A Phase II, Randomized, Multicenter, Double-Blind, Controlled Study of Tobemstomig Plus Platinum-Based Chemotherapy Versus Pembrolizumab Plus Platinum-Based Chemotherapy in Patients With Previously Untreated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase II, Randomized, Multicenter, Double-Blind, Controlled Study 
of Tobemstomig Plus Platinum-Based Chemotherapy Versus 
Pembrolizumab Plus Platinum-Based Chemotherapy in Patients with 
Previously Untreated Locally Advanced or Metastatic Non-Small Cell 
Lung Cancer 
NCT Number: 
NCT05775289 
Document Date: 
Protocol Amendment Version 4: 09-Nov-2024 
 
 
 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Tobemstomig—F. Hoffmann-La Roche Ltd 
Protocol BO44178, Version 4 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, CONTROLLED STUDY OF 
TOBEMSTOMIG PLUS PLATINUM-BASED 
CHEMOTHERAPY VERSUS PEMBROLIZUMAB 
PLUS PLATINUM-BASED CHEMOTHERAPY IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
LOCALLY ADVANCED OR METASTATIC 
NONSMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO44178  
VERSION NUMBER: 
4 
TEST COMPOUND: 
Tobemstomig (RO7247669) 
STUDY PHASE: 
Phase II 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  164130 
EU CT Number:  2023-505211-21-00 
EudraCT Number:  2022-001440-18 
NCT Number:  NCT05775289 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4058 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the 
final page of this document. 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
2/Protocol BO44178, Version 4 
PROTOCOL HISTORY 
 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
4 
See electronic date 
stamp on the final page 
of this document. 
3 
11 May 2023 
 
 
 
2 
31 October 2022 
United States 
1 
19 December 2022 
1 
24 May 2022 
 
 
 
  
 
 
 
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Tobemstomig—F. Hoffmann-La Roche Ltd 
3/Protocol BO44178, Version 4 
PROTOCOL AMENDMENT, VERSION 4:  
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Tobemstomig—F. Hoffmann-La Roche Ltd 
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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. 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
6/Protocol BO44178, Version 4 
 
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
1. 
PROTOCOL SUMMARY ............................................................... 14
1.1 
Synopsis .................................................................................. 14
1.2 
Study Schema ......................................................................... 21
1.3 
Schedule of Activities and Sample Collection Schedule .......... 22 
2. 
INTRODUCTION ........................................................................... 30
2.1 
Study Rationale ....................................................................... 30
2.2 
Background.............................................................................. 30
2.2.1 
The PD-L1/PD-1 Pathway ....................................................... 31
2.2.2 
The LAG3 Pathway .................................................................. 31
2.3 
Benefit–Risk Assessment ........................................................ 32
3. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS.......................... 37 
4. 
STUDY DESIGN ........................................................................... 41
 
 ...................................................... 41
 
 .......................................................... 42
4.2                   Overall Design .......................................................................... 42
4.2.1 
Screening Phase ..................................................................... 43
4.2.2 
Treatment Phase ..................................................................... 44
4.2.3 
Safety Run-In Evaluation ......................................................... 44
4.2.4 
Assessments ........................................................................... 45
4.2.5 
Treatment Beyond Progression ............................................... 47
4.2.6 
Safety Follow-Up Phase........................................................... 47
4.2.7 
Safety Monitoring ................................................................... 47
4.3 
Rationale for Original Study Design ....................................... 47
4.3.1 
Rationale for Study Population ................................................ 48
4.3.2 
Rationale for Testing Tobemstomig in Combination with
Platinum-Based Chemotherapy in Participants with
NSCLC across All PD-L1 Expression Subgroups and
Histologies ............................................................................... 48

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
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6.3 
Treatment Assignment and Blinding ........................................ 70 
6.3.1 
Treatment Assignment ............................................................. 70 
6.3.2 
Blinding .................................................................................... 71 
6.4 
Study Treatment Compliance .................................................. 71 
6.5 
Dose Modification .................................................................... 71 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 71 
6.7 
Treatment of Overdose ............................................................ 71 
6.8 
Concomitant Therapy .............................................................. 72 
6.8.1 
Permitted Therapy ................................................................... 72 
6.8.2 
Cautionary Therapy ................................................................. 73 
6.8.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors ............................................. 73 
6.8.2.2 
Herbal Therapies ..................................................................... 73 
6.8.2.3 
Other Cautionary Therapy ....................................................... 74 
6.8.3 
Prohibited Therapy .................................................................. 74 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............ 74 
7.1 
Discontinuation of Study Treatment ......................................... 74 
7.2 
Participant Discontinuation or Withdrawal from the Study ....... 75 
7.3 
Participants Lost to Follow-Up ................................................. 76 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 76 
8.1 
Efficacy Assessments .............................................................. 77 
8.1.1 
Tumor and Response Evaluations ........................................... 77 
8.1.1.1 
Radiographic Assessments ..................................................... 78 
8.1.1.2 
Response Evaluation ............................................................... 79 
8.1.2 
Clinical Outcome Assessments ............................................... 79 
8.1.2.1 
Data Collection Methods for Clinical Outcome 
Assessments 
 .................................. 79 
8.1.2.2 
EORTC Item Libraries 85, 132, 188, and 17 ............................ 80 
8.2 
Safety Assessments ................................................................ 80 
8.2.1 
Physical Examinations ............................................................. 80 
8.2.2 
Vital Signs ................................................................................ 80 
8.2.3 
Electrocardiograms .................................................................. 81 

 
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8.2.4 
Clinical Safety Laboratory Tests .............................................. 82 
8.2.5 
Pregnancy Testing ................................................................... 82 
8.2.6 
Clinical Outcome Assessments ............................................... 82 
8.2.6.1 
PRO-CTCAE ............................................................................ 83 
8.2.6.2 
EORTC Item Library 46 ........................................................... 83 
8.3 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 83 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 84 
8.3.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................................... 84 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 85 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 85 
8.3.5 
Pregnancy................................................................................ 86 
8.3.6 
Cardiovascular and Death Events ........................................... 86 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting ..... 86 
8.3.8 
Adverse Events of Special Interest .......................................... 87 
8.3.9 
Medical Monitors and Emergency Medical Contacts ............... 87 
8.4 
Pharmacokinetics .................................................................... 87 
8.5 
Pharmacodynamics ................................................................. 88 
8.6 
Genetics .................................................................................. 88 
8.7 
Biomarker Assessments .......................................................... 88 
8.8 
Immunogenicity Assessments ................................................. 90 
8.9 
Health Economics and Medical Resource Utilization ............... 90 
8.10 
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ........................................................ 90 
8.10.1 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing with a Focus on Germline Variants 
(Participants at Participating Sites) .......................................... 90 
8.10.2 
Tumor Biopsies (Participants Providing Separate Consent) .... 91 
8.10.3 
Samples for Research Biosample Repository (Participants 
Providing Separate Consent at Participating Sites) ................. 92 
8.10.3.1 
Overview of the Research Biosample Repository .................... 92 

 
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10/Protocol BO44178, Version 4 
8.10.3.2 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 92 
8.10.3.3 
Sample Collection .................................................................... 92 
8.10.3.4 
Data Protection, Use, and Sharing .......................................... 93 
8.10.3.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 94 
8.10.3.6 
Withdrawal from the Research Biosample Repository ............. 94 
8.10.3.7 
Monitoring and Oversight ......................................................... 95 
9. 
STATISTICAL CONSIDERATIONS .............................................. 95 
9.1 
Statistical Hypotheses ............................................................. 95 
9.1.1 
Sample Size Determination ..................................................... 95 
9.2 
Analysis Sets ........................................................................... 96 
9.3 
Statistical Analyses .................................................................. 96 
9.3.1 
General Considerations ........................................................... 96 
9.3.2 
Estimation Methods for the Primary Endpoints ........................ 97 
9.3.2.1 
Objective Response Rate ........................................................ 97 
9.3.2.2 
Progression-Free Survival ....................................................... 98 
9.3.3 
Estimation Methods for the Secondary Endpoints ................... 98 
9.3.3.1 
Overall Survival ........................................................................ 98 
9.3.3.2 
Duration of Response .............................................................. 98 
9.3.3.3 
Investigator-Assessed PFS and OS in Selected PD-L1 
Expression Subgroups ............................................................. 99 
9.3.3.4 
Patient-Reported Outcomes .................................................... 99 
9.3.3.5 
Safety Analyses ....................................................................... 99 
9.3.3.6 
Pharmacokinetic Analyses ....................................................... 99 
9.3.3.7 
Immunogenicity Analyses ...................................................... 100 
9.3.4 
Exploratory Analyses ............................................................. 100 
9.3.4.1 
Subgroup Analysis ................................................................. 100 
9.3.4.2 
Patient-Reported Outcomes .................................................. 100 
9.3.4.3 
Summaries of Conduct of Study ............................................ 100 
9.3.4.4 
Summaries of Demographics and Baseline Characteristics .. 101 
 
 ..................................................................... 101 
 
 ................................................................... 101 
 
 ....................................................... 101 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
12/Protocol BO44178, Version 4 
Appendix 11 
Eastern Cooperative Oncology Group Performance Scale ....... 210 
Appendix 12 
Genetics:  Use and Analysis of DNA for Mandatory Samples ... 211 
Appendix 13 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations (for Use in 
European Economic Area) ........................................................ 212 
Appendix 14 
Protocol Amendment History .................................................... 213 
Appendix 15 
Abbreviations ............................................................................ 219 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
13/Protocol BO44178, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, CONTROLLED STUDY OF 
TOBEMSTOMIG PLUS PLATINUM-BASED 
CHEMOTHERAPY VERSUS PEMBROLIZUMAB 
PLUS PLATINUM-BASED CHEMOTHERAPY IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
LOCALLY ADVANCED OR METASTATIC  
NONSMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO44178  
VERSION NUMBER: 
4 
TEST COMPOUND: 
Tobemstomig (RO7247669) 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.  
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
14/Protocol BO44178, Version 4 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
CONTROLLED STUDY OF TOBEMSTOMIG PLUS PLATINUM-
BASED CHEMOTHERAPY VERSUS PEMBROLIZUMAB PLUS 
PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH 
PREVIOUSLY UNTREATED LOCALLY ADVANCED OR 
METASTATIC NON-SMALL CELL LUNG CANCER 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number: 164130 
EU CT Number:  2023-505211-21-00 
EudraCT Number:  2022-001440-18  
NCT Number:  NCT05775289 
 
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of 
tobemstomig (also known as RO7247669) in combination with platinum-based chemotherapy 
compared with pembrolizumab plus platinum-based chemotherapy in participants with 
previously untreated, locally advanced, unresectable (Stage IIIB/IIIC) or metastatic (Stage IV) 
nonsmall cell lung cancer (NSCLC) who are not eligible to receive curative surgery and/or 
definitive chemoradiotherapy. 
Patients with advanced or metastatic solid tumors present a great unmet need.  Benefit from 
cancer immunotherapy with checkpoint inhibitor monoclonal antibodies, such as those targeting 
programmed death1/programmed deathligand 1 (PD-1/PD-L1), is predominantly observed in 
a subset of patients with inflamed tumor phenotypes.  However, response is not guaranteed 
even in this patient subset owing to either primary or acquired resistance mechanisms.  
Upregulated lymphocyte activation gene 3 (LAG3) expression on T cells is associated with 
T-cell dysfunction, potentially resulting in adaptive resistance to antiPD-1/PD-L1 therapies.  
Therefore, LAG3 blockade of tumor-infiltrating lymphocytes may overcome or prevent 
resistance mechanisms to anti-PD1/PD-L1 and help restore or increase T-cell proliferation and 
cytotoxic effector functions. 
Tobemstomig concurrently targets two dominant immune checkpoint receptors, PD-1, and 
LAG3.  Such targeting may serve to overcome resistance by means of synergic ligand blockade 
and subsequent re-invigoration of tumor-infiltrating lymphocytes, regardless of T-regulatory 
cells, and potentially delay or prevent the development of LAG3 mediated adaptive resistance 
mechanisms.  
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
15/Protocol BO44178, Version 4 
OBJECTIVES AND ENDPOINTS 
Primary Objectives 
Estimand Definitions 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 Population:  participants with previously untreated, locally 
advanced, unresectable NSCLC who are ineligible for 
definitive chemoradiotherapy (Stage IIIB/IIIC) or 
metastatic (Stage IV) NSCLC of SQ or NSQ histology 
with no known EGFR or ALK genomic tumor aberrations  
 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 
RECIST v1.1 
 Treatment 
 
Experimental arm 
NSQ NSCLC:  tobemstomig in combination with 
pemetrexed and carboplatin, followed by 
maintenance tobemstomig with pemetrexed 
SQ NSCLC:  tobemstomig in combination with 
paclitaxel and  carboplatin, followed by 
tobemstomig 
 
Control arm 
NSQ NSCLC:  pembrolizumab in combination with 
pemetrexed and carboplatin, followed by 
maintenance pembrolizumab with pemetrexed  
SQ NSCLC:  pembrolizumab in combination with 
paclitaxel and carboplatin, followed by 
pembrolizumab  
 Intercurrent events and handling strategies: 
 
Early discontinuation from study treatment for any 
reason prior to the respective event of interest:   
treatment policy strategy 
 
Start of non-protocol-specified anti-cancer therapy 
prior to the respective event of interest:  treatment 
policy strategy 
 Population-level summary:  hazard ratio for PFS 
ALK  anaplastic lymphoma kinase; EGFR  epidermal growth factor receptor; 
HRQoL  health-related quality of life; PFS  progression-free survival; NSCLC  nonsmall cell lung 
cancer; NSQ  non-squamous; ORR  objective response rate; OS  overall survival; 
SQ  squamous; RECIST  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
 
 
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
16/Protocol BO44178, Version 4 
Primary Objectives (cont.) 
Estimand Definitions (cont.) 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B)  
 Population:  as defined above; participants must have 
measurable disease at baseline, as determined by the 
investigator according to RECIST v1.1 
 Endpoint:  ORR, defined as the proportion of 
participants with a complete response or a partial 
response on two consecutive occasions  4 weeks 
apart, as determined by the investigator according to 
RECIST v1.1 
 Treatment:  as defined above 
 Intercurrent events and handling strategies:  as 
defined above 
 Population-level summary:  difference in ORR 
ALK  anaplastic lymphoma kinase; EGFR  epidermal growth factor receptor; 
HRQoL  health-related quality of life; PFS  progression-free survival; NSCLC  nonsmall cell 
lung cancer; NSQ  non-squamous; ORR  objective response rate; OS  overall survival; 
SQ  squamous; RECIST  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
  
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 OS after randomization, defined as the time from 
randomization to death from any cause  
 Duration of response for participants with confirmed 
objective response, defined as the time from the first 
occurrence of a confirmed objective response to 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1  
 PFS and OS in participants with PD-L1 expression, 
 Change from baseline to Week 12 in patient-reported 
outcomes of lung cancer symptoms, physical 
functioning, role functioning, and global health 
status/quality of life, as assessed through the use of 
the European Organisation for Research and 
Treatment of Cancer Item Libraries 
 To evaluate the safety of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 Incidence and severity of adverse events, with severity 
determined according to the NCI Common 
Terminology Criteria for Adverse Events, Version 5.0 
 The severity of cytokine release syndrome will be 
determined according to the ASTCT Consensus 
Grading Scale. 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
NCI  National Cancer Institute; OS  overall survival; PD‑L1  programmed deathligand 1; 
PFS  progression‑free survival; PK  pharmacokinetic; RECIST v1.1  Response Evaluation 
Criteria in Solid Tumors, Version 1.1;
 
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
17/Protocol BO44178, Version 4 
Secondary Objectives (cont.) 
Corresponding Endpoints (cont.) 
 To investigate the
pharmacokinetics of tobemstomig
 PK profiles and parameters derived for tobemstomig, 
including, but not limited to, the following parameters, 
as appropriate and when data allow: 
– Maximum concentration 
– Time of maximum concentration 
– Clearance  
– Volume of distribution at steady state 
– Area under the concentrationtime curve 
– Half‑life 
 Concentrations of tobemstomig in serum at 
specified timepoints 
 To evaluate the immune response 
to tobemstomig 
 Prevalence of ADAs to tobemstomig at baseline and 
incidence of ADAs to tobemstomig during the study 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
NCI  National Cancer Institute; OS  overall survival; PD‑L1  programmed deathligand 1; 
PFS  progression‑free survival; PK  pharmacokinetic; RECIST v1.1  Response Evaluation 
Criteria in Solid Tumors, Version 1.1; 
 
The primary objective for the study is expressed using the estimand framework in accordance 
with the International Council for Harmonisation (ICH) E9(R1) statistical principles for clinical 
trials (ICH 2020) (see Section 3).  
In this protocol, “study treatment” refers to the combination of treatments assigned to patients 
as part of this study (i.e., tobemstomig or pembrolizumab in combination with pemetrexed and 
carboplatin or paclitaxel and carboplatin). 
OVERALL DESIGN AND STUDY POPULATION 
This is a randomized, Phase II, global, multicenter, double-blind study designed to evaluate the 
efficacy, safety, and pharmacokinetics of tobemstomig in combination with platinum-based 
chemotherapy compared with pembrolizumab plus platinum-based chemotherapy in patients 
with previously untreated, locally advanced unresectable (Stage IIIB/IIIC) or metastatic 
(Stage IV) NSCLC who are not eligible for curative surgery and/or definitive chemoradiotherapy. 
Approximately 180 patients will be randomized in the study in a 1:1 ratio to receive either 
tobemstomig plus platinum-based chemotherapy (Arm A) or pembrolizumab plus 
platinum-based chemotherapy (Arm B). 
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
18/Protocol BO44178, Version 4 
Several key aspects of the study design and study population are summarized below. 
Phase: 
Phase II 
Population Type: 
Adult patients 
Control Method: 
Active comparator  Population Diagnosis 
or Condition: 
Previously untreated, 
locally advanced 
unresectable (Stage 
IIIB/IIIC) or metastatic 
(Stage IV) NSCLC who 
are not eligible for 
curative surgery and/or 
definitive 
chemoradiotherapy. 
Interventional 
Model: 
Parallel group 
Population Age: 
18 years or over 
Test Compound{s}: Tobemstomig (also 
known as 
RO7247669) 
Site Distribution: 
Multi-site  
Active Comparator: Pembrolizumab  
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 180  
 
STUDY TREATMENT 
The investigational medicinal products for this study are tobemstomig (experimental test 
product), pembrolizumab (comparator), carboplatin, pemetrexed, and paclitaxel. 
Blinded Tobemstomig and Blinded Pembrolizumab 
Participants will receive blinded tobemstomig (
mg every 3 weeks [Q3W]) or blinded 
pembrolizumab (200 mg Q3W) by IV infusion.  Administration of study treatment will be 
performed in a monitored setting where there is immediate access to trained personnel and 
adequate equipment and medicine to manage potentially serious reactions.  The 
-mg dose 
of tobemstomig Q3W and the 200-mg dose of pembrolizumab Q3W will remain the same 
throughout the study.   
The initial dose of tobemstomig or pembrolizumab will be delivered over
minutes by IV 
infusion.  If the
-minute infusion is tolerated without infusion-associated adverse events (fever 
or chills), the second infusion may be delivered over
minutes.  If the
-minute infusion 
is well tolerated, all subsequent infusions may be del
er 
minutes. 
Paclitaxel, Pemetrexed, and Carboplatin 
Paclitaxel 
Paclitaxel 200 mg/m2 will be administered as an IV infusion to participants over 3 hours Q3W for 
four cycles as per local practice and labels.  All participants should be premedicated with oral or 
an IV steroid and antihistamines according to the approved product label and/or standard 
practice.  Additional premedications should be administered as per standard practice.  
Paclitaxel should be completely administered before initiating carboplatin dose. 
Pemetrexed 
Pemetrexed 500 mg/m2 will be administered to participants as an IV infusion over 10 minutes 
Q3W until progression or unacceptable toxicity. 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
19/Protocol BO44178, Version 4 
All participants should receive the appropriate supplementation with vitamin B12 and folic acid 
and corticosteroid prophylaxis as listed below (or as per local label): 
 
Folic acid 3501000 g orally (PO):  Participants must take at least five doses of folic acid 
during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must 
continue during the full course of therapy and for 21 days after the final dose of 
pemetrexed. 
 
Vitamin B12 1000 g intramuscular (IM) injection:  Participants will receive an IM injection 
the week preceding the first dose of pemetrexed and once every three cycles thereafter.  
Subsequent vitamin B12 injections may be given the same day as pemetrexed 
administration. 
 
Anti-emetic prophylaxis with dexamethasone 4 mg (or equivalent) PO twice per day:  
Participants should take dexamethasone the day before, the day of, and the day after 
pemetrexed administration.  Higher or additional doses are permitted for anti-emetic 
prophylaxis during Cycles 14 are but not to exceed doses per the Multinational Association 
of Supportive Care and European Society of Medical Oncology. 
 
Carboplatin 
Carboplatin area under the concentrationtime curve (AUC) 5 mg/mL  min:  Participants will 
receive carboplatin as an IV infusion over 3060 minutes Q3W for four cycles immediately after 
paclitaxel or pemetrexed as per local practice and labels.  The dose of carboplatin should be 
calculated using Calvert formula (see below) and should not exceed 750 mg.  
Calvert Formula: 
Total dose (in milligrams [mg])  (target AUC)  (creatine clearance [CrCl} 25). 
The estimated glomerular filtration rate used in the Calvert formula should not exceed 
125 mL/min. 
Maximum carboplatin dose (mg)  target AUC 
5 (mg/mL  min)  (125  25)  5  150 mL/min  750 mg. 
Paclitaxel, pemetrexed, and carboplatin will be administered to participants as outlined in the 
following table. 
Treatment Regimen for Pemetrexed, Paclitaxel, and Carboplatin 
Study 
Treatment 
Dose and Route of 
Administration 
Induction Period 
(Four 21-Day Cycles) 
Maintenance 
(until PD) 
Pemetrexed 
500 mg/m2  
by IV infusion 
Over approximately 
10 minutes on Day 1 Q3W 
Over approximately 
10 minutes on Day 1 
Q3W 
Paclitaxel 
200 mg/m2  
by IV infusion 
Over approximately 
3 hours on Day 1 Q3W 
Not applicable 
Carboplatin 
AUC 5 mg/mL  min 
by IV infusion 
Over approximately 
3060 minutes on Day 1 
Q3W 
Not applicable 
AUC  area under the concentrationtime curve; PD  progressive disease; 
Q3W  every 3 weeks. 
 
Dose modifications of tobemstomig, including dose reductions, will not be allowed in this study. 
DURATION OF PARTICIPATION 
Treatment will continue until disease progression per Response Evaluation Criteria in Solid 
Tumors version 1.1, unacceptable toxicity, or loss of clinical benefit as determined by the 
investigator (see Section 7.1 for additional details), up to 24 months, or until the Sponsor 
decides to terminate the study, whichever comes first.  The total duration of study participation 
for each individual is expected to range from 1 day to approximately 28 months.  Participants 
will be allowed to continue treatment beyond disease progression for up to 24 months if 
prespecified criteria are met (Section 4.2.5). 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
20/Protocol BO44178, Version 4 
COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Not applicable 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
22/Protocol BO44178, Version 4 
1.3 
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION SCHEDULE 
Table 1 
Schedule of Activities 
Procedure or Assessment 
Screening a 
Treatment Cycle 
(21-Day Cycles or Q3W) b 
Treatment 
Discontinuation 
Visit c 
Safety Follow-
Up Visit d 
Days  
 28 to  1 
Induction (Cycles 14) e 
Maintenance (Cycles 5) 
 30 Days after 
Final Dose of 
Study 
Treatment 
90 Days after 
Final Dose of 
Study 
Treatment 
Day 1  
( 3 
Days) 
Day 8 
( 3 
days)  
Day 15 
( 3 
days)  
Day 
1 ( 3 
days) 
Day 8 
( 3 
days)  
Day 15 
( 3 
days)  
Informed Consent Forms:  f 
Main ICF for study participation 
Research Biosample Repository (RBR) 
ICF  
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical and cancer history and 
baseline conditions g 
x 
 
 
 
 
 
 
 
 
Vital signs h 
x 
x 
 
 
x 
 
 
x
Weight 
x 
x 
 
 
x 
 
 
x
Height 
x
Complete physical examination i 
x
Limited physical examination j 
 
x 
 
 
x 
 
 
x 
ECOG Performance Status k 
x 
x 
 
 
x 
 
 
x 
12-Lead ECG l  
x 
Perform Cycle 1 & 5 and as clinically indicated. l 
x 
TTE or MUGA m 
x
Hematology n, o 
x  
x  
 
 
x  
 
 
x 
Serum chemistry panel p, o 
x 
x 
 
 
x  
 
 
x

Table 1 
Schedule of Activities (cont.) 
 
Tobemstomig—F. Hoffmann-La Roche Ltd 
23/Protocol BO44178, Version 4 
Procedure or Assessment 
Screening a 
Treatment Cycle 
(21-Day Cycles or Q3W) b 
Treatment 
Discontinuation 
Visit c 
Safety Follow-
Up Visit d 
Days  
 28 to  1 
Induction (Cycles 14) e 
Maintenance (Cycles 5) 
 30 Days after 
Final Dose of 
Study 
Treatment 
90 Days after 
Final Dose of 
Study 
Treatment 
Day 1  
( 3 
Days) 
Day 8 
( 3 
days)  
Day 15 
( 3 
days)  
Day 
1 ( 3 
days) 
Day 8 
( 3 
days)  
Day 15 
( 3
days)
Coagulation:  INR and aPTT o 
x 
 
 
 
 
 
 
x
Cardiac enzymes:  troponin T or
troponin I  
x 
x 
 
 
x
Thyroid function:  TSH, free T3, and
free T4 q 
x 
x q 
 
 
x q 
 
 
x
HIV, HBV, HCV serology r 
x
Urinalysis s 
x 
Perform as clinically indicated.
Pregnancy test (for women of
childbearing potential only) t 
x 
x 
 
 
x 
 
 
x
CT scan with contrast of brain (or MRI
scan) 
x u
Induction treatment administration e
Arm A, participants with NSQ 
NSCLC:
tobemstomig
 pemetrexed  carboplatin
 
x 
 
 
 
 
 
 
 
Arm A, participants with SQ 
NSCLC:  tobemstomig  
paclitaxel   
carboplatin 
 
x 
 
 
 
 
 
 
 

Table 1 
Schedule of Activities (cont.) 
 
Tobemstomig—F. Hoffmann-La Roche Ltd 
24/Protocol BO44178, Version 4 
Procedure or Assessment 
Screening a 
Treatment Cycle 
(21-Day Cycles or Q3W) b 
Treatment 
Discontinuation 
Visit c 
Safety Follow-
Up Visit d 
Days  
 28 to  1 
Induction (Cycles 14) e 
Maintenance (Cycles 5) 
 30 Days after 
Final Dose of 
Study 
Treatment 
90 Days after 
Final Dose of 
Study 
Treatment 
Day 1  
( 3 
Days) 
Day 8 
( 3 
days)  
Day 15 
( 3 
days)  
Day 
1 ( 3 
days) 
Day 8 
( 3 
days)  
Day 15 
( 3 
days)  
Arm B, participants with NSQ 
NSCLC: pembrolizumab    
pemetrexed  carboplatin 
 
x 
 
 
 
 
 
 
 
Arm B, participants with SQ 
NSCLC: pembrolizumab   
paclitaxel  
carboplatin 
 
x 
 
 
 
 
 
 
 
Maintenance treatment 
administration 
Arm A, participants with NSQ 
NSCLC:  tobemstomig  
 pemetrexed 
 
 
 
 
x 
 
 
 
 
Arm A, participants with SQ 
NSCLC:  tobemstomig 
 
 
 
 
x 
 
 
 
 
Arm B, participants with NSQ 
NSCLC:  pembrolizumab  
 pemetrexed 
 
 
 
 
x 
 
 
 
 
Arm B, participants with SQ 
NSCLC:  pembrolizumab  
 
 
 
 
x 
 
 
 
 
Tumor response u, v 
x 
Every 12 weeks ( 7 days) for 48 weeks following Day 1 of Cycle 1 and every 12 weeks 
( 7 days) thereafter, regardless of treatment delays 

Table 1 
Schedule of Activities (cont.) 
 
