified subsequent 
visits.  If a urine pregnancy test is positive, dosing will be delayed until the patient's status is determined by a serum pregnancy test. 
u Investigators may collect CRP and ferritin ad-hoc for work-up of inflammatory or immune mediated adverse events.  
v TSH, free T3, and free T4 will be assessed during screening (Part B), on Day 1 of Cycle 4 and every 4 cycles thereafter (i.e., Day 1 of Cycles 8, 12, 
16, and so on). 
w Serum samples will be obtained for autoantibody testing including, but not necessarily limited to, anti-nuclear antibody, antidouble-stranded DNA, 
anti-neutrophil cytoplasmic antibodies, and thyroid peroxidase antibody, to be performed based on clinical events during the study, either in 
individual patients or across the study population.  If inflammatory arthritis develops, CCP and RF antibody titers will also be evaluated.  Additional 
serum collection for autoantibody testing should be performed as clinically indicated. 
x All patients will be tested for HIV locally during screening (Part A); HIV-positive patients will be excluded from the study.  Perform HBsAg, anti-HBc, 
and anti-HBs at local laboratory during screening (Part A).  In patients who have positive serology for the anti-HBc antibody, HBV DNA should also 
be collected.  Patients who are positive for HBc antibody are eligible only if negative for HBV DNA.  Patients who are positive for HCV antibody are 
eligible only if PCR is negative for HCV RNA.  Patients will also be tested for TB only if investigator considers patient to be at an increased risk for 
infection; latent TB diagnostic procedures must be followed according to local practice standards. 
y Collection of cancer-related medical, surgical, and radiation procedures will begin on Day 1 of Cycle 1 and continue through the end of the treatment 
period and during the follow-up period. 
z All PRO questionnaires (EORTC scales and PRO-CTCAE scales) are required to be completed prior to the administration of study treatment and/or 
prior to any other study assessment(s) that could bias patients' responses.  The EORTC scales and PRO-CTCAE scales should be completed on 
Day 1 of each cycle and at the treatment discontinuation visit.  In the event that other assessments associated with Day 1 are done in advance of 
study treatment within protocol-specified time windows (e.g., per footnote n), then PRO questionnaires can also be done at that earlier timepoint.  
PRO-CTCAE scales and single-item bother will be completed when available in the local language of the investigational site. 
aa The WPAI questionnaire is required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) that 
could bias patients' responses.  The WPAI should be completed Day 1 of Cycles 1, 4, 13, and at the treatment discontinuation visit.  In the event 
that other assessments associated with Day 1 are done in advance of study treatment within protocol -specified time windows (e.g., per 
footnote n), then the WPAI questionnaire can also be done at that earlier timepoint.   
bb All infusions of pembrolizumab should be followed by a 30-minute observation period.  See the pharmacy manual for more details. 
 
 
 

Appendix 1: Schedule of Activities:  Arm A (Pembrolizumab) (cont.) 
 
RO7198457—Genentech, Inc. 
154/Protocol GO40558, Version 5 
jj Patients will be asked to return to the clinic within 30 days after the last dose of study treatment for a discontinuation visit.  Tumor assessment scans 
performed within 6 weeks prior to the treatment discontinuation visit do not need to be repeated.  The visit at which a response assessment shows 
progressive disease resulting in treatment discontinuation may be used as the treatment discontinuation visit, in which case all assessments 
associated with the treatment discontinuation visit should be performed at that time. 
kk After study treatment completion or discontinuation, information on survival status, new anti-cancer therapy (including targeted therapy and 
immunotherapy), and cancer-related procedures will be collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from 
follow-up, this request must be documented in the source documents and signed by the investigator.  If the patient withdraws from study, study staff 
may use a public information source (e.g., county records) to obtain information about survival status only. 
 

