Interventional Platform Study Investigating the Impact of Digital Health Solutions on Health Outcomes and Health-Care Resource Utilization in Participants Receiving Systemic Treatment in Clinical Practice
Phase: PHASE2
Conditions: Cancer
Sponsor: Hoffmann-La Roche

 
Official Title: 
Interventional Platform Study Investigating The Impact Of Digital 
Health Solutions On Health Outcomes And Health-Care Resource 
Utilization In Participants Receiving Systemic Treatment In Clinical 
Practice (Origama) 
NCT Number: 
NCT05694013 
Document Date: 
Protocol Amendment Version 2: 23-May-2023 
 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
Protocol MO42720, Version 2 
PROTOCOL 
PROTOCOL TITLE: 
INTERVENTIONAL PLATFORM STUDY INVESTIGATING 
THE IMPACT OF DIGITAL HEALTH SOLUTIONS ON 
HEALTH OUTCOMES AND HEALTH-CARE RESOURCE 
UTILIZATION IN PARTICIPANTS RECEIVING SYSTEMIC 
TREATMENT IN CLINICAL PRACTICE (ORIGAMA) 
PROTOCOL NUMBER: 
MO42720 
VERSION NUMBER: 
2 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
EudraCT Number: 2021-001415-90 
EU CT Number: 2023-504342-55-00 
NCT Number: NCT05694013 
INVESTIGATIONAL MEDICINAL 
PRODUCT: 
Atezolizumab (RO5541267) (Cohort B) 
SPONSOR/FUNDING SOURCE: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 
 
 

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
2/Protocol MO42720, Version 2 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
2 
See electronic date stamp on final page of this document. 
1 
8 March 2022 

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
3/Protocol MO42720, Version 2 
PROTOCOL AMENDMENT, VERSION 2 
RATIONALE 
Protocol MO42720 Version 2 has been amended to update it based on current 
experience with the trial, new advancements in the field, and feedback from the approval 
process, as well as to align with the new European CTR process.  Changes to the 
protocol, along with a rationale for each change, are summarized below: 
•
The study has been registered at ClinicalTrials.gov.  The registration number is
NCT05694013 (global update).
•
The study has been registered with the European Clinical Trials Information System
(CTIS).  The registration number is 2023-504342-55-00 (global update).
•
The term ‘flex care’ has been corrected throughout to ‘at-home treatment,’ which is
clearer (global update).
•
The term ‘participant(s)’ has been corrected throughout to ‘patient(s)’ as appropriate
(global update).
•
It has been clarified that the Kaiku Health Digital Patient Monitoring (DPM) Solution
used in the study is not considered an investigational medical device but rather a
medical device as this device is CE marked in Europe and registered in Australia
and used within its intended purpose (global update).
•
The synopsis has been simplified to align with CTR, Sponsor processes,
recommendations from TransCelerate and the Clinical electronic Structured
Harmonised Protocol (CeSHarP) M11 (Section 1.1).
•
A section describing duration of participation has been added to the synopsis to
align with CTR requirements.
•
Details on U.S. Food and Drug Administration (FDA) regulatory enforcement
discretion, General Data Protection Regulation (GDPR) compliance in active
European Union markets, and details on transfer of the Kaiku Health device legal
manufacturer role to Elekta Solutions AB have been included/updated (Section 2.4).
•
Background information on rHuPH20 (an excipient to Atezolizumab SC) has been
added to the protocol and removed reference to the IB.  Instead, the US package
insert is referenced (Section 2.7).
•
Study results from IMscin001 have been updated (Section 2.8).
•
The platform nature of the trial has been detailed (Section 3).
•
The exploratory efficacy objective “care team satisfaction with workflow efficiency”
has been removed, as it will be addressed separately in a research project focusing
on selected countries and clinics (Section 3.1.1.3).
•
The exploratory endpoint for Cohort A “utilization (e.g., adherence) of Roche DPM
Atezolizumab Module” has been extended with “and platform” to allow analysis of
not only the Roche modules but also the DPM platform itself (Section 3.1.1.3). 

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
4/Protocol MO42720, Version 2 
•
Safety related exploratory endpoints have been moved to safety endpoints, as
requested by the Norwegian health authority (Section 3.1.2.4).
•
A definition of the end of the study has been provided and the timing for closing
each cohort has been clarified separately, as the cohorts are independent and
expected to finish at different time points (Section 4.2).
•
End of DPM provision has been clarified with the aim to provide DPM as soon as
possible to patients on the treatment, and on safety follow-up, while taking
operational complexities into consideration (Section 4.2.1 and 4.2.2).
•
Cohort A inclusion criterion “Participant is systemic therapy naive (except for
participants with EGFR mutant or ALK positive NSCLC who may have received prior
systemic therapy with tyrosine kinase inhibitors as per the local approval)” has been
removed as there should be no impact from previous treatments on DPM on patient
reported symptom burden and other DPM related outcomes (Section 5.1.3.2).
•
An inclusion criterion (Cohort B) has been included where the patients confirm to the
investigator ensuring that their patient home is adequate to perform the at-home
treatment visits, in accordance with European Medicines Agency (EMA)
recommendation paper on decentralized elements in clinical trials released on
13 December 2022 (Section 5.1.3.3).
•
The exclusion criteria from “participants currently participating in another
interventional trial” has been updated to “participants currently enrolled in another
clinical study, unless it is an observational (non-interventional) clinical study or the
follow-up period of an interventional study” to avoid ambiguous patient selection
(Section 5.1.4.1).
•
It has been clarified that the exclusion criteria “history of malignancy within 5 years
prior to initiation of study treatment, with the exception of the cancer under
investigation in this study and malignancies with a negligible risk of metastasis or
death” is only applicable to only Cohort B (Section 5.1.4.3).
•
The exclusion criteria of “uncontrolled tumor-related pain” has been updated; details
on “uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures; history of leptomeningeal disease” have been removed as
there will be no metastatic patients in Cohort B (Section 5.1.4.3).
•
The medical term “Wegener granulomatosis” has been replaced by the term
“granulomatosis with polyangiitis” to align with the updated preferred term in
MedDRA (Section 5.1.4.3, Appendix 5).
•
Details on discontinuation of Atezolizumab in patients under Cohorts A and B have
been described.  In the case of discontinuation, the DPM modules used in the study
are no longer applicable and suitable for the patient.  Therefore, patients will stop
using DPM and all other study assessments.  In Cohort A, patients will continue to
report patient-reported outcomes until Week 24 (Sections 5.3.1.1.2, 5.3.1.2.6, and
5.6.1.1).
•
The detail on collection of household income has been removed as this has been
demonstrated to have minimal or no impact on DPM utilization (Section 5.5.2).

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
5/Protocol MO42720, Version 2 
•
Details on the collection of the estimated travel time from the patients’ home to the
study site have been included.  The time required for the patient to travel to the
study site might influence the patient’s decision to receive the treatment at-home or
at the study site (Section 5.5.2.1).
•
The weight measurements on Day 1 of each cycle have been removed.  Weight will
only be measured during the hospital visits in Cohort B and not during the treatment
at-home phase.  The dosing of the study medication is not weight-dependent.
Weight changes will be monitored during the disease control visits only as an
indicator of potential side effects (Section 5.5.3).
•
It has been clarified that laboratory samples will only be analyzed per standard of
care (Section 5.5.7.2).
•
The treatment at-home visit in Cohort B and the availability of the lab results for the
treatment administration at-home have been clarified (Section 5.5.7.3).
•
It has been explained that the samples collected during screening, treatment cycle
1−3 and disease control visits will be analyzed by the local laboratory and during the
at-home treatment visits, samples will be analyzed by the central laboratory
(Section 5.5.7.3 and Schedule of Activities).
•
It has been clarified that the recall period used for the MD Anderson Symptom
Inventory (MDASI) interference questionnaire is 7 days.  This clarification was
included as the pivotal literature referenced and summarized used the 24-hour recall
period (Section 5.5.8.2).
•
The text “in addition, 3 items from an MDASI tumor-specific module will allow
patients to rate RCC and treatment-related symptoms (skin rash or change, sores in
throat and mouth, and headache)” has been removed as the tumor-specific module
for RCC is not included in the study (Section 5.5.8.2).
•
The list of identified risks for Atezolizumab has been updated to include pericardial
disorders, myelitis, and facial paresis (Sections 5.5.9.1, 6.2.1.1, and Appendix 7).
•
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an
identified risk associated with Atezolizumab (Sections 5.5.9.1 and 6.2.1.1).
•
The list of adverse events of special interest has been revised to include myelitis
and facial paresis (Sections 5.5.9.2 and 6.2.1.1).
•
The requirement of patient initials for patients in Cohort B, in injection or
infusion-related reaction (IRR) site reaction photography has been removed, as this
is not required to capture with this kind of event and documentation (Section 5.5.9.2
and 6.2.2.4).
•
It has been clarified that because the device is made as per CE mark, device
medical complaints are no longer needed (Section 5.5.9.4).

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6/Protocol MO42720, Version 2 
•
Personal identifiable information (i.e., name and telephone number) for the medical
monitors from the protocol has been removed.  Medical monitor contact information
has been replaced with a sentence indicating that this information will be provided
separately to the sites (title page, protocol amendment acceptance form, and
Sections 5.5.9.4, and 6.2.4.1).
•
•
An email address has been included to report adverse device incidents to a generic
inbox and providing more instructions regarding the requirements for reported
information. (Section 6.1.3.4).
•
A description of the technical and organizational security measures taken to protect
personal data has been added to align with Roche practices (Section 9.4).
•
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 (Section
10.6)
•
Language has been clarified in Section 10.7 to indicate that 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.
•
It has been specified that screening and enrollment in Cohort A can occur on the
same day.  The schedule of activities has been updated (Appendix 1).
•
A time window of 72 hours to laboratory assessments has been added at Day 1 of
Cycle 1 in Cohort A and B to prevent repeated laboratory tests (Appendix 1).
•
The symptom of hypertension has been removed from Appendix 3.  This symptom
can only be reported by patients who regularly measure their blood pressure, which
is not feasible in the study setting.  Instead, patients can report symptoms
associated with hypertension such as shortness of breath, chest pain, nausea and
headaches.
•
Appendix 5 has been revised to indicate that caution should be used when
considering Atezolizumab for patients who have previously experienced a
pericardial disorder while receiving another immunostimulatory anti-cancer agent.
•
Appendix 5 has been revised to include autoimmune myelitis.

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
7/Protocol MO42720, Version 2 
• 
It has been clarified that in at-home treatment settings, emergency medical services 
are to be called immediately and the provided rescue medication (epinephrine) is to 
be used as applicable to stabilize the patient until emergency medical services 
arrive (Appendix 6) although it is already described under procedures of Appendix 6.  
In line with the current EAACI guidelines, it was decided to not provide the rescue 
medication kit drugs for the treatment of acute anaphylaxis, but rather to concentrate 
on Epinephrine, USP Auto-Injector 0.3 mg for IM injection.  As per EMA 
recommendation, 2 of these will be provided to each patient throughout the at-home 
treatment phase, as a provision for the initial acute management of symptoms by a 
qualified healthcare provider, in the event of suspected anaphylaxis. 
• 
The adverse event management guidelines have been updated to align Appendix 7 
with the Atezolizumab Investigator’s Brochure, Version 19 and associated Addenda 
1 and 2. 
• 
A comprehensive list of investigational medicinal products (IMPs), and non-IMPs 
has been included to align with CTR requirements (Appendix 8). 
• 
Administrative changes: 
– 
The Australian Register of Therapeutic Goods (ARTG) number has been 
included for completeness, as Kaiku Health is already registered and had 
registration number in Australia (Section 6.1.1.1). 
– 
The reference for EAACI guidelines has been included: Anaphylaxis 
(References). 
– 
The time window has been clarified to complete questionnaires ( ± 3 days) in 
Cohort A and B (Appendix 1, schedule of activities for Cohort A). 
– 
It has been clarified that the patients in Cohort B who stop receiving the at-
home treatment may continue to receive the treatment during hospital visits as 
long as Atezolizumab SC is not discontinued (Appendix 1). 
– 
Socioeconomic status has been added to the schedules of activities for 
Cohorts A and B (Appendix 1), while it was already mentioned in the protocol 
body of Section 5.5.2. 
– 
A serology test has been added to the schedule of activities for Cohort B 
(Appendix 1, schedule of activities for Cohort B) while it was earlier mentioned 
in the protocol body of Section 5.5.7.3. 
– 
A 3−day window has been allowed for randomization in Cohort A and to provide 
more flexibility in site workflow (Appendix 1, schedule of activities for Cohort A). 
– 
The need for disease control visits has been specified in Cohort B only during 
the at-home treatment phase. It has also been clarified that this visit type takes 
place in the hospital (Appendix 1), while this was previously mentioned in the 
protocol body of Section 2.7, 4.1.2. 
– 
The at-home treatment cycle length for Cohort B has been clarified (Appendix 
1, schedule of activities for Cohort B). 

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
8/Protocol MO42720, Version 2 
– 
Testing and documentation of programmed cell death-ligand 1 (PD-L1)-
positivity status during screening assessment has been added to the schedule 
of activities (Appendix 1). 
– 
An item, “Other symptoms” has been added to the symptom list in Appendix 3 
to reflect actual software implementation.  This allows patients to report any 
other symptom they experience that is not in the predefined symptom list. 
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. 

Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
9/Protocol MO42720, Version 2 
TABLE OF CONTENTS 
1.
PROTOCOL SUMMARY ............................................................... 18 
Synopsis............................................................................................. 18 
2.
BACKGROUND ............................................................................ 26 
2.1 
Digital Health Solutions ............................................................ 26 
2.2 
Web-based, Digital Patient Monitoring Systems ...................... 26 
2.3 
Roche DPM Module ................................................................. 27 
2.3.1 
Roche DPM Module Indications ............................................... 28 
2.3.2 
Roche DPM Module Installation ............................................... 28 
2.4 
The Kaiku Health DPM Solution .............................................. 28 
2.5 
Background on Cancers, Treatment-related Symptoms, 
and Treatment Administration .................................................. 30 
2.6 
Background on Atezolizumab .................................................. 31 
2.7 
Background on Recombinant Human Hyaluronidase 
(rHuPH20) .............................................................................. 33 
2.8 
Rationale and Benefit-Risk Assessment .................................. 34 
3.
OBJECTIVES AND ENDPOINTS ................................................. 38 
3.1 
Efficacy and Safety Objectives ................................................ 39 
3.1.1 
Cohort A .................................................................................. 39 
3.1.1.1 
Primary Efficacy Objective ....................................................... 39 
3.1.1.2 
Secondary Efficacy Objectives ................................................ 39 
3.1.1.3 
Exploratory Efficacy Objectives ............................................... 39 
3.1.1.4 
Safety Objective ....................................................................... 40 
3.1.1.5 
Biomarker Objective ................................................................ 40 
3.1.2 
Cohort B .................................................................................. 40 
3.1.2.1 
Primary Efficacy Objective ....................................................... 40 
3.1.2.2 
Secondary Efficacy Objectives ................................................ 40 
3.1.2.3 
Exploratory Efficacy Objectives ............................................... 40 
3.1.2.4 
Safety Objective ....................................................................... 41 
3.1.2.5 
Biomarker Objective ................................................................ 41 
4.
STUDY DESIGN ........................................................................... 41 
4.1 
Description of the cohorts ........................................................ 42 

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4.1.1 
Cohort A .................................................................................. 42 
4.1.2 
Cohort B .................................................................................. 44 
4.1.3 
Data Collection ........................................................................ 46 
4.2 
End of Study and Length of Study ........................................... 47 
4.2.1 
Cohort A .................................................................................. 47 
4.2.2 
Cohort B .................................................................................. 47 
4.3 
Rationale for Study Design ...................................................... 47 
4.3.1 
Cohort A .................................................................................. 47 
4.3.1.1 
Rationale for Cohort A Population ........................................... 47 
4.3.1.2 
Rationale for Cohort A Procedures and Schedule ................... 48 
4.3.1.3 
Rationale for Choice of Cohort A Control Group ...................... 48 
4.3.1.4 
Rationale for Cohort A Biomarker Assessments ...................... 48 
4.3.1.5 
Rationale for Cohort A Non-Standard Clinical Outcome 
Assessments ........................................................................... 49 
4.3.2 
Cohort B .................................................................................. 49 
4.3.2.1 
Rationale for Atezolizumab SC Dose and Schedule ................ 49 
4.3.2.2 
Rationale for Cohort B Population ........................................... 49 
4.3.2.3 
Rationale for Cohort B Procedures and Schedule ................... 50 
4.3.2.4 
Rationale for Choice of Cohort B Control Group ...................... 50 
4.3.2.5 
Rationale for Cohort B Biomarker Assessments ...................... 50 
4.3.2.6 
Rationale for Cohort B Non-Standard Clinical Outcome 
Assessment ............................................................................. 50 
5. 
MATERIALS AND METHODS ...................................................... 50 
5.1 
Participants .............................................................................. 50 
5.1.1 
Cohort A .................................................................................. 50 
5.1.2 
Cohort B .................................................................................. 50 
5.1.3 
Inclusion Criteria ...................................................................... 51 
5.1.3.1 
All Participants ......................................................................... 51 
5.1.3.2 
Cohort A .................................................................................. 51 
5.1.3.3 
Cohort B .................................................................................. 51 
5.1.4 
Exclusion Criteria ..................................................................... 53 
5.1.4.1 
All Participants ......................................................................... 53 
5.1.4.2 
Cohort A .................................................................................. 54 