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26/Protocol BO44178, Version 4 
e During the induction phase, the number of chemotherapy cycles counts toward the prespecified number of induction cycles (four), provided that 
at least one chemotherapy component has been administered.  Cycles when no chemotherapy is given do not count toward the total number of 
induction chemotherapy cycles. 
f Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.   
g Medical history, including clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and use of drugs of abuse, and baseline medical conditions will be recorded at baseline. 
h Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature 
(see Table 6 for details regarding recording of vital signs during administration of study treatment).  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
i A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
j Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  New or worsened clinically significant 
abnormalities should be recorded as adverse events in the Adverse Event eCRF.  Limited physical examinations may be performed  96 hours 
before Day 1 of each cycle. 
k Status will be measured with use of the ECOG Performance Status Scale and may be performed  96 hours before Day 1 of each cycle. 
l Single 12-lead ECG is required at screening, at the treatment discontinuation visit, Cycle 1 and Cycle 5 predose and end of study treatment 
infusion (30 [ 10] minutes after completion) and when clinically indicated.  Electrocardiograms for each participant should be obtained from 
the same machine wherever possible.  Lead placement should be as consistent as possible.  Electrocardiogram recordings must be performed 
after the participant has been resting in a supine position for at least 10 minutes. 
m TTE or MUGA scan will be performed at screening if no scan is available within 6 months prior to randomization.  Scans may be repeated at the 
investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
n Hematology includes WBC count with differential (neutrophils, eosinophils, basophils, monocytes, lymphocytes), RBC count, hemoglobin, 
hematocrit, platelet count, and differential count.  Assessment may be performed  96 hours before Day 1 of each cycle. 
o Screening laboratory tests must be performed within 14 days prior to initiation of study treatment.  For details, refer to Section 5.1 (Inclusion 
Criteria). 
p Chemistry panel (serum) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, magnesium, 
potassium, chloride, calcium, phosphate, glucose, BUN or urea, creatinine, total protein, albumin, total bilirubin, ALP, ALT, AST, and lactate 
dehydrogenase.  Assessment may be performed  96 hours prior to Day 1 of each cycle.  
q Thyroid-stimulating hormone and free T3 (or total T3 at sites where T3 is not performed), and free T4 will be assessed at screening, on Day 1 of 
Cycle 1, every fourth cycle thereafter (e.g., Cycles 5, 9, 13, and so forth), and at treatment discontinuation.  Assessment may be performed  96 
hours prior to Day 1 of each cycle when it is required. 
r At screening, all patients will be tested for HIV, HbsAg, HbsAb, total HBcAb, and HCV antibodies.  If a patient has negative HBsAg and HBsAb 
tests and a positive total HBcAb test at screening, an HBV DNA test must also be performed.  If a patient has a positive HCV antibody test at 

Table 1 
Schedule of Activities (cont.) 
 
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27/Protocol BO44178, Version 4 
screening, an HCV RNA test must also be performed.  Individuals with a positive HIV test at screening are eligible, provided they are stable on 
anti-retroviral therapy, have a CD4 count   200/mL, and have an undetectable viral load.  
s Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).  Urinalysis is required at screening and will be obtained when 
clinically indicated.  Assessment may be performed  96 hours before Day 1 of each cycle. 
t All women of childbearing potential will have a serum pregnancy test during screening within 14 days prior to initiation of study drug.  
Urine pregnancy tests will be performed 96 hours prior to Day 1 of every cycle and at the study treatment discontinuation visit.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  An at-home pregnancy test will be provided.  The test has to be 
conducted 4 months after the final dose (for women of childbearing potential), and the site will inquire about the result during the second follow-
up visit. 
u All known sites of disease, including measurable and/or non-measurable disease, must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Screening and subsequent tumor assessments must include CT scans (with oral or IV contrast unless 
contraindicated).  A CT scan of the pelvis is required at screening and as clinically indicated or as per local standard of care at subsequent 
response evaluations.  MRI scans with contrast of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may be used for 
participants for whom CT scans with contrast are contraindicated (i.e., participants with contrast allergy or impaired renal clearance).  A CT (with 
contrast if not contraindicated) or MRI scan of the head must be performed at screening to evaluate CNS metastasis in all participants.  MRI 
scan of the brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  At subsequent 
(postscreening) tumor assessments, participants with a history of irradiated brain metastases at screening are not required to undergo brain 
scans unless clinically indicated (e.g., in participants with neurologic symptoms).  If a CT scan for tumor assessment is performed in a positron 
emission tomography/CT scanner, CT acquisition must be consistent with the standards for a full contrast diagnostic CT scan.  Further 
investigations, such as bone scans and CT scans of the neck, should also be performed if clinically indicated. 
v Participants will undergo tumor assessments at baseline and every 12 weeks ( 7 days) for 48 weeks following Day 1 of Cycle 1 regardless of 
treatment delays.  After the completion of the Week 48 tumor assessment, tumor assessments are required every 12 weeks ( 7 days) 
regardless of treatment delays until radiographic disease progression per RECIST v1.1 (see Appendix 10), withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.  Participants who are treated beyond disease progression per RECIST v1.1 will 
undergo tumor assessments every 12 weeks (2 weeks) after initial documentation of progression or more frequently, if clinically indicated, 
regardless of time in study, until treatment is discontinued.   
At the investigator’s discretion, scans may be performed at any time if progressive disease or loss of clinical benefit is suspected.  The 
investigator’s assessment of overall tumor response at all timepoints should be based on RECIST v1.1 only.  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 at the 
next cycle.  Participants who discontinue treatment for reasons other than radiographic disease progression (e.g., toxicity, symptomatic 
deterioration) will continue the same schedule of tumor assessments as described above until radiographic disease progression, withdrawal of 
consent, death, or study termination by Sponsor, whichever occurs first.  In the absence of radiographic disease progression, tumor assessments 
should continue regardless of whether a participant starts a new anti-cancer therapy.   

Table 1 
Schedule of Activities (cont.) 
 
Tobemstomig—F. Hoffmann-La Roche Ltd 
28/Protocol BO44178, Version 4 
w After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the final dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  All serious adverse events will continue to be reported until 
90 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  In addition, adverse 
events of special interest (refer to Section A3–5) will continue to be reported until 90 days after the final dose of study treatment, regardless of 
initiation of new systemic anti-cancer therapy.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor 
should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment.  
Every effort should be made to follow all serious adverse events considered to be related to study treatment or protocol-related procedures until 
a final outcome can be reported. 
x Medication (e.g., prescription drugs, over-the counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) and vaccines 
used by a patient in addition to protocol-mandated treatment used within 7 days prior to the initiation of study treatment should be documented.  
At subsequent visits, changes to current medications or medications used since the last documentation will be recorded. 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of 
tobemstomig (also known as RO7247669) in combination with platinum-based 
chemotherapy compared with pembrolizumab plus platinum-based chemotherapy in 
participants with previously untreated, locally advanced, unresectable (Stage IIIB/IIIC) or 
metastatic (Stage IV) nonsmall cell lung cancer (NSCLC) who are not eligible to receive 
curative surgery and/or definitive chemoradiotherapy. 
2.2 
BACKGROUND 
Lung cancer remains the leading cause of cancer deaths worldwide.  NSCLC accounts 
for approximately 85% of all cases of lung cancer (Molina et al. 2008; Howlader et al. 
2018).  NSCLC can be divided into two subcategories:  squamous (SQ) and 
non-squamous (NSQ).  SQ cell histology accounts for approximately 25% of NSCLCs 
(Langer et al. 2010).  NSQ NSCLC includes several histologic subtypes, the most 
common of which is adenocarcinoma, which accounts for more than half of all NSCLC 
cases.  The remaining cases of NSCLC are represented by other NSQ NSCLC 
histologies, including large cell carcinoma, neuroendocrine tumors, sarcomatoid 
carcinoma, and those with poorly differentiated histology. 
Standard of care treatment for patients with advanced NSQ NSCLC in the first-line 
setting is largely driven by results of molecular profiling.  The preferred first-line 
treatment for patients with tumors harboring an oncogenic driver mutation utilizes an 
approved targeted therapy, if available.  For patients whose tumors lack a targetable 
oncogenic aberration, current standard of care treatment regimens in the first-line setting 
typically consist of an immune checkpoint inhibitor (CPI), including programmed death1 
(PD-1) and programmed death-ligand 1 (PD-L1)blocking antibodies, with or without 
platinum-based doublet chemotherapy and bevacizumab.  The current standard of care 
for newly diagnosed patients with advanced-stage SQ NSCLC includes paclitaxel or 
gemcitabine in combination with a platinum agent. 
Despite significant advances with combination immunotherapy and the approval of 
immune CPI agents in combination with chemotherapy as first-line therapy for patients 
with advanced NSCLC, the majority of patients with advanced NSCLC progress during 
treatment and ultimately experience disease progression and succumb to this disease.  
Therefore, a high unmet medical need persists for patients with advanced NSCLC.  
To improve treatment outcomes for patients with NSCLC, multiple combinations with 
antiPD-L1 therapies are being assessed. 
Tobemstomig is a novel, fragment crystallizable (Fc)-silent IgG1-based bispecific 
antibody (BsAb) in a 1  1 format that incorporates monovalent binding to the checkpoint 
receptors, PD-1 and lymphocyte activation gene 3 (LAG3).  Use of a natural IgG-like 
monovalent heterodimeric IgG1 format allows the antibody to concurrently bind to PD-1 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
31/Protocol BO44178, Version 4 
and LAG3.  The tobemstomig BsAb is engineered to preferentially bind to T cells that 
co-express both PD-1 and LAG3 and to a lesser extent, either PD-1 or LAG3 alone.  
Monovalent binding to LAG3 reduces internalization of the antibody upon binding to the 
T-cell surface, and the retention time of tobemstomig on T-cell surface is higher when 
bound to PD-1 and LAG3.  PGLALA mutations have been introduced into the 
IgG1-based Fc region of tobemstomig.  This avoids drug-shaving and thus development 
of tumor-associated macrophage resistance mechanisms that have been observed with 
IgG4-based antibodies such as Keytruda (pembrolizumab) and Opdivo (nivolumab) 
(Arlauckas et al. 2017). 
A detailed description of the chemistry, pharmacology, and safety of tobemstomig is 
provided in the Tobemstomig Investigator’s Brochure. 
2.2.1 
The PD-L1/PD-1 Pathway 
Encouraging clinical data in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a 
significant survival benefit in patients with advanced malignancies (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012). 
The PD-1/PD-L1 pathway serves as an immune checkpoint to temporarily dampen 
immune responses in states of chronic antigen stimulation, such as chronic infection or 
cancer.  PD-1 is an inhibitory receptor that is expressed on activated and exhausted 
T cells, including tumor-infiltrating CD8  T cells that recognize mutated tumor antigens 
(neo-antigens).  Binding of PD-L1 to PD-1 inhibits T-cell proliferation, activation, cytokine 
production, and cytolytic activity, leading to a functionally inactivated and exhausted 
T-cell state (Butte et al. 2007; Yang et al. 2011).  Therapeutic targeting of the 
PD-1/PD-L1 pathway to enhance anti-tumor T-cell responses has been clinically 
validated across multiple solid tumors when given both as a single-agent treatment and 
in combination with chemotherapy and other targeted agents. 
2.2.2 
The LAG3 Pathway 
LAG3 is an immune checkpoint protein involved in the regulation of anti-tumor immunity 
and chronic infection.  LAG3 is expressed on activated T cells, B cells, natural killer 
cells, and a subset of tolerogenic plasmacytoid dendritic cells, and constitutively on 
T-regulatory cells (Huard et al. 1994).  Structurally similar to CD4, LAG3 is a member of 
the Ig superfamily and binds to major histocompatibility complex class II (MHC-II).  
The interaction of LAG3 with MHC-II inhibits T-cell proliferation, activation, cytolytic 
function, and proinflammatory cytokine production (Goldberg and Drake 2011).  
The effect of LAG3 expression on T-regulatory cells is controversial.  An early report 
concluded that LAG3 expression promotes T-regulatory cellmediated immune 
suppression (Camisaschi et al. 2010).  However, a more recent report describes LAG3 
limiting T regulatory cellmediated immune suppression (Zhang et al. 2017). 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
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Expression of LAG3 has been reported across various tumor types, including NSCLC, 
hepatocellular carcinoma, breast cancer, ovarian cancer, melanoma, renal cell 
carcinoma, and prostate cancer, and is associated with poor prognosis (Matsuzaki et al. 
2010; Baitsch et al. 2011; Thommen et al. 2015; He et al. 2016; Norström et al. 2016).  
Clinical evaluation of anti-LAG3 agents, given as a single agent and in combination with 
other CPIs, is ongoing in several early-phase studies in patients with advance solid 
tumors (Long et al. 2018).  Preliminary data demonstrate that anti-LAG3 therapy is well 
tolerated as a single agent and in combination with antiPD-1 therapies, and the safety 
profiles were consistent with those of other CPI treatments (Ascierto et al. 2017; 
Hong et al. 2018; Stratton et al. 2018). 
Taken together, therapeutic targeting of LAG3 may represent an attractive strategy for 
the treatment of patients with NSCLC. 
2.3 
BENEFIT–RISK ASSESSMENT 
The purpose of this study is to assess the efficacy, safety, and pharmacokinetics of 
tobemstomig, a novel immunomodulating therapy, in combination with platinum-based 
chemotherapy to address a significant unmet medical need in patients with previously 
untreated, locally advanced unresectable (Stage IIIB/IIIC) or metastatic (Stage IV) 
NSCLC who are not eligible for curative surgery and/or definitive chemoradiotherapy. 
Patients with advanced or metastatic solid tumors present a great unmet need.  Benefit 
from cancer immunotherapy with CPI monoclonal antibodies, such as those targeting 
PD-1/ PD-L1, is predominantly observed in a subset of patients with inflamed tumor 
phenotypes.  However, response is not guaranteed even in this patient subset owing to 
either primary or acquired resistance mechanisms.  Upregulated LAG3 expression on 
T cells is associated with T-cell dysfunction, potentially resulting in adaptive resistance to 
antiPD-1/PD-L1 therapies (Sharma et al. 2017).  Therefore, LAG3 blockade of 
tumor-infiltrating lymphocytes (TILs) may overcome or prevent resistance mechanisms 
to antiPD-1/PD-L1 and help restore or increase T-cell proliferation and cytotoxic 
effector functions. 
Tobemstomig concurrently targets two dominant immune-checkpoint receptors, PD-1 
and LAG3.  Such targeting may serve to overcome resistance by means of synergic 
ligand blockade and subsequent re-invigoration of TILs, regardless of T-regulatory cells, 
and potentially delay or prevent the development of LAG3-mediated adaptive resistance 
mechanisms.  
Up to the clinical cut-off date of 1 March 2022, tobemstomig has been tolerated at doses 
of up to 2100 mg every 2 weeks (Q2W); AEs have been manageable, and the safety 
profile is observed to be consistent across different solid tumor indications including 
NSCLC as well as with approved PD-1 directed antibodies.  

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
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Relevant efficacy and safety data up to the data cut-off date of 1 March 2022 for 
tobemstomig are currently available from Study NP41300, a Phase I study in patients 
with advanced and/or metastatic solid tumors.  
In the dose escalation part of the study NP41300 the disease control rate (DCR) was 
51.4% (18 of 35 evaluable participants) and the objective response rate (ORR) was 
17.1% (6 of 35 participants).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
Preliminary clinical results suggest that combination treatment with antiPD-1 
(nivolumab) and anti-LAG3 (relatlimab) agents has the potential for increased benefit 
compared with antiPD-1 therapy alone, while having an acceptable safety profile 
similar to the safety profile of nivolumab monotherapy.  In patients with advanced 
melanoma previously treated with antiPD-1/PD-L1 therapy, the objective response rate 
(ORR) of the combination was 11.5% (n  61), with a disease control rate of 49% 
(Ascierto et al. 2017). 
Tawbi et al. (2022) reported results from the completed Phase III trial, RELATIVITY-047 
(CA224-047; NCT03470922), assessing the efficacy and safety of dual inhibition of 
LAG3 and PD-1 therapies in combination with relatlimab, a human IgG4 LAG3-blocking 
antibody, and nivolumab, a PD-1–blocking antibody, compared with standard-care 
nivolumab alone.  The study enrolled 714 previously untreated patients with 

 
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histologically confirmed, unresectable Stage III or IV melanoma.  Patients were stratified 
according to LAG3 expression, PD-L1 expression, BRAF mutation status, and metastatic 
stage.  The primary efficacy endpoint was PFS, as determined by blinded independent 
central review (BICR) per Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1).  Secondary endpoints included overall survival (OS) and ORR (Tawbi et 
al. 2022).  
Blinded independent assessment of PFS was longer with relatlimab plus nivolumab than 
with nivolumab.  Patients treated with relatlimab plus nivolumab had twice the median 
PFS and a 25% lower risk of disease progression or death than nivolumab alone 
(hazard ratio [HR]: 0.75; p  0.006 by the log-rank test).  A 12% difference in landmark 
PFS between the groups was observed at 12 months.  The longer PFS with relatlimab 
plus nivolumab than with single-agent nivolumab was associated with a slightly greater 
incidence of adverse events and a health-related quality of life (HRQoL) measures 
similar to that observed with nivolumab.  Combination treatment with relatlimab and 
nivolumab also showed a PFS benefit over nivolumab in prespecified subgroups.  
Patients with characteristics that are typically associated with a worse prognosis, such 
as visceral metastases, high tumor burden, elevated levels of serum lactate 
dehydrogenase, or mucosal or acral melanoma, had improved outcomes.  Expression of 
LAG3 or PD-L1 was not predictive of PFS benefit with combination treatment with 
relatlimab plus nivolumab over nivolumab.  However, a benefit of combination treatment 
with relatlimab and nivolumab over nivolumab was observed across BRAF-mutant and 
wild-type subgroups (Tawbi et al. 2022).  
Confirmed ORR by BICR was numerically increased from 32.6% (95% CI: 27.8 to 37.7) 
with nivolumab alone to 43.1% (95% CI: 37.9 to 48.4) in the relatlimab plus nivolumab 
treatment group.  Moreover, a non-statistically significant improvement in OS was also 
observed with relatlimab plus nivolumab over nivolumab alone corresponding to an HR 
of 0.80 (95% CI: 27.8 to 37.7).  Median OS was not reached (95% CI: 34.2 to not 
reached) compared with 34.1 months (95% CI: 25.2 to not reached), respectively.  
A total of 470 patients (65.8%) discontinued treatment (237 patients [66.8%] in the 
relatlimab plus nivolumab group and 233 patients [64.9%] in the nivolumab group), with 
most discontinuations attributed to disease progression (reported in 36.3% and 46.0% of 
patients, respectively) (Tawbi et al. 2022).  
Infusion-related adverse reactions occurred in 5.9% of patients who received 
combination treatment with relatlimab and nivolumab compared with 3.6% of patients 
who received nivolumab.  Grade 3 or 4 treatment-related adverse events occurred in 
18.9% of patients in the relatlimab plus nivolumab group and in 9.7% in the nivolumab 
group.  The most common Grade 3 or 4 treatment-related adverse events in the 
relatlimab plus nivolumab group included increased levels of lipase (in 1.7% of the 
patients), ALT (1.4%), and AST (1.4%), as well as fatigue (1.1%).  Treatment-related 
adverse events (of any grade) leading to discontinuation were experienced by 14.6% of 

 
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patients in the relatlimab plus nivolumab group compared with 6.7% of those in the 
nivolumab group.  In all, five treatment-related deaths were reported and considered by 
investigators to be related to treatment:  three deaths in patients in the relatlimab plus 
nivolumab group (0.8%) (hemophagocytic lymphohistiocytosis, acute pulmonary edema, 
and pneumonitis) and two deaths in the nivolumab group (0.6%) (sepsis and myocarditis 
in 1 patient and pneumonia in 1 patient).  The most common categories of 
immune-related adverse events reported in the relatlimab plus nivolumab group were 
hypothyroidism or thyroiditis (in 18.0% of the patients), rash (9.3%), and diarrhea or 
colitis (6.8%) (Tawbi et al. 2022). 
Given that the mechanisms for optimal targeting of immune regulation in the tumor 
environment are still under exploration, rational new approaches to increase response 
rates to first-line CPI therapy are warranted.  Untreated patients with advanced and 
metastatic NSCLC may benefit from first-line treatment with a PD-1/LAG3 BsAb if in fact 
the additional targeting of LAG3 conveys additive anti-tumor activity beyond that 
expected with PD-1 targeting alone. 
Treatment-related adverse events with antiPD-1 CPI monotherapy include events 
associated with autoimmune activation, such as thyroiditis, hepatitis, colitis, 
nephrotoxicity, adrenal insufficiency, pneumonitis, and less commonly, neurotoxicity, and 
myocarditis.  The costimulatory action of tobemstomig on PD-1 and LAG3 receptors, 
might bear the risk of exaggerated immune cell (IC) activation, particularly given LAG3 
modulation.  The preliminary data from recent early-phase studies of anti-LAG3 
antibodies showed generally anti-LAG3 therapy was well tolerated given as a 
monotherapy and in combination with antiPD-1 therapies and that the safety profile was 
consistent with that of the other CPI agents (Ascierto et al. 2017; Hong et al. 2018; 
Stratton et al. 2018). 
Precautions against general risks for patients have been taken into account in the safety 
measures in this study, which include stringent inclusion and exclusion criteria 
(Section 5) and rules for treatment interruption and withdrawal from the study 
(Section 7).  The re-invigorating action of tobemstomig on immune effector cells may 
result in the occurrence of enhanced, untoward, immune-mediated adverse events and 
increase in cytokine releasemediated toxicities.  Recommendations for prophylaxis and 
management of specific and known PD-1/PD-L1mediated adverse events are 
presented in Appendix 6. 
Administration of therapeutic antibodies may cause infusion-related reactions (IRRs) and 
the formation of anti-drug antibodies (ADAs).  IRR is an identified risk associated with 
tobemstomig that has been reported across the tobemstomig clinical development 
program, most commonly at mild-to-moderate severity or intensity.  Additionally, 
 
 

 
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In a nonGood Laboratory Practice (GLP), dose rangefinding, pharmacokinetic (PK) 
and progressive disease study and a 4-week GLP study in cynomolgus monkeys, ADA 
development was observed independent of dose.  No adverse findings were observed, 
and no toxicity related to ADA formation was observed.  To date, no ADA impact on 
exposure has been detected at the population level.   Any clinical signs and symptoms 
suggestive of a hypersensitivity reaction, in particular an immune complexmediated 
reaction, will be carefully investigated.  Participants with these signs and symptoms will 
be monitored for development of ADA formation. 
Refer to Appendix 6 for information on the anticipated risks for tobemstomig and 
risk-mitigation measures, including guidelines for managing adverse events associated 
with tobemstomig. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of tobemstomig are presented in the Tobemstomig 
Investigator’s Brochure. 
Based on the considerations above, and the planned safety monitoring and 
management guidance, the proposed study treatments are considered to have an 
appropriate benefitrisk profile for the population included in this study. 
COVID-19 BenefitRisk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities (including those with cancer) are a more vulnerable population.  Infection 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses.  It is unclear how immunotherapy affects the incidence or 
severity of COVID-19.  It is not anticipated that treatment with tobemstomig will increase 
the risk of infection with SARS-CoV-2.  Severe COVID-19 is associated with cytokine 
release syndrome (CRS) involving the inflammatory cytokines interleukin‑6, 
interleukin‑10, interleukin‑2, and interferon-.  Tobemstomig has a low-risk of CRS and, 
while it is not known, there may be a potential for an increased risk of an enhanced 
inflammatory response if a participant develops SARS‑CoV-2 infection while receiving 
tobemstomig.  At this time, there is insufficient evidence for causal association between 
tobemstomig and an increased risk of severe outcomes from COVID-19. 
There are limited data concerning the possible interactions between cancer 
immunotherapy and COVID‑19 vaccination, and it is recognized that human immune 
responses are highly regulated and that immune-modifying therapies may positively or 
negatively affect the efficacy and safety of COVID‑19 vaccination (Society for 
Immunotherapy of Cancer [SITC] 2020). 

 
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Per recommendations of the National Cancer Comprehensive Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID‑19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune CPIs), with the 
understanding that there are limited safety and efficacy data in such patients (NCCN 
2021).  Given the lack of clinical data, currently no recommendations can be made 
regarding the optimal sequence of COVID‑19 vaccination in patients who are receiving 
cancer immunotherapy (SITC 2020).  For patients enrolling in this study and receiving 
tobemstomig, a decision to administer the vaccine to a participant should be made by 
the investigator on an individual basis in consultation with the participant. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving tobemstomig to receive COVID‑19 
vaccination include the following:  the risk of SARS-CoV-2 infection and potential 
benefits from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID‑19 vaccines.  When 
administered, COVID‑19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  In this study, receipt of a COVID‑19 vaccine is considered a 
concomitant medication and should be documented as such (see Section 6.8.1). 
3. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
This Phase II study will evaluate the efficacy, safety, and pharmacokinetics of 
tobemstomig in combination with platinum-based chemotherapy (Arm A) compared with 
pembrolizumab plus platinum-based chemotherapy (Arm B) in participants with 
previously untreated, locally advanced, unresectable (Stage IIIB/IIIC) or metastatic 
(Stage IV) NSCLC who are not eligible to receive curative surgery and/or definitive 
chemoradiotherapy.  
In this protocol, “study treatment” refers to the combination of treatments assigned to 
patients as part of this study (i.e., tobemstomig or pembrolizumab in combination with 
pemetrexed and carboplatin or paclitaxel and carboplatin). 
Table 3 presents the primary objectives for the study expressed using the estimand 
framework in accordance with the International Council for Harmonisation (ICH) E9(R1) 
statistical principles for clinical trials (ICH 2020).  Table 4 presents the secondary and 
exploratory objectives and corresponding endpoints. 

 
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Table 3 
Primary Objectives and Corresponding Estimands 
Primary Objectives 
Estimand Definitions 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 Population:  participants with previously untreated, locally 
advanced, unresectable NSCLC who are ineligible for 
definitive chemoradiotherapy (Stage IIIB/IIIC) or 
metastatic (Stage IV) NSCLC of SQ or NSQ histology 
with no known EGFR or ALK genomic tumor aberrations 
(Refer to Section 5.2)  
 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 
RECIST v1.1 
 Treatment 
 
Experimental arm 
NSQ NSCLC:  tobemstomig in combination with 
pemetrexed and carboplatin, followed by 
maintenance tobemstomig with pemetrexed 
SQ NSCLC:  tobemstomig in combination with 
paclitaxel and carboplatin, followed by 
tobemstomig 
 
Control arm 
NSQ NSCLC:  pembrolizumab in combination with 
pemetrexed and carboplatin, followed by 
maintenance pembrolizumab with pemetrexed  
SQ NSCLC:  pembrolizumab in combination with 
paclitaxel and carboplatin, followed by 
pembrolizumab  
 Intercurrent events and handling strategies: 
 
Early discontinuation from study treatment for any 
reason prior to the respective event of interest:   
treatment policy strategy 
 
Start of nonprotocol-specified anti-cancer therapy 
prior to the respective event of interest:  treatment 
policy strategy 
 Population-level summary:  hazard ratio for PFS 
ALK  anaplastic lymphoma kinase; EGFR  epidermal growth factor receptor; 
HRQoL  health-related quality of life; PFS  progression-free survival; NSCLC  nonsmall cell lung 
cancer; NSQ  non-squamous; ORR  objective response rate; OS  overall survival; 
SQ  squamous; RECIST  Response Evaluation Criteria in Solid Tumors, Version 1.1. 