 
RO7198457—Genentech, Inc. 
155/Protocol GO40558, Version 5 
Appendix 2  
Schedule of Activities:  Safety Run-In, Arm B, and Crossover (RO7198457 Plus Pembrolizumab) 
Safety Run-in, Arm B, and Crossover aScreening Parts A and B and Cycles 112 
Screening b 
Treatment Period (Initial) 
Part 
A 
Part B 
Cycle 1 
Cycle 2 
Cycle 3  c 
Cycles 
4, 6 
Cycles 
5,7 
Cycles 
8, 10, 12 
Cycles 
9, 11 
UV 
d 
Day (Window) 
28 
14 
1 (±2) 
1 (2) 
8 (2) e 
15 (2) e 
1 (2) 
8 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
Signed informed 
consent f  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria g  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, 
cancer histories, 
demographic data h 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments i, j 
 
x 
 
x k 
 
Digital photography, 
cutaneous lesions m 
 
x 
 
x 
 
Concomitant 
medications n  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events o  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs p 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance 
Status q 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination r  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical 
examination r  
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG s  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology t  
 
 
x 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (RO7198457 Plus Pembrolizumab) (cont.) 
Screening Parts A and B and Cycles 112 
 
RO7198457—Genentech, Inc. 
156/Protocol GO40558, Version 5 
Screening b 
Treatment Period (Initial) 
Part 
A 
Part B 
Cycle 1 
Cycle 2 
Cycle 3  c 
Cycles 
4, 6 
Cycles 
5,7 
Cycles 
8, 10, 12 
Cycles 
9, 11 
UV 
d 
Day (Window) 
28 
14 
1 (±2) 
1 (2) 
8 (2) e 
15 (2) e 
1 (2) 
8 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
Serum/plasma 
chemistry u 
x u 
 
x 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 
Coagulation (PT, aPTT, 
INR) 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Amylase, lipase 
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
 
Urinalysis v  
 
 
x 
 
x 
 
 
 
 
x   
(C6 
only) 
 
x  
(C10 
only) 
 
 
Pregnancy test w  
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
 
Serum ferritin and 
CRP x  
 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
TSH, free T3, and free 
T4 y 
 
 
x 
 
 
 
 
 
 
x  
(C4 
only) 
 
x  
(C8, C12 
only) 
 
 
Autoantibody tests z  
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV, TB 
serology tests aa 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer-related 
procedures bb 
 
 
 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 
EORTC scales cc 
 
 
 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 
PRO-CTCAE scales 
and single-item 
bother cc 
 
 
 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (RO7198457 Plus Pembrolizumab) (cont.) 
Screening Parts A and B and Cycles 112 
 
RO7198457—Genentech, Inc. 
157/Protocol GO40558, Version 5 
Screening b 
Treatment Period (Initial) 
Part 
A 
Part B 
Cycle 1 
Cycle 2 
Cycle 3  c 
Cycles 
4, 6 
Cycles 
5,7 
Cycles 
8, 10, 12 
Cycles 
9, 11 
UV 
d 
Day (Window) 
28 
14 
1 (±2) 
1 (2) 
8 (2) e 
15 (2) e 
1 (2) 
8 (2) 
1 (2) 
1 (2) 
1 (3) 
1 (3) 
WPAI dd 
 
 
 
x 
 
 
 
 
 
x  
(C4 
only) 
 
 
 
 
Pembrolizumab 
infusion ee 
 
 
 
x 
x 
 
 
x 
 
x 
x 
x 
x 
 
See Appendix 3 
 
See Appendix 3 
 
Serum 
(pembrolizumab) PK 
sample  
See Appendix 3 
 
Plasma sample for 
biomarkers  
See Appendix 3 
 
Blood sample 
WGS (optional)  jj  
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Stool sample for RBR 
(optional) kk 
 
 
x 
 
 
 
 
 
 
x   
 (C4 only) 
 
 
x 
(C9 only) 
 
Baseline tumor tissue ll  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-treatment tumor 
biopsies mm 
 
 
x 
 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.)  
Cycles 1334, Treatment Discontinuation, and Follow-Up 
 
RO7198457—Genentech, Inc. 
158/Protocol GO40558, Version 5 
Cycles 13-34, Treatment Discontinuation, and Follow-Up 
  