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5.1.4.3 
Cohort B .................................................................................. 54 
5.2 
Method of Intervention Assignment and Blinding ..................... 57 
5.2.1 
Study Arm Assignment ............................................................ 57 
5.2.1.1 
Cohort A .................................................................................. 57 
5.2.1.2 
Cohort B .................................................................................. 57 
5.2.2 
Blinding .................................................................................... 57 
5.3 
Study Intervention and Other Treatments Relevant to the 
Study Design ........................................................................... 58 
5.3.1 
Study Treatment ...................................................................... 58 
5.3.1.1 
Cohort A (Atezolizumab IV) ..................................................... 58 
5.3.1.2 
Cohort B (Atezolizumab SC) .................................................... 58 
5.3.2 
Medical Device ........................................................................ 62 
5.3.2.1 
The Roche DPM Atezolizumab Module on the Kaiku 
Health DPM Solution (Cohorts A and B) .................................. 62 
5.3.2.2 
Comparator Arm for Cohort A - Anti-cancer Regimen 
Containing Atezolizumab (IV) and Local Standard of Care 
Support Only ............................................................................ 65 
5.4 
Concomitant Therapy .............................................................. 66 
5.4.1 
Concomitant Therapy for Cohort A .......................................... 66 
5.4.1.1 
Permitted Therapy ................................................................... 66 
5.4.1.2 
Prohibited Therapy .................................................................. 66 
5.4.2 
Concomitant Therapy for Cohort B .......................................... 66 
5.4.2.1 
Permitted Therapy ................................................................... 66 
5.4.2.2 
Cautionary Therapy ................................................................. 67 
5.4.2.3 
Prohibited Therapy .................................................................. 67 
5.4.3 
Additional Restrictions ............................................................. 68 
5.5 
Study Assessments ................................................................. 68 
5.5.1 
Informed Consent Forms and Screening Log (All Cohorts) ..... 69 
5.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, Demographic Data, and Socioeconomic Status 
Data (All Cohorts) .................................................................... 69 
5.5.2.1 
Cohort B .................................................................................. 69 
5.5.3 
Physical Examinations (All Cohorts) ........................................ 69 
5.5.4 
Vital Signs ................................................................................ 70 
5.5.4.1 
All Cohorts ............................................................................... 70 

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5.5.4.2 
Cohort B .................................................................................. 70 
5.5.5 
Tumor and Response Evaluations (Cohort B) ......................... 70 
5.5.5.1 
Radiographic Assessments (Cohort B) .................................... 70 
5.5.6 
Biomarkers............................................................................... 71 
5.5.7 
Laboratory and Other Biological Samples ............................... 71 
5.5.7.1 
All Cohorts ............................................................................... 71 
5.5.7.2 
Cohort A .................................................................................. 72 
5.5.7.3 
Cohort B .................................................................................. 72 
5.5.8 
Clinical Outcome Assessments (All Cohorts)........................... 73 
5.5.8.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 73 
5.5.8.2 
Description of Clinical Outcome Assessment Instruments ....... 75 
5.5.9 
Anti-cancer Treatment Associated Adverse Events ................. 76 
5.5.9.1 
Safety Plan .............................................................................. 76 
5.5.9.2 
Safety parameters and definitions ........................................... 77 
5.5.9.3 
Methods and Timing for Capturing and Assessing Safety 
Parameters .............................................................................. 80 
5.5.9.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 89 
5.5.9.5 
Follow-up of Patients after Adverse Events ............................. 91 
5.5.9.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 92 
5.5.9.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, And Ethics Committees .............. 92 
5.6 
Intervention, Participant, Study, and Site Discontinuation ....... 93 
5.6.1 
Study Intervention Discontinuation .......................................... 93 
5.6.1.1 
DPM Discontinuation (Cohort A and Cohort B) ........................ 93 
5.6.1.2 
Atezolizumab SC Discontinuation (Cohort B) .......................... 93 
5.6.2 
Patient Discontinuation from the Study ................................... 94 
5.6.3 
Study Discontinuation .............................................................. 94 
5.6.4 
Site Discontinuation ................................................................. 95 
6. 
ASSESSMENT OF SAFETY ......................................................... 95 
6.1 
Device Safety (Cohorts A and B) ............................................. 95 
6.1.1 
Safety Plan .............................................................................. 95 

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6.1.1.1 
Risks Associated with the Kaiku Health DPM Solution ............ 95 
6.1.1.2 
Management of Patients Who Experience Adverse Device 
Incidents .................................................................................. 96 
6.1.2 
Safety Parameters and Definitions .......................................... 97 
6.1.2.1 
Medical Device Adverse Incident ............................................ 97 
6.1.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 97 
6.1.3.1 
Device Incident Reporting Period ............................................ 97 
6.1.3.2 
Assessment of Severity of Adverse Device Incidents .............. 97 
6.1.3.3 
Assessment of Causality of Adverse Device Incidents ............ 98 
6.1.3.4 
Procedures for Reporting Adverse Device Incidents ............. 100 
6.2 
Atezolizumab Safety (Cohort B) ............................................. 100 
6.2.1 
Safety Plan ............................................................................ 100 
6.2.1.1 
Risks Associated with Atezolizumab ...................................... 101 
6.2.1.2 
Risks Associated with rHuPH20 ............................................ 102 
6.2.2 
Safety Parameters and Definitions ........................................ 102 
6.2.2.1 
Adverse Events ...................................................................... 102 
6.2.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 103 
6.2.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 103 
6.2.2.4 
Selected Adverse Events ....................................................... 104 
6.2.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 104 
6.2.3.1 
Adverse Event Reporting Period ............................................ 105 
6.2.3.2 
Eliciting Adverse Event Information ....................................... 105 
6.2.3.3 
Assessment of Severity of Adverse Events ........................... 105 
6.2.3.4 
Assessment of Causality of Adverse Events.......................... 106 
6.2.3.5 
Procedures for Recording Adverse Events ............................ 107 
6.2.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 114 
6.2.4.1 
Medical Monitors and Emergency Medical Contacts ............. 115 
6.2.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 115 
6.2.4.3 
Reporting Requirements for Pregnancies .............................. 116 

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6.2.5 
Follow-Up of Patients after Adverse Events .......................... 117 
6.2.5.1 
Investigator Follow-Up ........................................................... 117 
6.2.5.2 
Sponsor Follow-Up ................................................................ 117 
6.2.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 118 
6.2.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 118 
7. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 118 
7.1 
Cohort A ................................................................................ 118 
7.2 
Cohort B ................................................................................ 119 
7.3 
Determination of Sample Size ............................................... 120 
7.3.1 
Cohort A ................................................................................ 120 
7.3.2 
Cohort B ................................................................................ 121 
7.4 
Summaries of Conduct of Study (All Cohorts) ....................... 121 
7.5 
Summaries of Study Group Comparability (All Cohorts) ........ 121 
7.6 
Efficacy Analyses ................................................................... 122 
7.6.1 
Cohort A ................................................................................ 122 
7.6.1.1 
Primary Efficacy Endpoint ...................................................... 122 
7.6.1.2 
Secondary Efficacy Endpoints ............................................... 124 
7.6.1.3 
Exploratory Efficacy Endpoints .............................................. 127 
7.6.2 
Cohort B ................................................................................ 130 
7.6.2.1 
Primary Efficacy Endpoint ...................................................... 130 
7.6.2.2 
Exploratory Endpoints ............................................................ 131 
7.7 
Safety Analyses ..................................................................... 132 
7.7.1 
Cohort A ................................................................................ 132 
7.7.2 
Cohort B ................................................................................ 133 
..................................................... 133 
..................................................... 133 
..................................................... 133 
7.8.3 
Analysis of Data to Inform Device Changes .......................... 133 
8. 
DATA COLLECTION AND MANAGEMENT ............................... 134 
8.1 
Data Quality Assurance ......................................................... 134 
8.2 
Electronic Case Report Forms ............................................... 134 

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Electronic PATIENT-Reported Outcome Data ...................... 134 
8.4 
Device Data ........................................................................... 135 
8.5 
Source Data Documentation .................................................. 135 
8.6 
Use of Computerized Systems .............................................. 136 
8.7 
Retention of Records ............................................................. 136 
9. 
ETHICAL CONSIDERATIONS .................................................... 136 
9.1 
Compliance with Laws and Regulations ................................ 136 
9.2 
Informed Consent .................................................................. 136 
9.3 
Institutional Review Board or Ethics Committee .................... 137 
9.4 
Confidentiality ........................................................................ 138 
9.5 
Financial Disclosure ............................................................... 139 
10. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 139 
10.1 
Study Documentation ............................................................ 139 
10.2 
Protocol Deviations ................................................................ 139 
10.3 
Management of Study Quality ................................................ 139 
10.4 
Site Inspections ..................................................................... 140 
10.5 
Administrative Structure ......................................................... 140 
10.6 
Dissemination of Data and Protection of Trade Secrets ........ 140 
10.7 
Protocol Amendments ........................................................... 141 
11. 
REFERENCES............................................................................ 142 
APPENDIX 1: SCHEDULE OF ACTIVITIES .................................................... 150 
Schedule of activities for Cohort A .............................................................. 150 
Schedule of activities for Cohort B .............................................................. 153 
APPENDIX 2  EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS SCALE ............................................ 159 
APPENDIX 3  SELECTED PRO-CTCAE AND OTHER SYMPTOMS ............... 160 
APPENDIX 4 PARTICIPANT ACCEPTABILITY QUESTIONNAIRE ................ 162 
APPENDIX 5  PREEXISTING AUTOIMMUNE DISEASES AND IMMUNE 
DEFICIENCIES ........................................................................... 164 
APPENDIX 6  ANAPHYLAXIS PRECAUTIONS ............................................... 165 

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APPENDIX 7  RISKS ASSOCIATED WITH ATEZOLIZUMAB AND 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS 
ASSOCIATED WITH ATEZOLIZUMAB ...................................... 166 
APPENDIX 8  INVESTIGATIONAL MEDICINAL PRODUCT AND NON-
INVESTIGATIONAL MEDICINAL PRODUCT 
DESIGNATIONS  (FOR USE IN EUROPEAN ECONOMIC 
AREA) ......................................................................................... 197 
 
 
LIST OF TABLES 
Table 1 
Cohort A Population and Treatments .......................................... 43 
Table 2 
Administration of First and Subsequent Atezolizumab SC 
Injections ..................................................................................... 60 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 81 
Table 4 
Causal Attribution Guidance ....................................................... 82 
Table 5 
Severity Classification for Adverse Device Incidents .................. 98 
Table 6 
Assessment of Event Relationship to Device or  
Device-Related Procedure .......................................................... 99 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 106 
Table 8 
Causal Attribution Guidance ..................................................... 107 
Table 9 
Analysis of EORTC QLQ-C30 Global Health Status Score 
from Historical Atezolizumab Pivotal Trails ............................... 121 
 
 
LIST OF FIGURES 
Figure 1 
Digital Patient Monitoring Solutions Enable Patients to 
Report Symptoms Systemically .................................................. 27 
Figure 2 
Roche DPM Module Overview .................................................... 28 
Figure 3 
Study Schema ............................................................................. 42 
 

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
 
PROTOCOL TITLE: 
INTERVENTIONAL PLATFORM STUDY 
INVESTIGATING THE IMPACT OF DIGITAL 
HEALTH SOLUTIONS ON HEALTH OUTCOMES 
AND HEALTH-CARE RESOURCE UTILIZATION 
IN PARTICIPANTS RECEIVING SYSTEMIC 
TREATMENT IN CLINICAL PRACTICE 
(ORIGAMA) 
PROTOCOL NUMBER: 
MO42720 
VERSION NUMBER: 
2 
TEST COMPOUND: 
Atezolizumab (RO5541267) (Cohort B) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 

 
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1. 
PROTOCOL SUMMARY 
SYNOPSIS 
 
PROTOCOL TITLE: 
INTERVENTIONAL PLATFORM STUDY INVESTIGATING THE 
IMPACT OF DIGITAL HEALTH SOLUTIONS ON HEALTH 
OUTCOMES AND HEALTH-CARE RESOURCE UTILIZATION IN 
PARTICIPANTS RECEIVING SYSTEMIC TREATMENT IN 
CLINICAL PRACTICE (ORIGAMA) 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
EudraCT number: 2021-001415-90 
EU CT Number: 2023-504342-55-00 
NCT Number: NCT05694013 
 
STUDY RATIONALE 
This study will evaluate the impact of digital health solutions (DHS) on health outcomes and 
health-care resource utilization in people receiving systemic anti-cancer treatment (approved or 
non-approved) in clinical practice.  DHS have the potential to improve clinical practice so that it 
is more data-driven and more personalized (Imison et al. 2016). 
This study is designed to become a platform for the evaluation of an individual DHS in 
combination with a pre-specified drug treatment or group of treatments in one or more treatment 
settings, in separate cohorts.  Initially, two cohorts will be opened (Cohorts A and B).  Cohorts 
may use the same software as a medical device, collect and analyze the same solution data 
(e.g., use and workflow efficiency), or use the same patient-reported outcome (PRO) measures. 
In Cohort A, the DHS “Roche Digital Patient Monitoring (DPM) Atezolizumab Module” will be 
assessed.  “Roche DPM Atezolizumab Module” refers to the treatment-specific patient module, 
installed on a Digital Patient Monitoring solution.  "Treatment" refers to the prescribed 
anti-cancer treatment regimen (i.e., Atezolizumab (intravenous [IV]) regimen or any new 
regimen thereafter) that participants are receiving. 
In Cohort B, the combination of the DHS “Roche DPM Atezolizumab Module” and subcutaneous 
(SC) Atezolizumab administered in the at-home treatment setting will be explored.  "Treatment" 
refers to Atezolizumab SC, administered in the hospital setting (Cycles 1−3) followed by the at-
home setting (Cycles 4−16), if appropriate. 
 
 
 
 
 

 
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OBJECTIVES AND ENDPOINTS  
 
Primary Objective 
Corresponding Endpoint  
• Cohort A: 
To evaluate the efficacy of a locally 
approved anti-cancer regimen 
containing Atezolizumab (IV) and local 
standard of care (SOC) support plus 
the Roche DPM Atezolizumab Module 
compared to an anti-cancer regimen 
containing Atezolizumab (IV) with local 
SOC support only.   
 
• Cohort B: 
To evaluate the feasibility of combining 
the Roche DPM Atezolizumab Module 
and Atezolizumab SC administered in 
the at-home treatment setting. 
 
• 
Mean difference in change of Week 12 value 
from baseline of the patient-reported Total 
Symptom Interference Score from the MD 
Anderson Symptom Inventory (MDASI) Core 
Items 
 
 
 
 
 
• 
At-home treatment adoption at Cycle 6 
Secondary Objectives 
Corresponding Endpoints  
• Cohort A: 
To evaluate the efficacy of a locally 
approved anti-cancer regimen 
containing Atezolizumab (IV) and local 
standard of care (SOC) support plus 
the Roche DPM Atezolizumab Module 
compared to an anti-cancer regimen 
containing Atezolizumab (IV) with local 
SOC support only.   
 