 
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Table 3 
Primary Objectives and Corresponding Estimands (cont.) 
Primary Objectives 
Estimand Definitions 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B)  
 Population:  as defined above; participants must have 
measurable disease at baseline, as determined by the 
investigator according to RECIST v1.1 
 Endpoint:  ORR, defined as the proportion of participants 
with a complete response or a partial response on two 
consecutive occasions  4 weeks apart, as determined by 
the investigator according to RECIST v1.1 
 Treatment:  as defined above 
 Intercurrent events and handling strategies:  as defined 
above 
 Population-level summary:  difference in ORR 
ALK  anaplastic lymphoma kinase; EGFR  epidermal growth factor receptor; 
HRQoL  health-related quality of life; PFS  progression-free survival; NSCLC  nonsmall cell 
lung cancer; NSQ  non-squamous; ORR  objective response rate; OS  overall survival; 
SQ  squamous; RECIST  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
 
 
 

 
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Table 4 
Secondary and Exploratory Objectives and Endpoints 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of 
tobemstomig in combination with 
platinum‑based chemotherapy 
(Arm A) compared with 
pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 OS after randomization, defined as the time from 
randomization to death from any cause  
 Duration of response for participants with confirmed 
objective response, defined as the time from the first 
occurrence of a confirmed objective response to 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1  
 PFS and OS in participants with PD-L1 expression, 
 Change from baseline to Week 12 in patient-reported 
outcomes of lung cancer symptoms, physical 
functioning, role functioning, and global health 
status/quality of life, as assessed through the use of 
the European Organisation for Research and 
Treatment of Cancer Item Libraries 
 To evaluate the safety of 
tobemstomig plus platinum‑based 
chemotherapy (Arm A) compared 
with pembrolizumab plus 
platinum‑based chemotherapy 
(Arm B) 
 Incidence and severity of adverse events, with severity 
determined according to the NCI CTCAE, Version 5.0 
 The severity of cytokine release syndrome will be 
determined according to the ASTCT Consensus 
Grading Scale. 
 To investigate the 
pharmacokinetics of tobemstomig 
 PK profiles and parameters derived for tobemstomig, 
including, but not limited to, the following parameters, 
as appropriate and when data allow: 
– Maximum concentration 
– Time of maximum concentration 
– Clearance  
– Volume of distribution at steady state 
– Area under the concentration time curve 
– Half‑life 
 Concentrations of tobemstomig in serum at 
specified timepoints 
 To evaluate the immune response 
to tobemstomig 
 Prevalence of ADAs to tobemstomig at baseline and 
incidence of ADAs to tobemstomig during the study 
ADA  anti-drug antibody; ASTCT American Society of Transplantation and Cellular Therapy; 
NCI  National Cancer Institute; OS  overall survival; PD‑L1  programmed deathligand 1; 
PFS  progression‑free survival; PK  pharmacokinetic; RECIST v1.1  Response Evaluation 
Criteria in Solid Tumors, Version 1.1;

 
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4.2 
OVERALL DESIGN
This is a randomized, Phase II, global, multicenter, double-blind study designed to 
evaluate the efficacy, safety, and pharmacokinetics of tobemstomig in combination with 
platinum-based chemotherapy compared with pembrolizumab plus platinum-based 
chemotherapy in patients with previously untreated, locally advanced unresectable 
(Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who are not eligible for curative surgery 
and/or definitive chemoradiotherapy.

 
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Approximately 180 patients will be randomized in the study in a 1:1 ratio to receive either 
tobemstomig plus platinum-based chemotherapy (Arm A) or pembrolizumab plus 
platinum-based chemotherapy (Arm B) as follows: 
 
Arm A (n  ~90):  Tobemstomig plus platinum-based chemotherapy 
 
Participants with NSQ NSCLC will receive induction treatment with blinded 
tobemstomig in combination with pemetrexed and carboplatin, all on Day 1 
every 3 weeks (Q3W) for four 21-day cycles, followed by Q3W maintenance 
therapy with blinded tobemstomig together with pemetrexed until disease 
progression or treatment discontinuation for a maximum of 24 months of 
treatment. 
 
Participants with SQ NSCLC will receive blinded tobemstomig in combination 
with paclitaxel and carboplatin, all on Day 1 Q3W for four 21-day cycles, 
followed by blinded tobemstomig (on Day 1) Q3W until disease progression or 
treatment discontinuation for a maximum of 24 months of treatment. 
 
Arm B (n  ~90):  Pembrolizumab plus platinum-based chemotherapy 
 
Participants with NSQ NSCLC will receive induction treatment with blinded 
pembrolizumab in combination with pemetrexed and carboplatin, all on Day 1 
Q3W for four 21-day cycles, followed by a maintenance therapy with blinded 
pembrolizumab together with pemetrexed Q3W until disease progression or 
treatment discontinuation for a maximum of 24 months of treatment. 
 
Participants with SQ NSCLC will receive blinded pembrolizumab in 
combination with paclitaxel and carboplatin, all on Day 1 Q3W for four 21-day 
cycles, followed by blinded pembrolizumab (on Day 1) Q3W until disease 
progression or treatment discontinuation for a maximum of 24 months of 
treatment. 
 
An overview of the study is presented in Figure 1.  The schedule of activities is provided 
in Section 1.3, Table 1. 
 
 
The study will consist of three phases: screening, treatment, and follow-up. 
4.2.1 
Screening Phase 
After providing informed consent, patients will be evaluated for study eligibility during a 
28-day screening period (Days  28 to  1), as presented in the schedule of activities 
(see Section 1.3, Table 1).  Patients who are determined to be eligible on the basis of 
screening assessments will be randomized to study treatment. 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per patient) at the 
investigator's discretion.  Patients are required to re-sign the Informed Consent Form if 
they are re-screened.  For patients who are re-screened, all eligibility criteria must be 
re-evaluated and the screening assessment should be repeated as applicable to meet 

 
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the eligibility criteria.  The investigator will maintain a record of reasons for screen 
failure. 
Patients whose tumors have a known EGFR mutation or ALK genetic aberrations will be 
excluded from the study.  Patients with tumors of non-squamous histology with unknown 
EGFR or ALK mutational status will be required to be tested (by local or central testing 
with a validated health authority approved test or CE-marked test in the European Union 
per the assay’s intended use according to local laws and regulations) prior to enrollment.  
Patients with tumors of squamous histology who have an unknown EGFR or ALK 
mutational status will not be required to be tested at pre-screening/screening.  
4.2.2 
Treatment Phase 
Approximately 180 participants will be randomly assigned to each treatment arm in a 
1:1 ratio, enrolling approximately 90 participants per Arm.  The study treatment regimens 
and instructions for administration are presented in Section 6.1.   
 
 
 
 
 
 
For additional details on treatment assignment and blinding, refer to Section 6.3. 
4.2.3 
Safety Run-In Evaluation 
An initial safety run-in evaluation will be implemented to assess the safety and 
tolerability of the novel combination of blinded tobemstomig and chemotherapy.  During 
the safety run-in evaluation, a minimum of 
 participants with NSCLC of each histology 
(SQ and NSQ) are required.  This would comprise a minimum of 
participants per 
histology per arm, corresponding to a total of approximately 
participants.  These 
participants will be evaluated for safety after they have had the opportunity to complete 

 
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two cycles of treatment.  Participants from each 
patient group who withdraw from 
treatment before completing two cycles of treatment will also be included in the safety 
run-in evaluation.  After enrollment of the first 
patients per histology group, 
randomization will continue but will be temporarily suspended if a cap of 
participants 
per NSCLC histology (approximately 
participants in Arm A and 
in Arm B) is 
reached before the safety run-in is cleared by an Internal Monitoring Committee (IMC).  
The safety run-in evaluation will be performed by the IMC.  The Sponsor may conduct 
one IMC review per histology or a combined IMC review of data arising from both 
histologies, according to the recruitment rate per histology.  If enrollment of participants 
with a specific histology is suspended as a result of reaching the 
participant 
enrollment cap, it will be resumed following the IMC’s review, taking into consideration 
any recommendations from that review.  No crossover will be allowed from the control 
arm to the experimental arms. 
 
 
 
 
 
 
 
 
 
 
  
4.2.4 
Assessments 
Participants will undergo a series of assessments as detailed in the schedule of activities 
(see Section 1.3, Table 1) 
 
  As a result of the 
 
the schedule of activities has been changed. 

 
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Tumor assessments will be performed at baseline and every 12 weeks ( 7 days) 
regardless of treatment dose delays, until radiographic disease progression per 
Response Criteria in Solid Tumors, Version 1.1 (RECIST v1.1; see Appendix 10), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
Participants who are treated beyond disease progression per RECIST v1.1 will undergo 
tumor assessments every 12 weeks ( 2 weeks) after initial documentation of 
progression, or more frequently if clinically indicated, regardless of time in the study, until 
treatment is discontinued.   
Participants who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments at the same frequency as would have been followed if the 
participant had continued study treatment (i.e., every 12 weeks [ 7 days], until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, study 
termination by the Sponsor, or death, whichever occurs first), regardless of whether the 
patient starts a new anti-cancer therapy.   
Participants randomized into the study will be asked to complete PRO questionnaires 
(see Section 1.3, Table 1).  Item Libraries (ILs) 85, 132, 188, and 17 from the European 
Organisation for Research and Treatment of Cancer (EORTC) will assess symptoms of 
lung cancer (i.e., fatigue, cough, chest pain, bone pain, and dyspnea), physical and role 
functioning, and global HRQoL.  Selected items from the National Cancer Institute (NCI) 
Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) and the EORTC IL46 will focus on presence, frequency of occurrence, 
severity, and/or degree of interference with daily function and bother of symptomatic 
treatment toxicities related to treatment with tobemstomig, pembrolizumab, and 
chemotherapy.  As a result of the 
 PRO 
assessments for all remaining patients will no longer be required. 
Safety assessments at study visits will include the incidence, nature, and severity of 
adverse events, protocol-mandated vital signs, laboratory abnormalities, and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study.  
The severity of adverse events will be assessed by investigators according to the 
NCI Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), 
with the exception of CRS; the severity of CRS will be determined according to the 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus 
Grading Scale (Lee et al. 2019). 
During the study,
(see Section 1.3, Table 2).  Participant samples, including archival and 
fresh tumor tissue, serum, plasma, and blood samples, were to be collected for 

 
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exploratory biomarker assessments, but, as a result of the 
 
 samples for exploratory biomarker assessments will no longer be collected. 
4.2.5 
Treatment Beyond Progression 
During the study, participants who meet the criteria for disease progression as assessed 
by the investigator according to RECIST v1.1 (see Appendix 10) and show evidence of 
clinical benefit may continue treatment with tobemstomig or pembrolizumab for up to 
24 months as part of the study at the investigator’s discretion, provided that participants 
meet all of the following criteria: 
 
Evidence of clinical benefit: 
– 
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease 
– 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) 
Performance Status that can be attributed to disease progression 
– 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
The participant must provide written informed consent to acknowledge deferring 
other treatment options in favor of continuing study treatment at the time of initial 
radiographic progression per RECIST v1.1 
 
Investigator assessment of overall tumor response at all timepoints will be based only on 
RECIST v1.1 (see Appendix 10).  However, the size of measurable new lesions will also 
be captured in the eCRF. 
4.2.6 
Safety Follow-Up Phase 
After participants discontinue study treatment, they will be followed for safety for 
90 days. 
4.2.7 
Safety Monitoring 
safety will be monitored at regular intervals by the 
study team. 
4.3 
RATIONALE FOR ORIGINAL STUDY DESIGN 
Lung cancer remains the leading cause of cancer deaths worldwide.  In the 
United States, it was estimated that there were 228,820 new cases of lung cancer in 
2019 and 135,720 lung cancer deaths (Siegel et al. 2020).  Similar data from Europe 
estimated that in 2018, there were 387,900 lung cancer deaths (Ferlay et al. 2018).  
Despite significant advances with combination immunotherapy and the approval of 
immune CPI agents in combination with chemotherapy as first-line therapy for patients 
with advanced NSCLC.  The majority of patients with advanced NSCLC progress while 
receiving currently available treatment and ultimately experience disease progression 
and succumb to this disease.  Therefore, a high unmet medical need persists for 

 
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patients with advanced NSCLC.  To improve treatment outcomes for patients with 
NSCLC, multiple combinations with antiPD-1/PD-L1 agents are being assessed (for 
previous discussion, see Section 2.3). 
A detailed description of the chemistry, pharmacology, and safety of tobemstomig is 
provided in the Tobemstomig Investigator’s Brochure.  
4.3.1 
Rationale for Study Population 
This study will enroll previously untreated individuals with locally advanced unresectable 
(Stage IIIB/IIIC) or metastatic (Stage IV) NSQ or SQ NSCLC who are not eligible for 
curative surgery and/or definitive chemoradiotherapy.  Patients without known EGFR or 
ALK genetic aberrations with any level of PD-L1 expression are eligible for enrollment.  
Patients whose tumors have a known EGFR mutation or ALK genetic aberrations will be 
excluded from the study.  Patients with tumors of non-squamous histology with unknown 
EGFR or ALK mutational status will be required to be tested (by local or central testing 
with a validated health authority-approved test or CE-marked test in the EU per the 
assay’s intended use according to local laws and regulations) prior to enrollment.  
Patients with tumors of squamous histology who have an unknown EGFR or ALK 
mutational status will not be required to be tested at pre-screening/screening. 
Expression of LAG3 has been reported across various tumor types, including breast, 
ovarian, NSCLC, melanoma, renal, and prostate (Matsuzaki et al. 2010; Baitsch et al. 
2011; Thommen et al. 2015; He et al. 2016; Norström et al. 2016).  LAG3 is frequently 
co-expressed with PD-1 on TILs, and dual blockade of PD-1 and LAG3 has been shown 
to enhance CD8+ T-celleffector function and potentiate anti-tumor immunity in 
preclinical mouse models.  Given the available extensive clinical data and approval of 
CPI agents (alone or in combination with chemotherapy) for the treatment of patients 
with NSCLC in the first-line setting, tobemstomig with its blocking action of both PD-1 
and LAG3 is hypothesized to generate additional benefit over the combination containing 
only a PD-1 CPI and in a broad NSCLC patient population. 
4.3.2 
Rationale for Testing Tobemstomig in Combination with 
Platinum-Based Chemotherapy in Participants with NSCLC 
across All PD-L1 Expression Subgroups and Histologies 
Several Phase III studies (Gandhi et al. 2018; Paz-Ares et al. 2018; Socinski et al. 2018; 
West et al. 2019) have demonstrated the benefit of immunotherapy combined with 
chemotherapy in patients with NSQ NSCLC regardless of PD-L1 expression.  This 
Phase II study design is based on the hypothesis that tobemstomig in combination with 
platinum-based chemotherapy may improve overall ORR and prolong progression-free 
survival (PFS) compared with pembrolizumab plus platinum-based chemotherapy in 
patients with NSCLC in the first-line setting. 

 
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4.3.6 
Rationale for Exclusion of Patients with an EGFR Mutation or 
ALK Rearrangements 
Patients with tumors harboring an EGFR mutation or ALK rearrangements are not 
eligible for enrollment in this study.  Genotype-directed therapy, rather than 
immunotherapy, remains the standard of care in the first-line treatment setting for such 
patients. 
4.3.7 
Rationale for Confirmed Objective Response Rate and 
Progression-Free Survival as Primary Endpoints 
Confirmed ORR is a common primary endpoint in proof-of-concept Phase II studies 
given its usefulness as an early indicator of clinical activity (Food and Drug 
Administration [FDA] 2007; European Medicines Agency [EMA] 2012).  
Although confirmed ORR can reflect tumor growth and can be assessed earlier and with 
a smaller sample size compared with survival studies, confirmed ORR may not always 
correlate with survival. 
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit.  In addition, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the 
effect and the benefitrisk profile of the new treatment compared with available therapies 
(EMA 2012; FDA 2018). 
 
 
 
 
 
 
4.3.9 
Rationale for Collection of Information on Race and 
Ethnicity 
Data pertaining to participant race and ethnicity represents a component of the broad 
demographic profile of the study population.  Collection of demographic data, including 
information on race and ethnicity, is of importance to the future interpretation of 
results from the clinical trial, including identification of potential differences in 
efficacy, safety, and pharmacokinetics among participants.  Collection of race and 
ethnicity data may enable investigation of potential relationships between biomarkers 
and race or ethnicity, including determination of whether race or ethnicity could be a 
prognostic factor.  Collection of these data may also contribute to a better 
understanding of the distribution of NSCLC according to race or ethnicity. 

 
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4.3.10 
Rationale for Exploratory Safety Biomarker Assessments 
Tobemstomig is a novel IgG1-based BsAb that targets the checkpoint receptors PD-1 
and LAG3 on immune effector cells, particularly T cells, with the aim to reinvigorate 
T cells.  The costimulatory action of tobemstomig on PD-1 and LAG3 receptors might 
bear the risk of exaggerated immune cell activation, particularly given LAG3 modulation.  
This may result in the occurrence of enhanced or untoward immune-mediated adverse 
events.  Immune-mediated adverse events can involve any organ or tissue, although 
some events occur much more frequently than others (for details, refer to the 
Tobemstomig Investigator’s Brochure). 
The mechanisms that result in immune-mediated adverse events with CPI therapies are 
still being elucidated and are likely to be multifactorial (e.g., increasing T-cell activity 
against antigens that are present in tumors and healthy tissue, expansion of 
T cellreceptor diversity and expansion of T-cell clones, increased levels of pre-existing 
autoantibodies, and an increase in the level of inflammatory cytokines (Sullivan et al. 
2018).  Understanding the mechanisms of such side effects and how they can be used 
to distinguish between the anti-tumor effects of CPI agents, as well as to identify 
biomarkers that may be predictive of development of immune-related toxicities, will 
facilitate the conduct of trials to limit their onset and improve patient outcomes (Friedman 
and Postow 2016). 
In this study, exploratory research on safety biomarkers may be conducted to support 
future drug development and to understand the mechanistic basis of immune-mediated 
adverse events.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
The samples for assessment are presented in Section 8.7 and may be used for this 
exploratory research.  Adverse event reports will not be derived from safety biomarker 
data by the Sponsor, and safety biomarker data will not be included in the formal safety 
analyses for this study.  In addition, safety biomarker data will not be used to inform 
decisions on patient management. 
4.3.11 
Rationale for Exploratory Biomarker Assessments 
Exploratory biomarker analysis will be performed in an effort to understand the 
association of such markers with study treatment response, efficacy (including 
pathological response), and/or adverse events.  The tumor biomarkers from tissue and 
blood samples include, but are not limited to, PD-L1, CD-8, LAG3, tumor mutational 
burden, and circulating tumor DNA.  Methods for assessment include, but are not limited 
to, IHC, gene expression, etc. 
4.3.12 
Rationale for Whole Genome and Whole Exome Sequencing 
Blood samples that were collected for DNA extraction under previous versions of the 
protocol may be used to enable whole genome sequencing (WGS) or whole exome 

 
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sequencing (WES) with a special focus on germline to identify variants that are 
predictive of response to study drug, are associated with progression to a more severe 
disease state, are associated with acquired resistance to study drug, 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.  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 that may be predictive of which patients 
are more likely to respond to a drug or develop adverse events.  Data will be analyzed in 
the context of this study but may 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.  In this study, blood samples that have been obtained under previous 
versions of this protocol may be submitted for WGS or WES and are contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body (see Section 8.10.3.2). 
4.3.13 
Rationale for Patient-Reported Outcome Assessments 
In the treatment of lung cancer, it is important to increase both survival and palliate 
symptoms since disease symptoms negatively impact HRQoL (Hyde and Hyde 1974; 
Hopwood and Stephens 1995; Sarna et al. 2004).  This is especially true for studies that 
have ORR and PFS as primary endpoints to inform how delays in radiographic 
progression might be associated with delays in clinical progression of symptoms and 
their interference with role and physical functioning, including maintaining low disease 
burden.  As such, validated PRO questionnaires have been incorporated in this study to 
assess symptom severity and symptom impact on functioning, including HRQoL and 
treatment tolerability, as assessed by the EORTC ILs (see Appendix 7). 
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events.  Recent research has shown that clinicians may 
underreport the incidence and severity of symptoms experienced by patients receiving 
treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; 
Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting 
adverse event information directly from participants can improve the understanding of 
treatment characteristics and their effects.  In order to evaluate the tolerability of 
tobemstomig, pembrolizumab, and platinum-based chemotherapy participants will be 
asked to report on their experience related to decreased appetite, nausea, vomiting, 
diarrhea, rash, hair loss, itching and joint pain, treatment-related symptoms selected 
from the validated PRO-CTCAE item bank (see Appendix 7).  Such symptoms were 
identified as being salient to patients' experience with tobemstomig, pembrolizumab, and 
platinum-based chemotherapy based on their license agreements.  

 
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Data generated from these PRO questionnaires will inform patients’ experience with 
disease burden and treatment tolerability as part of the totality of evidence generated to 
inform the benefitrisk profile of tobemstomig. 
4.4 
JUSTIFICATION FOR 
MG DOSE AND SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
4.5 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all 
phases of the study, including the last visit/last scheduled procedure specified in the 
schedule of activities (see Section 1.3, Table 1). 
The end of this study is defined as the date of the last visit of the last participant in the 
study.  The end of the study is expected to occur no later than 28 months after the last 
participant is enrolled, which includes screening, up to 2 years of study treatment, and 
90 days of safety follow-up after the last dose of study treatment. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.6 
DURATION OF PARTICIPATION 
Treatment will continue until disease progression per RECIST v1.1, unacceptable 
toxicity, or loss of clinical benefit as determined by the investigator (see Section 7.1 for 
additional details), up to 24 months, or until the Sponsor decides to terminate the study, 
whichever comes first.  The total duration of study participation for each individual is 
expected to range from 1 day to approximately 28 months.  Participants will be allowed 

 
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to continue treatment beyond disease progression for up to 24 months if prespecified 
criteria are met (Section 4.2.5). 
5. 
STUDY POPULATION 
Approximately 180 previously untreated participants with locally advanced, unresectable 
metastatic NSCLC of SQ or NSQ histology who are not eligible for curative surgery or 
definitive chemoradiotherapy, with no EGFR mutations or ALK genetic aberrations, will 
be enrolled in this study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.  
5.1 
INCLUSION CRITERIA 
Potential participants are eligible to be included in the study only if all of the following 
criteria apply: 
 
Signed Informed Consent Form  
 
Age  18 years at the time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
ECOG Performance Status of 0 or 1 (see Appendix 11) 
 
Histologically or cytologically documented locally advanced, unresectable 
(Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who are not eligible for curative 
surgery and/or definitive chemoradiotherapy (8th edition of the UICC/AJCC-staging 
system) 
Patients with NSCLC of mixed histology and patients with small-cell lung cancer 
are not eligible for enrollment in the study. 
 
No prior systemic treatment for metastatic NSCLC 
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic 
disease must have experienced a treatment-free interval of at least 12 months 
from randomization since the last dose of chemotherapy and/or radiotherapy. 
 
Known tumor PD-L1 status through a documented local assessment using a 
health authorityapproved PD-L1 IHC assay  
 
Confirmed availability of representative tumor specimens in formalin-fixed, 
paraffin-embedded (FFPE) blocks (preferred) or 15 (or an absolute minimum of 12) 
unstained serial slides, along with an associated pathology report 
If central testing for EGFR mutations and/or ALK rearrangements is required, an 
additional 5 unstained slides must be provided. 
Tumor tissue should be of good quality based on total and viable tumor content 
(i.e., a minimum number of 100 viable TCs with preserved cellular context and 
tissue architecture).  Acceptable samples include samples from resections, 
core-needle biopsies for deep tumor tissue (with a minimum of three cores for 

 
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freshly collected biopsies) or excisional, incisional, punch, or forceps biopsies for 
cutaneous, subcutaneous, or mucosal lesions, or endobronchial ultrasound 
(EBUS) core-needle biopsy. 
EBUS-transbronchial needle aspiration is acceptable (particularly if a larger 
gauge needle is used), provided tissue is of good quality as described above 
(i.e., a minimum number of 100 viable TCs with preserved cellular context and 
tissue architecture).  For EBUS-needle aspirations, an 18-gauge or larger needle 
is recommended. 
Fine-needle aspirations that do not preserve tissue architecture and yield cell 
suspension and/or cell smears, brushings, cell pellets from pleural effusions, and 
lavage samples are not acceptable. 
Tumor tissue from bone metastases is not evaluable for tumor PD-L1 expression 
by immunohistochemistry and is therefore not acceptable. 
If archival tissue is either insufficient or unavailable, the patient may undergo a 
biopsy at screening if the biopsy site is safely accessible.  If collection of a fresh 
biopsy is not medically feasible, the patient will be eligible if a minimum of 
12 unstained, serial slides can be provided.  If central testing for EGFR mutations 
and/or ALK rearrangements are required, an additional 5 unstained slides must 
be submitted. 
 
Measurable disease, as defined by RECIST v1.1 (see Appendix 10) 
Previously irradiated lesions can only be considered measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of measurable 
disease. 
 
Life expectancy  12 weeks 
 
Adequate hematologic and end-organ function, as defined by the following 
laboratory test results, obtained within 14 days prior to initiation of study treatment 
(Day 1 of Cycle 1): 
 
ANC  1.5  109/L ( 1500/L) without granulocyte colony-stimulating factor 
support with the following exception:  Patients with benign ethnic neutropenia 
(BEN) and ANC  1.3  109/L ( 1300/L) are eligible. 
BEN (also known as constitutional neutropenia) is an inherited cause of 
mild or moderate neutropenia that is not associated with any increased risk 
for infections or other clinical manifestations (Atallah-Yunes et al. 2019).  
BEN is referred to as ethnic neutropenia because of its increased 
prevalence in people of African descent and other specific ethnic groups.  
 
Lymphocyte count  0.5  109/L ( 500/L) 
 
Platelet count  100 109/L ( 100,000/L) without transfusion 
 
Hemoglobin  90 g/L ( 9 g/dL) 
Patients may be transfused or receive erythropoietic treatment as per 
local standard of care to meet this criterion. 

 
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 
AST, ALT, and ALP  2.5  upper limit of normal (ULN), with the following 
exceptions: 
Patients with documented liver metastases:  AST and ALT  5  ULN 
Patients with documented liver or bone metastases:  ALP  5  ULN 
 
Total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  bilirubin level  3  ULN 
 
Creatinine clearance (CrCl)  45 mL/min, calculated with use of the 
Cockcroft-Gault formula (Cockcroft and Gault 1976; see Section 6.1.2) or by 
24-hour urine collection for determination of CrCl 
 
Albumin  25 g/L ( 2.5 g/dL) 
 
For patients not receiving therapeutic anticoagulation:  INR and aPTT 
 1.5  ULN 
For patients receiving therapeutic anticoagulation:  stable anticoagulant 
regimen 
 
Negative HIV test at screening, with the following exception:   
Individuals with a positive HIV test at screening are eligible, provided they are 
stable on anti-retroviral therapy, have a CD4 count  200/L, and have an 
undetectable viral load. 
 
Negative hepatitis B surface antigen test at screening 
 
Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb 
at screening accompanied by either of the following:  
 
Negative total hepatitis B core antibody (HBcAb) 
 
Positive total HBcAb test followed by a negative (per local laboratory definition) 
hepatitis B virus (HBV) DNA test 
 
The HBV DNA test must be performed for individuals who have a negative 
HBsAg test, a negative HBsAb test, and a positive HBcAb test. 
 
Negative hepatitis C virus (HCV) antibody test at screening or positive HCV 
antibody test followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
Adequate cardiovascular function, as evidenced by the following: 
 
New York Heart Association Heart Failure Class II or less 
 
Baseline-corrected QT (through use of Fridericia's formula [QTcF]) interval 
 480 ms 
If the QTcF interval is longer than 480 ms but is shorter than 500 ms, the 
patient may undergo a cardiac evaluation and will be considered for 
treatment in case of no clinically significant findings. 