Treatment Period (Maintenance) nn 
TX 
DC oo 
FU 
Cycles 13, 
21, 29 
Cycles 14, 
20, 22, 28, 
30 
Cycles 15, 
23, 31 
Cycles 16, 
24, 32 
Cycles 17, 
25, 33 
Cycles 18, 
26, 34 
Cycles 19, 
27 
Days (Window) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
 
Tumor assessments i, j   
x k 
 
xl 
Digital photography, 
cutaneous lesions m 
x 
 
x 
Concomitant medications n 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events o 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital signs p 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance 
Status q 
x 
x 
x 
x 
x 
x 
x 
x 
 
Weight  
x 
x 
x 
x 
x 
x 
x 
x 
 
Limited physical 
examination r  
x 
x 
x 
x 
x 
x 
x 
x 
 
12-lead ECG s  
 
 
 
  
 
 
 
x 
 
Hematology t  
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum/plasma chemistry u  
x 
x 
x 
x 
x 
x 
x 
x 
 
Amylase, lipase  
 
x 
 
x 
 
x 
 
x 
 
Urinalysis v  
 
x  
(C14, C22, 
C30 only) 
 
 
 
x 
 
x 
 
Pregnancy test w  
 
x 
 
x 
 
x 
 
x 
 
Serum ferritin and CRPx  
x 
 
 
 
x 
 
 
x 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.) 
Cycles 1334, Treatment Discontinuation, and Follow-Up 
 
RO7198457—Genentech, Inc. 
159/Protocol GO40558, Version 5 
  
Treatment Period (Maintenance) nn 
TX 
DC oo 
FU 
Cycles 13, 
21, 29 
Cycles 14, 
20, 22, 28, 
30 
Cycles 15, 
23, 31 
Cycles 16, 
24, 32 
Cycles 17, 
25, 33 
Cycles 18, 
26, 34 
Cycles 19, 
27 
Days (Window) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
1 (3) 
 
TSH, free T3, and free T4 y  
 
x  
(C20, C28 
only) 
 
x 
 
 
 
x 
 
Cancer-related 
procedures bb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EORTC scales cc 
x 
x 
x 
x 
x 
x 
x 
x 
 
PRO-CTCAE scales and 
single-item bother cc  
x 
x 
x 
x 
x 
x 
x 
x 
 
WPAI dd 
x  
(C13 only) 
 
 
 
 
 
 
x 
 
Survival, anti-cancer 
therapy, and follow-up pp  
 
 
 
 
 
 
 
 
x 
Pembrolizumab infusion ee  
x 
x 
x 
x 
x 
x 
x 
 
 
Serum (pembrolizumab) PK 
sample  
See Appendix 3 
Blood and plasma sample 
for biomarkers  
See Appendix 3 
Blood sample (PBMC-I) for 
biomarkers hh 
 
x 
(C14, C22 
and C30) 
 
 
 
 
 
x 
 
On-treatment tumor 
biopsies mm 
x 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.) 
 