 
 
 
 
 
 
 
• 
Number of hospitalizations and number of 
cumulative days hospitalized due to serious 
adverse events (SAEs) 
• 
Unscheduled visits to the emergency room (ER) 
or clinic visits for symptom management 
• 
Incidence, nature, and severity of all anti-cancer 
treatment associated adverse events (AEs) 
graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse 
Events Version 5.0 (CTCAE v5.0. 
• 
Change from baseline in Global Health Status 
(GHS) score/Quality of Life (QoL) score from the 
European Organisation for Research and 
Treatment of Cancer (EORTC) Item Library 6 
(IL6) GHS/QoL 
• 
Change from baseline in EuroQol EQ-5D-5L 
index-based and visual analogue scale (VAS) 
instrument 
• 
Change from baseline in the mean symptom 
severity score from the MDASI Core Items 
 
OVERALL DESIGN AND STUDY POPULATION 
This is an interventional, open-label, multi-country, platform study to investigate the impact of 
the Roche DPM Atezolizumab Module (installed on a DPM solution) on health outcomes in 
people prescribed a locally approved anti-cancer regimen containing Atezolizumab (IV) in the 
following indications: 
• 
Metastatic non-small cell lung carcinoma (mNSCLC) 
• 
Extensive-stage small-cell lung carcinoma (ES-SCLC) 
• 
Advanced or unresectable hepatocellular carcinoma (HCC) 
 

 
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There will be two cohorts. The study will evaluate one DHS per cohort in combination with a 
pre-specified treatment or group of treatments in one or more treatment settings.  In general, 
primary efficacy outcomes will be measured based on patient--reported outcomes.  Initially, two 
cohorts testing the efficacy and safety of the Roche DPM Atezolizumab Module in combination 
with Atezolizumab IV (Cohort A) or the clinical utility of the Roche DPM Atezolizumab Module in 
combination with Atezolizumab SC in the at-home setting (Cohort B) will be opened.  Additional 
cohorts will be added through future protocol amendments.  Each cohort may have separate 
endpoints, screening, and treatment requirements.  Cohorts within this study will run in parallel.   
Several key aspects of the study design and study population are summarized below. 
Phase: 
Phase II/III 
Population Type: 
Adults 
Control Method: 
Patients receiving 
the same 
anti-cancer therapy 
and SOC support 
only 
Population Diagnosis 
or Condition: 
Histologically 
confirmed diagnosis 
via local labs for one 
of the following 
indications: 
• mNSCLC 
• ES-SCLC 
• HCC (Child Pugh 
A) 
Interventional 
Model: 
Parallel groups in 
Cohort A 
Population Age: 
≥ 18 years 
Test 
Compound{s}: 
Atezolizumab SC 
(RO5541267) 
Site Distribution: 
Multi-country 
Active 
Comparator: 
Not Applicable 
Study Intervention 
Assignment Method: 
Randomization 
(Cohort A) 
Number of Arms: 
2 arms in Cohort A 
and 1 arm in Cohort 
B 
Number of 
Participants to Be 
Enrolled: 
400 in Cohort A 
in Cohort B 
ES-SCLC =  extensive-stage small-cell lung carcinoma; HCC  =  hepatocellular carcinoma; 
mNSCLC  =  metastatic non-small cell lung cancer. 

 
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STUDY TREATMENT 
The study treatment is detailed in the table below. 
Population (as per local 
approval) 
Atezolizumab anti-cancer therapy (regimens 
as per local approval) 
mNSCLC 
 
Atezolizumab 840 mg IV Q2W or 1200 mg Q3W or 
1680 mg Q4W (until disease progression or 
unmanageable toxicity) monotherapy.  Treatment 
beyond disease progression may be considered at 
the discretion of the physician. 
mNSCLC 
(non-squamous) 
Four to six 21-day cycles of Atezolizumab 1200 mg 
IV + chemotherapy (bevacizumab + carboplatin + 
paclitaxel, or carboplatin + nab-paclitaxel) induction 
therapy, followed by Atezolizumab 1200 mg Q3W 
+ bevacizumab maintenance therapy (until disease 
progression or unmanageable toxicity).  Treatment 
beyond disease progression with Atezolizumab 
monotherapy may be considered at the discretion 
of the physician.  
ES-SCLC 
Four 21-day cycles of Atezolizumab 1200mg IV + 
chemotherapy (carboplatin + etoposide) induction 
therapy, followed by Atezolizumab 840 mg IV Q2W 
or 1200 mg Q3W or 1680 mg Q4W maintenance 
therapy, including bevacizumab where locally 
approved (until disease progression or 
unmanageable toxicity).  Treatment beyond 
disease progression may be considered at the 
discretion of the physician. 
Advanced or unresectable HCC 
(Child Pugh A) 
Atezolizumab 1200mg IV Q3W + bevacizumab 
15 mg/kg IV Q3W (until loss of clinical benefit or 
unmanageable toxicity)a 
 
ES-SCLC = extensive-stage small-cell lung carcinoma; HCC = hepatocellular carcinoma; 
mNSCLC = metastatic non-small cell lung cancer; Q2W =  every 2 weeks; Q3W =  every 3 weeks. 
a 
If bevacizumab is discontinued due to toxicity, Atezolizumab regimen may continue until loss of clinical 
benefit or unmanageable toxicity. 
 
DURATION OF PARTICIPATION 
Based on a total recruitment duration of 16 months and a follow up of 12 months for all patients, 
unless they withdraw from the study sooner, the time from randomization of the first patient to 
the end of Cohort A, is expected to be approximately 28 months.  DPM provision for all 
patients will be discontinued 12 months after last patient is randomized. 
Based on a total recruitment duration of 16 months and a follow up of 15 months for all patients, 
unless they withdraw from the study sooner, the time from enrollment of the first patient to the 
end of Cohort B, is expected to be approximately 31 months.  DPM provision for each patient 
will be discontinued 3 months after the last dose of study treatment has been administered. 
 

 
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COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Not applicable 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADE 
adverse device effect 
AFP 
alpha-fetoprotein 
ALK 
anaplastic lymphoma kinase 
ARTG 
Australian Register of Therapeutic Goods 
CIF 
cumulative incidence function 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CRS 
cytokine-release syndrome 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DHS 
Digital Health Solution 
DPM 
Digital Patient Monitoring  
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
EMA 
epidermal growth factor receptor 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EORTC OUT-PATSAT7 
EORTC satisfaction with out-patient cancer care 
ePRO 
electronic patient-reported outcome 
ER 
emergency room 
ESAB 
Elekta Solutions AB 
ES-SCLC 
extensive-stage small-cell lung carcinoma 
FDA 
(U.S.) Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FSCA 
field safety corrective action 
GDPR 
General Data Protection Regulation 
GHS 
GMR 
global health status 
geometric mean ratios 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV/HCV 
hepatitis B/C virus 
HCC 
hepatocellular carcinoma 
HCP 
healthcare professional 

 
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Abbreviation 
Definition 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
HUS 
hemolytic-uremic syndrome 
IB 
Investigator Brochure 
IC 
immune cells 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IL6 
item library 6 
IMP 
investigational medicinal product 
INR 
International Normalized Ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRR 
injection or infusion-related reaction 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MAS 
macrophage activation syndrome 
MDASI 
MD Anderson Symptoms Inventory 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
(m)NSCLC 
(metastatic) non-small cell lung carcinoma 
MRI  
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NIMP 
non-investigational medicinal product 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-ligand 1 
PFS 
progression free survival 
PK 
Pharmacokinetic 
popPK 
population PK 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rHuPH20 
recombinant human hyaluronidase enzyme 
SADE 
serious adverse device effect 

 
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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SITC 
Society for Immunotherapy of Cancer 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
TNBC 
triple-negative breast cancer 
TTD 
time to discontinuation 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WBC 
white blood cell 
WHO 
World Health Organization 
WTS 
weighted toxicity score 
 
 
 

 
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2. 
BACKGROUND 
2.1 
DIGITAL HEALTH SOLUTIONS 
Digital health solutions (DHS) use digital technology, including software and connectivity 
platforms, for health-related uses (FDA 2020).  There is increasing interest in the use of 
technology-based digital health solutions to improve patient engagement, better inform 
disease diagnosis and drug treatment, and enhance clinical care inside or outside the 
clinic (EXPH 2018). 
2.2 
WEB-BASED, DIGITAL PATIENT MONITORING SYSTEMS 
As time spans between clinic appointments for drug infusions and the availability of oral 
or subcutaneous drug formulations increase, there is an increasing need for remote 
monitoring of patients for symptoms and quality of life between clinic appointments 
(Aapro et al. 2020).  Several web-based systems and apps have been developed to help 
monitor and manage people undergoing cancer treatments.  These include features 
such as online symptom and quality of life reporting and monitoring 
(Absolom et al. 2021; Denis et al. 2017; Fjell et al. 2020), healthcare professional 
(HCP) patient online communication (Fann et al. 2017; Fjell et al. 2020) and education 
services (Fann et al. 2017; Fjell et al. 2020) (Figure 1).  These can be accessed from 
web−enabled devices and have been shown to effectively prompt HCPs to more 
frequently monitor, and better manage patient-reported symptoms (Basch et al. 2016; 
Warrington et al. 2019;  Denis et al. 2017; Fjell et al. 2020; Borosund et al. 2014; 
Fann et al. 2017).  Most of these web-based solutions allow people to use their own 
electronic devices (such as computers, tablets, or mobile phones) to report in real-time 
and communicate with their HCPs (Warrington et al. 2019) (Figure 1). 
Several solutions which combine all or selected features of those listed above have been 
investigated in clinical trials or introduced into clinical practice already 
(Warrington et al. 2019; Aapro et al. 2020).  Besides enabling continuous tracking and 
aggregation of symptom information, such solutions have been shown to improve patient 
overall survival (OS), and duration of drug treatment (Basch et al. 2017; 
Basch et al. 2016), reduce the rate of severe or serious adverse events 
(Degenhardt et al. 2020; Mir et al. 2020), improve health-related quality of life (HRQoL) 
(Schmalz et al. 2020; Basch et al. 2016; Basch et al. 2017; Denis et al. 2017; 
Denis et al. 2019), reduce symptom severity or interference (Mooney et al. 2021; 
Rasschaert et al. 2021; Fjell et al. 2020; Kolb et al. 2018; Cleeland et al. 2011; 
Borosund et al. 2014), and depression or anxiety (Fann et al. 2017; 
Borosund et al. 2014; Maguire et al. 2021).  Furthermore, these solutions have 
demonstrated health-economic benefits, including a reduction in hospital admission 
rates and unscheduled visits, increased use of ambulatory care, and a reduction in the 
need for patient phone calls and time for patient visits (Schmalz et al. 2020; 
Basch et al. 2016; Basch et al. 2017; Denis et al. 2017; Denis et al. 2019; 

 
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Pritchett et al. 2021; Mir et al. 2020; Mooney et al. 2021; Mooney et al. 2020; 
Hough et al. 2020; Hough et al. 2021). 
Figure 1 Digital Patient Monitoring Solutions Enable Patients to Report 
Symptoms Systemically 
 
2.3 
ROCHE DPM MODULE 
The Roche Digital Patient Monitoring (DPM) Module is tailored to Roche requirements 
including but not limited to the patient-facing user interface, questionnaire instruments, 
and content (such as treatment/disease-specific patient information material and self-
management instructions for mild/moderate symptoms), and algorithms for symptom 
alerting.  It is mobile-enabled and accessible through a web browser or an app (with iOS 
or Android operating system) on internet capable devices such as personal computers 
(PCs), laptops, mobile phones, and tablets.  In the module, patients can input data that 
is visible to care teams in real time (once the questionnaire has been submitted).  
Patients can also communicate with care teams via message on the DPM platform. 
In this protocol, “patient” refers to the individual receiving anti-cancer treatment who is 
enrolled in this study. 
An overview of the Roche DPM Module is illustrated in Figure 2 

 
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Figure 2 Roche DPM Module Overview 
 
2.3.1 
Roche DPM Module Indications 
A Roche DPM Module can cover several indications and treatments.  However, only 
symptom questions or information relevant to the individual patient’s disease and 
treatment will be displayed to the patient. 
In Cohort A of this study, the Roche DPM Atezolizumab Module is used in patients with 
extensive-stage small-cell lung carcinoma (ES-SCLC); metastatic non-small cell lung 
carcinoma (mNSCLC); and advanced or unresectable hepatocellular carcinoma (HCC); 
who have not received prior anti-cancer systemic therapy.  In Cohort B of this study, the 
Roche DPM Atezolizumab Module is used in participants with resected Stage IIB-IIIB 
(early-stage) NSCLC who have had a complete resection of NSCLC, are adequately 
recovered from surgery, and have completed up to four cycles of adjuvant platinum-
based chemotherapy without evidence of disease relapse/recurrence. 
2.3.2 
Roche DPM Module Installation 
The Roche DPM Module is hosted on the Kaiku Health DPM Solution but is technically 
separable from the Kaiku Health DPM Solution and could be integrated to other 
compatible DPM Solutions than the Kaiku Health DPM Solution after the study.  During 
the study, centers will use the Roche DPM Modules installed on the Kaiku Health DPM 
Solution. 
2.4 
THE KAIKU HEALTH DPM SOLUTION 
The Kaiku Health DPM Solution is a digital platform for symptom tracking and 
patient-reported outcomes monitoring.  It has been developed to assist the care team in 
tracking and managing participant symptoms and triaging those symptoms based on 

 
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severity, as defined by a scoring algorithm that generates a single composite numerical 
grade for each patient-reported outcome−Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) symptom (Basch et al. 2021).  The solution can alert the HCP of 
new symptom events and facilitate triage by assisting with patient prioritization based on 
severity of reported symptoms.  It can provide an overview of participants’ symptom 
burden and interaction history.  Further details on the Kaiku Health DPM Solution 
functionalities can be found in Section 5.3.1.1. 
 
 
 
 
 
 
 
 
 
Indication for the Kaiku Health Platform 
Kaiku Health is intended for all cancer diseases at all stages of treatment and follow-up. 
Intended Use Statement for Kaiku Health Platform 
• 
In the European Union: Kaiku Health is intended for use in cancer care and follow-
up for non-urgent communication between an adult patient and a medical 
professional and for collecting patient-reported data, displaying and analysing 
clinical and patient-reported data, and instructing the patient.  The data processed 
by Kaiku Health are intended to be used in supporting treatment decisions and in 
supporting diagnoses. 
 
Kaiku Health has regulatory approval in, but not limited to, the following countries:  the 
European Union, Australia, New Zealand, Switzerland, and United Kingdom, and can be 
used under enforcement discretion in the United States.  In countries where 
Kaiku Health is approved, it should be used in line with the locally approved intended 
use statement. 