 
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 
Resting systolic blood pressure  150 mmHg and diastolic blood 
pressure   100 mmHg (average of three or more readings during two or more 
sessions with a short break between sessions) or no clinically significant 
hypertension 
 
Resting heart rate between 45 and 100 bpm (or no clinically significant 
tachycardia) 
 
Left ventricular ejection fraction  50%, as assessed by either transthoracic 
echocardiogram (TTE) or multiple-gated acquisition (MUGA) scan (TTE 
preferred test) within 6 months prior to initiation of study treatment 
 
For female participants of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraception, and agreement to 
refrain from donating eggs, as defined below: 
Female participants must remain abstinent or use contraceptive methods with a 
failure rate of  1% per year during the treatment period and for 4 months after 
the final dose of tobemstomig, 4 months after the final dose of pembrolizumab, 
and 6 months after the final dose of platinum-based chemotherapy.  Women 
must refrain from donating eggs during this same period. 
A female participant is considered to be of childbearing potential if she is 
postmenarchal, 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 regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of contraception.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
Women who would like to become pregnant after discontinuation of study 
treatment should seek advice about oocyte preservation prior to initiation of study 
treatment because of the possibility of irreversible infertility due to treatment with 
carboplatin. 

 
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 
For male participants:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive methods, and agreement to refrain from donating 
sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, men must 
remain abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year during the treatment period and 
for 4 months after the final dose of tobemstomig, 4 months after the final dose of 
pembrolizumab, 3 months after the final dose of pemetrexed, and 6 months after 
the final dose of paclitaxel and carboplatin.  Men must refrain from donating 
sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 4 months after the final dose of tobemstomig, 
4 months after the final dose of pembrolizumab, 3 months after the final dose of 
pemetrexed, and 6 months after the final dose of paclitaxel and carboplatin to 
avoid exposing the embryo. 
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 adequate methods of contraception.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
Men who would like to father a child after initiation of study treatment should seek 
advice about sperm preservation prior to initiation of study treatment because of 
the possibility of irreversible infertility due to treatment with pemetrexed or 
carboplatin. 
 
5.2 
EXCLUSION CRITERIA 
Potential participants are excluded from the study if any of the following criteria apply: 
 
NSCLC known to have a mutation in the EGFR gene or an ALK fusion oncogene  
Patients with tumors of non-squamous histology with unknown EGFR or ALK 
mutational status will be required to be tested (by local or central testing with a 
validated health authority approved test or CE-marked test in the EU per the 
assay’s intended use according to local laws and regulations) prior to 
enrollment.  Patients with tumors of squamous histology who have an unknown 
EGFR or ALK mutational status will not be required to be tested at pre-
screening/screening. 
EGFR and/or ALK status may be assessed locally or at a central laboratory. 
EGFR status assessed locally must be performed on tissue with use of a test 
that detects mutations in Exons 1821. 
EGFR and/or ALK testing should be performed with a validated, health 
authorityapproved test (i.e., commercially available test approved by your 
country or local government), and sample requirements and testing must be 

 
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performed per the assay’s intended use and according to the assay 
manufacturer's specifications.  If EGFR and/or ALK testing does not meet these 
criteria, EGFR and/or ALK must be assessed centrally. 
If samples are submitted for central EGFR and/or ALK testing, an additional 
5 slides must be provided. 
 
Symptomatic, untreated, or actively progressing CNS metastases 
Asymptomatic patients with treated 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. 
 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage. 
 
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to randomization, whole-brain radiotherapy within 14 days prior to 
randomization, or neurosurgical resection within 28 days prior to 
randomization. 
 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. 
 
If the patient is receiving anti-convulsant therapy, the dose is considered 
stable. 
 
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord). 
 
There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment. 
 
There is no evidence of significant vasogenic edema. 
Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to 
repeat the screening brain scan. 
 
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 initiation of study treatment 
 
History of leptomeningeal disease 
 
Uncontrolled tumor-related pain 
 
Patients requiring pain medication must be on a stable regimen at study entry. 
 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to initiation of study treatment.  Patients should be recovered from the effects of 
radiation.  There is no required minimum recovery period. 
 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 

 
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currently associated with spinal cord compression) should be considered for 
locoregional therapy, if appropriate, prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once a month or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium 
 12 mg/dL, or corrected calcium greater than ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix 8) with the following 
exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
 
Rash must cover  10% of body surface area 
 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on the screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis (TB), as documented by a positive purified protein derivative 
(PPD) skin test or TB blood test and confirmed by a positive chest X-ray within 
3 months prior to initiation of study treatment 
Patients with a positive PPD skin test or TB blood test followed by a negative 
chest X-ray may be eligible for the study.  
 
Untreated latent TB 
 
Current treatment with anti-viral therapy for HBV or HCV 

 
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 
Significant cardiovascular disease within 3 months prior to randomization, including 
any of the following: 
 Hypertensive crisis or encephalopathy 
 Unstable angina 
 Transient ischemic attack or stroke 
 Congestive heart failure (according to the New York Heart Association 
classification, refer to the inclusion criteria in Section 5.1) 
 Serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, 
paroxysmal supraventricular tachycardia) 
 History of thromboembolic events (such as myocardial infarction, stroke, or 
pulmonary embolism) 
 Troponin T (TnT) or troponin I (TnI) greater than or equal to the institutional ULN  
Patients with TnT or TnI levels between  1 and  2  ULN will be permitted to 
enroll in the study if repeat levels are  1  ULN.  If repeat levels are between 
 1 and  2  ULN, the patient may undergo a cardiac evaluation and will be 
considered for treatment in case of no clinically significant findings. 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during 
the study 
 
History of malignancy other than NSCLC within 5 years prior to randomization, with 
the exception of malignancies with a negligible risk of metastasis or death 
(e.g., 5-year OS] rate  90%), such as adequately treated carcinoma in situ of the 
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast 
carcinoma in situ, or Stage I uterine cancer 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that could affect patient safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high-risk from treatment 
complications 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during study treatment or within 
5 months after the final dose of study treatment 

 
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 
Treatment with investigational therapy within 28 days prior to initiation of 
study treatment 
 
Any anti-cancer therapy, including hormonal therapy, within 21 days prior to 
initiation of study treatment 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including, but not limited to, anti-cytotoxic T lymphocyteassociated protein 4, 
antiT-cell immunoreceptor with Ig and tyrosine-based inhibition motif domains, 
antiPD-1 and antiPD-L1 therapeutic antibodies, and anti-LAG3) agents 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin‑2) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [TNF] agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication during 
study treatment, with the following exceptions: 
 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or 
low-dose corticosteroids for chronic obstructive pulmonary disease or asthma, 
or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency 
are eligible for the study. 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies, fusion proteins, or platinum-containing compounds 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the tobemstomig or pembrolizumab formulation 
 
Known allergy or hypersensitivity or other contraindication to any component of the 
chemotherapy regimen the patient may receive during the study 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study, 
within 4 months after the final dose of tobemstomig and pembrolizumab, or 
6 months after the final dose of paclitaxel, pemetrexed, or carboplatin 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 
Known targetable c-ROS1, BRAFV600E or RET proto-oncogene genomic aberrations 
Patients with known targetable ROS1, BRAFV600E or RET genomic aberrations 
are permitted for trial enrollment only if they are ineligible to receive available 
targeted therapy. 
 

 
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5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
This study has no meal or dietary restrictions. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, participants must use contraception or take other precautions as 
described in Section 5.1. 
5.4 
SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per individual) at 
the investigator's discretion.  Individuals must re-sign the consent form prior to 
re-screening.  The investigator will maintain a record of reasons for screen failure 
(see Section 8). 
6. 
STUDY TREATMENT, OTHER TREATMENTS RELEVANT TO 
THE STUDY DESIGN, AND CONCOMITANT THERAPY 
The investigational medicinal products (IMPs) for this study are tobemstomig, 
pembrolizumab, carboplatin, pemetrexed, and paclitaxel.   
6.1 
STUDY TREATMENT ADMINISTERED 
A description of assigned study treatments for this study is presented in Table 5. 

 
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Table 5 
Study Treatment Description 
 
Tobemstomig 
Pembrolizumab 
Paclitaxel 
Carboplatin 
Pemetrexed 
Use 
Experimental 
Comparator 
Experimental 
Experimental 
Experimental 
Type of medicinal 
product 
Roche IMP 
Non-Roche IMP 
Non-Roche IMP 
Non-Roche IMP 
Non-Roche IMP 
Drug form 
Liquid 
Concentrate 
solution for IV 
infusion 
Concentrate 
solution for IV 
infusion 
Concentrate 
solution for IV 
infusion 
Powder for 
concentrate solution 
for IV infusion 
Unit dose strength 
mg per vial 
100 mg/4 mL per 
vial 
6 mg/mL 
10 mg/mL 
500 mg per vial 
Dosage level 
 mg Q3W 
200 mg Q3W 
200 mg/m2 Q3W 
AUC 5 mg/mL  min 
Q3W 
500 mg/m2 Q3W 
Formulation 
Refer to pharmacy 
manual and 
Tobemstomig 
Investigator's Brochure. 
Refer to 
pembrolizumab 
USPI or SmPC. 
Refer to paclitaxel 
USPI or SmPC 
Refer to carboplatin 
USPI or SmPC. 
Refer to pemetrexed 
USPI or SmPC. 
Packaging 
 
10-mL vial 
100 and  
150 mg vials 
450 mg vials 
500 mg/vial 
Labeling 
Per local requirement 
Per local 
requirements 
Per local 
requirements 
Per local 
requirements 
Per local  
requirements 
Route of 
administration 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
Source 
Sponsor 
Sponsor 
Sponsor 
Sponsor 
Sponsor 
AUC  area under the concentrationtime curve; IMP  investigational medicinal product; Q3W  every 3 weeks; SmPC  Summary of 
Product Characteristics; USPI  U.S. Package Insert. 
 

 
 
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In this protocol, "study treatment" refers to the following combination of treatments 
assigned to participants in Arm A or Arm B as part of this study: 
 
Arm A 
 For patients with NSQ NSCLC, induction treatment with blinded tobemstomig in 
combination with pemetrexed and carboplatin Q3W for four cycles, followed by 
Q3W maintenance therapy with blinded tobemstomig in combination with 
pemetrexed Q3W 
 For patients SQ NSCLC, blinded tobemstomig in combination with paclitaxel and 
carboplatin Q3W for four cycles, followed by blinded treatment with 
tobemstomig Q3W 
 
Arm B  
 For patients with NSQ NSCLC, induction treatment with blinded pembrolizumab 
in combination with pemetrexed and carboplatin Q3W for four cycles, followed by 
maintenance therapy with blinded pembrolizumab in combination with 
pemetrexed Q3W  
 For patients with SQ NSCLC, blinded treatment with pembrolizumab in 
combination with paclitaxel and carboplatin Q3W for four cycles, followed by 
blinded pembrolizumab Q3W 
 
Guidelines for dose modification and treatment interruption or discontinuation 
for participants who experience adverse events are provided in Appendix 6. 
The induction phase of the study will consist of 4 cycles of blinded tobemstomig or 
pembrolizumab plus histology-based chemotherapy.  On Day 1 of each cycle, all eligible 
patients will be administered study drug infusions in the following order:  
 
Arm A NSQ: blinded tobemstomig → pemetrexed → carboplatin  
 
Arm A SQ: blinded tobemstomig → paclitaxel → carboplatin  
 
Arm B NSQ: blinded pembrolizumab → pemetrexed → carboplatin  
 
Arm B SQ: blinded pembrolizumab → paclitaxel → carboplatin 
 
6.1.1 
Blinded Tobemstomig and Blinded Pembrolizumab 
Participants will receive blinded tobemstomig (
mg Q3W) or blinded pembrolizumab 
(200 mg Q3W) by IV infusion.  Administration of study treatment will be performed in a 
monitored setting where there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  The 
-mg dose of 
tobemstomig Q3W and the 200-mg dose of pembrolizumab Q3W will remain the same 
throughout the study.   
The initial dose of tobemstomig or pembrolizumab will be delivered over
minutes by IV infusion.  If the 
-minute infusion is tolerated without infusion-associated 
adverse events (fever or chills), the second infusion may be delivered over

 
 
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minutes.  If the 
-minute infusion is well tolerated, all subsequent infusions may be 
delivered over
minutes. 
Participants who experience an infusion-associated adverse event may be premedicated 
with an antihistamine and/or antipyretic medication for subsequent doses and beyond at 
the discretion of the investigator, but the infusion time may not be decreased for that 
infusion.  
Tobemstomig and pembrolizumab infusions will be administered to participants per the 
instructions outlined in Table 6. 

 
 
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Table 6 
Administration of First and Subsequent Infusions of 
Tobemstomig or Pembrolizumab 
Study Drug 
First Infusion 
Subsequent Infusions 
Tobemstomig or 
pembrolizumab 
infusion 
 No premedication is permitted 
for the first infusion of 
tobemstomig and 
pembrolizumab. 
 Vital signs (pulse rate, 
respiratory rate, blood 
pressure, and temperature) 
should be recorded within 
60 minutes prior to starting the 
infusion. 
 Tobemstomig and 
pembrolizumab should be 
infused over
minutes. 
 If clinically indicated, vital signs 
should be recorded every 
15 ( 5) minutes during the 
infusion. 
 If the patient experienced an IRR 
with any previous infusion of 
tobemstomig or pembrolizumab, 
premedication with an antihistamine 
and/or antipyretic may be 
administered for subsequent doses 
and beyond at the discretion of the 
investigator. 
 Vital signs should be recorded 
within 60 minutes prior to the 
infusion. 
 Tobemstomig and pembrolizumab 
should be infused over 
minutes if the previous 
infusion was tolerated without an 
IRR o
minutes if the 
patient experienced an IRR with the 
previous infusion. 
 If clinically indicated, vital signs 
should be recorded during the 
infusion. 
Observation 
period after 
tobemstomig or 
pembrolizumab 
infusion 
 After the infusion of 
tobemstomig or 
pembrolizumab, the patient 
begins a 
-minute observation 
period. 
 Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion of tobemstomig or 
pembrolizumab. 
 Patients should be informed 
about the possibility of delayed 
post-infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient tolerated the previous 
tobemstomig or pembrolizumab 
infusion well without 
infusion-associated adverse events, 
the observation period after the next 
and following infusions may be 
reduced to 
minutes. 
 If the patient experienced 
infusion-associated adverse events 
in the previous infusion, the 
observation period should be 
minutes. 
 If clinically indicated, vital signs 
should be recorded at 
30 ( 10) minutes after the infusion 
of tobemstomig or pembrolizumab. 
IRR  infusion-related reaction. 
  
6.1.2 
Paclitaxel, Pemetrexed, and Carboplatin 
Paclitaxel 
Paclitaxel 200 mg/m2 will be administered as an IV infusion to participants over 3 hours 
Q3W for four cycles as per local practice and labels.  All participants should be 
premedicated with oral or an IV steroid and antihistamines according to the approved 
product label and/or standard practice.  Additional premedications should be 

 
 
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administered as per standard practice.  Paclitaxel should be completely administered 
before initiating carboplatin dose. 
Pemetrexed 
Pemetrexed 500 mg/m2 will be administered to participants as an IV infusion over 
10 minutes Q3W until progression or unacceptable toxicity.   
All participants should receive the appropriate supplementation with vitamin B12, folic 
acid, and corticosteroid prophylaxis as listed below (or as per local label): 
 
Folic acid 3501000 g orally (PO):  Participants must take at least five doses of 
folic acid during the 7 days preceding the first dose of pemetrexed, and folic acid 
dosing must continue during the full course of therapy and for 21 days after the final 
dose of pemetrexed. 
 
Vitamin B12 1000 g intramuscular (IM) injection:  Participants will receive an IM 
injection the week preceding the first dose of pemetrexed and once every three 
cycles thereafter.  Subsequent vitamin B12 injections may be given the same day as 
pemetrexed administration. 
 
Anti-emetic prophylaxis with dexamethasone 4 mg (or equivalent) PO twice per day:  
Participants should take dexamethasone the day before, the day of, and the day 
after pemetrexed administration.  Higher or additional doses are permitted for 
anti-emetic prophylaxis during Cycles 14 but not to exceed doses per the 
Multinational Association of Supportive Care (MASCC) and ESMO guidelines 
(Roila et al. 2016). 
 
Carboplatin 
Carboplatin AUC 5 mg/mL  min:  Participants will receive carboplatin as an IV infusion 
over 3060 minutes Q3W for four cycles immediately after paclitaxel or pemetrexed as 
per local practice and labels.  The dose of carboplatin should be calculated using Calvert 
formula (see below) and should not exceed 750 mg.  
Calvert Formula: 
Total dose (in mg)  (target AUC)  (CrCl  25). 
The estimated glomerular filtration rate used in the Calvert formula should not exceed 
125 mL/min. 
Maximum carboplatin dose (mg)  target AUC 
5 (mg/mL  min)  (125  25)  5  150 mL/min  750 mg. 
Paclitaxel, pemetrexed, and carboplatin will be administered to participants as outlined in 
Table 7. 
 

 
 
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Table 7 
Treatment Regimen for Pemetrexed, Paclitaxel, and Carboplatin 
Study 
Treatment 
Dose and Route of 
Administration 
Induction Period 
(Four 21-Day Cycles) 
Maintenance 
(until PD) 
Pemetrexed 
500 mg/m2  
by IV infusion 
Over approximately 
10 minutes on Day 1 Q3W 
Over approximately 
10 minutes on Day 1 
Q3W 
Paclitaxel 
200 mg/m2  
by IV infusion 
Over approximately 
3 hours on Day 1 Q3W 
Not applicable 
Carboplatin 
AUC 5 mg/mL  min 
by IV infusion 
Over approximately 
3060 minutes on Day 1 
Q3W 
Not applicable 
AUC  area under the concentrationtime curve; PD  progressive disease; 
Q3W  every 3 weeks. 
  
Details regarding dose modification of paclitaxel, pemetrexed, and carboplatin are 
presented in Section A4–6.4.2.   
Guidelines for medical management of IRRs are provided in the Appendix 6. 
6.2 
PREPARATION, HANDLING, STORAGE, 
AND ACCOUNTABILITY 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each participant, and disposition or return of unused IMP, thus enabling reconciliation of 
all IMP received, and for ensuring that participants are provided with doses specified by 
the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor, through an 
interactive voice or web-based response system (IxRS) to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  The investigator or 
designee must confirm that appropriate temperature conditions have been maintained 
during transit, either by time monitoring (shipment arrival date and time) or temperature 
monitoring, for all IMPs received and that any discrepancies have been reported and 
resolved before use of the IMPs.  All IMPs must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions, with access limited to the investigator and authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
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 with the appropriate 

 
 
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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 accountability log. 
Refer to the pharmacy manual and the Tobemstomig and Pembrolizumab 
Investigator's Brochures or local prescribing information for information on IMP 
preparation, storage, handling, and accountability.  
6.3 
TREATMENT ASSIGNMENT AND BLINDING 
6.3.1 
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a participant, the study site will obtain the participant's 
identification number and treatment assignment through the IxRS. 
Participants will be randomly assigned to one of two treatment arms:  Arm A 
(tobemstomig in combination with platinum-based chemotherapy) or Arm B 
(pembrolizumab in combination with platinum-based chemotherapy).  
 
 
 
Patients should receive their first dose of study drug on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 days after 
randomization.  
 treatment beyond 24 months is no longer permitted 
in either treatment arm.  Patients who are continuing treatment beyond 24 months 
must discontinue from the study and seek other treatment options outside of the study. 

 
 
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6.3.2 
Blinding 
Originally, study site personnel (with the exception of the 
 pharmacist or 
equivalent) and participants were blinded to treatment assignment during the study.  
 
. 
6.4 
STUDY TREATMENT COMPLIANCE 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed.  
When participants are treated at the site, they will receive study treatment directly from 
the investigator or designee under medical supervision.   
Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration electronic Case Report Form (eCRF).  
Cases of accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Section A3–7.12. 
6.5 
DOSE MODIFICATION 
Dose modifications of tobemstomig, including dose reductions, will not be allowed in 
this study. 
6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER 
THE END OF THE STUDY 
Currently, the sponsor does not have any plans to provide tobemstomig or any other 
study treatments to participants who have completed the study.  The Sponsor may 
evaluate whether to continue providing tobemstomig in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
https://assets.cwp.roche.com/f/176343/x/92d6b13ee6/policy_continued_access_to_invest
igational_medicines.pdf 
 
6.7 
TREATMENT OF OVERDOSE 
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose.  Cases of overdose, along with any associated adverse events, should be 
reported as described in Section A3–7.12. 
In the event of an overdose, the investigator should take the following steps: 
1. 
Contact the Medical Monitor immediately. 

 
 
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2. 
Closely monitor the participant for any adverse event or serious adverse event and 
laboratory abnormalities until study treatment can no longer be detected 
systemically (at least 90 days). 
 
6.8 
CONCOMITANT THERAPY 
Any medication and/or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) used by a participant in addition to 
protocol-mandated treatment from 7 days prior to initiation of study treatment to the 
treatment discontinuation visit must be recorded on the Concomitant Medications eCRF 
along with the following information: 
 
Reason for use 
 
Dates of administration, including start and end dates 
 
Dosage information, including dose and frequency 
 
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 
6.8.1 
Permitted Therapy 
Use of the following concomitant therapies is permitted as described below: 
 
Oral contraceptives with a failure rate of  1% per year (see Section 5.1) 
 
Hormone replacement therapy 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
In participants without documentation of radiographic disease progression, it is 
strongly encouraged to maximize supportive care for symptomatic management 
and to avoid radiotherapy that will interfere with the assessment of tumor target 
lesions.  Treatment with tobemstomig and pembrolizumab may be continued 
during palliative radiotherapy. 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID‑19) 
Live, attenuated vaccines are not permitted (see Section 6.8.3). 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled or low-dose corticosteroids administered for chronic obstructive pulmonary 
disease or asthma 
 
Low-dose mineralocorticoids administered for orthostatic hypotension or low-dose 
mineralocorticoids and corticosteroids for adrenocortical insufficiency 
 
Premedication for pemetrexed, paclitaxel, and carboplatin is permitted.  Premedication 
with antihistamines, antipyretic medications, and/or analgesics may be administered for 

 
 
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the second and subsequent tobemstomig and pembrolizumab infusion only, at the 
discretion of the investigator. 
In general, investigators should manage a participant’s care with supportive therapies 
other than those defined as cautionary or prohibited therapies as clinically indicated, per 
local standard practice.  Participants who experience infusion-associated symptoms may 
be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists). 
Participants must abstain from taking prescription and non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 drug-elimination half-lives (whichever is longer) before 
the start of study treatment until completion of the follow-up visit, unless, in the opinion of 
the investigator after consulting the Medical Monitor, the medication will not interfere with 
the study. 
6.8.2 
Cautionary Therapy 
6.8.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF inhibitors may 
attenuate potential beneficial immunologic effects of treatment with tobemstomig and/or 
pembrolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF inhibitors 
may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with tobemstomig and pembrolizumab therapy. 
6.8.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 6.8.1) may be used during the study at the discretion of the investigator. 

 
 
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6.8.2.3 
Other Cautionary Therapy 
For information regarding medications that should be used with caution in combination 
with pemetrexed, paclitaxel, and carboplatin, please refer to the local prescribing 
information. 
6.8.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) within 
28 days prior to initiation of study treatment and during study treatment 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority approved or experimental, for various time 
periods prior to starting study treatment, depending on the agent (see Section 5.2), 
and during study treatment, until disease progression is documented and the 
participant has discontinued study treatment, with the exception of palliative 
radiotherapy, radiotherapy to the brain, and local therapy under certain 
circumstances (see Section 6.8.1 for details) 
 
Live, attenuated vaccines within 4 weeks prior to initiation of study treatment, during 
study treatment, and for 5 months after the final dose of study treatment 
 
Systemic immunomodulatory agents (including, but not limited to, interferons and 
interleukin‑2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with study treatment 
 
For information regarding medications that are contraindicated with pemetrexed, 
paclitaxel, and carboplatin, please refer to the local prescribing information. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
Study and site closure is described in Section A1–9. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
It may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment.  If study treatment is definitively discontinued, the 
participant will remain in the study for additional assessments.  Refer to the schedule of 
activities (see Section 1.3, Table 1) for data to be collected at the time of discontinuation 
of study treatment and for any further follow-up evaluations that need to be completed. 
Participants must permanently discontinue study treatment if any of the following criteria 
are met: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 

 
 
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given the individual participant’s potential response to therapy and severity of the 
event 
 
Any medical condition that the investigator determines may jeopardize the 
participant's safety if he or she continues to receive study treatment 
 
Investigator determination that treatment discontinuation is in the best interest of the 
participant 
 
Pregnancy 
 
Use of a nonprotocol-specified anti-cancer therapy  
 
Symptomatic deterioration attributed to disease progression 
 
Radiographic disease progression per RECIST v1.1 (unless study treatment is 
continued beyond radiographic progression) 
 
For participants treated beyond radiographic disease progression per RECIST v1.1, 
loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 4.2.5 for details) 
 
24 months have elapsed from the start of study treatment  
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Participants will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Participants 
who discontinue study treatment for any reason other than progressive disease per 
RECIST v1.1 will continue to undergo tumor response assessments  
Refer to the schedule of activities in Section 1.3 (see Table 1) for details on follow-up 
assessments to be performed for participants who permanently discontinue study 
treatment.  If a participant requests to be withdrawn from treatment or follow-up 
assessments, this request must be documented in the source documents and signed by 
the investigator. 
7.2 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
FROM THE STUDY 
A participant may withdraw from the study at any time at his or her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a participant requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 

 
 
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At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the schedule of activities (see Section 1.3, Table 1).  
Refer to the schedule of activities for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from study treatment and from the 
study at that time. 
If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent.  Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) 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.  
7.3 
PARTICIPANTS LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule.  If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic and determine if there are ways to support patient participation.  
 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant.  These contact attempts 
should be documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up and will be withdrawn from the study.  
 
Note:  Before a participant is deemed lost to follow-up, the site should attempt three 
telephone calls to the participant and, if necessary, send a certified letter to the 
participant’s last known mailing address or local equivalent methods when possible.   
8. 
STUDY ASSESSMENTS AND PROCEDURES 
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 individuals and for individuals who are not subsequently 
enrolled will be maintained at the study site. 

 
 
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Study procedures and their timing are summarized in the schedule of activities 
(see Section 1.3, Table 1).  Protocol waivers or exemptions are not allowed.   
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct.  
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a detailed record of 
all participants screened, to document eligibility or record reasons for screening failure, 
as applicable. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., complete blood count) and obtained before signing of the Informed Consent Form 
may be utilized for screening or baseline purposes provided the procedures meet the 
protocol-specified criteria and are performed within the timeframe defined in the 
schedule of activities (see Section 1.3, Table 1). 
Medical history and baseline conditions, including clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history and use of drugs of abuse will be recorded at screening.  Any 
medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) and vaccines used by the participant within 7 days prior to initiation of 
study treatment will be recorded.  Demographics, including age, sex, and self-reported 
race or ethnicity, will also be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. 
Participants will be closely monitored for safety throughout the study.  Participants 
should be assessed for toxicity prior to each dose; treatment will be administered only if 
the clinical assessment and local laboratory test values are acceptable. 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Tumor and Response Evaluations 
Participants will undergo tumor assessments  every 12 weeks ( 7 days), regardless of 
dose delays until radiographic disease progression per RECIST v1.1 (see Appendix 10) 
or loss of clinical benefit (for participants who continue treatment after radiographic 
treatment progression), as determined by the investigator, withdrawal of consent, death, 
or study termination by the Sponsor, whichever occurs first.   