RO7198457—Genentech, Inc. 
161/Protocol GO40558, Version 5 
g A limited review of the eligibility checklist (e.g., ECOG Performance Status, blood chemistry, serology for HIV, HBV, and HCV) may be 
performed during the first part of screening (Part A).  The rest of the eligibility checklist will be reviewed during the second part of screening 
(Part B). 
h Medical history includes cancer history (including, but not limited to, prior cancer therapies and/or prior CITs and procedures and tumor 
characteristics such as hormone receptor status or mutation status), other clinically significant diseases, surgeries, smoking history, use of 
alcohol and/or drugs of abuse, reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, and nutritional supplements) used by the patient within 7 days prior to the screening visit.  Demographic information includes sex, 
age, and self-reported race/ethnicity. 
i All sites of disease should be assessed and documented at this visit.  Baseline CT assessments should be performed within 28 days prior to the 
start of study treatment (Cycle 1, Day 1).  If available, a scan prior to the baseline (up to 3 months) may also be obtained to evaluate changes in 
tumor growth rate.  Screening and subsequent tumor assessments should include CT scans (with IV contrast unless contraindicated and oral 
contrast per institutional standards) of the chest, abdomen, and pelvis.  Patients who have a contraindication to IV contrast may have MRI scans 
of the abdomen and pelvis performed in lieu of CTs and a non-contrast CT of the chest.  A CT or MRI scan (with IV contrast unless 
contraindicated) 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 CT scan (see Section 4.5.5).  Bone scans and CT scan of neck 
or extremities should also be performed if clinically indicated.  If a CT scan for tumor assessment is performed in a PET-CT scanner, the CT 
acquisition must be consistent with standards of a full-contrast CT scan.  The same radiographic procedure used to define measurable lesions 
at baseline should be used throughout the study for each patient.   
j Patients who continue treatment beyond radiographic disease progression (see Section 3.1.3) will be monitored with a follow-up scan in 
6 ( 1) weeks (i.e., at the next scheduled tumor assessment when the scan frequency is every 6 weeks or as an unscheduled tumor 
assessment when the scan frequency is every 12 [±1] weeks) or earlier if clinically indicated.  Tumor assessments should be continued until two 
consecutive scans demonstrate stability or improvement with respect to the first scan that showed radiographic disease progression, at which 
point the scan frequency should revert or transition to at least every 12 weeks), if applicable.  For patients who consented to treatment beyond 
progression, new lesions will also be assessed according to iRECIST (see Section 3.1.3) and applicable measurements entered into eCRF.  
While the Sponsor will derive overall tumor assessment as per iRECIST, investigator assessment of overall tumor response at all timepoints 
should be only based on RECIST v1.1 (see Section 3.1.3). 
k The timing of tumor assessments will be based on weeks from first study treatment (C1D1; pembrolizumab monotherapy) and will not be 
tied to Cycle-specific visits.  Tumor assessments will occur during Week 12 (based from C1D1) and every 6 weeks thereafter until Week 48 
(i.e., during Weeks 12, 18, 24, 30, 36, 42, and 48).  "During week" is defined as the first day/Day 1 of each targeted week (e.g., 12, 18, 
or 24 weeks from C1D1 date) plus 6 calendar days.  After Week 48, tumor assessments will occur every 12 ( 1) weeks through 
Week 96 (i.e., during Weeks 60, 72, 84, and 96).  After Week 96, follow-up tumor assessments will occur approximately every 12 weeks 
through Week 156 (i.e., Weeks 108, 120, 132, 144, and 156).  After Week 156, follow-up tumor assessments will occur approximately every 
24 weeks (i.e., Weeks 180, 204, 228, and 252). 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.) 
 