 
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2.5 
BACKGROUND ON CANCERS, TREATMENT-RELATED 
SYMPTOMS, AND TREATMENT ADMINISTRATION 
Cancer is a global public health issue and one of the leading causes of death globally 
(Global Burden of Disease Cancer Collaboration 2019; WHO 2020a; Bray et al. 2021).  
In 2020, there were an estimated 19.3 million new cancer cases and 10 million 
cancer-related deaths worldwide (WHO 2020b).  The global incidence of new cases 
continues to rise, reflecting the ageing population as well as lifestyle changes that 
increase the prevalence of cancer risk factors (Warrington et al. 2019; Torre et al. 2016).  
The number of new cancer cases worldwide is expected to increase to 30.2 million in 
2040 (WHO 2020b). 
Early diagnosis and advances in cancer treatments have resulted in improved cancer 
survival rates (Arnold et al. 2019; Allemani et al. 2018).  Individuals are now living for 
many years after cancer diagnosis and the number of cancer survivors is increasing 
(Alfano et al. 2018).  However, treatment-related symptoms or adverse events 
experienced during treatment, as well as long-term consequences of anti-cancer 
treatment, are frequent and a common concern for people with cancer and HCPs and 
can cause increased risk of hospitalization and health care utilization (Rashid et al. 
2015; George et al. 2021) and be a reason for early anti-cancer treatment 
discontinuation (Warrington et al. 2019; Nurgali et al. 2018).  People living with cancer 
may experience acute and chronic effects due to treatment that can negatively impact 
their HRQoL and may even become life-threatening, with some individuals developing 
severe cases of neutropenia-related infection or other complications, or offsetting the 
improvement in outcomes seen with modern cancer treatments (Warrington et al. 2019; 
Bhattacharya et al. 2012; Gallegos-Kearin et al. 2018; Smith et al. 2021).  A reduction of 
the adverse consequences of cancer treatment is therefore a priority for cancer research 
(Smith et al. 2021). 
Symptom and adverse event monitoring and management by HCPs is an essential part 
of cancer care (Chindaprasirt et al. 2013) and earlier and better integrated cancer care 
was shown to improve outcomes (Temel et al. 2017).  As stated in Section 2.2, digital 
patient monitoring and management of symptoms has been shown to positively impact 
outcomes and health care resource utilization (Schmalz et al. 2020; Basch et al. 2016; 
Basch et al. 2017; Denis et al. 2017; Denis et al. 2019; Pritchett et al. 2021; Mir et al. 
2020; Mooney et al. 2021; Mooney et al. 2020; Hough et al. 2020; Hough et al. 2021). 
Cancer treatment is traditionally provided in a hospital or oncology clinic setting and 
administered through intravenous (IV) infusion (Wardley et al. 2021).  Treatment of 
people with cancer in these settings can be resource-intensive, time-consuming, and 
burdensome for those living with cancer, impacting HRQoL (Wardley et al. 2021; 
Aumann et al. 2015).  At-home treatment describes care that is administered outside of 
the oncology ward, oncological outpatient clinic, or office-based oncologist setting.  At-
home treatment may take place in various settings, including the patient’s home, primary 

 
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care, or community care, offering benefits for both people with cancer and hospitals.  
Programs that bring cancer treatment closer to the patient or provide care within the 
patient’s home have been shown to improve quality of life, increase satisfaction with 
treatment and adherence, reduce costs and burden, and improve outcomes (Borras et 
al. 2001; Leff et al. 2005; Shepperd et al. 2009; Cryer et al. 2012; Mitchell. 2013; Cool et 
al. 2019).  At-home treatment may also increase hospital capacity and save time for 
HCPs (De Cock et al. 2016). 
2.6 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (Tecentriq®) is a fully humanized, engineered monoclonal antibody of IgG1 
isotype that targets programmed cell death-ligand 1 (PD-L1) and inhibits the interaction 
between PD-L1 and its receptors, programmed cell death protein 1 (PD-1) and B7-1 
(also known as CD80), both of which function as inhibitory receptors expressed on T-
cells.  Therapeutic blockade of PD-L1 binding by Atezolizumab has been shown to 
enhance the magnitude and quality of tumor-specific T-cell responses, resulting in 
improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc-
effector function and associated antibody-mediated clearance of activated effector T-
cells. 
Atezolizumab shows antitumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved as IV infusion for the treatment of urothelial carcinoma, 
Stage II to IIIA NSCLC (PD-L1 positive), mNSCLC, hepatocellular carcinoma (HCC), 
ES-SCLC, melanoma, and locally advanced unresectable or metastatic triple-negative 
breast cancer (mTNBC; PD-L1 positive).  In Cohort A, an anti-cancer regimen containing 
Atezolizumab (IV) will be prescribed according to the local approval. 
A formulation of Atezolizumab for SC administration is currently undergoing clinical 
evaluation in Study BP40657 (IMscin001) and Study MO43576 (IMscin002).  
Study BP40657 is a Phase Ib/III multicenter study investigating the pharmacokinetics, 
efficacy, and safety of SC administered Atezolizumab compared with Atezolizumab IV in 
patients with previously treated locally advanced or mNSCLC. 
Sixty-seven patients were enrolled in Part 1: 13 patients in cohort 1, 15 in cohort 2, 
and 39 in cohort 3 (Felip et al. 2021).  SC Atezolizumab 1800 mg every 3 weeks and 
1200 mg every 2 weeks provided similar Ctrough and area under the curve (AUC) values 
in Cycle 1 to the corresponding IV Atezolizumab reference.  Ctrough values were 
121 μg/mL in cohort 1 (1800 mg SC every 3 weeks, thigh), 83.2 μg/mL in cohort 2 
(1200 mg SC every 2 weeks, thigh), and 97.3 μg/mL in cohort 3 (1800 mg SC every 

 
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3 weeks, abdomen).  Exposure following SC injection in the abdomen was lower (20%, 
28%, and 27% for Ctrough, maximum concentration, and area under the concentration-
time curve from time 0 to day 21, respectively) than in the thigh. 
Atezolizumab SC was well tolerated, and the safety profile was consistent with the 
known risks of Atezolizumab IV.  Injection-site reactions were low grade and well 
tolerated.  Seven of 11 patients experienced an injection site reaction in Cycle 1; six 
were Grade 1 and one was Grade 2 which resolved without sequelae. 
Based on these results, a SC dose/regimen of 1875 mg q3w was selected for evaluation 
in Part 2 of the study (Dose confirming, Phase III, randomized).  Part 2 will aim to 
confirm that this SC dose yields drug exposure that is comparable to that of IV 
Atezolizumab. 
In IMscin001 Part 2 (randomized Phase III of the study), adults with previously 
treated locally advanced/metastatic NSCLC (no prior cancer immunotherapy) and 
ECOG PS 0 or 1 were randomized 2:1 to receive 2L Atezolizumab SC (1875 mg) or IV 
(1200 mg) every 3 weeks.  Primary endpoints were non-inferiority for Cycle 1 observed 
serum Ctrough and model-predicted AUC0–21 days; secondary endpoints were steady-state 
pharmacokinetics, safety, efficacy (PFS, ORR), patient-reported outcomes and 
immunogenicity. 
There were 247 and 124 patients in the Atezolizumab SC and IV arms, respectively 
(median follow-up: 4.6 months; data cut-off: 26 April 2022).  Median age was 
64.0 years (range: 27–85), 69% were male and 74% had ECOG PS 1.  The lower 
bounds of the 90% CI of the geometric mean ratios (GMRs) for Ctrough (GMR 1.05 
[90% CI: 0.88, 1.24]) and AUC (GMR 0.87 [90% CI: 0.83, 0.92]) were above the 
predefined non-inferiority margin of 0.8.  Efficacy, immunogenicity, and safety were 
similar between arms (Burotto et al. 2022). 
Atezolizumab SC demonstrated non-inferior exposure versus IV for both co-primary 
pharmacokinetic (PK) endpoints.  Efficacy and safety were similar between arms and 
consistent with the known Atezolizumab IV profile.  Atezolizumab immunogenicity 
was comparable between arms and within the historical range for Atezolizumab IV 
across indications.  
 
  
Study MO43576 is an ongoing Phase II randomized, multicenter, open-label, cross-over 
study evaluating patient and HCP reported preference for Atezolizumab SC compared 
with Atezolizumab IV in patients with NSCLC.  In Cohort B of this study, all patients will 
receive Atezolizumab SC. 

 
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2.7 
BACKGROUND ON RECOMBINANT HUMAN 
HYALURONIDASE (RHUPH20) 
The feasibility and patient acceptability of SC administration of any drug are dependent 
on the volume of drug that must be administered.  The recombinant human 
hyaluronidase enzyme (rHuPH20) (Hylenex recombinant) is a hyaluronidase for 
human injection that has been developed by Halozyme Therapeutics, Inc., and is 
approved in the European Union and United States as a permeation enhancer to 
improve dispersion and absorption of SC formulations, enabling larger volumes to be 
administered without reduced tolerability and with improved patient acceptability.  
Hyaluronidase depolymerizes hyaluronan, a component of the SC matrix, leading to 
reduced viscosity of the extracellular matrix of the hypodermis and, thus, to an 
improved delivery of subcutaneously administered drugs to the systemic circulation.  
The hyaluronan in the SC space is restored within 24–48 hours.  rHuPH20, 
a recombinant human molecule, has a higher purity and is associated with improved 
tolerability compared with the animal-derived enzyme (Hylenex recombinant U.S. 
Package Insert). 
The safety and efficacy of hyaluronidase products have been widely established.  The 
most significant safety risk identified is hypersensitivity/allergenicity, which is thought 
to be related to the lack of purity of the animal-derived preparations.  This is not a 
safety concern for the human recombinant rHuPH20.  The concentration of rHuPH20 
is guided by data from a mini-pig study in which trastuzumab was administered 
subcutaneously.  In the presence of either 2000 or 6000 U/mL of rHuPH20, there was a 
more rapid absorption of subcutaneously administered trastuzumab from 
rHuPH20-containing formulations, while the effect on the absorption rate of 
trastuzumab was comparable with both rHuPH20 concentrations.  Therefore, the lower 
rHuPH20 concentration of 2000 U/mL was selected. 
The highest total rHuPH20 dose administered in a clinical study was 96,000 U.  This 
Phase I study investigated the SC injection of adalimumab with different rHuPH20 
concentrations in healthy volunteers using different volumes of injection (2, 8, and 16 
mL).  All injections were well tolerated with no serious adverse events reported.  
Common injection-site reactions observed were erythema, ecchymosis, pain, and 
induration.  All injection-site reactions, such as erythema, pain, and induration, were 
mild (98%) or moderate (2%). 
To date, four monoclonal antibodies co-formulated with rHuPH20, are approved for SC 
therapy in oncology in the United States (PHESGO U.S. Package Insert; 
DARZALEX® U.S. Package Insert; HERCEPTIN HYLECTA™ U.S. Package Insert; 
RITUXAN HYCELA™ U.S. Package Insert) and four in the European Union 
(Darzalex® SmPC; Herceptin® SmPC; MabThera SmPC; HyQvia® SmPC). 
 

 
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2.8 
RATIONALE AND BENEFIT-RISK ASSESSMENT 
Digital Patient Monitoring 
DPM solutions have been shown to improve OS, with median OS increasing by 
5 months in people with advanced cancers, and 9 months in people with lung cancer 
compared with standard care (Basch et al. 2017; Denis et al. 2019).  Offering web-based 
support and education to people undergoing cancer treatment has also been shown to 
better help individuals self-manage their illness, enhance satisfaction with care, HRQoL, 
symptom severity or interference, and significantly improve psychosocial outcomes 
(Fjell et al. 2020; Borosund et al. 2014; Fann et al. 2017; Absolom et al. 2021; Mooney 
et al. 2021; Rasschaert et al. 2021; Fjell et al. 2020; Kolb et al. 2018; Cleeland et al. 
2011; Borosund et al. 2014).  Studies have shown significant improvements in 
depression, anxiety and physical wellbeing scores versus usual care (Borosund et al. 
2014; Fann et al. 2017; Absolom et al. 2020). 
Further studies suggest that DPM solutions may reduce the incidence of SAEs and thus 
the need for dose reductions (Degenhardt et al. 2020) and have also been associated 
with significantly higher relative dose intensity (Mir et al. 2020) and longer continued 
chemotherapy treatment than with usual care (Basch et al. 2017). 
Identifying treatment-related symptoms promptly in people undergoing anti-cancer 
treatment can help HCPs with more effective management of treatment-related 
symptoms.  Some web-based systems have been shown to enable care teams to 
intervene before symptoms worsen, leading to an improvement in symptom control 
(Mooney et al. 2021; Mooney et al. 2017; Berry et al. 2014; Fjell et al. 2020; 
Maguire et al. 2021; Kolb et al. 2018). 
At-home Treatment 
Anti-cancer therapy administered in the hospital setting is often burdensome to patients 
due to the need to travel and disruption of daily activities (Wardley et al. 2021; 
Aumann et al. 2015).  The administration of anti-cancer therapy in a at-home 
treatment setting (outside of the oncology ward, oncological outpatient clinic, or office-
based oncologist setting), has been shown to reduce patient burden as well as improve 
quality of life, increase satisfaction with treatment and adherence, reduce costs, and 
improve outcomes (Borras et al. 2001; Leff et al. 2005; Shepperd et al. 2009; Cryer et al. 
2012; Mitchell. 2013; Cool et al. 2021).  The SC formulations of anti-cancer treatments 
may offer the preferred method of treatment administration in the at-home treatment 
setting due to quicker infusion times and easier administration. 
Study MO42720 
This study will evaluate a DHS in combination with a specified anti-cancer treatment in 
separate cohorts. 

 
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In Cohort A of this study, patients prescribed a locally approved anti-cancer regimen 
containing Atezolizumab (IV) in different indications will be enrolled and randomized to 
the Roche DPM Atezolizumab Module plus local standard of care (SOC) support or local 
SOC support only.  Considering the high unmet medical need for the early detection and 
management of cancer treatment-related adverse events, the evidence presented above 
indicating that DPM solutions are safe and can improve outcomes and HRQoL in 
individuals with cancer, and robust procedures for risk minimization and mitigation 
employed in this study (see Section 6.1), the benefit−risk profile for Cohort A is 
considered to be favorable. 
In Cohort B of this study, patients with early-stage NSCLC will receive three cycles of 
Atezolizumab SC administered in the hospital setting followed by up to 13 cycles of 
Atezolizumab SC administered in the at-home treatment setting, if appropriate, 
alongside the Roche DPM Atezolizumab Module. 
The SC delivery of biotherapeutics is well-established as a route of administration that is 
effective and well-tolerated across many therapeutic areas (Collins et al. 2020).  It can 
offer several advantages over IV administration, including the convenience of 
self-administration, improved patient experience, reduced treatment burden, and lower 
healthcare costs.  Atezolizumab SC was shown to be well tolerated and exhibited a 
safety profile consistent with the known risks of Atezolizumab IV monotherapy in 
Study BP40657 (IMscin001).  No new or significant safety concerns were identified.  
Patient and HCP reported preference for Atezolizumab SC compared with Atezolizumab 
IV is currently undergoing clinical evaluation in Study MO43576 (IMscin002). 
There have been successful examples of drugs initially approved for IV administration 
that can now be safely administered as an SC injection in the at-home treatment setting 
by HCPs (Denys et al. 2020; Wolfromm et al. 2017; Walsh et al. 2007).  Administration in 
the at-home treatment setting improves the quality of life and is more convenient, 
particularly for individuals who live far from a hospital or have difficulty travelling.  In 
Cohort B of this study, the first three cycles of Atezolizumab SC will be administered in 
the hospital setting, as events that require immediate medical intervention, such as 
injection related reactions (IRRs), most commonly occur during the first three 
administrations.  Patients may then receive up to 13 cycles of Atezolizumab SC 
administered in the at-home treatment setting.  For patients who develop IRRs (or 
symptoms suggestive of IRR that require immediate medical intervention during infusion) 
during the first three cycles of Atezolizumab SC administration, all subsequent 
Atezolizumab SC administration will be done in the hospital setting only.  For low grade 
(Grade 1–2) IRR events during the first three cycles, administration in the at-home 
treatment setting may be considered with premedication.  Atezolizumab SC will be 
administered in the at-home treatment setting by a qualified mobile HCP with access to 

 
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adequate equipment to manage adverse events.  The following additional risk mitigation 
strategies will be mandated by the protocol: 
• 
Results from laboratory samples will be reviewed by the investigator prior to first 
Atezolizumab SC administration.  From Cycle 4 onwards (treatment at home 
setting), laboratory samples will be collected 3 to 7 days prior to Atezolizumab SC 
administration so that results will be available by the time of treatment 
administration. 
• 
Laboratory samples will be collected by a qualified mobile HCP in the at-home 
treatment setting or at the site as needed. 
• 
A phone or video call will be established between the qualified mobile HCP and the 
treating clinic HCPs during Atezolizumab SC administration in the at-
home treatment setting. 
• 
Patients will be prompted to complete symptom questionnaires via the Roche DPM 
Atezolizumab Module every 7 days as well as 24 hours after each Atezolizumab SC 
administration.  The symptom questionnaire will include symptoms relevant to SC 
administration. 
• 
Patients will visit the clinic HCP for a disease control and safety visit every three 
months during the at-home treatment period. 
 
Considering the evidence that the safety profile of Atezolizumab SC is consistent with 
the known risks of Atezolizumab IV monotherapy, the high burden of hospital 
administration of anti-cancer treatment and the evidence presented above indicating that 
administration of anti-cancer treatment in the at-home treatment setting improves the 
quality of life and outcomes for people with cancer, and the risk minimization and 
mitigation strategies outlined above and in Section 6.2, the benefit−risk profile for Cohort 
B is considered to be favorable. 
The overall risk for patients in all cohorts of this study receiving treatment with 
Atezolizumab (IV or SC) is expected to be low.  Atezolizumab IV is an approved 
treatment for people with urothelial carcinoma, Stage II to IIIA NSCLC (PD-L1 positive), 
mNSCLC, HCC, ES-SCLC, melanoma, and locally advanced unresectable or metastatic 
triple-negative breast cancer (mTNBC; PD-L1 positive).  The safety profile of 
Atezolizumab SC has been evaluated in Study BP40657 and was consistent with the 
known risks of Atezolizumab IV monotherapy. 
This study is being conducted in compliance with ISO 14155 and incorporates a number 
of strategies to manage risk to the patient, including regular monitoring for AEs.  Risk to 
the patient has been further minimized by completion of product testing for the Kaiku 
Health DPM Solution prior to its use in this study.  A risk evaluation has been conducted 
by Kaiku Health, in accordance with ISO 14971.  Identified residual risks and warnings 
presented to users of the Kaiku Health DPM Solution are outlined in Section 6.1.1.1. 