 
 
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Participants who are treated beyond disease progression per investigator-assessed 
RECIST v1.1 will undergo tumor assessments every 12 weeks ( 2 weeks) after initial 
documentation of progression, or more frequently if clinically indicated, regardless of 
time in the study until treatment is discontinued (see Section 4.2.5 for details).  At the 
investigator's discretion, tumor assessments may be repeated at any time if progressive 
disease is suspected.  Participants who discontinue study treatment (for any reason, 
including, but not limited to, clinical decline or toxicity) in the absence of radiographic 
disease progression per investigator-assessed RECIST v1.1 will be followed for safety 
for 90 days after last dose of study treatment.  
All measurable and/or evaluable lesions should be assessed and documented at 
screening.  Tumor assessments performed as standard of care prior to obtaining 
informed consent and within 28 days prior to initiation of study treatment do not have to 
be repeated at screening, so long as they meet criteria outlined below.   
8.1.1.1 
Radiographic Assessments 
Screening and subsequent tumor assessments must include CT scans of the chest and 
abdomen with contrast (per institutional standard operating procedures).  A CT scan with 
contrast of the pelvis is required at screening and as clinically indicated or as per local 
standard of care at subsequent response evaluations.  If a CT scan with contrast is 
contraindicated (e.g., in participants with contrast allergy or impaired renal clearance), a 
non-contrast CT scan of the chest may be performed and magnetic resonance imaging 
(MRI) scans (with contrast, if feasible) of the abdomen and pelvis should be performed.  
CT or MRI scans of other disease sites should be performed as clinically indicated. 
All participants must undergo an MRI or CT scan (with contrast) of the brain at 
screening.  In the event of an equivocal CT scan at screening, an MRI scan of the brain 
is required to confirm or refute the diagnosis of CNS metastases.  Subsequent brain 
scans should be performed only if clinically indicated (i.e., if a participant becomes 
symptomatic).  Patients with active or untreated CNS metastases are not eligible for the 
study (see Section 5.2).  At subsequent (post-screening) tumor assessments, 
participants with a history of irradiated brain metastases at screening are not required to 
undergo brain scans unless clinically indicated (e.g., in participants with neurologic 
symptoms); irradiated brain metastases do not need to be categorized and followed as 
target or non-target lesions at baseline or at subsequent tumor assessments. 
At the investigator's discretion, other methods of assessment of disease as per 
RECIST v1.1 may be used.  If a CT scan for tumor assessment is performed in a 
positron emission tomography/CT scanner, the CT acquisition must be consistent with 
the standards for a full-contrast diagnostic CT scan.  Further investigations, such as 
bone scans and CT scans of the neck, should also be performed if clinically indicated. 
All measurable and/or evaluable lesions identified at screening should be re-assessed at 
subsequent tumor evaluations according to the schedule described above.  The same 

 
 
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radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (e.g., the same contrast protocol for CT scans).  Tumor 
assessments must be continued after disease progression per RECIST v1.1 for 
participants who receive treatment beyond progression.  The investigator’s assessment 
of overall tumor response at all timepoints should be based on RECIST v1.1 only.  
Results must be reviewed by the investigator before dosing at the next cycle. 
Radiographic images, whether reviewed locally or centrally, must be evaluated by a 
qualified, certified expert.   
8.1.1.2 
Response Evaluation 
Objective response will be determined by the investigator at specified timepoints 
according to RECIST v1.1 (see Appendix 10).  Assessments should be performed by the 
same individual, if possible, to ensure internal consistency across visits.  
Other endpoints (e.g., PFS, OS, DOR) will be calculated programmatically by the 
Sponsor on the basis of investigator assessments of response at each specified 
timepoint. 
8.1.2 
Clinical Outcome Assessments 
PRO questionnaires will be completed to assess the treatment benefit of tobemstomig 
plus platinum-based chemotherapy.  In addition, PRO questionnaires enable the capture 
of each participant's direct experience with tobemstomig plus platinum-based 
chemotherapy.  PRO data will be collected through use of the following questionnaires:  
EORTC IL85, IL132, IL188, and IL17.  
The order of administration for the PROs is outlined in the schedule of activities 
(see Section 1.3, Table 1).  
, PRO questionnaires for 
participants continuing in the study will no longer be required. 
8.1.2.1 
Data Collection Methods for Clinical Outcome Assessments 
 
The PRO questionnaires, translated into the local language as appropriate, will be 
completed in their entirety at specified timepoints during the study (see Section 1.3, 
Table 1).  Paper versions of the PRO questionnaires will be self-administered by 
participants during the treatment period and site personnel will administer the NCI 
PRO-CTCAE and EORTC IL46 to participants over the telephone at the Day 8 visit, at 
follow-up visits, and in exceptional circumstances if a participant cannot attend a site 
visit.  Source documentation should be obtained that includes, among other information, 
that the questionnaires were administered by telephone.  Site personnel will enter PRO 
data on the eCRF. 
To ensure instrument validity and that data standards meet health authority 
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completed in their entirety by the participant prior to receiving any information on disease 
status, and prior to the administration of study treatment, unless otherwise specified (see 
Section 1.3, Table 1). 
8.1.2.2 
EORTC Item Libraries 85, 132, 188, and 17 
The IL85 is composed of five lung cancerspecific items from the EORTC, assessing 
cough, shortness of breath, and chest pain (see Section A7–1.1.1).  The IL85 takes 
approximately 3 minutes to complete. 
The IL132 consists of three items of relevance to patients with cancer from the EORTC, 
assessing fatigue (see Section A7–1.1.2).  The IL132 takes approximately 2 minutes to 
complete. 
The IL188 is a single-item from the EORTC, evaluating bone pain in patients with cancer 
(see Section A7–1.1.3).  The IL188 takes approximately 1 minute to complete. 
The IL17 is composed of nine items of relevance to patients with cancer from the 
EORTC, assessing physical functioning, role functioning, and GHS/QoL (see 
Section A7–1.1.4).  The IL17 takes approximately 4 minutes to complete. 
The recall period for these IL assessments is specified to be during the past week.  
The administration schedule and requirements are described in Section 1.3, Table 1.  
8.2 
SAFETY ASSESSMENTS 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessment of a 
participant’s weight and height, the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.   
A limited physical examination will include, at a minimum, symptom-directed physical 
examination.  Investigators should pay special attention to clinical signs related to 
previous serious illnesses.  Changes from abnormalities identified at screening should 
be recorded in participant notes.  After initiation of study treatment, any new or worsened 
clinically significant abnormalities (i.e., beyond expected variation or normal age-related 
changes) should be recorded as adverse events on the Adverse Event eCRF. 
Any abnormality identified at screening or prior to initiation of study treatment should be 
recorded on the General Medical History and Baseline Conditions eCRF (unless 
considered related to a protocol-mandated intervention).  
8.2.2 
Vital Signs 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed as 
specified in the schedule of activities (see Section 1.3, Table 1). 

 
 
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Blood pressure and pulse measurements will be assessed {while the participant is in a 
seated position) with a completely automated device.  Manual techniques will be used 
only if an automated device is not available.  
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of one 
pulse and three blood pressure measurements (three consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute).  The average of the three 
blood pressure readings will be recorded on the eCRF. 
See Table 6 for details on the measurements of vital signs during administration of study 
treatment.  
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the schedule of activities (see 
Section 1.3, Table 1) using an ECG machine that automatically calculates the heart rate 
and measures PR interval, QRS interval, QT interval, and QTcF interval.   
All ECG recordings must be performed through use of a standard high-quality, 
high-fidelity digital electrocardiograph machine.  Lead placement should be as consistent 
as possible.  ECG recordings must be performed after the participant has been resting in 
a supine position for at least 10 minutes.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
reports.  Paper copies of ECG tracings will be kept as part of the participant's permanent 
study file at the site.  Digital recordings will be stored at the study site.  The following 
should be recorded on the appropriate eCRF:  heart rate, RR interval, QRS interval, PR 
duration, uncorrected QT interval, and QTcF based on machine readings of the 
individual ECG tracings.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF.  If considered appropriate by the 
Sponsor, ECGs may be analyzed retrospectively at a central laboratory. 
If at a particular postdose timepoint the mean 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 at the investigator's discretion.  If a PK sample is not scheduled for that 

 
 
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timepoint, a PK sample should be obtained.  A decision on study drug discontinuation 
should be made, as described in Appendix 6.  The investigator should also evaluate the 
participant for potential concurrent risk factors (e.g., electrolyte abnormalities, 
concomitant medications known to prolong the QT interval, severe bradycardia). 
Transthoracic Echocardiogram or MUGA  
TTE or MUGA scan will be performed at screening as specified in the schedule of 
activities (see Section 1.3, Table 1) if no scan is available from within 6 months prior to 
randomization.  Scans may be repeated at the investigator’s discretion if there are signs 
or symptoms of cardiotoxicity. 
8.2.4 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
schedule of activities (see Section 1.3, Table 1) for the timing and frequency.  Clinical 
laboratory tests conducted by a central laboratory must be conducted in accordance with 
the laboratory manual. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study on the Adverse Event eCRF 
(see Appendix 3). 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days of the final dose of study treatment should be 
repeated until the values return to normal or baseline or are considered to be stable and 
no longer considered clinically significant by the investigator.  If such values do not 
return to normal or baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the Sponsor notified. 
If laboratory values from nonprotocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event or 
adverse event or dose modification), the results must be recorded on the eCRF. 
Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final Clinical Study Report. 
8.2.5 
Pregnancy Testing 
The schedule for pregnancy testing for enrolled female participants is outlined in 
Section 1.3, Table 1, and will be conducted as outlined in Section 8.3.5.  
8.2.6 
Clinical Outcome Assessments 
PRO questionnaires will be completed to assess the treatment effects of tobemstomig 
plus platinum-based chemotherapy versus pembrolizumab plus platinum-based 

 
 
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chemotherapy.  In addition, PRO questionnaires will enable the capture of each 
participant's direct experience with tobemstomig in combination with platinum-based 
chemotherapy. 
PRO data will be collected through use of the following questionnaires: selected items 
from the NCI PRO-CTCAE and the EORTC IL46.   
The order of administration for PRO questionnaires is specified in the schedule of 
activities (see Section 1.3, Table 1) and are presented in Appendix 7.  
 PRO questionnaires will no longer be required. 
8.2.6.1 
PRO-CTCAE 
The NCI PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015).  The NCI PRO-CTCAE comprises 124 questions that are rated either 
dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale 
(for determination of frequency of occurrence, severity, and interference with daily 
function).  Treatment toxicities can occur with observable signs (e.g., vomiting) or 
non-observable symptoms (e.g., nausea).  The standard NCI PRO-CTCAE recall period 
is the previous 7 days.  
A subset of eight signs and symptoms deemed most applicable to the current study 
treatments have been selected for this study (see Section A7–1.2).  The signs and 
symptoms have been selected on the basis of the known side effects of the marketed 
drugs included in the standard of care, namely pembrolizumab and platinum-based 
chemotherapy.  
8.2.6.2 
EORTC Item Library 46 
The EORTC IL46 is a validated single-item questionnaire assessing the overall impact of 
side effects (see Section A7–1.3).  The standard EORTC IL46 recall period is during the 
previous week. 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
The definitions of adverse event and serious adverse event are presented in 
Sections A3–1 and A3–2, respectively. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are 

 
 
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considered related to the study treatment or study procedures, or caused the participant 
to discontinue study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(see Section A3–3.4).  All other medical occurrences that begin before the start of study 
treatment but after obtaining informed consent will be recorded on the General Medical 
History and Baseline Conditions eCRF, not the Adverse Event eCRF. 
All adverse events will be reported from the start of treatment until the end of the 
adverse event reporting period, 90 days after the final dose of study treatment at the 
timepoints specified in the schedule of activities (see Section 1.3, Table 1) and as noted 
below. 
Adverse events will be reported until 30 days after the final dose of study treatment or 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Serious adverse 
events will be reported until 90 days after the final dose of study treatment or initiation of 
new systemic anti-cancer therapy, whichever occurs first. 
Adverse events of special interest will be reported until 90 days after the final dose of 
study treatment regardless of the initiation of new systemic anti-cancer therapy. 
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation.  However, if the investigator learns of 
any serious adverse event, including a death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify the 
Sponsor. 
8.3.2 
Method of Detecting Adverse Events and 
Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 3. 

 
 
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Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about adverse event occurrences. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts.  All 
adverse events will be followed until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, or the participant is lost to follow-up 
(as defined in Section 7.3), or the participant withdraws consent.  Additional information 
on follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification (i.e., within 24 hours of awareness) by the investigator to the Sponsor 
of a serious adverse event is essential so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety of 
a study treatment under clinical investigation.  The Sponsor will comply with regulatory 
requirements for expedited safety reporting to regulatory authorities (which includes the 
use of applicable systems, such as EudraVigilance), IRBs/ECs, and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed in the following table. 
Drug 
Document 
Tobemstomig 
Tobemstomig Investigator's Brochure  
Pembrolizumab 
Pembrolizumab E.U. Summary of Product Characteristics 
Pemetrexed 
Pemetrexed E.U. Summary of Product Characteristics  
Carboplatin 
Carboplatin U.K. Summary of Product Characteristics  
Paclitaxel 
Paclitaxel U.K. Summary of Product Characteristics  
EU  European Union; U.K.  United Kingdom. 
  

 
 
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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. 
An investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 
events) from the Sponsor will review and then file it along with the respective 
Investigator’s Brochure and Summary of Product Characteristics and will notify the 
IRB/EC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or 4 months after the final dose of tobemstomig, 4 months after the final dose of 
pembrolizumab, and 6 months after the final dose of platinum-based chemotherapy. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
4 months after the final dose of tobemstomig, 4 months after the final dose of 
pembrolizumab, 3 months after the final dose of pemetrexed, and 6 months after the final 
dose of paclitaxel and carboplatin. 
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section A5–1. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Section A5–2.  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. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.  
8.3.6 
Cardiovascular and Death Events 
Information on reporting deaths is provided in Section A3–7.8. 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting 
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Instructions for the collection and handling of biological samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples will be used to evaluate the pharmacokinetics of tobemstomig.  Serum samples 
collected for analysis of tobemstomig concentrations may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on these samples unless consent for this was 
included in an Informed Consent Form.  Participant confidentiality will be maintained.   
PK samples will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed to allow for assay development and validation (if needed). 
8.5 
PHARMACODYNAMICS 
Refer to Section 8.7 for information on pharmacodynamic biomarkers. 
8.6 
GENETICS 
Refer to Sections 8.7 and 8.10.1 for information on genetic biomarkers. 
8.7 
BIOMARKER ASSESSMENTS 
 samples for exploratory biomarker assessments will no 
longer be collected.  Samples collected under previous versions of the protocol may be 
used for exploratory biomarker assessments as detailed below. 
The following biomarker samples were collected under previous versions of the protocol, 
as applicable, from participants at all sites: 
 
Blood, plasma, serum and PBMC samples for exploratory research on biomarkers, 
including biomarker assay development  
 
Archival or newly collected tissue sample obtained at screening for EGFR or ALK 
mutational status assessment (if required), retrospective assessment of PD-L1 and 
LAG3 expression levels and for exploratory research on biomarkers, including 
biomarker assay development. 
A representative FFPE tumor specimen in a paraffin block (preferred) or 
preferably 15 slides (with an absolute minimum of 12 slides) containing 
unstained, freshly cut, serial sections must be submitted along with an 
associated pathology report prior to study enrollment.   
Tumor tissue should be of good quality based on total and viable tumor content 
(i.e., a minimum number of 100 viable TCs with preserved cellular context and 
tissue architecture).  Acceptable samples include samples from resections, 
core-needle biopsies for deep tumor tissue (with a minimum of three cores for 
freshly collected biopsies) or excisional, incisional, punch, or forceps biopsies for 
cutaneous, subcutaneous, or mucosal lesions, or EBUS core-needle biopsy. 

 
 
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EBUS-transbronchial needle aspiration is acceptable (particularly if a larger 
gauge needle is used), provided tissue is of good quality as described above 
(i.e., a minimum number of 100 viable TCs with preserved cellular context and 
tissue architecture).  For EBUS-needle aspirations, an 18-gauge or larger needle 
is recommended.  
Fine-needle aspirations that do not preserve tissue architecture and yield cell 
suspension and/or cell smears, brushings, cell pellets from pleural effusions, and 
lavage samples are not acceptable.  Tumor tissue from bone metastases is not 
evaluable for tumor PD-L1 expression by IHC and is therefore not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required.  A pretreatment tumor 
biopsy may also be performed if an individual's archival tissue test results do not 
meet eligibility criteria. 
 
Biomarker samples collected at participating sites and biomarker samples 
requiring separate consent are described in Sections 8.10.1 and 8.10.2. 
Exploratory biomarker research may include, but will not be limited to, analysis of 
circulating tumor DNA, genes or gene signatures associated with tumor immunobiology, 
lymphocytes, LAG3 and others, cytokines associated with T-cell activation, etc.  
Research may involve extraction of DNA, cell-free DNA, or RNA; analysis of mutations, 
single nucleotide polymorphisms, and other genomic variants; and genomic profiling. 
Genomic research with a focus on somatic variants may be conducted by comparing 
DNA extracted from blood or PBMCs with DNA extracted from tissue to distinguish 
somatic variants from germline variants.  Genomic profiling may include whole genome 
sequencing (WGS) or whole exome sequencing (WES) of blood samples, with a focus 
on somatic variants.  WGS or WES of blood samples with a focus on germline variants 
may also be conducted, but only at participating sites (see Section 8.10.1). 
Instructions for the collection and handling of biomarker samples, including sampling 
procedures, storage conditions, and shipment instructions, are provided in the laboratory 
manual. 
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.10.3), biomarker samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed, 
with the following exceptions: 
For enrolled participants, remaining archival tissue blocks will be returned to the site 
upon request or no later than completion of the final Clinical Study Report, 
whichever occurs first.  For individuals who are not enrolled, remaining archival 
tissue blocks will be returned to the site no later than 6 weeks after eligibility 
determination. 
 

 
 
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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to investigators or participants 
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. 
8.8 
IMMUNOGENICITY ASSESSMENTS 
Antibodies to tobemstomig will be evaluated in serum samples collected from  
participants according to the 
 
respectively).  These samples will be tested by the Sponsor or the Sponsor's designee. 
Serum samples will be screened for antibodies binding to tobemstomig and the titer of 
confirmed positive samples will be reported.  Other analyses may be performed to verify 
the stability of antibodies to tobemstomig and/or to further characterize the 
immunogenicity of tobemstomig. 
The detection and characterization of antibodies to tobemstomig will be performed 
through use of a validated assay method by or under the supervision of the Sponsor.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize 
the activity of the study treatment.  Samples may be stored for a maximum of 5 years 
(or according to local regulations) after the final Clinical Study Report has been 
completed at a facility selected by the Sponsor to enable further analysis of immune 
responses to tobemstomig. 
8.9 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economic and medical resource utilization assessments will not be performed in 
this study. 
8.10 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
8.10.1 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing with a Focus on Germline Variants 
(Participants at Participating Sites) 
At participating sites, blood samples that were collected for DNA extraction under 
previous versions of this protocol may be used to enable WGS or WES to identify 
variants that are predictive of response to study treatment, 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.  Research may include exploration of germline variants.  Samples may be 
sent to one or more laboratories for analysis. 

 
 
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Collection and submission of blood samples for WGS or WES 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 or 
WES, this section of the protocol (Section 8.10.1) will not be applicable at that site. 
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 will be analyzed in the context of this study but may 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.  
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no identification 
and reporting of incidental findings to investigators or participants. 
If permitted by local law, a participant may request access to uninterpreted WGS or 
WES data derived from analysis of his or her blood sample.  If a participant wishes to 
access these data, the investigator must inform the Sponsor, using the following email 
address:  global.return-genomics-results@roche.com.  The Sponsor will provide 
available data to the investigator in the form of a raw genomic sequencing data file but 
will not provide any interpretation of the data.  The investigator should not include the 
data file in the participant’s medical record.  Samples may be stored and analyzed in the 
future, and some samples may never be analyzed.  Thus, data may not be available at 
the time of the request or may never be available. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication (see Section A1–10). 
8.10.2 
Tumor Biopsies (Participants Providing Separate Consent) 
 optional tumor biopsies will no longer be collected.  

 
 
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Samples collected under previous versions of this protocol may be used for exploratory 
biomarker research as described in Section 8.7.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual.  Refer to Section 8.7 
for information on duration of sample storage and availability of data from biomarker 
analyses. 
8.10.3 
Samples for Research Biosample Repository (Participants 
Providing Separate Consent at Participating Sites) 
8.10.3.1 
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 were collected under previous versions of this protocol from 
participants who gave specific consent to participate in this optional research.  RBR 
samples will be analyzed to achieve one or more of 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 
 
8.10.3.2 
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 
been granted approval for RBR sampling, this section of the protocol (Section 8.10.3) 
will not be applicable at that site. 
8.10.3.3 
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 tobemstomig, diseases, 
or drug safety: 
 
Blood, plasma, serum, and PBMC samples collected under previous versions of 
this protocol   

 
 
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 
Leftover blood, serum, plasma, peripheral blood mononuclear cells, 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). 
 
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 may 
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). 
8.10.3.4 
Data Protection, Use, and Sharing 
RBR samples and associated data will be labeled with a unique participant identification 
number. 
Participant 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 
participant, unless permitted or required by law. 
Data generated from RBR samples will be analyzed in aggregate rather than on an 
individual patient basis.  Thus, there will be no identification and reporting of incidental 
findings to investigators or patients.  In addition, 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 participants, unless required by law, with the 
exception of data generated from blood samples collected for WGS or WES as 
described below.   
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access 
these data, the investigator must inform the Sponsor, using the following email address:  
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the investigator in the form of a raw genomic sequencing data file but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available.  
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. 
8.10.3.5 
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 participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to choose not to provide optional RBR samples 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 participant's agreement to 
provide optional RBR samples.  Participants who choose not to provide optional RBR 
samples will not provide a separate signature.  The investigator should document 
whether or not the participant has given consent to provide optional RBR samples and 
(if applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal 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. 
8.10.3.6 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  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 
participant 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 participant's 
wishes through use of the appropriate RBR Subject Withdrawal Form and must enter the 
date of withdrawal on the Sample Informed Consent/Withdrawal eCRF.  If a participant 
wishes to withdraw consent to the testing of his or her RBR samples after closure of the 

 
 
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site, the investigator must inform the Sponsor by emailing the study number and 
participant number to the following email address: 
global.rcr-withdrawal@roche.com 
A participant's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a participant's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study. 
8.10.3.7 
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 an individual's 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. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
The purpose of this study is hypothesis generation regarding the effect of tobemstomig 
in combination with platinum-based chemotherapy (Arm A) compared with 
pembrolizumab plus platinum-based chemotherapy (Arm B) on the basis of the primary 
endpoints, investigator-assessed ORR and PFS.  No formal statistical hypotheses will be 
tested for this study. 
9.1.1 
Sample Size Determination 
A total of approximately 180 patients is planned for this study.   
 
 
  
 
 
  Table 8 and Table 9 show the CIs for 
several possible true underlying improvements in ORR and PFS in favor of Arm A. 
 
 

 
 
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Table 8 
Confidence Intervals for Several Possible True Underlying ORR 
Values 
 
True Underlying ORR 
ORR  objective response rate. 
a Calculated using Newcombe method. 
  
Table 9 
Confidence Intervals for Several Possible True Underlying PFS 
HR Values 
 
True Underlying PFS HR 
HR  hazard ratio; PFS  progression-free survival. 
  
9.2 
ANALYSIS SETS 
The participant analysis sets for the purposes of analyses are defined in Table 10. 
Table 10 Participant Analysis Sets 
Participant Analysis Set 
Description 
Full analysis set  
All randomized participants 
Participants will be included in the analyses according to the 
intervention to which they are randomized. 
Measurable at baseline 
All randomized participants with measurable disease at baseline, 
as determined by the investigator according to RECIST v1.1 
Participants will be included in the analyses according to the 
intervention to which they are randomized. 
Safety analysis set 
All participants exposed to study intervention; participants will be 
analyzed according to the intervention they actually receive 
A participant will be included in Arm A 
(tobemstomig  chemotherapy) or Arm B 
(pembrolizumab  chemotherapy) in the safety analysis if the 
participant receives any amount of tobemstomig or 
pembrolizumab, regardless of the initial treatment assignment 
at randomization, respectively. 
RECIST v1.1  Response Evaluation Criteria is Solid Tumors, Version 1.1. 
  
9.3 
STATISTICAL ANALYSES 
9.3.1 
General Considerations 
All efficacy analyses will be performed on the full analysis set, unless otherwise 
specified.  The analysis of ORR will be performed for participants in all randomized 
participants with measurable disease at baseline, as determined by the investigator 

 
 
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according to RECIST v1.1.  No formal hypothesis testing will be conducted; any 
treatment arm comparison and their associated p-value will be generated for descriptive 
purpose only. 
All safety analyses will be performed on the safety-evaluable population, unless 
otherwise specified. 
 
 
 
 
 
 
  
9.3.2 
Estimation Methods for the Primary Endpoints 
The primary efficacy endpoints are confirmed ORR and PFS, as assessed by the 
investigator according to RECIST v1.1. 
The analysis population for ORR will be all randomized patients with measurable 
disease at baseline.  The primary analysis of the primary endpoint of 
investigator-assessed ORR will occur once all randomized patients have been treated 
and followed until their post-baseline tumor assessment 12 weeks or 3 months after last 
patient has been randomized, whichever occurs first. 
Investigator-assessed PFS will be analyzed in all patients randomized.  
 
 
  The primary analysis of the primary endpoint of investigator-assessed 
PFS will occur after approximately 
 have been observed. 
9.3.2.1 
Objective Response Rate 
ORR is defined as the percentage of participants who experience a complete response 
or partial response on two consecutive occasions  4 weeks apart, as determined by the 
investigator according to RECIST v1.1.  Participants without post-baseline 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 using the Newcombe method.  The 95% CI of the confirmed ORR will be 
calculated for each treatment arm using the Wilson score method.  The Cochran-Mantel-
Haenszel test will be used to compare the ORR between the two treatment arms, 
stratified according to the protocol-defined stratification factors. 

 
 
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9.3.2.2 
Progression-Free Survival 
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.  Data from 
participants who have not experienced disease progression or who have not died at the 
time of analysis will be censored at the time of the last tumor assessment.  Data from 
participants with no post-baseline tumor assessment will be censored at the date of 
randomization. 
 
 
 
 be used to estimate the PFS curve and 
median PFS for each treatment arm.  
 will be 
used to construct the 95% CI for the median PFS for each treatment arm (Brookmeyer 
and Crowley 1982). 
9.3.3 
Estimation Methods for the Secondary Endpoints 
9.3.3.1 
Overall Survival 
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are alive at the time of the data cut-off will be censored at the last date they were 
known to be alive.  Data from participants without post-baseline information will be 
censored at the date of randomization. 
 
will be used to estimate the OS curve and 
median OS for each treatment arm.  
 will be used 
to construct the 95% CI for the median OS for each treatment arm (Brookmeyer and 
Crowley 1982).  
 
9.3.3.2 
Duration of Response 
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.  Data 
from participants who have not progressed and who have not died at the time of analysis 
will be censored at the time of the last tumor assessment date.  The analysis of DOR will 
include only patients who achieve an objective response to study treatment.  DOR curve 
and median DOR for each treatment arm will be estimated according to the 
 will be used to 
construct the 95% CI for the median DOR for each treatment arm (Brookmeyer and 
Crowley 1982). 