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l Patients who discontinue study treatment for reasons other than disease progression (e.g., toxicity) should continue to undergo scheduled 
tumor assessments approximately every 12 weeks until Week 156, then approximately every 24 weeks until disease progression, death, 
initiation of another systemic anticancer therapy, loss-to-follow-up, withdrawal of consent, or study termination, whichever occurs first.   
m  Photographs of cutaneous lesions will be taken at screening and on the same day a tumor assessment is obtained or at the first clinic visit after 
each tumor assessment if timing is preferable to the patient and clinical site study team.  See Section 4.5.6 for more details. 
n Concomitant medications any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment (including prophylactic treatment after RO7198457 
administration and medications as a result of an adverse event) from 7 days prior to screening to the study completion/discontinuation visit.  All 
such medications should be reported to the investigator and recorded on the Concomitant Medications eCRF. 
o After informed consent has been obtained but prior to initiation of study treatment, report only serious adverse events caused by a protocol-
mandated intervention.  After initiation of study treatment, report all adverse events until 90 days after the final dose of study treatment or until 
initiation of another systemic anti-cancer therapy, whichever occurs first.  Patients will be contacted at approximately 60 and 90 days after the 
final dose of study treatment to determine whether any new adverse events have occurred or if the patient has initiated another systemic 
anti-cancer therapy.  After this period, the investigator is not required to actively monitor patients for adverse events but should report any 
serious adverse events that are believed to be related to prior study treatment.  Deaths should be reported as described in Section 5.3.5.8.  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 treatment or trial-related procedures until a final outcome can be reported. 
p Vital signs include measurements of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a 
seated position.  See Section 4.5.4 for more details. 
q ECOG Performance Status, weight, limited physical examination, and local hematology and serum/plasma chemistry panels may be obtained 
 96 hours before each scheduled treatment and the treatment discontinuation visit, as applicable.   
r Complete and limited physical examinations are defined in Section 4.5.3. 
s Digitized, single ECGs will be performed as part of the screening assessment and at the treatment discontinuation visit.  If sustained QTc 
prolongation ( 500 ms and/or 60 ms longer than baseline value; at two consecutive readings) is noted, repeat ECG, and notify the Medical 
Monitor (see Section 4.5.8).  Single ECG recordings may be obtained at unscheduled timepoints as clinically indicated. 
t Hematology consists of CBC including RBC count, hemoglobin, hematocrit, platelet count, and WBC count with differential (neutrophils, 
eosinophils, lymphocytes, monocytes, basophils, and other cells).  A manual differential can be done if clinically indicated.  During screening, 
hematology results must be obtained within 14 days prior to Cycle 1, Day 1 (see Section 4.1.1). 
 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.) 
 
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u Serum/plasma chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, BUN or urea, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, ALP, LDH, total protein, and albumin.  
During first part of screening (Part A), results of standard-of-care tests or examinations performed prior to obtaining informed consent may be 
used for assessments rather than repeating such tests.  During second part of screening (Part B), serum/plasma chemistry results must be 
obtained within 14 days prior to Cycle 1, Day 1 (see Section 4.1.1). 
v Urinalysis/urine dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria) if warranted by dipstick results. 
w Serum pregnancy test (for women of childbearing potential, as defined in Section 4.1.1) must be performed and documented as negative within 
14 days prior to Day 1.  Urine or serum pregnancy tests (for women of childbearing potential only) will be performed at the specified subsequent 
visits.  If a urine pregnancy test is positive, dosing will be delayed until the patient's status is determined by a serum pregnancy test. 
x Investigators may collect CRP and ferritin ad-hoc for work-up of inflammatory or immune mediated adverse events. 
y TSH, free T3, and free T4 will be assessed during screening (Part B), on Day 1 of Cycle 4 and every 4 cycles thereafter (i.e., Day 1 of Cycles 8, 
12, 16, etc.). 
z Serum samples will be obtained for autoantibody testing including, but not necessarily limited to, anti-nuclear antibody, antidouble-stranded 
DNA, anti-neutrophil cytoplasmic antibodies, and thyroid peroxidase antibody, to be performed based on clinical events during the study, either 
in individual patients or across the study population.  If inflammatory arthritis develops, CCP and RF antibody titers will also be evaluated.  
Additional serum collection for autoantibody testing should be performed as clinically indicated. 
aa All patients will be tested for HIV locally during screening (Part A); HIV-positive patients will be excluded from the study.  Perform HBsAg, 
anti-HBc, and anti-HBs at local laboratory during screening (Part A).  In patients who have positive serology for the anti-HBc antibody, HBV 
DNA should also be collected.  Patients who are positive for HBc antibody are eligible only if negative for HBV DNA.  Patients who are positive 
for HCV antibody are eligible only if PCR is negative for HCV RNA.  Patients will also be tested for TB only if investigator considers patient to be 
at an increased risk for infection; latent TB diagnostic procedures must be followed according to local practice standards. 
bb Collection of cancer-related medical, surgical, and radiation procedures will begin on Day 1 of Cycle 1 and continue through the end of the 
treatment period and during the follow-up period. 
cc All PRO questionnaires (EORTC scales and PRO-CTCAE scales) are required to be completed prior to the administration of study treatment 
and/or prior to any other study assessment(s) that could bias patients' responses.  The EORTC scales and PRO-CTCAE scales and single-item 
bother should be completed on Day 1 of each cycle and at the treatment discontinuation visit.  In the event that other assessments associated 
with Day 1 are done in advance of study treatment within protocol-specified time windows (e.g., per footnote q), then PRO questionnaires 
can also be done at that earlier timepoint.  PRO-CTCAE questionnaires will be completed when available in the local language of the 
investigational site. 
 