 
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In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies, such as chemotherapy, targeted therapy, or immunotherapy, 
impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)-γ (Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving Atezolizumab.  At this time, there 
is insufficient evidence for causal association between Atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with Atezolizumab and clinical and radiologic 
features for SARS-CoV-2−related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving Atezolizumab treatment, a decision to administer the vaccine to a patient 

 
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should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving Atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 5.4). 
3. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the impact of DHS on health outcomes and health-care resource 
utilization in people receiving systemic anti-cancer treatment (approved or non-
approved) in clinical practice.  DHS have the potential to improve clinical practice so that 
it is more data-driven and more personalized (Imison et al. 2016). 
This study is designed to become a platform for the evaluation of an individual DHS in 
combination with a pre-specified drug treatment or group of treatments in one or more 
treatment settings, in separate cohorts. Initially, two cohorts will be opened (Cohorts A 
and B).  Cohorts may use the same software as a medical device, collect and analyze the 
same solution data (e.g., use and workflow efficiency), or use the same patient-reported 
outcome (PRO) measures. 
In Cohort A, the DHS “Roche DPM Atezolizumab Module” will be assessed.  “Roche 
DPM Atezolizumab Module” refers to the treatment-specific patient module, installed on 
a Digital Patient Monitoring solution. "Treatment" refers to the prescribed anti-cancer 
treatment regimen (i.e., Atezolizumab IV regimen or any new regimen thereafter) that 
patients are receiving. 
In Cohort B, the combination of the DHS “Roche DPM Atezolizumab Module” and 
Atezolizumab SC administered in the at-home treatment setting will be explored.  
"Treatment" refers to Atezolizumab SC, administered in the hospital setting (Cycles 1 to 
3) followed by the at-home treatment setting (Cycles 4 to 16), if appropriate. 
Specific objectives and corresponding endpoints for the study are outlined below. 

 
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3.1 
EFFICACY AND SAFETY OBJECTIVES 
3.1.1 
Cohort A 
3.1.1.1 
Primary Efficacy Objective 
Cohort A of this study will evaluate health outcomes in participants receiving a locally 
approved anti-cancer regimen containing Atezolizumab (IV) and local SOC support plus 
the Roche DPM Atezolizumab Module compared with participants receiving an 
anti-cancer regimen containing Atezolizumab (IV) with local SOC support only.  The 
primary efficacy objective is to demonstrate superiority of the Roche DPM Atezolizumab 
Module on symptom interference on the basis of the following endpoint: 
• 
Mean difference in change of Week 12 value from baseline of the participant-
reported Total Symptom Interference Score from the MDASI Core Items 
 
The primary comparison will be made regardless of whether patients discontinue anti-
cancer therapy or receive new anti-cancer therapy prior to Week 12, and in participants 
who have completed a minimum of two questionnaires only. 
3.1.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives for Cohort A of this study are to assess the impact of 
the Roche DPM Atezolizumab Module on: 
• 
Number of hospitalizations and number of cumulative days hospitalized due to 
SAEs 
• 
Unscheduled visits to the ER or clinic visits for symptom management 
• 
Incidence, nature, and severity of all anti-cancer treatment associated AEs graded 
according to the (NCI-CTCAE v5.0) with additional analyses on: 
– 
Grade ≥ 3 AEs 
– 
SAEs 
– 
Selected immune-related AEs (pneumonitis, thyroid disorders, diarrhea or 
colitis, nephritis, rash, and hepatitis) 
– 
Weighted toxicity score (WTS) (Carbini et al. 2018) 
– 
Interruption, modification, or discontinuation of Atezolizumab regimen due to 
AEs 
• 
Change from baseline in GHSscore/QoL score from the EORTC IL6 GHS/QoL 
• 
Change from baseline in EuroQol EQ-5D-5L index-based and VAS instrument 
• 
Change from baseline in the mean symptom severity score from the MDASI Core 
Items 
 
3.1.1.3 
Exploratory Efficacy Objectives 
The exploratory objectives for Cohort A of this study are to explore the impact of the 
Roche DPM Atezolizumab Module on: 
• 
Patient-reported satisfaction of healthcare treatment (EORTC OUT-PATSAT7 
instrument) 

 
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• 
Time to discontinuation (TTD) of any prescribed anti-cancer treatment 
• 
Time to clinical progression or death (PFS) 
• 
Overall survival at 12 months 
• 
Utilization of concomitant medication of special interest for management of AEs 
(e.g., steroids for irAEs; diarrhea medication; pain medication) 
• 
Anti-cancer regimen drug dose intensity and exposure 
• 
Utilization (e.g., adherence) of Roche DPM Atezolizumab Module and platform 
• 
Predictive value of associating symptoms, laboratory test results, and AEs 
 
3.1.1.4 
Safety Objective 
The safety objective for Cohort A of this study is to assess the safety of the Roche DPM 
Atezolizumab Module compared with local SOC support on the basis of the following 
endpoints: 
• 
Incidence and severity of adverse events assessed as related to device use and 
adverse device effects 
• 
Incidence, nature, and severity of anti-cancer treatment associated AEs as 
described in the secondary efficacy objectives (Section 3.1.1.2) 
 
3.1.1.5 
Biomarker Objective 
There are no biomarker objectives in this study. 
3.1.2 
Cohort B 
3.1.2.1 
Primary Efficacy Objective 
The primary efficacy objective in Cohort B is to evaluate the feasibility of combining the 
Roche DPM Atezolizumab Module and Atezolizumab SC administered in the at-home 
treatment setting on the basis of the following endpoint: 
• 
At-home treatment adoption at Cycle 6 
 
3.1.2.2 
Secondary Efficacy Objectives 
There are no secondary efficacy objectives for Cohort B in this study. 
3.1.2.3 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for Cohort B of this study are to explore the 
combined benefits of the Roche DPM Atezolizumab Module and Atezolizumab SC 
administered in the at-home treatment setting on: 
• 
Utilization of Roche DPM Atezolizumab Module 
• 
At-home treatment adherence at Cycles 9, 12, and 15 
• 
Unscheduled visits to the ER or clinic for symptom management within one day of 
Atezolizumab SC administration 
• 
Interruption, modification, or discontinuation of Atezolizumab due to AEs occurring 
within one day of Atezolizumab SC administration 

 
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• 
Time from first signs/symptoms to unscheduled clinic visit or hospitalization 
• 
Reasons for not continuing in at-home treatment setting (questionnaire for patients / 
HCPs) 
• 
Change from baseline in GHS/QoL from the EORTC IL6 GHS/QoL at Cycles 3, 6, 9, 
and 12 
• 
Change from baseline in EuroQol EQ-5D-5L index-based and VAS instrument at 
Cycles 3, 6, 9, and 12 
• 
Longitudinal description of symptom burden by MDASI at baseline and Cycles 3, 6, 
9, and 12 
• 
Characterize the safety of Atezolizumab SC administration in the hospital and at-
home treatment settings on the basis of the incidence of adverse events (of any 
grade) within 1 day of Atezolizumab SC administration in a hospital or at-home 
treatment setting 
• 
Patient acceptability of care and perception of safety culture in cancer care at 
Cycles 4, 6, and 8 
 
3.1.2.4 
Safety Objective 
• 
Number of hospitalizations within one day of Atezolizumab SC administration due 
to SAEs 
• 
Incidence, nature, and severity of all Atezolizumab SC associated AEs graded 
according to the NCI-CTCAE v5.0 with additional analyses on: 
– 
Grade ≥ 3 AEs 
– 
SAEs 
 
3.1.2.5 
Biomarker Objective 
There are no biomarker objectives in this study. 
4. 
STUDY DESIGN 
This is an interventional, open-label, multi-country, platform study.  The study will 
evaluate one DHS per cohort in combination with a pre-specified treatment or group of 
treatments in one or more treatment settings.  In general, primary efficacy outcomes will 
be measured based on patient-reported outcomes.  Initially, two cohorts testing the 
efficacy and safety of the Roche DPM Atezolizumab Module in combination with 
Atezolizumab IV (Cohort A) or the clinical utility of the Roche DPM Atezolizumab Module 
in combination with Atezolizumab SC in the at-home treatment setting (Cohort B) will be 
opened (see Figure 3).  Additional cohorts will be added through future protocol 
amendments.  Each cohort may have separate endpoints, screening, and treatment 
requirements.  Cohorts within this study will run in parallel.  Figure 3 shows an overview 
of the study design. 

 
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Figure 3 Study Schema 
  
 
 
Atezo = Atezolizumab; DHS = Digital Health Solution; DPM = Digital Patient Monitoring; 
ES−SCLC = extensive-stage small-cell lung carcinoma; HCC = hepatocellular carcinoma; 
NSCLC = non-small cell lung carcinoma; PD = progressive disease; SOC = standard of care. 
 
4.1 
DESCRIPTION OF THE COHORTS 
4.1.1 
Cohort A 
Cohort A will investigate the impact of the Roche DPM Atezolizumab Module (installed 
on the Kaiku Health DPM Solution; see Section 2.4) on health outcomes in people 
prescribed a locally approved anti-cancer regimen containing Atezolizumab (IV) in the 
following indications (Table 1): 
• 
Metastatic non-small cell lung carcinoma 
• 
Extensive-stage small-cell lung carcinoma 
• 
Advanced or unresectable hepatocellular carcinoma 
 
Each indication will make up no more than
% of the overall study population.  Patients 
will be randomized into two arms, stratified by disease indication and baseline ECOG 
performance status; Roche DPM Atezolizumab Module plus local SOC support or local 
SOC support alone.  Patients in the DPM arm will use the DPM solution to report 
symptoms, access educational materials, and communicate with care teams, as well as 
using their regular SOC methods of communication. 

 
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Table 1 
Cohort A Population and Treatments 
Population (as per local 
approval) 
Atezolizumab anti-cancer therapy (regimens 
as per local approval) 
mNSCLC 
 
Atezolizumab 840 mg IV Q2W or 1200 mg Q3W or 
1680 mg Q4W (until disease progression or 
unmanageable toxicity) monotherapy.  Treatment 
beyond disease progression may be considered at 
the discretion of the physician. 
mNSCLC 
(non-squamous) 
Four to six 21-day cycles of Atezolizumab 1200 mg 
IV + chemotherapy (bevacizumab + carboplatin + 
paclitaxel, or carboplatin + nab-paclitaxel) induction 
therapy, followed by Atezolizumab 1200 mg Q3W 
+ bevacizumab maintenance therapy (until disease 
progression or unmanageable toxicity).  Treatment 
beyond disease progression with Atezolizumab 
monotherapy may be considered at the discretion 
of the physician. 
ES-SCLC 
Four 21-day cycles of Atezolizumab 1200mg IV + 
chemotherapy (carboplatin + etoposide) induction 
therapy, followed by Atezolizumab 840 mg IV Q2W 
or 1200 mg Q3W or 1680 mg Q4W maintenance 
therapy, including bevacizumab where locally 
approved (until disease progression or 
unmanageable toxicity).  Treatment beyond 
disease progression may be considered at the 
discretion of the physician. 
Advanced or unresectable HCC 
(Child Pugh A) 
Atezolizumab 1200mg IV Q3W + bevacizumab 
15 mg/kg IV Q3W (until loss of clinical benefit or 
unmanageable toxicity)a 
ES-SCLC = extensive-stage small-cell lung carcinoma; HCC = hepatocellular carcinoma; 
mNSCLC = metastatic non-small cell lung cancer; Q2W =  every 2 weeks; Q3W =  every 3 weeks. 
a If bevacizumab is discontinued due to toxicity, Atezolizumab regimen may continue 
until loss of clinical benefit or unmanageable toxicity. 
 
Patients in Cohort A will be required to have a confirmed diagnosis from their treating 
physician for the relevant indication via local laboratory or radiological report in order to 
be enrolled into the study.  There will be no central pathology laboratory or central 
radiology review or confirmation for study inclusion; however, if needed, sites might be 
asked to provide digital diagnostic images for research purposes, not decision making. 
Patients that have been prescribed any of the cohort-specific anti-cancer systemic drug 
treatment in line with local approval and eligibility criteria, will be invited to discuss and 
sign informed consent (Table 1).  Once all study inclusion criteria are satisfied, patients 
will be randomized 1:1 to receive either the Roche DPM Atezolizumab Module and local 
SOC support, or local SOC support only.  Randomization will be stratified by disease 

 
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indication as outlined in Section 5.2.1 and by baseline ECOG performance status (0/1 
vs. 2). 
Upon randomization, patients will be asked to complete PRO assessment 
questionnaires before the first anti-cancer drug administration visit.  All patients will 
complete PROs remotely on a regular basis throughout the study, as outlined in the 
schedule of activities 
Patients in the DPM arm will receive access to the DPM solution and training on its use.  
Patients will return for visits as per their routine anti-cancer treatment administration 
schedule.  Procedures and schedule for patients in the DPM arm will follow the usual 
SOC treatment schedule as detailed in the schedule of activities.  No extra visits are 
mandated by this protocol.  Additional clinic visits may occur at the discretion of both the 
care team and patients 
Patients will continue to be assessed for the primary objective until Week 24 as per the 
schedule of activities, regardless of whether they have discontinued anti-cancer therapy 
or started a new line of therapy. 
The primary reason for discontinuation of anti-cancer treatment, discontinuation of DPM, 
and withdrawal from the trial should be documented on the appropriate eCRF page.  
Safety data for the efficacy analyses and HRQoL data will continue to be collected for 
90 days after the last dose of Atezolizumab and for 30 days after the last dose of an 
alternative cancer therapy that has started prior to the 24-week time point and has 
continued follow-up beyond this time point.  Early discontinuation will be handled as 
described in the statistical section. 
After 24 weeks, patients will continue to be followed as per the schedule of activities. 
All patients will be followed for OS until death, withdrawal of consent, loss-to-follow-up, 
12 months after randomization, or end of study, whichever occurs earliest. 
4.1.2 
Cohort B 
Cohort B will explore the benefits of the Roche DPM Atezolizumab Module (installed on 
the Kaiku Health DPM solution) in combination with Atezolizumab SC, administered by a 
HCP in the at-home treatment setting, on patient outcomes.  All patients will use the 
DPM solution to report symptoms, access educational materials, and communicate with 
care teams, as well as using their regular SOC methods of communication.  Patients 
with resected Stage IIB-IIIB (early-stage; per the UICC/AJCC staging system, 8th 
edition) NSCLC who have had a complete resection of NSCLC, are adequately 
recovered from surgery, and have completed up to four cycles of adjuvant 
platinum-based chemotherapy without evidence of disease relapse/recurrence will be 

 
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included.  An overview of the study design is provided in Figure 3.  The schedule of 
activities for Cohort B is provided in Appendix 1. 
Patients must have PD-L1-positive early-stage NSCLC to be enrolled in Cohort B of this 
study.  Patients that do not have prior PD-L1 testing will be prospectively tested for 
PD−L1 expression by an appropriate CE marked or in-vitro diagnostics regulation 
approved and as per manufacturers recommendations and requirements at screening 
(see Sections 5.1.3 and 5.5.7 for more details). 
Patients whose tumors have an EGFR -mutation or ALK rearrangement will be excluded 
from enrolment.  Patients with tumors of non-squamous histology with unknown EGFR 
or ALK mutational status will be required to be tested at screening (see the specific 
exclusion criteria in Sections 5.1.4 and 5.5.7). 
Eligibility for Cohort B of this study will be assessed within a 28-day screening period.  
Patients who do not meet the criteria for participation in Cohort B of this study (screen 
failure) may qualify for two rescreening opportunities (for a total of three screenings per 
patient) at the investigator's discretion, provided all initial and subsequent screening 
assessments are performed within 56 days prior to Day 1.  Re screened patients must 
meet all eligibility criteria and re-sign the Informed Consent Form prior to re screening.  
The investigator will record reasons for screen failure in the screening log (see Section 
5.5.1). 
Patients will undergo a tumor assessment at baseline to confirm eligibility criteria.  
Subsequent tumor assessments will be conducted as per local SOC (see Section 5.5.5). 
Patients will be asked to complete PRO assessment questionnaires before the first 
Atezolizumab SC administration visit.  All patients will complete PROs remotely on a 
regular basis throughout the study, as outlined in the schedule of activities.  All patients 
will receive access to the DPM solution and training on its use. 
Patients will receive three cycles of Atezolizumab SC Q3W in the hospital setting before 
receiving up to 13 cycles of Atezolizumab SC Q3W in the at-home treatment setting.  
Patients will receive three cycles in the hospital setting, as events that require immediate 
medical intervention, such as infusion related reactions, most commonly occur during 
the first three administrations.  For patients who develop IRRs (or symptoms suggestive 
of IRR that require immediate medical intervention during infusion) during the first three 
cycles of Atezolizumab SC administration, all subsequent Atezolizumab SC 
administration will be done in the hospital setting only.  For low grade (Grade 1–2) IRR 
events during the first three cycles, administration in the at-home treatment setting may 
be considered with premedication.  In the at-home treatment setting, Atezolizumab SC 
will be administered by a qualified mobile HCP with access to adequate equipment to 
manage AEs at the patient’s home.  During administration in the at-home treatment 
setting, a phone or video connection between the qualified mobile HCP and the treating 
clinic HCPs will be established.  Patients who cannot continue administration of 