 
 
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9.3.3.3 
Investigator-Assessed PFS and OS in Selected PD-L1 
Expression Subgroups 
Similar analysis methods to those described for the PFS and OS analyses will be 
performed for participants with PD-L1 expression,
9.3.3.4 
Patient-Reported Outcomes 
The change from baseline in PRO assessment of lung cancer symptoms, physical 
functioning, role functioning, and global health status/quality of life (GHS/QoL) as 
assessed through the use of the EORTC IL85, IL132, IL188, and IL17 will be analyzed 
for all randomized participants. 
Compliance rates will be summarized by listing the number and proportion of 
participants who complete the PRO questionnaires at each timepoint by treatment arm. 
9.3.3.5 
Safety Analyses 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs. 
Study treatment exposure (such as treatment duration, total dose received) will be 
summarized using descriptive statistics. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms.  Adverse event severity will be graded according to 
NCI CTCAE v5.0, with the exception of CRS event severity, which will be assessed by 
the investigator according to the ASTCT Consensus Grading Scale (Lee et al. 2019).  All 
adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, and adverse events leading to study treatment discontinuation 
that occur on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  
Deaths and cause of death will be summarized. 
Relevant laboratory and vital sign will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum post-baseline severity grade.  Changes in vital 
signs will be summarized.  
9.3.3.6 
Pharmacokinetic Analyses 
Individual and mean serum tobemstomig concentration versus time data will be tabulated 
and plotted.  The serum pharmacokinetics of tobemstomig will be summarized by 
estimating total exposure (AUC), maximum concentration, total clearance, volume of 
distribution at steady state, and terminal drug-elimination half-life (as appropriate for data 
collected).  Estimates for these parameters will be tabulated and summarized (mean, 

 
 
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standard deviation, coefficient of variation, median, and range).  Inter-participant 
variability and drug accumulation will be evaluated.   
Additional PK analyses will be conducted as appropriate. 
9.3.3.7 
Immunogenicity Analyses 
The number and proportion of ADA positive participants and ADA negative participants 
at baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining post-baseline incidence, 
participants are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60-titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Participants are considered 
to be ADA negative if they are ADA negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60-titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
9.3.4 
Exploratory Analyses 
9.3.4.1 
Subgroup Analysis 
To assess the consistency of the study results in subgroups defined according to 
demographics (e.g., age, sex) and baseline disease characteristics (e.g., NSCLC 
histology, ECOG Performance Status), the primary efficacy endpoints in such subgroups 
will be examined.  Summaries will be produced separately for each level of the 
categorical variables for comparison between treatment arms. 
9.3.4.2 
Patient-Reported Outcomes 
The number and proportion of participants in each category of symptomatic treatment 
toxicities as assessed through use of selected items from the NCI PRO-CTCAE will be 
summarized by visit. 
The number and proportion of participants in each category reporting they are troubled 
by treatment symptoms, as assessed through the single-item EORTC IL46 will be 
summarized by visit. 
9.3.4.3 
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 summarized by treatment arm. 

 
 
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10. 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
TABLE OF CONTENTS 
A1–1 
Regulatory and Ethical Considerations ..................................... 108 
A1–2 
Financial Disclosure .................................................................. 108 
A1–3 
Informed Consent Process........................................................ 109 
A1–4 
Data Protection ......................................................................... 109 
A1–5 
Administrative Structure ............................................................ 110 
A1–6 
Dissemination of Clinical Study Data ........................................ 110 
A1–7 
Data Quality Assurance ............................................................ 110 
A1–8 
Source Documents ................................................................... 112 
A1–9 
Study and Site Closure ............................................................. 112 
A1–10 
Publication Policy ...................................................................... 113 
A1–11 
Protocol Deviations ................................................................... 113 
 

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A1–1 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
 
Applicable laws and regulations 
 
The protocol, Informed Consent Form, Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board or 
Ethics Committee (IRB/EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 
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 
 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, or Clinical Trials Regulation (536/2014) (EEA sites only), and 
all other applicable local regulations 
 
A1–2 
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 
study and for 1 year after completion of the study (see definition of end of study in 
Section 4.5). 

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A1–3 
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study, including the 
risks and benefits, to the participant or his or her legally authorized representative and 
answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a participant's willingness to continue in the 
study, the participant or the participant's legally authorized representative must 
re-consent by signing the most current version of the Informed Consent Form or the 
addendum, in accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. 
A1–4 
DATA PROTECTION 
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. 
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; the 
participant's name or any information that would make the participant identifiable will not 
be transferred. 
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the Informed Consent Form. 

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Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A1–5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 70 sites globally will participate to enroll approximately 180 participants.  
Enrollment will occur through an interactive voice or web-based response system.  
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker, and pharmacokinetic analyses), as indicated 
in Section 8.2.4 and Appendix 2.  Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. 
An Internal Monitoring Committee was used to monitor and evaluate participant safety 
throughout the study, 
.   
A1–6 
DISSEMINATION OF CLINICAL STUDY DATA 
Study data, which may include imaging data and data on genomic variants, 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, 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 provided upon request.  For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants 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. 
A1–7 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed or electronic Case 
Report Forms (CRFs) unless transmitted to the Sponsor or designee electronically 

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(e.g., laboratory data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered on the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided prior to study 
initiation, in the various functional monitoring plans (including, but not limited to, Quality 
Tolerance Limit Management Plan and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered into the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, the ICH Guideline 
for Good Clinical Practice, and all applicable regulatory requirements. 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 

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A1–8 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered on the electronic Case Report Form (eCRF) that 
are transcribed from source documents must be consistent with the source documents, 
or the discrepancies must be explained.  The investigator may need to request previous 
medical records or transfer records, depending on the study.  Also, current medical 
records must be available. 
Definition of what constitutes source data and its origin can be found in the Trial 
Monitoring Plan. 
A1–9 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to participants. 
 
Participant enrollment is unsatisfactory. 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigators shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
Study sites will be closed upon study completion.  A study site is considered closed 
when all required documents and study supplies have been collected and a site closure 
visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 

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 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigator shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
A1–10 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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. 
A1–11 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
 

 
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Appendix 2  
Clinical Safety Laboratory Tests 
The tests detailed in Table A2-1 will be performed by the local laboratory/central 
laboratory/local or central laboratory, 
Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Section 5. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 
 
 

Appendix 2:  Clinical Safety Laboratory Tests  
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Table A2-1 Protocol-Required Safety Laboratory Assessments 
Local Laboratory Tests 
 Hematology:  WBC count with differential (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes), RBC count, hemoglobin, hematocrit, platelet count, and differential count 
 Chemistry panel (serum):  bicarbonate or total carbon dioxide (if considered standard of care 
for the region), sodium, magnesium, potassium, chloride, calcium, phosphate, glucose, BUN 
or urea, creatinine, total protein, albumin, total bilirubin, ALP, ALT, AST, and lactate 
dehydrogenase 
 Coagulation:  INR and aPTT 
 Cardiac enzymes:  troponin T or troponin I  
 Thyroid function testing:  thyroid-stimulating hormone, free T3 (or total T3 for sites where free 
T3 is not performed), and free T4 
 HIV serology:  HIV-1 antibody, HIV-1/2 antibody, and HIV-2 antibody 
 HBV serology:  HBsAg, HBsAb, and total HBcAb for all individuals; HBV DNA for individuals 
with negative HBsAg and HBsAb tests and a positive total HBcAb test  
Individuals with a positive quantitative HBV DNA at screening (must be  500 IU/mL per 
the eligibility criteria) will undergo additional HBV DNA tests as outlined in the schedule 
of activities (see Section 1.3). 
 HCV serology:  HCV antibody for all individuals; HCV RNA for individuals with a positive HCV 
antibody test 
 Pregnancy test:  All female participants of childbearing potential will have a serum pregnancy 
test performed at screening within 14 days prior to initiation of study treatment.  Urine or 
serum pregnancy tests will be performed  96 hours before Day 1 of every cycle and at the 
study treatment discontinuation visit.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
 Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and blood).  If 
blood or protein is abnormal, microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria) will be performed  
If there is a clinically significant positive result (confirmed by a repeat positive sample), 
urine will be sent to the laboratory for microscopy and culture.  If there is an explanation for 
the positive dipstick results (e.g., menses), it should be recorded, and there is no need to 
perform microscopy and culture.   
ADA  anti-drug antibody; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface 
antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; PCR  polymerase chain reaction; 
PD  pharmacodynamic; PK  pharmacokinetic. 
  
Investigators must document their review of each laboratory safety report.  
 
  

 
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Appendix 3  
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
TABLE OF CONTENTS 
A3–1 
Definition of Adverse Event ....................................................... 117 
A3–2 
Definition of Serious Adverse Event .......................................... 118 
A3–3 
Recording and Follow-Up of Adverse Events and/or Serious 
Adverse Events ......................................................................... 120 
A3–3.1 
Adverse Event and Serious Adverse Event Recording ............. 120 
A3–3.2 
Assessment of Severity ............................................................ 120 
A3–3.3 
Assessment of Causality ........................................................... 122 
A3–3.4 
Follow-Up of Adverse Events and Serious Adverse Events ...... 123 
A3–3.4.1 
Investigator Follow-Up .............................................................. 123 
A3–3.4.2 
Sponsor Follow-Up ................................................................... 124 
A3–4 
Reporting of Serious Adverse Events ....................................... 124 
A3–4.1 
Serious Adverse Event Reporting to the Sponsor via an 
Electronic Collection Tool.......................................................... 124 
A3–4.2 
Serious Adverse Event Reporting to the Sponsor via Paper 
CRF .......................................................................................... 125 
A3–5 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................... 125 
A3–5.1 
Events That Occur prior to Study Treatment Initiation .............. 125 
A3–5.2 
Events That Occur after Study Treatment Initiation .................. 125 
A3–6 
Reporting Adverse Events That Occur after the Adverse 
Event Reporting Period ............................................................. 126 
A3–7 
Procedures for Recording Adverse Events ............................... 126 
A3–7.1 
Infusion-Related Reactions ....................................................... 126 
A3–7.2 
Diagnosis Versus Signs and Symptoms ................................... 127 
A3–7.3 
Adverse Events That Are Secondary to Other Events .............. 127 
A3–7.4 
Persistent or Recurrent Adverse Events ................................... 127 
A3–7.5 
Abnormal Laboratory Values..................................................... 128 
A3–7.6 
Abnormal Vital Sign Values....................................................... 129 
A3–7.7 
Abnormal Liver Function Tests ................................................. 129 
A3–7.8 
Deaths ...................................................................................... 130 
A3–7.9 
Pre-Existing Medical Conditions ............................................... 130 
A3–7.10 
Lack of Efficacy or Worsening of NonSmall Cell Lung 
Cancer ...................................................................................... 131 
A3–7.11 
Hospitalization or Prolonged Hospitalization ............................. 131 
A3–7.12 
Cases of Accidental Overdose and Medication Error ................ 132 
A3–7.12.1 
Reporting Special Situations ..................................................... 132 
A3–7.12.2 
Reporting Adverse Events Associated with Special 
Situations .................................................................................. 132 
A3–7.13 
Cases of Medication Error ........................................................ 133 
A3–7.14 
Patient-Reported Outcome Data ............................................... 134 
A3–7.15 
Safety Biomarker Data .............................................................. 134 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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A3–1 
DEFINITION OF ADVERSE EVENT 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
participant temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease) 
 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
 
Signs, symptoms, or clinical sequelae of a suspected drugdrug interaction 
 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or 
self-harming intent.  Such overdoses should be reported regardless of 
sequelae. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as an adverse event 
or serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
 
The disease or disorder being studied or expected progression, signs, or symptoms 
of the disease or disorder being studied, unless more severe than expected for the 
participant’s condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 
The condition that leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of a pre-existing disease or condition present or 
detected at the start of the study that do not worsen 
 
A3–2 
DEFINITION OF SERIOUS ADVERSE EVENT 
If an event is not an adverse event per the definition in Section A3–1, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose:   
 
Results in death 
 
Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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119/Protocol BO44178, Version 4 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an adverse event. 
 
Results in persistent disability or incapacity 
The term "disability" means a substantial disruption of a person’s ability to 
conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly or birth defect 
 
Medically significant: 
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. 
 
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 National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], or the 
ASTCT CRS Consensus Grade Scale; see Section A3–3.2); 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 electronic Case Report Form (eCRF). 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event) (see Section A3–5 for reporting instructions). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
120/Protocol BO44178, Version 4 
A3–3 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS 
AND/OR SERIOUS ADVERSE EVENTS 
A3–3.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A3–3.2 
ASSESSMENT OF SEVERITY 
The investigator will assess the severity of each adverse event reported during the study 
through use of the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events, Version 5.0 (NCI CTCAE v5.0) grading scale, with the exception of 
CRS events. The severity of CRS will be determined according to the American Society 
of Transplantation and Cellular Therapy (ASTCT) Consensus Grading Scale.  The 
investigator will use the grading scale in Table A3-1 for assessing the severity of 
adverse events that are not specifically listed in the NCI CTCAE or ASTCT. 
 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
121/Protocol BO44178, Version 4 
Table A3-1 Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE or ASTCT CRS Grading Scale 
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 
ASTCT  American Society of Transplantation and Cellular Therapy; CRS  cytokine release 
syndrome; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer 
Institute. 
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 Examples of instrumental activities of daily living include 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 participants 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 A3–5 for reporting instructions), per the definition of serious 
adverse event in Section A3–2.  
d Grade 4 and 5 events must be reported as serious adverse events (see Section A3–5 for 
reporting instructions), per the definition of serious adverse event in Section A3–2. 
  
The ASTCT CRS Consensus Grading Scale (see Table A3-2) (Lee et al. 2019) should 
be used when reporting severity of CRS events (see Appendix 6 for details on CRS 
reporting). 
 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
122/Protocol BO44178, Version 4 
Table A3-2 ASTCT CRS Consensus Grading Scale 
Grade 
Symptom(s) 
1 
 Fever a, with or without constitutional symptoms 
 No hypotension 
 No hypoxia 
2 
 Fever a combined with at least one of the following: 
 Hypotension not requiring vasopressors 
 Hypoxia requiring low flow oxygen b by nasal cannula or blow-by 
3 
 Fever a combined with at least one of the following: 
 Hypotension requiring one vasopressor, with or without vasopressin 
 Hypoxia requiring high flow oxygen b by nasal cannula, face mask, 
non-rebreather mask, or Venturi mask 
4 
 Fever a combined with at least one of the following: 
 Hypotension requiring multiple vasopressors (excluding vasopressin) 
 Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, 
intubation, and mechanical ventilation) 
5 
 Death due to CRS for which the cause is not the principal factor leading to 
this outcome 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine release 
syndrome. 
a Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive antipyretic, anticytokine, or corticosteroid therapy, fever is no 
longer required when determining CRS severity (grade).  In this case, the CRS grade is 
driven by the presence of hypotension and/or hypoxia. 
b Low flow is defined as oxygen delivered at  6 mL/min, and high flow is defined as  6 L/min. 
  
A3–3.3 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
123/Protocol BO44178, Version 4 
The investigator will also consult the Investigator’s Brochure and/or prescribing 
information (for marketed products) in his or her assessment. 
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
For participants receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.  
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A3–3.4 
FOLLOW-UP OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS 
A3–3.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor with a copy of any post-mortem findings, 
including histopathology.  
New or updated information should be recorded on the originally completed Adverse 
Event eCRF.  For serious adverse events and adverse events of special interest, the 
investigator must report new significant follow-up information to the Sponsor immediately 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
124/Protocol BO44178, Version 4 
(i.e., no more than 24 hours after the investigator becomes 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 
 
During the adverse event reporting period (defined in Section 8.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the 
participant's medical record to facilitate source data verification. 
A3–3.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, 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. 
A3–4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A3–4.1 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA AN ELECTRONIC COLLECTION TOOL 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A3–5. 
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations Form, as described in Section A3–5, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study participant or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken off line, the site can report this information 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
125/Protocol BO44178, Version 4 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A3–5. 
A3–4.2 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA PAPER CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations Form, as 
described in Section A3–5. 
A3–5 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A3–5.1 
EVENTS THAT OCCUR PRIOR TO STUDY TREATMENT 
INITIATION 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., biopsy, 
discontinuation of medications) should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators. 
A3–5.2 
EVENTS THAT OCCUR AFTER STUDY TREATMENT 
INITIATION 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after the investigator becomes aware of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse Event/ 
Special Situations Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after the 
investigator becomes aware 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 more than 90 days after the 
final dose of study treatment are provided in Section A3–6. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
126/Protocol BO44178, Version 4 
A3–6 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that occurs after the end of the adverse event reporting period (defined as 90 days 
after the final dose of study treatment), if the event is believed to be related to prior 
exposure to study treatment.  These events should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Special Situations Form, 
using the fax number or email address provided to investigators. 
A3–7 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the participant's medical records to the Medical Monitor in lieu of 
completion of the eCRF.  Investigators should use correct medical terminology and 
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 of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
A3–7.1 
INFUSION-RELATED REACTIONS 
Adverse events that occur during or after study drug administration and are judged to be 
related to study treatment infusion should be captured as a diagnosis (e.g., infusion-
related reaction [IRR]) on the Adverse Event eCRF. If possible, avoid ambiguous terms 
such as “systemic reaction.” Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF. If a participant 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. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
127/Protocol BO44178, Version 4 
A3–7.2 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
For adverse events other than infusion-related reactions, 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. 
A3–7.3 
ADVERSE EVENTS THAT ARE SECONDARY TO 
OTHER EVENTS 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
A3–7.4 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant 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 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
128/Protocol BO44178, Version 4 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware that the event became 
serious; see Section A3–5 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 participant evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
A3–7.5 
ABNORMAL LABORATORY VALUES 
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 
laboratory value abnormality that is not associated with the underlying disease 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., dose 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  
 
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  upper limit of normal [ULN] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
129/Protocol BO44178, Version 4 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A3–7.4 for 
details on recording persistent adverse events). 
A3–7.6 
ABNORMAL VITAL SIGN VALUES 
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 
vital sign abnormality that is not associated with the underlying disease 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., dose 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 (e.g., 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 A3–7.4 for 
details on recording persistent adverse events). 
A3–7.7 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN 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 A3–7.2) 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
130/Protocol BO44178, Version 4 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A3–5). 
A3–7.8 
DEATHS 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 8.3.1) that are attributed 
by the investigator solely to progression of nonsmall cell lung cancer should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, regardless of relationship to study 
treatment, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section A3–5).  An Internal Monitoring Committee monitored the 
frequency of deaths from all causes 
.  
Deaths will continue to be monitored at regular intervals by the study management 
team. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section A3–6. 
A3–7.9 
PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Tobemstomig—F. Hoffmann-La Roche Ltd 
131/Protocol BO44178, Version 4 
A3–7.10 
LACK OF EFFICACY OR WORSENING OF NONSMALL CELL 
LUNG CANCER 
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event.  When recording an unanticipated worsening of nonsmall cell lung cancer on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated worsening of nonsmall 
cell lung cancer").  Events that are clearly consistent with the expected pattern of 
progression of the underlying disease should not be recorded as adverse events.  These 
data will be captured as efficacy assessment data only.  In most cases, the expected 
pattern of progression will be based on Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (see Appendix 10).  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. 
A3–7.11 
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 A3–2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a pre-existing condition, provided that both of the following criteria 
are met: 
 
The participant was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when treatment 
became necessary because of the expected normal progression of the 
condition. 
 
The participant has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of participant requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
A3–7.12 
CASES OF ACCIDENTAL OVERDOSE AND 
MEDICATION ERROR 
Accidental overdose and medication error 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. 
 
Special situations and adverse events associated with special situations are to be 
reported separately on the Adverse Event eCRF, as outlined in the sections below. 
A3–7.12.1 
Reporting Special Situations 
All special situations associated with tobemstomig, pembrolizumab, pemetrexed, 
carboplatin, and paclitaxel regardless of whether they result in an adverse event, should 
be recorded on the Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  tobemstomig, 
pembrolizumab, pemetrexed, carboplatin, and paclitaxel 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. 
 
A3–7.12.2 
Reporting Adverse Events Associated with Special Situations 
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 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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Sponsor immediately (i.e., no more than 24 hours after the investigator becomes aware 
of the event; see Section A3–5).  For tobemstomig, pembrolizumab, pemetrexed, 
carboplatin, and paclitaxel adverse events associated with special situations should be 
recorded as described below for each situation: 
 
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. 
 
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 
(special situation) and one entry to report the adverse event (headache).  The 
"Accidental overdose" and "Medication error" boxes would need to be checked for 
both entries. 
 
A3–7.13 
CASES OF MEDICATION ERROR 
A medication error is defined as an accidental deviation in the administration of a drug 
(e.g., wrong drug dose administered, sham procedure performed in participant assigned 
to active drug, drug administered in wrong location, sham procedure performed 
incorrectly, expired drug administered).  In some cases, a medication error may be 
intercepted prior to administration of the drug. 
Medication errors are not in themselves adverse events but may result in adverse 
events.  The unmasked treating physician will record each adverse event associated 
with a medication error on a paper adverse event reporting worksheet and will indicate 
that a "medication error" has occurred.  The unmasked treating physician will not 
indicate the type of medication error or provide any other information that could reveal 
the participant's treatment assignment.  The masked assessor physician will then assess 
the causality of the adverse event and enter this information on the worksheet.  
A masked site team member will record each adverse event on the Adverse Event eCRF 
by entering the adverse event term and checking the "Medication error" box.  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 the investigator becomes aware of the event; see Section A3–5). 
The unmasked treating physician will record information about each medication error, 
regardless of whether it resulted in an adverse event, on a two-page paper study 
treatment administration worksheet.  The unmasked treating physician will provide 
detailed information on the first page of the worksheet and will indicate on the second 
page that a "medication error" has occurred.  The second page of the worksheet will not 
indicate the type of medication error or provide any other information that could reveal 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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the participant's treatment assignment.  The first page will be archived with study records 
that are accessible only to unmasked personnel.  The second page will be forwarded to 
a masked site team member, who will record the medication error on the Adverse Event 
eCRF by entering "Medication error" as the event term and checking the "Medication 
error" box. 
As an example, a medication error that resulted in a headache would require two entries 
on the Adverse Event eCRF, one entry to report a medication error and one entry to 
report the headache.  The "Medication error" boxes would need to be checked for 
both entries. 
A3–7.14 
PATIENT-REPORTED OUTCOME DATA 
Adverse event reports will not be derived from NCI Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) or other 
patient-reported outcome (PRO) data by the Sponsor.  In addition, the Sponsor will 
make no attempt to reconcile participant reports of treatment-related symptoms (through 
the use of the PRO-CTCAE) with investigator reports of adverse events.  Sites are not 
expected to review the PRO-CTCAE or other PRO data for adverse events. 
A3–7.15 
SAFETY BIOMARKER DATA 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on participant 
management. 
REFERENCES 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
 
 

 
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Appendix 4  
Safety Plan:  Management of Identified and Potential Risks 
TABLE OF CONTENTS 
A4–1 
Risks Associated with Tobemstomig ......................................... 136 
A4–2 
Risks Associated with Pembrolizumab ..................................... 136 
A4–3 
Risks Associated with Pemetrexed ........................................... 136 
A4–4 
Risks Associated with Carboplatin ............................................ 136 
A4–5 
Risks Associated with Paclitaxel ............................................... 137 
A4–6 
Management of Participants Who Experience Adverse 
Events ....................................................................................... 137 
A4–6.1 
Dose Modifications for Tobemstomig and Pembrolizumab ....... 137 
A4–6.2 
Dose Modifications for Chemotherapy ...................................... 137 
A4–6.2.1 
Hematologic Toxicity ................................................................. 137 
A4–6.2.2 
Non-Hematologic Toxicity ......................................................... 138 
A4–6.3 
Treatment Interruption for Tobemstomig and Pembrolizumab .. 139 
A4–6.4 
Management Guidelines ........................................................... 140 
A4–6.4.1 
Management Guidelines for Adverse Events Associated with 
Tobemstomig and Pembrolizumab ........................................... 140 
A4–6.4.2 
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events ......................................................................... 140 
A4–6.4.3 
Potential Overlapping Toxicities ................................................ 140 
 

Appendix 4:  Safety Plan:  Management of Identified and Potential Risks 
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A4–1 
RISKS ASSOCIATED WITH TOBEMSTOMIG 
Infusion-related reactions are an identified risk with tobemstomig, and 
 
. .  The potential risks associated with 
tobemstomig are comparable to the potential risks of therapeutic antibodies generally 
and the potential risks generally associated with programmed deathligand 1 (PD-1) and 
lymphocyte activation gene 3 (LAG3) receptortargeting agents and include 
immunogenicity and immune-mediated adverse events.  For more details relating to the 
risks associated with tobemstomig, refer to the Tobemstomig Investigator’s Brochure. 
A4–2 
RISKS ASSOCIATED WITH PEMBROLIZUMAB 
Pembrolizumab has been associated with immune-mediated risks, such as pneumonitis, 
colitis, hepatitis, nephritis, endocrinopathies (adrenal insufficiency, hypophysitis, 
Type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism), 
skin adverse reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis), and 
other immune-mediated adverse reactions (uveitis, arthritis, myositis, myocarditis, 
pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, hemolytic anemia, 
sarcoidosis, encephalitis, myelitis, cholangitis sclerosing, gastritis, and non-infective 
cystitis).  Infusion-related reactions are identified risks with pembrolizumab.  
Pembrolizumab in combination with chemotherapy should be used with caution in 
participants who are  75 years old after careful consideration of the potential benefits 
and risks on a case-by-case basis. 
For more details regarding the safety profile of pembrolizumab, refer to the 
pembrolizumab prescribing information. 
A4–3 
RISKS ASSOCIATED WITH PEMETREXED 
Pemetrexed is known to cause gastrointestinal toxicities (nausea, vomiting, diarrhea, or 
constipation), renal toxicities, neuropathy, myelosuppression, infection, fatigue, 
stomatitis, alopecia, and rash. 
For more details regarding the safety profile of pemetrexed, refer to the prescribing 
information for pemetrexed. 
A4–4 
RISKS ASSOCIATED WITH CARBOPLATIN 
Carboplatin is known to cause bone marrow suppression, including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to be 
moderately emetogenic.  Participants will be monitored for carboplatin-related adverse 
events. 

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For more details regarding the safety profile of carboplatin, refer to the carboplatin 
prescribing information. 
A4–5 
RISKS ASSOCIATED WITH PACLITAXEL 
Paclitaxel is known to cause bone marrow suppression (e.g., myelosuppression, anemia 
and thrombocytopenia), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), 
hepatotoxicity, peripheral neuropathy, hypersensitivity reactions, arthralgia or myalgia, 
injection site reactions, alopecia, and cardiovascular effects such as hypotension, 
bradycardia, hypertension, arrhythmias, and other ECG abnormalities.  Patients will be 
monitored for paclitaxel-related adverse events.  For more details regarding the safety 
profile of paclitaxel, refer to the paclitaxel prescribing information. 
A4–6 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS 
A4–6.1 
DOSE MODIFICATIONS FOR TOBEMSTOMIG AND 
PEMBROLIZUMAB 
There will be no dose modifications, including dose reductions for tobemstomig and 
pembrolizumab in this study. 
A4–6.2 
DOSE MODIFICATIONS FOR CHEMOTHERAPY 
Dose modifications for pemetrexed, paclitaxel, and carboplatin are permitted for toxicity 
according to the prescribing information and local standard of care.  
Dose modification guidelines are provided below.  Once reduced, the dose cannot be 
increased back to 100%.  
Treatment with pemetrexed and carboplatin should be discontinued if a patient 
experiences any hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two 
dose reductions or treatment is delayed for more than 63 days due to toxicities. 
A4–6.2.1 
Hematologic Toxicity  
At the start of each cycle, the ANC should be   1500/L and the platelet count should 
be   100,000/L.  Treatment may be delayed for up to 63 days to allow sufficient time for 
recovery.  Growth factors may be used in accordance with American Society of Clinical 
Oncology and National Comprehensive Cancer Network (NCCN) guidelines (Smith et al. 
2015; NCCN 2019).  Upon recovery, dose adjustments at the start of a subsequent cycle 
will be made on the basis of the lowest platelet and neutrophil values from the previous 
cycle (see Table A4-1). 
 

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Table A4-1 Chemotherapy Dose Modifications for Hematologic Toxicities 
Toxicity a  
Dose 
ANC  500/L and platelets  50,000/L 
75% of previous dose 
Platelets  25,000/L, regardless of ANC 
75% of previous dose 
Platelets  50,000/L with Grade  2 bleeding, 
regardless of ANC 
50% of previous dose 
ANC  1000/L plus fever of  38.5°C 
75% of previous dose 
a Nadir at prior cycle. 
  
In the event that dose adjustments are needed for both ANC and platelets, participants 
are to receive the lower dose. 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Participants should be made aware of these signs and 
encouraged to seek medical attention at the earliest opportunity.  
If chemotherapy is withheld because of hematologic toxicity, complete blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  Treatment can then be resumed.  
No dose reductions are recommended for anemia.  Participants should be supported per 
the investigator’s institution’s guidelines. 
A4–6.2.2 
Non-Hematologic Toxicity 
For a non-hematologic toxicity (see Table A4-2), treatment should be delayed for up to 
63 days until resolution to less than or equal to the participant’s baseline value or 
Grade 1 or better if the participant did not have that toxicity at baseline).  
Dose reductions at the start of the subsequent cycle should be made on the basis of 
non-hematologic toxicities from the dose administered in the preceding cycle.  
The recommended dose modifications for non-hematologic toxicities are presented in 
Table A4-2. 
 