Appendix 2: Schedule of Activities:  Safety Run-In, Arm B, and Crossover (Pembrolizumab Plus RO7198457) (cont.) 
 
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pp After study treatment completion or discontinuation, information on survival status, new anti-cancer therapy (including targeted therapy 
and immunotherapy), and cancer-related procedures will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests 
to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator.  If the patient 
withdraws from study, study staff may use a public information source (e.g., county records) to obtain information about survival status only.  
 

 
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Appendix 3  
Schedule of Pharmacokinetic and Biomarker Samples 
 
 
Treatment Period 
TX 
DC 
FU 
 
 
Initial 
Maintenance a 
 
 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 b 
Cycle 4 
Cycles 5, 6, 7  Cycles 13, 21, 29 
Days (window) 
1 ( 2) 
1 (2) 
8 (2) c 
15 (2) c 
1 (2) 
8 (2) 
1 (2) 
1 (2) 
1 (3) 
Serum 
pembrolizumab 
PK sample e, f 
Pre-dose, 
and 
30 (5) min 
after 
pembro 
infusion 
Pre-
dose  
 
 
 
 
Pre-dose  
 
 
 
2 months 
post EOT 
(1 
week) f 
Plasma 
Biomarker 
(Cytokines) 
(safety run-in, 
Arm B, and 
crossover only)   
g, h 
Pre-dose,  
46 hr 
post-dose 
 
Pre-dose, 
46 hr 
post-dose  
Pre-dose, 
46 hr 
post-dose 
Pre-
dose,  
46 hr 
post-
dose  
 Pre-dose, 
46 hr 
post-dose 
Pre-dose, 
46 hr 
post-dose 
C5, C6, C7: 
pre-dose, 
46 hr post-
dose  
Pre-dose, 46 hr 
post-dose 
 
 
Blood Biomarker 
(ctDNA)  
Pre-dose 
 
 
 
 
 
 
C7D1 only 
(pre-dose) 
C13D1 only 
(pre-dose) 
 
 
 

 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 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 as measurable or 
non-measurable as follows. 
a. 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 imagining (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. 
b. 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. 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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c. 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 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.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
a. 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. 
b. 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. 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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Clinical Lesions.  Clinical lesions will be considered measurable only 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 on the basis of 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 
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 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 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. 
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 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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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. 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
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. 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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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 
a. 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 
 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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b. 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 on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact 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 BML (below measurable limit) 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. 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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c. 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.  Although 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. 
 
d. 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. 
e. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
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 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
a. 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. 
 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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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 trials; thus, 
assigning "stable disease" when no lesions can be measured is not advised. 
 
b. 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. 
c. Best Overall Response:  All Timepoints 
The best overall response is determined once all data for the patient is known, and is 
interpreted as in Table 3.  Complete or partial responses may be claimed if the criteria 
for each are met at a subsequent timepoint  4 weeks later.   
 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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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. 
 
d. 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. 
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 

Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (cont.) 
 
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objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1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. 
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression. 
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 CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion. 