 
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Atezolizumab SC in the at-home treatment setting will be allowed to continue treatment 
in the hospital setting if there is clinical benefit, as judged by the investigator.  
Atezolizumab will be administered on Day 1 of each 21-day cycle.  Patients will continue 
to receive Atezolizumab SC until Cycle 16. 
Patients will undergo a post last treatment safety follow-up visit 28 days after completing 
study treatment and will undergo a safety follow-up telephone call 90 days after the last 
dose of study treatment. 
Patients will be assessed for safety by regular evaluation of adverse events, vital signs, 
and routine clinical laboratory tests (hematology, blood chemistry), and by physical 
examinations.  Adverse events will be graded according to the NCI CTCAE v5.0.  In the 
at-home treatment setting, safety assessments will be carried out at every visit by the 
qualified mobile HCP in the patient’s home or by an HCP at the site based on 
investigator and patient decision.  Patients in the at-home treatment setting will also 
visit the clinic HCP every 3 months for a disease control and safety visit.  Patients 
receiving treatment in the hospital setting will be assessed by the clinic HCP accordingly.  
The primary reason for discontinuation of Atezolizumab SC, discontinuation of DPM, and 
withdrawal from the trial should be documented on the appropriate eCRF page.  Early 
discontinuation will be handled as described in the statistical section. 
4.1.3 
Data Collection 
Electronic Case Report Form (eCRF) 
An eCRF will be used by care teams to collect and report patient clinical data across all 
arms at each scheduled anticancer drug administration visit.  Data will be collected as 
per the schedule of activities and entered into the eCRF. 
Electronic Patient-Reported Outcomes (ePROs) 
HRQoL data measuring patients’ ability to cope with disease and treatment will be 
collected via electronic PRO (ePRO) instrument questionnaires (as detailed in 
Section 5.5.8) and will be collected remotely as per indication every 6 weeks (± 3 days).  
Patients will complete the ePRO questionnaires through an app downloaded on an 
electronic device.  A web link can be provided to capture PRO data if the patient does 
not have access to a suitable electronic device. 
DPM solution 
The DPM solution will be used to report symptoms and communicate via message with 
care teams.  Patients will be required to report symptoms as they occur and at least 
every 7 days if not completed the DPM will send a reminder to patients.  In addition, 
patients in Cohort B will be prompted to complete symptom questionnaires 24 hours 
after Atezolizumab SC administration.  Data capturing use of the DPM solution by the 
patient or care teams is collected within the DPM.  Additional qualitative data may also 
be collected via interviews with the patients and/or care teams. 

 
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4.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date of the last patient, last visit or when 
assessment occurs for the collection of the last data point for the last cohort, whichever 
occurs later.  Any of the cohorts may close before the end of the entire study when all 
predefined treatment, follow-up, and data collection are completed for that cohort.  
In addition, the Sponsor may decide to terminate a cohort or the study at any time. 
4.2.1 
Cohort A 
The end of the study for Cohort A is defined as the date at which the last data point 
required for statistical analysis is received from the last patient.  Based on a total 
recruitment duration of 16 months and a follow up of 12 months for all patients, unless 
they withdraw from the study sooner, the time from randomization of the first patient to 
the end of Cohort A, is expected to be approximately 28 months.  DPM provision for all 
patients will be discontinued 12 months after last patient is randomized. 
4.2.2 
Cohort B 
The end of the study for Cohort B is defined as the date at which the last data point 
required for statistical analysis is received from the last patient.  Based on a total 
recruitment duration of 16 months and a follow up of 15 months for all patients, unless 
they withdraw from the study sooner, the time from enrollment of the first patient to the 
end of Cohort B, is expected to be approximately 31 months.  DPM provision for each 
patient will be discontinued 3 months after the last dose of study treatment has been 
administered. 
4.3 
RATIONALE FOR STUDY DESIGN 
4.3.1 
Cohort A 
4.3.1.1 
Rationale for Cohort A Population 
Patients undergoing anti-cancer therapy typically experience unwanted symptoms, 
which they are often only able to report to their care teams at infrequent scheduled 
follow-up appointments.  Use of DPM allows individuals to regularly self-report 
symptoms and HRQoL measures (via PRO), access support materials, and 
communicate with care teams at their convenience (Warrington et al. 2019).  Use of 
DHS in patients with cancer has been shown to effectively prompt HCPs to more 
frequently monitor, and better manage symptoms - which in turn can improve outcomes 
and wellbeing (Basch et al. 2016; Warrington et al. 2019; Absolom et al. 2020; Denis et 
al. 2017; Fjell et al. 2020; Borosund et al. 2014; Fann et al. 2017). 
DPM has been shown to improve OS, HRQoL (Basch et al. 2016; Denis et al. 2017; 
Denis et al. 2019), duration of treatment (Basch et al. 2016), and reduce the rate of 
severe or serious adverse events (Degenhardt et al. 2020; Mir et al. 2020), among other 
benefits.  Furthermore, these DPM solutions have demonstrated health-economic 
benefits, including a reduction in hospital admission rates and unscheduled visits; and 

 
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the need for patient phone calls and time for patient visits (Schmalz et al. 2020; 
Basch et al. 2016; Denis et al. 2017; Denis et al. 2019). 
As the described benefits of DPM appear to be independent of the tumor type, Cohort A 
of this study will include different tumors and tumor type will be included as a 
stratification factor.  Only patients prescribed anti-cancer treatment with an Atezolizumab 
(IV) regimen will be included, to prevent the need for another stratification factor, which 
would require an increased cohort size. 
4.3.1.2 
Rationale for Cohort A Procedures and Schedule 
Cohort A aims to demonstrate that use of the Roche DPM Atezolizumab Module will 
result in a lower MDASI Total Symptom Interference Score in patients undergoing anti-
cancer treatment with an Atezolizumab (IV) regimen compared with SOC support.  A 
lower score indicates a reduction in symptom interference for patients. 
All patients will complete MDASI at baseline, every 6 weeks until Week 24, and at the 
90-day follow-up telephone call to determine the Symptom Interference Score change of 
Week 12 value from baseline.  Patients will also be followed the efficacy safety 
endpoints for 90 days after the last dose of Atezolizumab and for 30 days after the last 
dose of an alternative cancer therapy that has started prior to the 24-week time point 
and has continued follow-up beyond this time point. 
The time point Week 12 was chosen based on evidence on symptom burden or 
interference improvements or stabilization reported for DPM solutions in other clinical 
trials (Mooney et al. 2021; Rasschaert et al. 2021; Fjell et al. 2020; Kolb et al. 2018), 
median duration of first-line treatment with an Atezolizumab regimen of 3–7 months in 
clinical trials, and expected adherence to PRO-CTCAE reporting over time (Basch et al. 
2020).  We will validate the adherence for PRO-CTCAE reporting in the Roche DPM 
Atezolizumab Module for the time point Week 12 in a Roche real-world scientific 
research project (KAISER). 
Patients randomized to the DPM arm will use the Roche DPM Atezolizumab Module for 
the duration of the study and can continue using it until 3 months after their last 
Atezolizumab dose, if they feel it is beneficial to their care and if their care team supports 
use of the DPM solution. 
4.3.1.3 
Rationale for Choice of Cohort A Control Group 
In order to study the impact of DPM, anti-cancer treatments need to be consistent across 
both arms.  Therefore, the control group consists of patients receiving the same 
anti-cancer therapy and SOC support only. 
4.3.1.4 
Rationale for Cohort A Biomarker Assessments 
Not applicable. 

 
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4.3.1.5 
Rationale for Cohort A Non-Standard Clinical Outcome 
Assessments 
Not applicable. 
4.3.2 
Cohort B 
4.3.2.1 
Rationale for Atezolizumab SC Dose and Schedule 
Atezolizumab SC will be administered at a fixed dose of 1875 mg every 3 weeks (Q3W) 
(1875 mg on Day 1 of each 21-day cycle) into the thigh.  This dose and administration 
site was chosen based on the results of Study BP40657 (IMscin001).  In Part 1 of 
Study BP40657, Atezolizumab SC co-mix (an SC formulation of Atezolizumab for co-mix 
with rHuPH20, manually mixed at the local pharmacy), given at a dose of 1800 mg Q3W 
in the thigh, provided similar observed Cycle 1 Ctrough and AUC0–21 d values as 
Atezolizumab given at a dose of 1200 mg IV Q3W in Phase III study GO28915 (OAK) 
(observed Cycle 1 Ctrough [CV %]: 121.1 µg/mL [42.8%] and 76.0 µg/mL [53.9%], 
respectively; Cycle 1 AUC0–21 d: 3868 µg•  day/mL [38.6%] (observed) and 
2978 µg • day/mL [26.1%] [model-predicted], respectively). 
Atezolizumab pharmacokinetic (PK) data after both SC and IV administrations from 
Part 1 of Study BP40657 were modeled using a population PK (popPK) approach.  A 
higher bioavailability was estimated for administration in the thigh (82.9%) compared 
with in the abdomen (71.1%), with an inter individual variability of 124%.  Using the 
popPK model, simulations of the proposed Phase III study in Part 2 indicated that a SC 
dose of 1875 mg Q3W given in the thigh had a  > 99% probability of providing 
comparable PK exposures to Atezolizumab IV 1200 mg Q3W, in terms of Cycle 1 and 
steady state Ctrough and AUC0–21 d. 
Overall, Atezolizumab administered subcutaneously in Study BP40657 was well 
tolerated and exhibited a safety profile consistent with the known risks of Atezolizumab 
IV monotherapy.  No new or significant safety concerns were identified.  Refer to the 
Atezolizumab Investigator’s Brochure for additional information. 
4.3.2.2 
Rationale for Cohort B Population 
Patients in Cohort B will have early-stage NSCLC that is PD-L1 positive.  All patients in 
Cohort B will be treated with Atezolizumab SC.  Atezolizumab IV is currently FDA-
approved as adjuvant treatment following resection and platinum-based chemotherapy 
for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression 
on  ≥  1% of tumor cells based on the results of the Phase III Study GO29527 
(IMpower010) (TECENTRIQ U.S. Package Insert).  The SC formulation of 
Atezolizumab is currently undergoing clinical evaluation in patients with previously 
treated locally advanced or metastatic NSCLC in Study BP40657 (IMscin001) and in 
early- and late-stage NSCLC in Study MO43576 (IMscin002). 

 
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4.3.2.3 
Rationale for Cohort B Procedures and Schedule 
Cohort B aims to be a pilot for investigating the feasibility of Atezolizumab SC 
administered in the at-home treatment setting combined with the Roche DPM 
Atezolizumab Module.  The procedures and schedules within this cohort have been 
designed to support patient safety monitoring.  Details of the criteria for administration in 
the at-home treatment setting and risk mitigation strategies mandated by this protocol 
are outlined in Section 2.7.  Objectives are described in Section 3.1.2. 
All patients in Cohort B will use the Roche DPM Atezolizumab Module for the duration of 
the study and can continue using it until 3 months after their last Atezolizumab dose, if 
they feel it is beneficial to their care and if their care team supports use of the DPM 
solution. 
4.3.2.4 
Rationale for Choice of Cohort B Control Group 
Not applicable. 
4.3.2.5 
Rationale for Cohort B Biomarker Assessments 
Not applicable. 
4.3.2.6 
Rationale for Cohort B Non-Standard Clinical Outcome 
Assessment 
Not applicable. 
5. 
MATERIALS AND METHODS 
5.1 
PARTICIPANTS 
5.1.1 
Cohort A 
Approximately 400 participants with the following indications will be enrolled in Cohort A 
of this study (see Table 1 for more details): 
• 
mNSCLC 
• 
ES-SCLC 
• 
HCC 
Each indication will make up no more than
% of the overall study population.  
Treatment per indication must be locally approved in each country taking part in the 
study and reimbursed.  Absence of local reimbursement does not preclude participant 
enrollment.  Treatment regimens will be as per local clinical practice and independent of 
participation in this study.  Atezolizumab (IV) anti-cancer treatment regimen will not be 
provided as part of the study. 
5.1.2 
Cohort B 
Approximately
participants with early-stage NSCLC will be enrolled in Cohort B of this 
study.  The investigational medicinal product (IMP) for Cohort B is Atezolizumab SC.  
IMP will be supplied by the Sponsor. 

 
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5.1.3 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
5.1.3.1 
All Participants 
• 
Participant is aged ≥ 18 years at time of signing Informed Consent Form. 
• 
Participant has signed an Informed Consent Form according to local regulations. 
• 
Be able to comply with the study protocol, according to investigator’s judgement. 
• 
Participant has an email address, access to an internet-capable device 
(smartphone, tablet, or PC), and access to an internet connection. 
 
5.1.3.2 
Cohort A 
• 
Participants must have a histologically confirmed diagnosis via local laboratories, 
except where alternative means for diagnosis is established (e.g., contrast 
enhanced imaging with or without alpha-fetoprotein [AFP] for HCC, or cytologically 
for lung cancer), for one of the following indications for which an Atezolizumab (IV) 
regimen is locally approved (see Table 1): 
– 
mNSCLC 
– 
ES-SCLC 
– 
HCC (Child Pugh A) 
• 
Participant is prescribed an Atezolizumab (IV) regimen and this decision must be 
made and documented prior to signing the Informed Consent Form and must follow 
local clinical practice, according to the Investigator’s judgement within the 
constraints of the local approval 
• 
ECOG Performance Status of 0, 1, or 2 (Appendix 2) 
• 
Life expectancy ≥ 12 weeks 
 
5.1.3.3 
Cohort B 
• 
Participants must confirm adequacy of their home to conduct trial related 
procedures at-home. 
• 
Participants must have a complete resection of a histologically or cytologically 
confirmed Stage IIB-IIIB (T3-N2) NSCLC (per the UICC/AJCC staging system, 
8th edition; Detterbeck et al. 2018) 
Accepted types of resection include any of the following:  lobectomy, sleeve 
lobectomy, bilobectomy, or pneumonectomy. 
If mediastinoscopy was not performed preoperatively, it is expected that, at a 
minimum, mediastinal lymph node systematic sampling will have occurred.  
Systematic sampling is defined as removal of at least one representative lymph 
node at specified levels.  For a right thoracotomy, sampling is required at levels 
4 and 7 and for a left thoracotomy, levels 5 and/or 6 and 7.  Levels 10 and 11 
are required irrespective of tumor laterality. 