 

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Table A4-2 Dose Modifications for Treatment Discontinuation for 
Non-Hematologic Toxicities 
Toxicity 
Adjusted Dose as  
Percentage of Previous Dose a 
Diarrhea 
Grade 3 or 4 b 
75% 
Nausea or vomiting 
Grade 3 or 4 c 
75% 
Neurotoxicity 
Grade 2 
75% 
Grade 3 or 4 
50% or permanent discontinuation 
Transaminase 
elevation 
Grade 3 
75% 
Grade 4 
Discontinue. 
Other  
Grade 3 or 4 
75% 
a 
If deemed appropriate by the investigator, adjust carboplatin dose to the specified 
percentage of the previous area under the concentrationtime curve.  
b 
Grade 3 or 4 diarrhea that occurs on adequate anti-diarrhea medication or any grade of 
diarrhea requiring hospitalization. 
c 
Despite the use of anti-emetic therapies. 
  
Diarrhea should be controlled with adequate antidiarrheal medication.  Nausea and/or 
vomiting may be controlled with adequate anti-emetic medications.  For Grade 3 or 4 
neurotoxicity chemotherapy should be resumed at 50% of the previous dose upon 
improvement or discontinued immediately (based on the investigator’s clinical judgment). 
A4–6.3 
TREATMENT INTERRUPTION FOR TOBEMSTOMIG AND 
PEMBROLIZUMAB 
Before permanently discontinuing tobemstomig or pembrolizumab (regardless of 
whether initiated by the participant, the investigator, or the Sponsor), an interruption 
should be considered.  Participants who have temporarily interrupted tobemstomig or 
pembrolizumab should be considered to restart treatment as soon as medically justified 
in the opinion of the investigator. 
Tobemstomig or pembrolizumab may be temporarily suspended for up to 12 weeks to 
allow for resolution of toxicity to NCI CTCAE Grade  2 for hematological toxicities or 
Grade 1 or better for non-hematological toxicities (with the exception of a toxicity 
considered by the investigator to be non-study treatment-related). If 
tobemstomig/pembrolizumab is withheld for  12 weeks, the participant will be 
discontinued from tobemstomig or pembrolizumab. 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed, and the acceptable length of interruption should be discussed between the 
investigator and the Medical Monitor.  Minor elective surgery will generally be permitted 

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during the study with resumption of tobemstomig or pembrolizumab as soon as possible 
post-procedure, assuming normal recovery.  This can be done to avoid the 
discontinuation of participants who could potentially benefit from study treatment. 
It should be noted that infusions and cycles not occurring at the anticipated schedule, 
are considered as delayed, not missed. 
If a participant has a complete response or achieves maximum clinical benefit as 
determined by the investigator and the Sponsor after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Tobemstomig and 
pembrolizumab may be paused at the discretion of the investigator after discussion with 
the Medical Monitor.  While treatment with tobemstomig or pembrolizumab is paused, 
assessments per the schedule of activities (see Section 1.3, Table 1) will be suspended, 
except for tumor assessments.  The length of the treatment pause is to be included in 
the calculation of the maximum duration of treatment (24 months from Day 1 of Cycle 1 
to the discontinuation visit) as per Section 4.5. 
A4–6.4 
MANAGEMENT GUIDELINES 
A4–6.4.1 
Management Guidelines for Adverse Events Associated with 
Tobemstomig and Pembrolizumab 
See Appendix 6 for details on the management of tobemstomig and 
pembrolizumab-associated adverse events.  See Appendix 9 for precautions for 
anaphylaxis. 
A4–6.4.2 
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events 
See Appendix 6 for details on chemotherapy dose modifications, treatment delays, or 
treatment discontinuation and management of specific adverse events. 
A4–6.4.3 
Potential Overlapping Toxicities 
The risk of overlapping toxicities between tobemstomig or pembrolizumab in 
combination with paclitaxel or pemetrexed and carboplatin is thought to be minimal.  
Nevertheless, the attribution and management of certain adverse events that have been 
associated with each agent separately (e.g., hepatotoxicity, skin, and gastrointestinal 
toxicity) may be ambiguous when the agents are administered together.  It is 
theoretically possible that allergic or inflammatory adverse events associated with 
pemetrexed, paclitaxel, and carboplatin (e.g., dermatitis, infusion-associated symptoms) 
could be exacerbated by the immunostimulatory activity of tobemstomig and 
pembrolizumab. 

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Toxicities should initially be managed according to the recommendations in Appendix 6 
with dose holds and modifications (if applicable) applied to the component of the study 
drug judged to be the primary cause.  If, in the opinion of the investigator, tobemstomig 
or pembrolizumab is a potential inciting factor, the dose of tobemstomig or 
pembrolizumab may be held for a maximum of 12 weeks (or four cycles) beyond the last 
infusion (see Appendix 6).  Tobemstomig and pembrolizumab can be resumed after 
being withheld for  12 weeks if the participant is likely to derive clinical benefit.  The 
decision to rechallenge participants with tobemstomig or pembrolizumab should be 
based on the investigator’s assessment of the benefits and risks and documented by the 
investigator.  Prompt symptomatic management is appropriate for mild 
immune-mediated adverse events.  In severe cases, immune-mediated toxicities may be 
acutely managed with systemic corticosteroids or tumor necrosis factor inhibitors.  The 
Medical Monitor is available to advise as needed. 
REFERENCES 
National Comprehensive Cancer Network Guidelines NonSmall-Cell Lung Cancer 
[resource on the internet]. 2019. [cited 31 March 2020]. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.  
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. 
J Clin Oncol 2015;33:3199212. 
 
 

 
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Appendix 5  
Collection of Pregnancy Information 
TABLE OF CONTENTS 
A5–1 
Pregnancies in Female Participants .......................................... 143 
A5–2 
Pregnancies in Female Partners of Male Participants .............. 143 
A5–3 
Abortions ................................................................................... 144 
A5–4 
Abnormal Pregnancy Outcomes ............................................... 144 
 

Appendix 5: Collection of Pregnancy Information 
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A5–1 
PREGNANCIES IN FEMALE PARTICIPANTS 
Female participants will be instructed through the Informed Consent Form to 
immediately inform the investigator if they become pregnant during the study or within 
4 months after the final dose of tobemstomig, 4 months after the final dose of 
pembrolizumab, and 6 months after the final dose of platinum-based chemotherapy.  
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 the 
investigator becomes aware 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 electronic Case Report Form 
(eCRF).  The investigator should discontinue study treatment and counsel the 
participant, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the participant 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 or 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.  
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A5–2 
PREGNANCIES IN FEMALE PARTNERS OF MALE 
PARTICIPANTS 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
4 months after the final dose of tobemstomig, 4 months after the final dose of 
pembrolizumab, 3 months after the final dose of pemetrexed, and 6 months after the final 
dose of paclitaxel and carboplatin.  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 participant 
exposed to study treatment.  When permitted by the site, the pregnant partner would 

Appendix 5: Collection of Pregnancy Information 
Tobemstomig—F. Hoffmann-La Roche Ltd 
144/Protocol BO44178, Version 4 
need to sign an Authorization for Use and Sharing 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.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male participant 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. 
A5–3 
ABORTIONS 
A spontaneous abortion in a female participant exposed to study treatment or the 
female partner of a male participant exposed to study treatment 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 the investigator becomes aware of the event; 
see Section A3–5). 
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 the investigator becomes aware of the event; 
see Section A3–5).  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.  
A5–4 
ABNORMAL PREGNANCY OUTCOMES 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment or the female partner of a male participant exposed to study treatment 

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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 the 
investigator becomes aware of the event; see Section A3–5). 
 

 
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Appendix 6  
Risks Associated with Tobemstomig and Pembrolizumab and 
Guidelines for Management of Adverse Events Associated with 
Tobemstomig or Pembrolizumab 
Toxicities associated or possibly associated with tobemstomig and pembrolizumab 
treatment should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of tobemstomig 
or pembrolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in the following subsections:  
 
Patients and family caregivers should receive timely and up to date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and survival follow-up.  There should be a high level of suspicion that new 
symptoms are treatment-related. 
 
In general, tobemstomig and pembrolizumab should be continued with close 
monitoring for Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding tobemstomig and pembrolizumab for most Grade 2 toxicities and 
resume when symptoms and/or laboratory values resolve to Grade 1 or better.  
Corticosteroids (initial dose of 0.51 mg/kg/day of prednisone or equivalent) may be 
administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold tobemstomig and pembrolizumab for Grade 3 toxicities and initiate treatment 
with high-dose corticosteroids (12 mg/kg/day prednisone or equivalent).  
Corticosteroids should be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent, before tobemstomig and pembrolizumab can be resumed.  If symptoms 
do not improve within 48 to 72 hours of high-dose corticosteroid use, other 
immunosuppressants may be offered for some toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of a tobemstomig 
and pembrolizumab treatment, with the exception of endocrinopathies that are 
controlled by hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance a given participant may be 
experiencing prior to further administration of tobemstomig or pembrolizumab.  

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
147/Protocol BO44178, Version 4 
Resumption of tobemstomig or pembrolizumab may be considered in participants 
deriving benefit and have fully recovered from the immune-mediated event.  
The decision to re-challenge participants with tobemstomig or pembrolizumab should be 
based on the investigator’s assessment of the benefits and risks and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional 
guidelines where relevant.  Management guidelines for pulmonary events are provided 
in Table A6-1. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
148/Protocol BO44178, Version 4 
Table A6-1 Management Guidelines for Pulmonary Events, 
Including Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1 
 Continue tobemstomig or pembrolizumab monitor closely. 
 Re-evaluate on serial imaging. 
 Consider participant referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding tobemstomig or 
pembrolizumab. 
Pulmonary 
event, Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after event 
onset. a 
 Refer participant to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue tobemstomig or 
pembrolizumab and contact Medical Monitor. c  d 
 For recurrent events or events with no improvement after 4872 hours of 
corticosteroids, treat as a Grade 3 or 4 event. 
BAL  bronchoscopic alveolar lavage. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
d In case of pneumonitis, tobemstomig or pembrolizumab should not be resumed after 
permanent discontinuation. 
  

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
149/Protocol BO44178, Version 4 
Table A6-1 Management Guidelines for Pulmonary Events, 
Including Pneumonitis (cont.) 
Event 
Management 
Pulmonary 
event, Grade 3 
or 4 
 
Permanently discontinue tobemstomig or pembrolizumab and contact 
the Medical Monitor. c 
 
Oral or IV broad-spectrum antibiotics should be administered in parallel 
to the immunosuppressive treatment. 
 
Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone. 
 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10  mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10  mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
d In case of pneumonitis, tobemstomig or pembrolizumab should not be resumed after 
permanent discontinuation. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
150/Protocol BO44178, Version 4 
HEPATIC EVENTS 
Participants eligible for study treatment must have adequate liver function, as manifested 
by measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table A6-2. 
Participants with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug(s). 
For participants with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
151/Protocol BO44178, Version 4 
Table A6-2 Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Monitor LFTs until values resolve to within normal limits or to 
baseline values. 
Hepatic event, Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values. 
Events of  5 days' duration: 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact Medical Monitor. c 
LFTs  liver function test. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
152/Protocol BO44178, Version 4 
Table A6-2 Management Guidelines for Hepatic Events (cont.) 
Event 
Management 
Hepatic event, Grade 3 
or 4 or liver metastasis 
with baseline Grade 2 
elevation of AST or ALT, 
hepatitis with AST or 
ALT increases  50% 
and lasts  1 week 
 Permanently discontinue tobemstomig or pembrolizumab and 
contact the Medical Monitor. c 
 Consider participant referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic injury. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
LFTs  liver function test. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
153/Protocol BO44178, Version 4 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table A6-3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
154/Protocol BO44178, Version 4 
Table A6-3 Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after event 
onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 Participant referral to GI specialist is recommended. 
 For recurrent events or events that persist   5 days, initiate treatment with 
corticosteroids equivalent to 12 mg/kg/day oral prednisone.  If the event 
does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue tobemstomig or 
pembrolizumab and contact Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after event 
onset. a 
 Refer participant to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue tobemstomig or 
pembrolizumab and contact the Medical Monitor. c 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
155/Protocol BO44178, Version 4 
Table A6-3 Management Guidelines for Gastrointestinal events (Diarrhea or 
Colitis) (cont.) 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue tobemstomig or pembrolizumab and contact the 
Medical Monitor. c 
 Refer participant to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
GI  gastrointestinal. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
  
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
156/Protocol BO44178, Version 4 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table A6-4. 
Participants with unexplained symptoms, such as headache, fatigue, myalgias, 
impotence, constipation, or mental status changes, should be investigated for the 
presence of thyroid, pituitary, or adrenal endocrinopathies.  The participant should be 
referred to an endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating 
hormone (TSH) and free triiodothyronine and thyroxine levels should be measured to 
determine whether thyroid abnormalities are present.  Pituitary hormone levels and 
function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating 
hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
157/Protocol BO44178, Version 4 
Table A6-4 Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue tobemstomig or pembrolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding tobemstomig or pembrolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume tobemstomig or pembrolizumab when symptoms are controlled 
and thyroid function is improving. 
Grade 3 and 4 
hypothyroidism 
 Withhold tobemstomig or pembrolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema (bradycardia, 
hypothermia, and altered mental status). 
 Resume tobemstomig or pembrolizumab when symptoms are controlled 
and thyroid function is improving. 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
the Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
158/Protocol BO44178, Version 4 
Table A6-4 Management Guidelines for Endocrine Events (cont.) 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10  mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 
 
 
Event 
Management 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue tobemstomig or pembrolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding tobemstomig or pembrolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume tobemstomig or pembrolizumab when symptoms are 
controlled and thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
 Withhold tobemstomig or pembrolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer to endocrinologist. 
 Resume tobemstomig or pembrolizumab when symptoms are 
controlled and thyroid function is improving. 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
the Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
159/Protocol BO44178, Version 4 
Table A6-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 24 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Refer participant to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better and participant is stable on 
replacement therapy, resume tobemstomig or pembrolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not stable 
on replacement therapy while withholding tobemstomig or 
pembrolizumab, permanently discontinue tobemstomig or 
pembrolizumab and contact Medical Monitor. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
160/Protocol BO44178, Version 4 
Table A6-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hyperglycemia, 
Grade 1 or 2 
 Continue tobemstomig or pembrolizumab. 
 Investigate for diabetes.  If participant has Type 1 diabetes, treat as 
a Grade 3 event.  If participant does not have Type 1 diabetes, treat 
as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold tobemstomig or pembrolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 Monitor for glucose control. 
 Resume tobemstomig or pembrolizumab when symptoms resolve, 
and glucose levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
161/Protocol BO44178, Version 4 
Table A6-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hypophysitis 
(panhypopituitarism-), 
Grade 2 or 3 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Refer participant to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 12  mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(panhypopituitarism-), 
Grade 4 
 Permanently discontinue tobemstomig or pembrolizumab and 
contact Medical Monitor. c 
 Refer participant to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10  mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
162/Protocol BO44178, Version 4 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table A6-5. 
Table A6-5 Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Participant referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Participant referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue tobemstomig or pembrolizumab and 
contact Medical Monitor. c 
 Refer participant to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
163/Protocol BO44178, Version 4 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table A6-6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any participant presenting with 
signs or symptoms suggestive of myocarditis, including, but not limited to, laboratory 
(e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a participant who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of pre-existing cardiac 
conditions, or progression of malignancy. 
All participants with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Participants with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-6. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post-myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
164/Protocol BO44178, Version 4 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table A6-6. 
Table A6-6 Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 24 
 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue tobemstomig or pembrolizumab 
and contact Medical Monitor. a 
 Refer participant to cardiologist. 
 Initiate treatment as per institutional guidelines and 
consider anti-arrhythmic drugs, temporary pacemaker, 
ECMO, VAD, or pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
165/Protocol BO44178, Version 4 
INFUSION-RELATED REACTIONS 
Administration of therapeutic antibodies may cause infusion-related reactions (IRRs), 
characterized by symptoms, such as fever, chills, dizziness, hypertension, hypotension, 
dyspnea, restlessness, sweating, flushing, skin rash, tachycardia, tachypnea, headache, 
tumor pain, nausea, and/or vomiting.  Respiratory and cardiac symptoms such as, 
bronchospasm, larynx, and throat irritation, wheezing, laryngeal edema, and atrial 
fibrillation may also occur.  Such reactions typically occur during or shortly after an 
infusion or within 24 hours after study treatment infusion, predominantly at the first 
infusion.  The incidence and severity typically decrease with subsequent infusions. 
Participants may also develop IgE-mediated hypersensitivity reactions.  IRRs may be 
indistinguishable from an anaphylactic reaction; however, in case of IgE-mediated 
hypersensitivity, symptoms typically occur after previous exposure and very rarely with 
the first infusion.  In case of confirmed IgE-mediated hypersensitivity reaction, treatment 
should be permanently discontinued. 
No premedication is indicated for the administration of Cycle 1 of pembrolizumab and 
tobemstomig.  However, participants who experience a Grade  2 IRR with tobemstomig 
or pembrolizumab should receive premedication for subsequent infusions (see 
Section 6.8.1) with antihistamines, antipyretic medications, and/or analgesics 
(e.g., acetaminophen) for subsequent infusions.  In case of Grade 4 IRR related to 
tobemstomig or pembrolizumab, the participant should be permanently discontinued 
from the study treatment.  If an IRR occurs during the infusion of tobemstomig or 
pembrolizumab.  Metamizole (dipyrone) is prohibited in treating pembrolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
Guidelines for medical management of IRRs during Cycle 1 are presented in Table A6-7.  
For subsequent cycles, IRRs should be managed according to institutional guidelines. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
166/Protocol BO44178, Version 4 
Table A6-7 Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grades 1 
and 2 
 Reduce infusion rate to  50% of the rate being given at the time of 
event onset or interrupt infusion. 
 Give supportive treatment. 
 Upon symptom resolution, the infusion may be resume (if interrupted) at 
50% of the starting rate.  The infusion must remain at the lower rate 
resulting in symptom resolution for the remainder of the infusion. 
 For Grade 2 IRRs, subsequent cycles of tobemstomig or 
pembrolizumab should be administered with premedication, including 
acetaminophen or paracetamol and an antihistamine, such as 
diphenhydramine. 
 For Grade 2 wheezing or urticaria, the participant must also be 
premedicated prior to subsequent doses as described above. 
 If symptoms recurs at the same or greater severity following the slower 
infusion rate or interruption, the infusion must be stopped immediately.  
No additional tobemstomig or pembrolizumab will be administered for 
that cycle. 
IRR, Grade 3 
and 4 
 Discontinue infusion immediately. 
 Administer aggressive symptomatic treatment (e.g., oral or 
IV antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor. a 
IRR  infusion-related reaction. 
a Resumption of tobemstomig and pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the event.  The decision to re-challenge 
patients with tobemstomig and pembrolizumab should be based on investigator's 
assessment of benefit-risk and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
  
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin‑6, interleukin‑10, interleukin‑2, and interferon- (Merad and Martin 
2020).  If a participant develops suspected CRS during the study, a differential diagnosis 
should include COVID-19, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
167/Protocol BO44178, Version 4 
CYTOKINE RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of tobemstomig or 
pembrolizumab.  However, participants who experience CRS with tobemstomig or 
pembrolizumab may receive premedication with antihistamines, antipyretic medications, 
and/or analgesics (e.g., acetaminophen) for subsequent infusions. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well-documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cellengager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including tobemstomig or pembrolizumab  
Guidelines for medical management of CRS are provided in Table A6-8. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
168/Protocol BO44178, Version 4 
Table A6-8 Management Guidelines for Cytokine Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in participants with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics, and monitor 
closely for CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low flow oxygen d by 
nasal cannula or 
blow-by 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, 
if appropriate).  Administer IV fluids as clinically indicated and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If 
no improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS as described in this appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. 
 Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
participant (monitoring in the ICU is recommended), permanently 
discontinue tobemstomig or pembrolizumab, and contact the Medical 
Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of tobemstomig or pembrolizumab may be administered.  For 
subsequent infusions, consider administration of oral premedication with 
antihistamines, antipyretic medications, and/or analgesics and monitor 
closely for CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Medical Monitor. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
169/Protocol BO44178, Version 4 
Table A6-8 Management Guidelines for Cytokine Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with or 
without vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor. e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring in 
an ICU is recommended.  Administer IV fluids as clinically indicated and 
manage constitutional symptoms and organ toxicities as per institutional 
practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. 
 Hospitalize participant until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
participant to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for 
participants who are refractory to anti-cytokine therapy, experimental 
treatments may be considered at the discretion of the investigator and 
in consultation with the Medical Monitor. 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure 
(e.g., CPAP, 
Bi-PAP, intubation 
and mechanical 
ventilation) 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor. e 
 Administer symptomatic treatment. c 
 Admit participant to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional symptoms 
and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  For participants who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
 Hospitalize participant until complete resolution of symptoms. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
170/Protocol BO44178, Version 4 
Table A6-8 Management Guidelines for Cytokine Release Syndrome (cont.) 
ASTCT  American Society for Transplantation and Cellular Therapy; Bi-PAP  bi-level positive 
airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive airway pressure; 
CRS  cytokine release syndrome; CTCAE v5.0  Common Terminology Criteria for Adverse 
Events, Version 5.0; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; IRR   infusion-related reaction; 
MAS  macrophage activation syndrome; NCCN  National Cancer Comprehensive Network; 
NCI  National Cancer Institute. 
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019). 
a The grading system for management guidelines is based on the ASTCT CRS Consensus 
Grading Scale (see Section A3–3.2 and Table A3-2).  The ASTCT CRS Consensus Grading 
Scale should be used when reporting severity of CRS on the Adverse Event eCRF.  
NCI CTCAE v5.0 should be used when reporting severity of organ toxicities associated with 
CRS on the dedicated Cytokine Release Syndrome eCRF.  Organ toxicities associated with 
CRS should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In participants 
who develop CRS and then receive antipyretic, anticytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed.  For subsequent infusions, administer oral 
premedication with antihistamines, antipyretic medications, and/or analgesics, and monitor 
closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the infusion 
time may also be considered after assessment of the benefitrisk ratio. 
f Refer to Riegler et al. (2019). 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
171/Protocol BO44178, Version 4 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table A6-9. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
172/Protocol BO44178, Version 4 
Table A6-9 Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue tobemstomig or pembrolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Refer participant to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue tobemstomig or 
pembrolizumab and contact the Medical Monitor. c 
GI  gastrointestinal; ULN  upper limit of normal. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s assessment of the benefits and risks and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are deriving 
benefit and have fully recovered from the immune-mediated event.  The decision to re‑challenge 
participants with tobemstomig or pembrolizumab should be based on the investigator’s 
assessment of the benefits and risks and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
173/Protocol BO44178, Version 4 
Table A6-9 Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
Immune-mediated 
pancreatitis,  
Grade 2 or 3 
 
Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 
Refer participant to GI specialist. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 
If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact the Medical 
Monitor. c 
 
For recurrent events, permanently discontinue tobemstomig or 
pembrolizumab and contact the Medical Monitor. c 
Immune-mediated 
pancreatitis, Grade 4 
 
Permanently discontinue tobemstomig or pembrolizumab and 
contact Medical Monitor. c 
 
Refer participant to GI specialist. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
GI  gastrointestinal; ULN  upper limit of normal. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
174/Protocol BO44178, Version 4 
DERMATOLOGIC EVENTS 
Treatment-emergent rash may be associated with tobemstomig or pembrolizumab.  
The majority of cases of rash reported with the use of pembrolizumab were mild in 
severity and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with pembrolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table A6-10. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
175/Protocol BO44178, Version 4 
Table A6-10 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, 
Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2 
 Continue tobemstomig or pembrolizumab.  
 Consider participant referral to dermatologist for evaluation and, 
if indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
Dermatologic event, 
Grade 3 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks 
after event onset. a 
 Refer participant to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact the Medical 
Monitor. c 
Dermatologic event, 
Grade 4 
 Permanently discontinue tobemstomig or pembrolizumab and 
contact the Medical Monitor. c 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period 
of time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
176/Protocol BO44178, Version 4 
Table A6-10 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 
Withhold tobemstomig or pembrolizumab and for suspected 
Stevens-Johnson syndrome or toxic epidermal necrolysis. 
 
Confirm diagnosis by referring participant to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) for 
evaluation and, if indicated, biopsy. 
 