 
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Appendix 5  
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immunotherapy-specific response criteria adaptations to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1; Eisenhauer et 
al. 2009) have been developed to allow for unconventional response and progression 
patterns.  These include modified RECIST v1.1 for immune-based therapeutics 
(iRECIST; Seymour et al. 2017), which was developed by the RECIST working group in 
an effort to create a common set of criteria that the cancer immunotherapy field could 
apply to clinical trials. 
Response evaluation through use of iRECIST requires collection of tumor assessment 
data after radiographic progression per RECIST v1.1.  Details regarding lesion 
evaluation are described below.  When not otherwise specified, RECIST v1.1 
conventions will apply. 
Criteria for determining overall response at a single timepoint per iRECIST are also 
summarized below.  Of note, overall response per iRECIST will not be captured in the 
electronic Case Report Form (eCRF), but will instead be calculated programmatically by 
the Sponsor on the basis of investigator-assessed individual lesion data recorded in the 
eCRF.   
iRECIST response status is not a specific component of treatment discontinuation 
criteria, including decisions about whether to continue treatment beyond progression per 
RECIST v1.1.  Investigators should instead take into account radiologic data and clinical 
status in making such decisions, as described in Section 3.3.17. 
EVALUATION OF LESIONS TO SUPPORT iRECIST RESPONSE 
ASSESSMENT AFTER DISEASE PROGRESSION PER RECIST v1.1  
iRECIST is an extension of RECIST v1.1 that allows for response assessment following 
disease progression per RECIST v1.1.  RECIST v1.1 rules for categorizing lesions as 
measurable or non-measurable and measuring lesions (see Appendix 4) also apply to 
iRECIST.  After disease progression per RECIST v1.1, the same target and non-target 
lesions selected at baseline will continue to be followed, along with any new lesions that 
develop, to support iRECIST response evaluations, as described below and summarized 
in Table 1.  Once a lesion has been categorized as a target, non-target, or new lesion, it 
will remain classified as such. 

Appendix 5: Immune Modified Response Evaluation Criteria in Solid Tumors (imRECIST)  
(cont.) 
 
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TARGET LESIONS 
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions. 
NON-TARGET LESIONS 
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1.  At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (progressive disease [PD]), or 
"present without unequivocal progression" (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were categorized as PD at the 
previous timepoint should be evaluated to determine whether there has been any further 
increase in size.   
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 v1.1 
(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 (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint.  New lesions that are 
not measurable at first appearance but meet measurability criteria at a subsequent 
timepoint should be measured from that point on, if the maximum number of measurable 
new lesions has not been reached.  However, for calculation of the sum of diameters for 
new lesions, iRECIST excludes measurements from new lesions that were not 
measurable at first appearance. 
All non-measurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions (in excess of five total or two per organ) should 
be assessed to determine whether there is any increase in size relative to the previous 
assessment timepoint. 
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 

Appendix 5: Immune Modified Response Evaluation Criteria in Solid Tumors (imRECIST)  
(cont.) 
 
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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.  Measurable new lymph node lesions 
should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to  15 mm (or even  10 mm). 
Table 1 
Guidelines for Evaluation of Lesions to Support iRECIST 
Response Assessment after Disease Progression per 
RECIST v1.1 
Lesion Type 
Evaluation of Lesions to Support iRECIST Response Assessment 
after Disease Progression per RECIST v1.1 
Target lesions 
 Measurements should be continued according to RECIST v1.1 
conventions. 
Non-target lesions 
 Non-target lesions should continue to be categorized as absent 
(CR), unequivocal progression (PD), or present without 
unequivocal progression (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were 
categorized as PD at the previous timepoint should be 
evaluated to determine whether there has been any further 
increase in size. 
New lesions 
 New lesions should be evaluated for measurability per 
RECIST v1.1. 
 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 (with a 
maximum of two lesions per organ) should be selected and 
measured at each timepoint. 
 All non-measurable new lesions (including those that 
subsequently become measurable) and additional measurable 
new lesions (in excess of five total or two per organ) should be 
assessed to determine whether there is any increase in size 
relative to the previous assessment timepoint. 
CR  complete response; iRECIST  modified RECIST v1.1 for immune-based therapeutics; 
PD  progressive disease; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, 
Version 1. 
 
SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A SINGLE 
TIMEPOINT 
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  A 
complete description of the iRECIST criteria can be found in a publication by Seymour et 
al. (2017). 

Appendix 5: Immune Modified Response Evaluation Criteria in Solid Tumors (imRECIST)  
(cont.) 
 