 
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• 
PD-L1 positive as documented through local testing performed per manufacturer’s 
recommendations and requirements of a representative tumor tissue specimen.  An 
appropriate CE marked or In-Vitro Diagnostics Device approved test should be 
used for local testing of PD-L1. 
• 
Participants must have completed adjuvant chemotherapy at least 4 weeks and up 
to 12 weeks prior to randomization and must be adequately recovered from 
chemotherapy treatment 
• 
ECOG Performance Status of 0 or 1 
• 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC ≥ 1.5 × 109/L (≥ 1500/µL) without granulocyte colony-stimulating factor 
support 
– 
Lymphocyte count ≥ 0.5 × 109/L (≥ 500/µL) 
– 
Platelet count ≥ 100 × 109/L (≥ 100,000/µL) without transfusion 
– 
Hemoglobin ≥ 90 g/L (≥ 9 g/dL) 
Participants may be transfused to meet this criterion. 
– 
AST, ALT, and ALP ≤ 2.5 × upper limit of normal (ULN), with the following 
exceptions: 
Participants with documented liver metastases:  AST and ALT ≤ 5 × ULN 
Participants with documented liver or bone metastases:  ALP ≤ 5 × ULN 
– 
Total bilirubin ≤ 1.5 × ULN with the following exception: 
Participants with known Gilbert disease:  total bilirubin ≤ 3 × ULN 
– 
Creatinine clearance ≥ 45 mL/min (calculated through use of the Cockcroft-
Gault formula) 
– 
Albumin ≥ 25 g/L (≥ 2.5 g/dL) 
– 
For participants not receiving therapeutic anticoagulation:  INR and aPTT 
≤ 1.5 × ULN 
• 
For participants receiving therapeutic anticoagulation:  stable anticoagulant regimen 
• 
Negative HIV test at screening, with the following exception:  participants with a 
positive HIV test at screening are eligible provided they are stable on anti-retroviral 
therapy, have a CD4 count ≥ 200/µL, and have an undetectable viral load 
• 
Negative hepatitis B surface antigen (HBsAg) test at screening 
• 
Negative hepatitis B surface antibody (HBsAb) at screening or positive HBsAb test 
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 

 
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The HBV DNA test must be performed for participants who have a negative 
HBsAg test, a negative HBsAb test, and a positive total 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 must be performed for participants who have a positive 
HCV antibody test. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of < 1% per year during the treatment period and for 5 months after the final 
dose of Atezolizumab. 
A woman 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 
participant.  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. 
 
5.1.4 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
5.1.4.1 
All Participants 
• 
Participants with any physical or cognitive condition that, according to clinical 
judgement, would prevent the participant from using the DHS (e.g., dementia, 
hepatic encephalopathy) 
• 
Participants not proficient with any of the available DHS language translations or 
with psychiatric/neurologic disorders or any condition that may impact the 
participant's ability to use the DPM solution 
• 
Participants currently enrolled in another clinical study, unless it is an 
observational (non-interventional) clinical study or the follow-up period of an 
interventional study 

 
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5.1.4.2 
Cohort A 
• 
Concomitant anti-cancer therapy at the time of starting Atezolizumab (IV) regimen 
on the index date which is not part of a locally approved combination therapy with 
Atezolizumab as per SmPC or local regulatory documents 
• 
Participants not receiving Atezolizumab, but an Atezolizumab biosimilar or non-
comparable biologic 
• 
Participants currently using another DPM or ePRO solution for symptom 
management and/or reporting 
 
5.1.4.3 
Cohort B 
• 
Participants known to have a sensitizing mutation in the EGFR gene or an ALK 
fusion oncogene 
Participants with unknown EGFR or ALK mutational status whose tumor may 
harbor a sensitizing EGFR mutation (i.e., participants with non-squamous 
histology (including those with a mixed histology that includes any non-
squamous component), and without any other known driver mutation) will be 
required to be tested at screening.  Participants with tumors of squamous 
histology who have an unknown EGFR or ALK mutational status will not be 
required to be tested at screening. 
EGFR and/or ALK will be assessed locally.  EGFR status must be performed on 
tissue using a test that detects mutations in exons 18–21.  The assays must be 
a Health Authority approved test (i.e., adhering to local drug/device regulations) 
and performed per manufacturer's recommendations and requirements. 
• 
History of malignancy within 5 years prior to initiation of study treatment, with 
the exception of the cancer under investigation in this study and 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 carcinoma in situ, or Stage I uterine cancer. 
• 
Uncontrolled tumor-related pain 
Participants requiring pain medication must be on a stable regimen at study 
entry. 
• 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected calcium > ULN) 

 
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• 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis (see Appendix 5 for a more comprehensive 
list of autoimmune diseases and immune deficiencies), with the following 
exceptions: 
Participants with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Participants with controlled Type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study. 
Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., participants with psoriatic arthritis are 
excluded) are eligible for the study provided all of the 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 
– 
There has been 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 screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Active tuberculosis 
• 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable 
angina 
• 
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 
• 
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 impact participant safety 
• 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 

 
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Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease (COPD) 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 participant 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 Atezolizumab treatment 
or within 5 months after the final dose of Atezolizumab 
• 
Current treatment with anti-viral therapy for HBV 
• 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti-CTLA-4, anti–PD-1, and anti–PD-L1 therapeutic antibodies 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and IL-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-α [TNF-α] 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: 
– 
Participants 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. 
– 
Participants who received mineralocorticoids (e.g., fludrocortisone), inhaled or 
low-dose corticosteroids for COPD 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 or fusion proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the Atezolizumab formulation 
• 
Pregnancy or breastfeeding, or intending to become pregnant during study 
treatment or within 5 months after the final dose of study treatment 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
• 
Known allergy or hypersensitivity to hyaluronidase, bee or vespid venom, or any 
other ingredient in the formulation of rHuPH20 

 
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• 
Pathology (e.g., lower extremity edema, cellulitis, lymphatic disorder or prior 
surgery, preexisting pain syndrome, previous lymph node dissection, etc.) that could 
interfere with any protocol-specified outcome assessment 
• 
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 randomization 
• 
Participants currently using another DPM or ePRO solution for symptom 
management and/or reporting 
 
5.2 
METHOD OF INTERVENTION ASSIGNMENT AND BLINDING 
5.2.1 
Study Arm Assignment 
This is an interventional, open-label, multi-country cohort 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 from an 
interactive web-based response system (IxRS). 
5.2.1.1 
Cohort A 
A total of 400 evaluable patients will be randomized to one of two study arms: 
• 
DPM arm (Roche DPM Atezolizumab Module plus local SOC support and a locally 
approved anti-cancer regimen containing Atezolizumab [IV]) 
• 
Comparator arm (local SOC support and a locally approved anti-cancer regimen 
containing Atezolizumab [IV] only) 
 
Randomization will occur in a 1:1 ratio through use of a permuted-block randomization 
method to ensure a balanced assignment to each study arm.  Randomization will be 
stratified according to the following criteria: 
• 
Disease indication (Table 1) 
• 
Baseline ECOG performance status (0/1 vs. 2) 
 
Patients in Cohort A will receive anti-cancer treatment as per their local SOC and the 
eligibility criteria. 
5.2.1.2 
Cohort B 
Cohort B of this study is an open-label, single-arm cohort that will enroll approximately 
patients. 
 
5.2.2 
Blinding 
This section is not applicable – this study is not blinded. 

 
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5.3 
STUDY INTERVENTION AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
5.3.1 
Study Treatment 
5.3.1.1 
Cohort A (Atezolizumab IV) 
5.3.1.1.1 
Atezolizumab IV Dosage, Administration, and Compliance 
Patients with any of the indications listed in Section 5.1 will receive a locally approved 
anti-cancer regimen containing Atezolizumab (IV) and local SOC support plus the Roche 
DPM Module, or a locally approved anti-cancer regimen containing Atezolizumab (IV) 
and local SOC support only.  The Atezolizumab (IV) anti-cancer treatment regimens for 
patients in both arms of Cohort A are summarized in Table 1.  The anti-cancer treatment 
schedule for all patients in Cohort A will follow local SOC practices for each indication.  
Details are listed in Appendix 1.  Details on anti-cancer treatment administration (e.g., 
frequency and timing) should be noted on the eCRF. 
5.3.1.1.2 
Discontinuation of Atezolizumab IV 
Patients who discontinue Atezolizumab IV based treatment or switch to an 
Atezolizumab biosimilar or non-comparable biologic will have the post-last treatment 
safety follow-up visit.  Patients access to Kaiku will be deactivated 90 days after the 
final Atezolizumab dose.  The collection of MDASI, HRQoL.  EORTC IL6, GHS/QoL, 
EQ-5D-5L and EORTC OUT-PATSAT7 will continue up until Week 24.  After Week 
24 the patient will discontinue from the study. 
5.3.1.2 
Cohort B (Atezolizumab SC) 
Patients with resected early NSCLC will receive Atezolizumab SC plus the Roche DPM 
Module.  After completion of three cycles of Atezolizumab SC in the hospital setting, 
eligible patients will receive up to 13 cycles of Atezolizumab SC in the at-home 
treatment setting (see Section 2.7 for criteria for administration in the at-home treatment 
setting and the qualified mobile HCP instruction manual for instructions on administration 
in the at-home treatment setting).  Patients who cannot continue administration of 
Atezolizumab SC in the at-home treatment setting for any reason will be allowed to 
continue treatment in the hospital setting if there is clinical benefit, as judged by the 
investigator. 
The medical device for Cohort B is the Roche DPM Atezolizumab Module (5.3.2.1).  The 
IMP for Cohort B is Atezolizumab SC (Appendix 8 identifies all investigational and non-
investigational medicinal products for this study).  IMP will be supplied by the Sponsor.  
Anaphylaxis medications (Section 5.3.1.2.3) are regarded as non-investigational 
medicinal products (NIMPs).  NIMPs will be obtained locally by the investigational sites 
or will be provided by the Sponsor as per country requirements for any on site 
administration (Appendix 8 identifies all investigational and non-investigational 
medicinal products for this study). 

 
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5.3.1.2.1 
Atezolizumab SC Formulation and Packaging 
Atezolizumab SC will be provided as a sterile liquid at a concentration of 125 mg/mL.  
rHuPH20 will be co-formulated with Atezolizumab in the Atezolizumab SC formulation at 
a concentration of 2000 U/mL. 
For information on the formulation and handling of Atezolizumab SC, see the pharmacy 
manual. 
5.3.1.2.2 
Atezolizumab SC Dosage, Administration, and Compliance 
Atezolizumab (1875 mg) SC injections will be administered subcutaneously by a HCP in 
the anterior thigh region per the instructions outlined in Table 2. 
The injection site should be alternated between the left and right thigh.  New injections 
should be given at least 2.5 cm from the old site and never into areas where the skin is 
red, bruised, tender, or hard.  In all cases, start and stop times of the SC injection should 
be captured. 
No premedication will be allowed for the first dose of Atezolizumab SC.  Premedication 
may be administered for Cycles ≥ 2 at the discretion of the treating physician.  Injection 
sites will be digitally photographed after a SC injection if a severe adverse reaction at the 
injection site is observed. 
In case a patient develops toxicity that is linked to the treatment with Atezolizumab SC, 
further continuation of treatment is not recommended.  Refer to Appendix 7 for further 
guidance on Atezolizumab toxicity management. 
Atezolizumab SC must always be administered by a HCP with access to adequate 
equipment to manage AEs.  The first three cycles of Atezolizumab SC will be 
administered in the hospital setting.  Patients may then receive up to 13 cycles of 
Atezolizumab SC in the at-home treatment setting administered by a qualified mobile 
HCP (see qualified mobile HCP instruction manual for instructions on administration in 
the at-home treatment setting).  During administration in the at-home treatment setting, a 
phone or video call will be established between the qualified mobile HCP and the 
treating clinic HCPs.  For patients who develop IRRs (or symptoms suggestive of IRR 
that require immediate medical intervention during infusion) during the first three cycles 
of Atezolizumab SC administration, all subsequent Atezolizumab SC administration will 
be done in the hospital setting only.  For low grade (Grade 1–2) IRR events during the 
first three cycles, administration in the at-home treatment setting may be considered with 
premedication. 
For anaphylaxis precautions, see Appendix 6. 
 
 

 
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Table 2 
Administration of First and Subsequent Atezolizumab SC 
Injections 
First and Subsequent SC Injections 
• No premedication is permitted prior to the first SC injection. 
• For subsequent SC injections, if the patient experienced an injection-related 
reaction with any previous injection, premedication with antihistamines, 
antipyretic medications, and/or analgesics may be administered at the discretion 
of the investigator. 
• Vital signs should be measured as described in Section 5.5.4. 
• Patients should be informed about the possibility of delayed post-injection 
symptoms and instructed to contact their study physician if they develop such 
symptoms 
PK = pharmacokinetic. 
 
5.3.1.2.3 
Anaphylaxis Medication 
The Sponsor will provide anaphylaxis kits for use in the at-home treatment setting to be 
used by the HCP in the event of a severe hypersensitivity reaction during or after 
administration of Atezolizumab SC. 
These kits must be available before the first administration of Atezolizumab SC in the at-
home treatment setting.  Additional kits will be provided if kits expire, are damaged or 
are used during the study. 
Anaphylaxis kits will contain two Epinephrine USP Auto-Injectors 0.3 mg for IM injection 
(Muraro et al. 2022). 
5.3.1.2.4 
Investigational Medicinal Product Handling and Accountability 
The IMP required for completion of Cohort B of this study (Atezolizumab SC) will be 
provided by the Sponsor.  The study site (i.e., investigator or other authorized personnel 
[e.g., pharmacist or qualified mobile HCP]) is responsible for maintaining records of IMP 
delivery to the site, IMP inventory at the site, IMP use by each patient, and disposition or 
return of unused IMP, thus enabling reconciliation of all IMP received, and for ensuring 
that patients 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 IMP supplied by the Sponsor, using the 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 IMP received and that any discrepancies have 
been reported and resolved before use of the IMP.  All IMP 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. 

 
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Only patients enrolled in Cohort B of this study may receive IMP, and only authorized 
staff may supply or administer IMP. 
IMP 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 
documentation.  The site's method of destroying Sponsor-supplied IMP 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 IMP 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/or the Atezolizumab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 
5.3.1.2.5 
Continued Access to Atezolizumab SC 
The Sponsor will offer continued access to Roche IMP (Atezolizumab SC) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMP (Atezolizumab SC) after completing the 
study if all of the following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being. 
• 
There are no appropriate alternative treatments available to the patient. 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive Roche IMP (Atezolizumab SC) after completing 
the study if any of the following conditions are met: 
• 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient). 
• 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for NSCLC. 
• 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
NSCLC. 
• 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
 

 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
5.3.1.2.6 
Discontinuation of Atezolizumab SC 
Patients that discontinue Atezolizumab SC treatment for any reason will have the post-
last treatment safety follow-up visit and discontinue the study.  Patient access to Kaiku 
will be deactivated 90 days after last Atezolizumab dose. 
5.3.2 
Medical Device 
5.3.2.1 
The Roche DPM Atezolizumab Module on the Kaiku Health 
DPM Solution (Cohorts A and B) 
The Roche DPM Atezolizumab Module on the Kaiku Health DPM Solution is intended for 
informing treatment management decisions and is accessible through internet capable 
devices.  It aims to facilitate non-urgent communication, including sharing of 
patient-reported data between patient and care team.  It should be used by treated 
patients and their care teams in accordance with the training provided and as indicated 
in the user guide. 
For the purposes of this study, the Roche DPM Atezolizumab Module on the Kaiku 
Health DPM Solution will be used for patient symptom reporting and non-emergency 
patient-care team communication only.  The care team includes nurses and physicians 
from the patient’s study site.  The care team triages according to local practice. 
Patients are able to report symptoms at pre-specified time points as well as when they 
happen, and notifications will be sent to care teams based on the severity of the 
symptom as reported by the patient.  An algorithm will be used to generate a single 
composite numerical grade for each PRO-CTCAE symptom, to categorize symptoms by 
severity (Basch et al. 2021) and send notifications to care teams.  The adverse event 
severity classification is independent of the algorithm symptom severity classification.  
The symptom severity classification generated by the scoring algorithm should not be 
used to determine the CTCAE grade of any AEs as determined by the investigator.  
Following submission of a symptom report, notifications are sent to the care team to help 
prioritize review and management of patient-reported symptoms.  Notifications are 
classified into categories, as detailed in the Kaiku Health DPM Solution care team user 
interface section below.  For selected mild or moderate symptoms, self-management 
instructions will be issued to patients in the DPM solution.  For any symptom reported as 
severe, the participant is urged to contact the care team immediately. 
This solution features two interfaces as outlined below: 
Roche DPM Atezolizumab Module Participant User Interface 
The participant user interface is accessible through internet capable devices such as 
PCs, laptops, mobile phones, or tablets.  Patients will be able to report their symptoms 