Follow the applicable treatment and management guidelines 
above. 
 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue tobemstomig or 
pembrolizumab. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period 
of time must be based on the investigator’s assessment of the benefits and risks and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
  
NEUROLOGIC DISORDERS 
Participants may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table A6-11. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
177/Protocol BO44178, Version 4 
Table A6-11 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Investigate etiology. 
Immune-mediated 
neuropathy, Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Investigate etiology and refer participant to neurologist. 
 Initiate treatment as per institutional guidelines. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue 
tobemstomig or pembrolizumab and contact Medical Monitor. c 
Immune-mediated 
neuropathy, Grade 3 
or 4 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor. c 
 Refer participant to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor.  
 Refer participant to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to 12 mg/kg/day oral 
or IV prednisone. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re-challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
178/Protocol BO44178, Version 4 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any participant 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, 
but not limited to, headache, neck pain, confusion, seizure, motor or sensory 
dysfunction, and altered or depressed level of consciousness.  Encephalopathy from 
metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of 
malignancy, or secondary to a paraneoplastic process. 
All participants being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed, and a neurologist should be consulted. 
Participants with signs and symptoms of meningoencephalitis, in the absence of 
an identified alternate etiology, should be treated according to the guidelines in 
Table A6-12. 
Table A6-12 
Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
Medical Monitor. a 
 Refer participant to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone or equivalent and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
179/Protocol BO44178, Version 4 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Participants with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-
steroidal anti-inflammatory drugs).  Refer the participant to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Participants with signs and symptoms of nephritis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-13. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
180/Protocol BO44178, Version 4 
Table A6-13 
Management Guidelines for Renal Events 
Event 
Management 
Renal event, Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values. 
Renal event, Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after 
event onset. a 
 Refer participant to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig, permanently discontinue tobemstomig or 
pembrolizumab and contact Medical Monitor. c 
Renal event, Grade 3 
or 4 
 Permanently discontinue tobemstomig or pembrolizumab and 
contact Medical Monitor. 
 Refer participant to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
181/Protocol BO44178, Version 4 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography or MRI) features and is confirmed with a muscle biopsy.  
Participants with possible myositis should be referred to a rheumatologist or neurologist.  
Participants with possible myositis should be monitored for signs of myocarditis. 
Participants with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-14. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
182/Protocol BO44178, Version 4 
Table A6-14 
Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
 Continue tobemstomig or pembrolizumab. 
 Refer participant to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after event 
onset a and contact Medical Monitor. 
 Refer participant to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue tobemstomig 
or pembrolizumab and contact the Medical Monitor. c 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
183/Protocol BO44178, Version 4 
Table A6-14 
Management Guidelines for Immune-Mediated Myositis 
(cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
 Withhold tobemstomig or pembrolizumab for up to 12 weeks after event 
onset a and contact the Medical Monitor. 
 Refer participant to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if participant is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tobemstomig or 
pembrolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tobemstomig or pembrolizumab, permanently discontinue tobemstomig 
or pembrolizumab and contact the Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
184/Protocol BO44178, Version 4 
Table A6-14 
Management Guidelines for Immune-Mediated Myositis 
(cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 4 
 Permanently discontinue tobemstomig or pembrolizumab and contact 
the Medical Monitor. c 
 Refer participant to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if participant is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tobemstomig or pembrolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s assessment of the benefits and risks and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before tobemstomig or pembrolizumab can be resumed. 
c Resumption of tobemstomig or pembrolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re‑challenge participants with tobemstomig or pembrolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
  
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or is prolonged. 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
185/Protocol BO44178, Version 4 
Participants with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A participant should be classified as having HLH if five of 
the following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
 
Hemoglobin  90 g/L ( 9 g/dL) ( 100 g/L [ 10 g/dL] for infants  4 weeks old) 
 
Platelet count  100  109/L ( 100,000/L) 
 
ANC  1.0  109/L ( 1000/L) 
 
Fasting triglycerides  2.992 mmol/L ( 265 mg/dL) and/or fibrinogen  1.5 g/L 
( 150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L ( 500 ng/mL) 
 
Soluble interleukin‑2 receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Participants with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile participant should 
be classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L ( 684 ng/mL) 
 
At least 2 of the following: 
 
Platelet count  181  109/L ( 181,000/L) 
 
AST  48 U/L 
 
Triglycerides  1.761 mmol/L ( 156 mg/dL) 
 
Fibrinogen  3.6 g/L ( 360 mg/dL) 
 
Participants with suspected HLH or MAS should be treated according to the guidelines in 
Table A6-15. 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
186/Protocol BO44178, Version 4 
Table A6-15 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected 
HLH or 
MAS 
 Permanently discontinue tobemstomig or pembrolizumab and contact the 
Medical Monitor. 
 Consider participant referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive agent, and/or 
anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact Medical Monitor 
and initiate treatment as appropriate according to published guidelines (La 
Rosée 2015; Schram and Berliner 2015; La Rosée et al. 2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
 
 

Appendix 6:  Risks Associated with Tobemstomig or Pembrolizumab and Guidelines for 
Management of Adverse Events Associated with Tobemstomig or 
Pembrolizumab 
Tobemstomig—F. Hoffmann-La Roche Ltd 
187/Protocol BO44178, Version 4 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti-programmed 
death-1 antibody: Raising awareness among community oncologists. J Oncol 
Pract 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Program 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT concensus grading for cytokine 
release syndrome and neologic toxicity associated with immune effector cells. Biol 
Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resouce on the internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hemophagoc
ytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 
 

 
Tobemstomig—F. Hoffmann-La Roche Ltd 
188/Protocol BO44178, Version 4 
Appendix 7  
Clinical Outcome Assessments 
TABLE OF CONTENTS 
A7–1 
Clinical Outcome Assessments ................................................. 189 
A7–1.1 
European Organisation for Research and Treatment of 
Cancer Item Libraries ................................................................ 190 
A7–1.1.1 
Item Library 85 .......................................................................... 190 
A7–1.1.2 
Item Library 132 ........................................................................ 191 
A7–1.1.3 
Item Library 188 ........................................................................ 192 
A7–1.1.4 
Item Library 17 .......................................................................... 193 
A7–1.2 
Selected Items from the National Cancer Institute 
Patient-Reported Outcomes Common Toxicity Criteria for 
Adverse Events ......................................................................... 194 
A7–1.3 
Item Library 46 .......................................................................... 196 
 

Appendix 7:  Clinical Outcome Assessments 
 
Tobemstomig—F. Hoffmann-La Roche Ltd 
189/Protocol BO44178, Version 4 
A7–1 
CLINICAL OUTCOME ASSESSMENTS 
Patient-reported outcome (PRO) questionnaires will be self-administered or interviewer 
administered (as appropriate) at the clinic or by site personnel by telephone at specified 
timepoints during the study (see the schedule of activities in Section 1.3, Table 1).  At 
the clinic, questionnaires will be administered before the participant receives any 
information on disease status, prior to the performance of non-PRO assessments, and 
prior to the administration of study treatment.  
PRO questionnaires, translated into the local language as appropriate, will be provided 
by the Sponsor in preprinted booklets to enable the appropriate questionnaires to be 
administered in the correct order at each specified timepoint. 
PRO assessments should be administered as outlined below: 
 
Participants' health status should not be discussed prior to administration of the 
questionnaires. 
 
Sites must administer the official version of each questionnaire, as provided by the 
Sponsor.  Questionnaires must not be copied from the protocol. 
 
Sites should allow sufficient time for participants to complete the questionnaires. 
 
Sites should administer the questionnaires in a quiet area with minimal distractions 
and disruptions. 
 
Participants should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers. 
 
Site staff should not interpret or explain questions but may read questions verbatim 
upon request. 
 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the questionnaires. 
 
Participants whose native language is not available with the questionnaires are 
exempted from completing all PRO assessments. 
 
Site staff should review all completed questionnaires and should ask the participants to 
rectify any response that is not clearly marked in the appropriate location.  If a response 
is missing, site staff should ask the participant to complete the item or confirm that the 
item was intentionally left blank. 
 
 

Appendix 7:  Clinical Outcome Assessments 
 
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A7–1.1 
EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER ITEM LIBRARIES 
A7–1.1.1 
Item Library 85 
 

Appendix 7:  Clinical Outcome Assessments 
 
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Item Library 132 
 
 

Appendix 7:  Clinical Outcome Assessments 
 
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Item Library 188 
 

Appendix 7:  Clinical Outcome Assessments 
 
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Item Library 17 
 

Appendix 7:  Clinical Outcome Assessments 
 
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A7–1.2 
SELECTED ITEMS FROM THE NATIONAL CANCER INSTITUTE 
PATIENT-REPORTED OUTCOMES COMMON TOXICITY 
CRITERIA FOR ADVERSE EVENTS 
NCI PRO-CTCAE ® ITEMS 
Item Library Version 1.0 
English 
Form Created on 8 April 2022 
As individuals go through treatment for their cancer they sometimes 
experience different symptoms and side effects. For each question, please 
select the one response that best describes your experiences over the 
past 7 days… 
1a.  In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its 
WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
1b.  In the last 7 days, how much did DECREASED APPETITE INTERFERE with your 
usual or daily activities? 
Ο Not at all 
ΟA little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
2a.  In the last 7 days, how OFTEN did you have NAUSEA? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
2b.  In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
3a.  In the last 7 days, how OFTEN did you have VOMITING? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
3b.  In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
4a.  In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA/DIARRHOEA)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
 

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5a.  In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
 
6a.  In the last 7 days, did you have any HAIR LOSS? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
7a.  In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
8a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
8b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS 
ELBOWS, KNEES, SHOULDERS) at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
8c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS) INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
 
 
 

Appendix 7:  Clinical Outcome Assessments 
 
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ITEM LIBRARY 46 
 
 

 
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Appendix 8  
Pre-Existing Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
tobemstomig and pembrolizumab for patients who have previously experienced a severe 
or life-threatening skin adverse reaction while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty about 
autoimmune exclusions. 
 
 

 
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Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Anti-phospholipid antibody 
syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune 
hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune 
thrombocytopenic purpura 
Behçet disease 
Bullous pemphigoid 
Chronic fatigue syndrome 
Chronic inflammatory 
demyelinating polyneuropathy 
Churg-Strauss syndrome 
Crohn disease  
Dermatomyositis 
Diabetes mellitus, type 1 
Dysautonomia 
Epidermolysis bullosa 
acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with 
polyangiitis 
Graves disease 
Guillain-Barré syndrome 
Hashimoto disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenia 
syndrome 
Lupus erythematosus 
Lyme disease, chronic 
Meniere syndrome 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus 
syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune 
syndrome 
Primary biliary cholangitis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren syndrome 
Stiff-Person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Koyanagi-Harada 
disease 

 
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Appendix 9  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
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 administration in a clinical setting: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for IM (preferred route), subcutaneous, intravenous, 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 administration, 
the following procedures should be performed: 
1. 
Stop the study treatment administration, if possible.  
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 participant status and as directed by the physician in charge. 
6. 
Continue to observe the participant and document observations. 
7. 
Collect laboratory sample of serum tryptase within 16 hours of the anaphylactic 
reaction after the patient stabilizes. 
8. 
Ask the participant to return for immunogenicity sample collection at 3 weeks 
postdose, if appropriate. 
 
 

 
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Appendix 10  
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009; Schwartz et al. 2016), are presented below, with 
the addition of explanatory text as needed for clarity. 
TUMOR MEASURABILITY 
At baseline, tumor lesions and lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lungs, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 

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SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, positron emission tomography (PET) scans, and plain 
films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other locoregional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and not usually more than 4 weeks prior to the beginning of treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter assessed using calipers (e.g., skin nodules).  For the case of skin 

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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 because CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (with or without MRI 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 (with or without MRI IV contrast) will be performed 
should also be based on the tumor type and the anatomic location of the disease, and 
should be optimized to allow for comparison with the prior studies if possible.  Each case 
should be discussed with the radiologist to determine if substitution of these other 
approaches is possible, and if not, the patient should be considered not evaluable from 
that point forward.  Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality because the 
same lesion may appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, AND HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
Assessment of Tumor Burden 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 

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

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CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, given that a normal lymph node is defined as 
having a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but is too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but is too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, 
that should be recorded, even if it is  5 mm, and in that case "too small to measure" 
should not be ticked. 
 
Measuring Lesions That Split or Coalesce during Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
the maximal diameter measurements of each individual lesion.  If the lesions have truly 

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coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in the short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "unequivocal progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the following criteria used to determine objective tumor response for target 
lesions are provided: 
 
Complete response (CR):  disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  at least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  neither sufficient shrinkage to qualify for a CR or a PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
 
CR:  disappearance of all non-target lesions  
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/non-PD:  persistence of one or more non-target lesions  
 
PD:  unequivocal progression of existing non-target lesions 
 

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SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of pre-existing 
lesions).  This is particularly important when the patient's baseline lesions show a PR or 
a 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.  In certain 
situations, as defined in Section 4.1.5, participants might be treated beyond 
progression. Therefore, the size of measurable new lesions will be captured in 
the eCRF to allow assessing the benefit of treating participants beyond 
progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it truly represents new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared as of the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table A10-1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients. 
 
 

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Table A10-1 
Criteria for Overall Response at a Single Timepoint 
Target Lesions 
Non-Target Lesions 
New Lesions 
Timepoint Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD or NE 
No 
PR 
PR 
CR, non-CR/non-PD, or NE 
No 
PR 
SD 
CR, non-CR/non-PD, or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR 
NED b 
No 
CR 
PR 
NED b 
No 
PR 
SD 
NED b 
No 
SD 
NED a 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NED a 
CR 
No 
CR 
NED a 
NE 
No 
NE 
NED a 
NED b 
No 
NED 
CR  complete response; NE  not evaluable; NED  not evaluable disease; PD  progressive 
disease; PR  partial response; SD  stable disease. 
a No target lesions identified at baseline  
b No non-target lesions identified at baseline. 
  
MISSING ASSESSMENTS AND NOT EVALUABLE DESIGNATION 
When no imaging or measurement is performed at all at a particular timepoint, the 
patient is not evaluable at that timepoint.  If measurements are made on only a subset of 
target lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 

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descriptor of an objective response; it is a reason for stopping study treatment.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table A10-1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Fluorodeoxyglucose (FDG)-PET is not yet validated for use in clinical trials to 
determine response but may complement CT/MRI in the assessment of progression. 
FDG-PET imaging to identify new lesions is described in the following table. 
Baseline FDG-PET 
Post-Baseline FDG-PET  
Determination 
Negative FDG-PET 
Positive FDG-PET  
New lesion (PD) 
None 
Positive FDG-PET corresponds 
to a new site of disease 
confirmed by CT/MRI 
New lesion (PD) 
None 
Positive FDG-PET not 
confirmed as a new site of 
disease on CT/MRI 
Additional follow-up CT/MRI scans 
are needed to determine if there is 
truly progression occurring at 
that site. 
If so, new lesion (PD) with the date of 
PD being the date of the initial 
abnormal FDG-PET scan date 
If not, it is not a new lesion. 
None 
Positive FDG-PET that 
corresponds to a pre-existing 
site of disease on CT/MRI that 
is not progressing on the basis 
of the anatomic images 
Not a new lesion 
CT  computed tomography; FDG  fluorodeoxyglucose; MRI  magnetic resonance imaging; 
PD  progressive disease; PET  positron emission tomography. 
Note:  A positive FDG-PET scan lesion indicates one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
 

Appendix 10:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
Tobemstomig—F. Hoffmann-La Roche Ltd 
209/Protocol BO44178, Version 4 
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. 
Schwartz LH., Litiére S, de Vries SE, et al. RECIST 1.1update and clarification: from 
RECIST Committee. Eur J Cancer 2016;62:1327. 
 

 
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Appendix 11  
Eastern Cooperative Oncology Group Performance 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 12  
Genetics:  Use and Analysis of DNA for Mandatory Samples 
Genetic variation may impact a participant’s response to study treatment and 
susceptibility to, and severity and progression of, disease.  Variable response to study 
treatment may be due to genetic determinants that impact drug absorption, distribution, 
metabolism, and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated.  Therefore, where local regulations and 
the Institutional Review Board or Ethics Committee allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
DNA samples will be used for research related to tobemstomig, and nonsmall cell lung 
cancer and related diseases.  They may also be used to develop tests or assays, 
including diagnostic tests related to tobemstomig and nonsmall cell lung cancer.  
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome. 
DNA samples will be analyzed for exploratory safety and efficacy analyses.  Additional 
analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to tobemstomig or study treatments of this class to understand 
nonsmall cell lung cancer or related conditions. 
The results of genetic analyses may be reported in the Clinical Study Report or in a 
separate study summary. 
The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
The samples will be retained while research on tobemstomig and nonsmall cell lung 
cancer continues but no longer than 15 years after the final Clinical Study Report has 
been completed or other period as per local requirements. 
 

 
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Appendix 13  
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations 
(for Use in European Economic Area) 
 
Product Name 
IMP/AxMP Designation 
Marketing Authorization 
Status in EEA 
Used within Marketing 
Authorization 
Tobemstomig 
(RO7247669) 
IMP (test product) 
Not authorized 
No
Pembrolizumab 
IMP (comparator) 
Authorized 
Yes 
Pemetrexed 
IMP (other) a 
Authorized 
No b 
Paclitaxel 
IMP (other) a 
Authorized 
No b 
Carboplatin 
IMP (other) a 
Authorized 
No b 
AxMP  auxiliary medicinal product; EEA  European Economic Area; IMP  investigational
medicinal product.
a A secondary objective of the study is to investigate the pharmacokinetics of tobemstomig in
combination with paclitaxel or pemetrexed and carboplatin.
b Pemetrexed, paclitaxel, and carboplatin are approved for the treatment of nonsmall lung cancer
but are not approved in combination with tobemstomig.
 

 
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Appendix 14  
Protocol Amendment History 
A rationale for the current amendment precedes the Table of Contents. 
PROTOCOL AMENDMENT, VERSION 2:  (31 OCTOBER 2022) 
Protocol BO44178 has been amended to address comments received from the Food 
and Drug Administration (FDA) along with other changes and clarifications.  Changes to 
the protocol, along with a rationale for each change, are summarized below. 
 
Following an FDA request, the following was updated to minimize the number of 
patients exposed to the experimental arm while an approved regimen exists: 
 
Randomization ratio updated from 2:1 to 1:1 (Figure 1, Section 4.1, 4.1.2). 
 
Sample size has been reduced from 210 to 180.  Specifically, the number of 
patients in each arm has been adjusted with experimental arm reduced from 
140 to 90, Arm B increased from 70 to 90 (Figure 1, Sections 4.1, 4.1.2, 4.1.3, 
5, 9.1.1, Appendix 1). 
 
 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol.  Medical Monitor contact information 
has been replaced with a sentence indicating that this information will be provided 
separately to sites (front matter and Section 8.3.9). 
 
The synopsis has been simplified in preparation for the Clinical Trial Regulation 
(CTR) in the EU (Section 1.1). 
 
 
 
 
The Independent Data Monitoring Committee has been replaced by an Internal 
Monitoring Committee (IMC) whose remit will include the safety run-in analysis 
 
.  Periodic reviews of safety data will be performed by an IMC, 
specifically to make recommendations regarding study conduct on the basis of 
emerging trial safety data to ensure patient safety while receiving study treatment. 
An IMC will be better positioned to incorporate the totality of data from Study 
BO44178 and other studies with RO7247669 to inform their recommendations 
(Figure 1, Sections 4.1.3, 4.1.8, 9.4.1). 
 
Epstein-Barr virus (EBV) exclusion is not relevant for this study, thus EBV testing is 
not required (Table 1, and Appendix 2, Table A2-1). 

Appendix 14: Protocol Amendment History 
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 
The schedule of activities has been updated to correct a typographic error regarding 
the patient-reported outcome questionnaires. Q356 has been corrected to IL188 
(Table 1). 
 
Optional blood sample collections for the Research Biosample Repository have 
been added for participants who give specific consent to participate in this optional 
exploratory research (Table 1, Table 2, Section 8.10.3.3). 
 
Transthoracic echocardiogram or multiple-gated acquisition scan has been added to 
schedule of activities to be performed at screening if no scan is available from within 
6 months prior to initiation of study treatment, as this is an inclusion criterion 
(Table 1, Section 8.2.3). 
 
Language has been updated to clarify that EGFR/ALK testing at screening is not 
required for squamous NSCLC patients with unknown mutational status prior to 
enrollment as EGFR/ALK genomic aberrations are uncommon in patients with this 
histology (Table 1, Section 4.1.1, 5.2). 
 
Blood sample collections for pemetrexed, carboplatin and paclitaxel 
pharmacokinetics at Cycle 1 and Cycle 5, 6 hours post dose have been removed in 
order to reduce patient burden (Table 2). 
 
Additional detail on safety and tolerability data from previous studies was added to 
the benefit-risk profile (Section 2.3). 
 
The number of participants in Arm A and Arm B of the safety run-in evaluation have 
been adjusted, based on the changes to the study design (Section 4.1.3). 
 
Language was added to allow capturing the size of new lesions in the eCRF, in 
order to allow assessing the benefit of treating participants beyond progression 
(Section 4.1.5, Appendix 10) 
 
The dose rationale has been expanded to provide further explanation for the 
 mg 
RO7247669 dose level (Section 4.3). 
 
Inclusion criteria have been updated to permit enrollment of locally advanced 
stage IIIC patients in alignment with most recent 8th edition of the lung cancer 
UICC/AJCC-staging system (Section 2.1, 2.3, 3, 4.1, 4.2.1, 5.1). 
 
Inclusion Criteria have been clarified to indicate that a documented local PD-L1 
immunohistochemistry assessment of any local health authority approved assay can 
be used (Section 5.1). 
 
The exclusion criteria for patients with pulmonary lymphoepithelioma-like carcinoma 
subtype of NSCLC has been removed in order to align with removal of EBV testing 
requirements (Section 5.2). 
 
The exclusion criteria have been updated to specify that patients with known 
rearranged during transfection mutations will not be permitted to enroll unless 
ineligible for available targeted therapies. Patients with actionable genomic 
aberrations should preferentially receive appropriate therapy with targeted 
treatments when available (Section 5.2). 

Appendix 14: Protocol Amendment History 
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215/Protocol BO44178, Version 4 
 
Radiographic assessment has been updated with the requirement for a CT scan of 
the pelvis, to be consistent with the schedule of activities (Section 8.1.1.1). 
 
The hypothesis testing has been removed as this study is only intended to be 
hypothesis generating (Section 9.1 and 9.3.1). 
 
 
 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Appendix 1). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Appendix 1). 
 
The Sponsor record retention policy has been clarified (Appendix 1). 
 
Language has been added to clarify that dedicated infusion-related reaction (IRR) 
eCRFs are necessary to report IRR events (Appendix 3). 
 
Adverse event management guidelines have been updated to align with the 
American Society of Clinical Oncology guidelines for management of immune-
related adverse events in patients treated with immune checkpoint inhibitor therapy 
(Appendix 6). 
 
PROTOCOL AMENDMENT, VERSION 3:  (11 MAY 2023) 
Protocol BO44178, Version 3, has been amended to incorporate changes made in 
Version 1 (United States) of the BO44178 protocol, which was created to address 
comments from the U.S. Food and Drug Administration.  Feedback received from other 
health authorities has also been addressed.  Changes to the protocol, along with a 
rationale for each change, are summarized below: 
 
The protocol has been updated to include the International Nonproprietary Name 
(INN) of the RO7247669 test compound (tobemstomig) throughout. 
 
 
It has been clarified that during survival follow-up, the following patient-reported 
outcome questionnaires will be completed at 3 months ( 30 days) and 6 months 
( 30 days):  European Organisation for Research and Treatment of Cancer, IL85, 
IL132, IL188, and IL17.  In addition, the last assessment of the PRO-Common 

Appendix 14: Protocol Amendment History 
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216/Protocol BO44178, Version 4 
Terminology Criteria for Adverse Events (CTCAE) and the single-item EORTC 
IL46 will be performed at the treatment discontinuation visit (Section 1.3 [Table 1, 
footnote d]).
 
The Schedule of Activities has been clarified to state that single 12-lead 
electrocardiograms should be performed in both Cycles 1 and 5, to be consistent
with footnote n (Section 1.3 [Table 1]).
 
For consistency with the inclusion criteria, a footnote has been added to the
Schedule of Activities to detail that screening laboratory tests (hematology, serum 
chemistry panel and coagulation) must be performed within 14 days prior to 
initiation of study treatment (Section 1.3 [Table 1 (footnote hh)]).
 
Collection of alcohol use history has been removed as alcohol use history is not a
risk factor for NSCLC (Section 1.3 [Table 1 (footnote l)] and Section 8).
 
Additional guidance for predose sample collection has been added; a 4 -hour time
window has been added for predose pharmacokinetic, biomarker and
immunogenicity sample collection on Day 1 of each cycle (Section 1.3 [Table 2] and 
Section 8.10.3.3).
 
Language has been added to define a time window for the collection of biomarker 
blood (plasma and serum) samples at time of disease progression.  Samples should
be collected within 40 days after progression or prior to the next anti-cancer 
therapy, whichever is sooner (Section 1.3 [Table 2, footnote g]).
 
Language has been updated to clarify that EGFR and ALK testing must be 
performed per the assay’s intended use according to local laws and regulations
(Sections 1.3, 4.1.1, 4.2.1, 5.2 and 8.7).
 
 
Language has been corrected to reflect that cytokine release syndrome (CRS) events
will be graded according to the American Society of Transplantation and Cellular 
Therapy (ASTCT) CRS Consensus Grading Scale, as opposed to both ASTCT and 
National Cancer Institute (NCI) CTCAE (Sections 3, 4.1.4 and 9.3.3.5;
Appendices A3-2, A3-3.2 and A6-8).
 
Language has been amended to remove the estimation that there will be
approximately 6 months between the date the first participant is randomized and
the initial safety run-in evaluation, to allow more flexibility (Section 4.1.3).  The 
initial safety run-in evaluation will take place no later than 6 months after the first 
participant is randomized.

Appendix 14: Protocol Amendment History 
Tobemstomig—F. Hoffmann-La Roche Ltd 
217/Protocol BO44178, Version 4 
 
 
 
An Internal Monitoring Committee (IMC) will perform a cumulative review of 
safety data approximately every 6 months.  However, to ensure patient safety, if
24 participants with non-small cell lung cancer of each histology (squamous or 
non-squamous) complete two cycles of treatment before a scheduled IMC review, an 
ad hoc IMC safety review will be added for a safety evaluation (Section  4.1.8).
 
Language has been added to the rationale for study population to clarify that 
patients whose tumors have known EGFR mutation or ALK genetic aberrations
will be excluded from the study, in order to be consistent with the Schedule of 
Activities (footnote h) and the eligibility criteria. Patients with tumors of non -
squamous histology with unknown EGFR or ALK mutational status will be 
required to be tested prior to enrollment.  Patients with tumors of squamous 
histology who have an unknown EGFR or ALK mutational status will not be 
required to be tested at pre-screening/screening (Section 4.2.1).
 
For consistency with the Schedule of Activities, language has been included to
detail that treatment will continue until disease progression per RECIST v1.1, 
unacceptable toxicity, loss of clinical benefit as determined by the investigator, or 
until the Sponsor decides to terminate the study, whichever comes first. 
Additionally, it has been clarified that the total duration of study participation for 
each individual is expected to range from 1 day to approximately 58 months. 
Participants will be allowed to continue treatment beyond disease progression if 
pre-specified criteria are met (Section 4.1.5).
 
The contraception guidelines have been amended for male patients with either a 
female partner of childbearing potential who is not pregnant, or a pregnant female
partner to state that men must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of    1% per 
year during the treatment period for 4 months after the final dose of 
pembrolizumab, to be in line with the prescribing information for pembrolizumab 
(Sections 5.1 and 8.3.5; Appendix A5-2).
 
The medical term “Wegener granulomatosis” has been replaced by the term 
“granulomatosis with polyangiitis” to align with the updated preferred term in
MedDRA (Section 5.2; Appendix 8).
 
Language has been added to clarify that the first dose of study drug administration
should occur within 5 days of randomization (Section 6.3.1).
 
It has been clarified that Medical Monitor contact information will be provided
separately to sites (Section 8.3.9).
 
The confidence interval range in Table 8 has been corrected to reflect the confidence
width of the objective response rate estimated with a targeted sample size of 180 
patients (Section 9.1.1).

Appendix 14: Protocol Amendment History 
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218/Protocol BO44178, Version 4 
 
Language has been added to clarify that the IMC will review both efficacy and 
safety data during the 
 
 
Language has been added to clarify that microscopic examination of urine samples 
will only be performed if there is a clinically significant positive dipstick result 
(confirmed by a repeat positive sample), unless there is an explanation for the 
positive dipstick result (Appendix A2-1). 
 
The adverse event management guidelines for Grade 3 infusion-related reactions 
have been revised to permanently discontinue tobemstomig or pembrolizumab to 
match the current U.S. Prescribing Information for pembrolizumab (Appendix 6 
[Table A6-7]). 
 

 
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Appendix 15  
Abbreviations 
 
Abbreviation or Term 
Definition 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
ALK 
anaplastic lymphoma kinase 
ASTCT 
American Society for Transplantation and 
Cellular Therapy 
AUC 
area under the concentrationtime curve 
BEN 
benign ethnic neutropenia 
BICR 
blinded independent central review 
BsAb 
bispecific antibody 
COA 
clinical outcome assessment 
COVID‑19 
coronavirus disease 2019 
CPI 
checkpoint inhibitor 
CrCl 
creatinine clearance 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
EBUS 
endobronchial ultrasound 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and 
Treatment of Cancer  
ESMO 
European Society of Medical Oncology 
Fc 
fragment crystallizable 
FDA 
(U.S.) Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed, paraffin-embedded 
GLP 
Good Laboratory Practice 
H0 
null hypotheses 
H1 
alternative hypothesis 
HBcAb 
hepatitis B core antibody 

Appendix 15:  Abbreviations 
Tobemstomig—F. Hoffmann-La Roche Ltd 
220/Protocol BO44178, Version 4 
Abbreviation or Term 
Definition 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IC 
immune cell 
ICH 
International Council for Harmonisation 
IHC 
immunohistochemistry 
IL 
Item Library 
IM 
intramuscular 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or web-based response 
system 
LAG3 
lymphocyte activation gene 3 
MHC 
major histocompatibility complex 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
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 
NSCLC 
nonsmall cell lung cancer 
NSQ 
non-squamous 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD-1 
programmed death1 
PD-L1 
programmed deathligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 

Appendix 15:  Abbreviations 
Tobemstomig—F. Hoffmann-La Roche Ltd 
221/Protocol BO44178, Version 4 
Abbreviation or Term 
Definition 
PO 
orally; by mouth 
PPD 
positive purified protein derivative  
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Common 
Terminology Criteria for Adverse Events 
Q3W 
every 3 weeks 
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 
RET 
rearranged during transfection 
ROS1 
c-ROS oncogene 1 
SARS‑CoV‑2 
severe acute respiratory syndrome 
coronavirus 2 
SITC 
Society for Immunotherapy for Cancer 
SQ 
squamous 
TB 
tuberculosis 
TIL 
tumor-infiltrating lymphocyte 
TNF 
tumor necrosis factor 
Tnl 
troponin l 
TnT 
troponin T 
TPS 
tumor proportion score 
TTE 
transthoracic echocardiogram  
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 

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