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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.   
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 2017;18:e14352 

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

 
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Appendix 7  
Pre-Existing Autoimmune Diseases 
Patients with a convincing history of any autoimmune disease listed in the table below 
are excluded from participating in the study.  Possible exceptions to this exclusion could 
be patients with a medical history of such entities as atopic disease or childhood 
arthralgias where the clinical suspicion of autoimmune disease is low.  Patients with a 
history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone may be eligible for this study.  In addition, transient autoimmune manifestations 
of an acute infectious disease that resolved upon treatment of the infectious agent are 
not excluded (e.g., acute Lyme arthritis).  The Medical Monitor is available to advise on 
any uncertainty over autoimmune exclusions. 
Examples of Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
encephalomyelitis 
Epidermolysis bullosa 
acquisita 
Opsoclonus myoclonus 
syndrome 
Addison disease 
Gestational pemphigoid 
Optic neuritis 
Ankylosing spondylitis 
Giant-cell arteritis 
Ord thyroiditis 
Antiphospholipid antibody 
syndrome 
Goodpasture syndrome 
Pemphigus 
Aplastic anemia 
Graves disease 
Pernicious anemia 
Autoimmune hemolytic anemia 
Guillain-Barré syndrome 
Polyarteritis nodosa 
Autoimmune hepatitis 
Hashimoto thyroiditis 
Polyarthritis 
Autoimmune hypoparathyroidism 
IgA nephropathy 
Polyglandular autoimmune 
syndrome 
Autoimmune hypophysitis 
Inflammatory bowel 
disease 
Primary biliary cirrhosis 
Autoimmune myocarditis 
Interstitial cystitis 
Psoriasis 
Autoimmune oophoritis 
Kawasaki's disease 
Reiter syndrome 
Autoimmune orchitis 
Lambert-Eaton 
myasthenia syndrome 
Rheumatoid arthritis 
Autoimmune thrombocytopenic 
purpura 
Lupus erythematosus 
Sarcoidosis 
Behcet disease 
Lyme disease - chronic 
Scleroderma 
Bullous pemphigoid 
Meniere syndrome 
Sjögren syndrome 
Chronic inflammatory 
demyelinating polyneuropathy 
Mooren ulcer 
Stiff-Person syndrome 
Churg-Strauss syndrome 
Morphea 
Takayasu arteritis 
Crohn's disease  
Multiple sclerosis 
Ulcerative colitis 
Dermatomyositis 
Myasthenia gravis 
Vogt-Koyanagi-Harada 
disease 
Diabetes mellitus Type 1 
Neuromyotonia 
Wegener's granulomatosis 
Dysautonomia 
 
 

 
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Appendix 8  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 12  
New York Heart Association Classification of Functional Cardiac 
Capacity 
Class 
Description 
I 
No limitation:  Ordinary physical activity does not cause undue fatigue, dyspnea, 
or palpitation. 
II 
Slight limitation of physical activity:  Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity:  Although patients are comfortable at rest, 
less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort:  Symptoms of 
congestive heart failure are present even at rest.  With any physical activity, 
increased discomfort is experienced. 
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels.  Nomenclature and criteria for diagnosis.  6th ed. Boston, Little, Brown and Co, 
1964:114. 

 
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Appendix 13  
Investigational and Auxiliary Medicinal Product Designations 
(for Use in European Economic Area) 
 
Table 1 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing 
Authorization Status 
in EEA 
Used within 
Marketing 
Authorization 
RO7198457 
IMP (test product) 
Unauthorized 
Not applicable 
Pembrolizumab 
IMP (test product) a 
Authorized 
No b 
AxMP   auxiliary medicinal product; EEA   European Economic Area; IMP   investigational 
medicinal product.  
a Pembrolizumab is considered to be an IMP test product as well as an IMP comparator. 
b Pembrolizumab is not approved in combination with RO7198457. 
 

Signature Page for Protocol - GO40558 - AUTOGENE CEVUMERAN - v5 - Published
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14-Nov-2023 19:35:45 GMT+0000