 
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spontaneously, when they happen, and will also be prompted to complete symptom data 
via an internet browser-based or app-based online questionnaire every 7 days.  In 
addition, patients in Cohort B will be prompted to complete symptom questionnaires 24 
hours after Atezolizumab SC administration.  Patients will receive an email when there is 
a new questionnaire to be completed.  If a patient has not completed that questionnaire, 
reminders will be sent more often during the first week and then less frequently. If a 
participant is using the DPM solution through the app downloaded on their mobile phone 
or tablet, they may opt to receive push notifications instead of emails.  Partially 
completed symptom questionnaires are saved as drafts.  Every patient can view their 
own symptom information provided in a dashboard at any time.  Patient cannot edit 
symptom reports once they have been sent.  Patients can send messages to their care 
team at any time. 
Patients should not obtain advice or help from others that may influence their 
assessment of symptoms (e.g., family members or friends) when completing the 
instruments beyond general help on device use. 
Patient-reported symptom data are processed and the care team notified as described 
above.  Based on populated symptoms, the user interface provides participants with 
feedback depending on the symptom severity - for selected mild to moderate symptoms 
the patient receives anti-cancer treatment regimen/disease-tailored educational 
materials (e.g., symptom severity assessment and self-management instructions). 
As part of the introduction to the DPM solution, participants will be educated to call the 
emergency services or visit the nearest hospital when experiencing a severe symptom 
or other emergency. 
Kaiku Health DPM Solution Care Team User Interface 
The Kaiku Health web application has its own dedicated user interface for care team 
users that is designed to support clinical decision making.  It enables care teams to track 
patient-reported symptoms between the clinic appointments, and triage participant 
information received.  Patient data is available in real-time and automatically analyzed to 
generate notifications for new events and highlight severe symptom reports.  
Notifications are classified into the following three urgency categories based on 
evaluation of the scoring algorithm severity classification as well as the change of 
symptom severity grade relative to baseline: 
• 
Alert: Symptom report contains a symptom of Grade 3 that was not included in the 
baseline report or a change of Grades ≥ 2 in any symptom 
• 
Warning: Symptom report contains a change from Grade 1 to Grade 2 in any 
symptom 
• 
Info: Symptom report contains a change from Grade 0 to Grade 1 in any symptom 
or contains a symptom that was reported as Grade 3 in the baseline report 
 

 
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Relevant care team members receive daily digest emails about new activity of the 
patients in their care.  If a patient reports a symptom triggering a notification in the 
“Alert” category, a separate email is sent to the relevant care team members within 
approximately 15 minutes after receiving the patients’ report. 
In the care team DPM web app, care team members can assign incoming notifications to 
themselves or another member of the care team.  Within approximately 15 minutes of 
assigning the patient report to a member of the care team, the member of the care team 
receives an email notifying them of the assignment.  Symptom reports are only visible to 
the care team once the patient has sent the report.  Members of the care team are not 
able to edit the symptom report. 
Linked to the patient interface, the care team can exchange messages with patients. 
The care team dashboard provides an overview of patients’ activities including symptom 
questionnaire input and care team-patient interaction.  The individual patient level 
decision support dashboard allows monitoring of disease progression and insights into 
patient history. 
It is expected that care teams review the system for new data on a daily basis on 
weekdays, depending on the number of ongoing participants in the DPM arm. 
Regulatory classification, data privacy, and technical requirements 
Kaiku Health is compliant with industry regulations and is a CE-marked Class IIa medical 
device in the European Union, and is fully GDPR compliant.  Data that will be shared 
between Kaiku Health and the Sponsor will be outlined in the data management plan. 
Kaiku Health is compatible with most web browsers.  The newest versions of Mozilla 
Firefox, Google Chrome, Microsoft Edge or Apple Safari are recommended for use.  The 
basic usage of Kaiku Health does not require the installation of any plug-ins or 
extensions.  For patient users, the mobile application is available for iOS (v 11.0 and 
later) and Android (v 5.0 and later). 
Patients can use the Kaiku Health DPM Solution with either a native iOS or Android 
application and the web application.  HCPs should use the web-based version of the 
platform only. 
For detailed specifications on the Roche DPM Atezolizumab Module see the technical 
documentation. 

 
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5.3.2.1.1 
Roche DPM Atezolizumab Module Schedule, Administration, 
and Compliance 
The DPM solution allows patients to: 
• 
report on their health and wellbeing using a predefined list of symptoms (including 
free text for other symptoms), as defined for the respective indication of the Roche 
DPM Atezolizumab Module (Appendix 3), 
• 
receive reminders, notifications and instructions related to reporting the predefined 
metrics, 
• 
send encrypted messages and attachments to the care team. 
 
Patients in Cohort A randomized to the DPM arm and all patients in Cohort B will 
undergo initial training by HCPs on the use of the DPM solution at the study baseline 
visit.  Patients will then be able to use the Roche DPM Atezolizumab Module to report 
their symptoms as they arise and will receive reminders to do so at least every 7 days.  
In addition, patients in Cohort B will be prompted to complete symptom questionnaires 
24 hours after Atezolizumab SC administration. 
 
5.3.2.1.2 
Roche DPM Atezolizumab Module Access, Handling, and 
Accountability 
The Roche DPM Module and access to the Kaiku Health DPM Platform required for 
completion of this study will be provided by the Sponsor. 
Only patients enrolled in the study and assigned to use the DPM may receive and use 
the Roche DPM Modules, and only authorized staff may provide access and training to 
the applicable patients. 
Patients will provide their own internet-capable device and internet connection required 
to securely access the DPM solution. 
5.3.2.1.3 
Continued Access to the DPM Solution 
For patients who wish to continue using the DPM, continued access will be available. 
5.3.2.2 
Comparator Arm for Cohort A - Anti-cancer Regimen 
Containing Atezolizumab (IV) and Local Standard of Care 
Support Only 
Patients in the comparator arm for Cohort A of this study will receive a locally approved 
anti-cancer regimen containing Atezolizumab (IV) (see Section 5.3.1.1) and local SOC 
support only.  Patients randomized to this arm will not receive access to the Roche DPM 
Atezolizumab Module on the Kaiku Health DPM Solution.  The randomization of patients 
to this arm will not result in any changes to their current treatment plan.  Symptom 
reporting for patients in the comparator arm will be done according to routine clinical 
practice.  Patients will complete activities as per the schedule of activities specified in 
Appendix 1 

 
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 and will receive supporting information and communication options as per local and 
individual site standards.  Patients will complete a minimum number of PRO 
questionnaires to collect data for the study endpoints.  This will occur outside of the DPM 
solution. 
5.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any intervention (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a participant in addition to the protocol-accepted SOC systemic anti-cancer therapy 
from 7 days prior to initiation of study procedures to the final survival follow-up visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF, as required. 
5.4.1 
Concomitant Therapy for Cohort A 
5.4.1.1 
Permitted Therapy 
In general, investigators should manage a participant's care with supportive therapies as 
clinically indicated, per local standard practice. 
Participants in Cohort A are permitted to use the following therapies during the study: 
• 
Palliative radiotherapy 
 
5.4.1.2 
Prohibited Therapy 
There are no concomitant therapies that are prohibited in Cohort A of this study.  The 
local approval for the Atezolizumab (IV) regimen must be followed. 
The investigator should contact the Medical Monitor if questions arise regarding potential 
prohibited therapies. 
5.4.2 
Concomitant Therapy for Cohort B 
5.4.2.1 
Permitted Therapy 
Participants in Cohort B are permitted to use the following therapies during the study: 
• 
Oral contraceptives with a failure rate of < 1% per year (see Section 5.1.3) 
• 
Hormone-replacement therapy 
• 
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 5.4.2.3) 
• 
Megestrol acetate administered as an appetite stimulant 
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Inhaled or low-dose corticosteroids administered for COPD or asthma (e.g.,10mg 
QD, prednisone or equivalent) 

 
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• 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered for the second and subsequent Atezolizumab administrations only, at the 
discretion of the investigator. 
In general, investigators should manage a patient’s care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 5.4.2.2 and 5.4.2.3) as clinically indicated, per local 
standard practice.  Patients who experience administration-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 administration-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and β2-adrenergic agonists; see Appendix 6). 
5.4.2.2 
Cautionary Therapy 
5.4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF-α 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF-α inhibitors may 
attenuate potential beneficial immunologic effects of treatment with Atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-α inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-α inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with Atezolizumab therapy (refer to Appendix 7 for details). 
5.4.2.2.2 
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 5.4.2.3) may be used during the study at the discretion of the investigator. 
5.4.2.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 

 
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• 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority−approved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 5.1.4), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 5.4.2.1 for 
details). 
• 
Investigational therapy within 28 days prior to initiation of study treatment and during 
study treatment. 
• 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during Atezolizumab treatment, and for 5 months after 
the final dose of Atezolizumab. 
• 
Systemic immunostimulatory agents (including, but not limited to, interferon (IFNs) 
and interleukin-2 (IL-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 Atezolizumab. 
 
5.4.3 
Additional Restrictions 
This section is not applicable. 
5.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
Patients will be closely monitored for safety and tolerability of the study intervention 
throughout the study. 
For patients in Cohort B during the at-home treatment period, certain study assessments 
may be performed by a qualified mobile HCP at the patients home, to improve access 
and convenience for patients in the study.  The Sponsor will select a healthcare 
company that will be responsible for providing qualified mobile HCP services for 
participating sites (the qualified mobile HCP vendor).  The qualified mobile HCP vendor 
is responsible for ensuring that all qualified mobile HCPs are licensed, qualified, and in 
good standing, as per applicable regulations, and that appropriate background checks 
have been performed.  The qualified mobile HCP network will communicate with the 
participant and the participant’s site.  Qualified mobile HCP visits will be scheduled on 
specified visit days, to allow for relevant assessments to be performed by the qualified 
mobile HCP.  The schedule of activities (See Appendix 1) will specify the assessments 
that may be performed by a qualified mobile HCP. 

 
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5.5.1 
Informed Consent Forms and Screening Log (All Cohorts) 
Written informed consent (and assent, if applicable) for participation in the study must be 
obtained before performing any study-related procedures (including screening 
evaluations).  Informed Consent Forms for enrolled participants and for participants who 
are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before enrollment.  The investigator will maintain a detailed 
record of all participants screened and to document eligibility or record reasons for 
screening failure, as applicable. 
5.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
Demographic Data, and Socioeconomic Status Data (All 
Cohorts) 
Medical history, including clinically significant diseases, will be recorded at baseline.  In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the participant within 
7 days prior to initiation of study treatment will be recorded.  At the time of each follow-
up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
For Cohort A, participant evaluation prior to the decision to prescribe an Atezolizumab 
(IV) regimen will be considered part of the medical history.  The date that Atezolizumab 
(IV) regimen was prescribed must be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity (where allowed 
by local regulations). 
Socioeconomic status data will be collected, including highest educational degree and 
occupation. 
5.5.2.1 
Cohort B 
For patients in cohort B, the time required to travel from the patients’ home to the 
study site will be collected as estimated by the patient. 
5.5.3 
Physical Examinations (All Cohorts) 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified post-
baseline visits and as clinically indicated.  Changes from baseline abnormalities should 

 
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be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
In Cohort B, limited, symptom-directed physical examinations may be performed by a 
qualified mobile HCP during treatment administration visits in the at-home treatment 
setting. 
Height and weight will be recorded at screening.  Weight will only be recorded during 
visits in the hospital at the treatment phase or whenever, the investigator considers 
there is a substantial change from baseline. 
5.5.4 
Vital Signs 
5.5.4.1 
All Cohorts 
Vital signs will be carried out as per local SOC.  Vital signs include measurements of 
respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a 
seated position, and temperature.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
5.5.4.2 
Cohort B 
Vital sign measurement may be performed by a qualified mobile HCP. 
Vital signs should be measured within 60 minutes prior to each Atezolizumab injection, 
at 30 ( ± 10) minutes after the injection, and as clinically indicated.  In addition, vital signs 
should be measured at other specified timepoints as outlined in the schedule of 
activities. 
5.5.5 
Tumor and Response Evaluations (Cohort B) 
Patients in Cohort B will undergo tumor assessments at screening to confirm eligibility 
criteria. 
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. 
During study treatment, patients will undergo regular tumor assessments as per local 
SOC.  Disease progression or loss of clinical benefit as determined by the investigator 
should be recorded on the eCRF. 
5.5.5.1 
Radiographic Assessments (Cohort B) 
Screening assessments must include CT scans with contrast or magnetic resonance 
imaging (MRI) scans of the chest, abdomen, pelvis, and brain.  A spiral CT scan of the 
chest may be obtained but is not a requirement.  If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 

 
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of the chest may be performed and MRI scans of the abdomen, pelvis, and brain should 
be performed.  A CT scan with contrast or MRI scan of the brain must be done at 
screening to evaluate CNS metastasis in all patients (MRI scan must be performed if CT 
scan is contraindicated).  An MRI scan of the brain is required to confirm or refute the 
diagnosis of CNS metastases at baseline in the event of an equivocal CT scan.   Bone 
scans and CT scans of the neck should also be performed if clinically indicated.  At the 
investigator's discretion, other methods of assessment of measurable disease may be 
used. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)−CT scanner, the CT acquisition must be consistent with the standards for a full-
contrast diagnostic CT scan. 
5.5.6 
Biomarkers 
This section is not applicable. 
5.5.7 
Laboratory and Other Biological Samples 
5.5.7.1 
All Cohorts 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
• 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, 
ALP, ALT, AST, and LDH 
• 
Coagulation:  INR, aPTT, and prothrombin time (PT) 
• 
Thyroid function testing:  thyroid-stimulating hormone, free T3 (or total T3 for sites 
where free T3 is not performed), and free T4 
• 
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood); dipstick 
permitted. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, will be subject to the confidentiality standards 
described in Section 9.4. 

 
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5.5.7.2 
Cohort A 
Laboratory samples (see Section 5.5.7.1) will be collected to assess the predictive value 
of associated symptoms, laboratory test results, and AEs.  It is expected that at every 
visit (scheduled or unscheduled) where AEs are reported, a corresponding laboratory 
sample (e.g., blood, urine) is taken and analyzed according to local SOC for 
management of the respective AE and results documented in the eCRF. 
Laboratory samples collected as per Cohort A schedule of activities and SOC are 
analyzed according to local SOC.  Therefore, not all of the analytes mentioned in 
Section 4.5.7.1 will be collected at all visits and samples can be taken prior to treatment 
administration. 
5.5.7.3 
Cohort B 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis during screening, treatment Cycle 1−3 and disease control visits as 
applicable per schedule of activities: 
• 
HIV serology 
• 
HBV serology:  HBsAg, HBsAb, and total HBcAb for all patients; HBV DNA for 
patients with negative HBsAg and HBsAb tests and a positive total HBcAb test 
• 
HCV serology:  HCV antibody for all patients; HCV RNA for patients with a positive 
HCV antibody test 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine (or serum, if urine is not feasible) tests will be performed at 
specified subsequent visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is 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). 
• 
Archival or newly collected tumor tissue sample obtained at baseline for 
determination of PD-L1 expression and EGFR/ALK mutation status 
• 
Hematology, chemistry, coagulation, thyroid function testing, urinalysis, and 
pregnancy test 
 
In the treatment at-home period, samples for the below laboratory tests will be collected 
by a qualified mobile HCP within 3 to 7 days prior to treatment administration and 

 
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sent to the central laboratory for analysis.  This is not required if there are valid local 
laboratory results available for that time window: 
• 
Hematology, chemistry, thyroid function testing, and pregnancy test (urine 
dipstick taken at the day of drug administration, before drug administration) 
 
Central laboratory results will be shared with the investigator prior to each planned 
drug administration at-home. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report. 
5.5.8 
Clinical Outcome Assessments (All Cohorts) 
Patient-reported outcome instruments will be completed to assess the benefit of the 
DPM solution. 
PRO data will be collected through use of the following instruments: 
• 
MDASI (Cohorts A and B) 
• 
EORTC IL6 GHS/QoL (Cohorts A and B) 
• 
EQ-5D-5L (Cohorts A and B) 
• 
EORTC OUT-PATSAT7 (Cohort A) 
• 
PRO-CTCAE (for participants using the DPM only) (Cohorts A and B) 
• 
Participant acceptability questionnaire (Cohort B) 
 
MDASI, EORTC IL6 GHS/QoL, and EQ-5D-5L will be used to assess patient-reported 
HRQoL, EORTC OUT-PATSAT7 will be used to assess patient satisfaction with out-
patient cancer care, and PRO-CTCAE will be used to assess patient-reported symptoms 
in patients using the DPM.  The participant acceptability questionnaire will be used to 
assess patient satisfaction with various aspects of the at-home treatment setting as well 
as patient perception of safety culture. 
5.5.8.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at-home or at the clinic at specified time 
points during the study (see schedule of activities).  At the clinic or at-home, MDASI, 
EORTC IL6 GHS/QoL, EQ-5D-5L, and EORTC OUT-PATSAT7 will be administered 
before the patient receives any information on disease status, prior to the performance 
of non-PRO assessments, and prior to the administration of anti-cancer treatment, 
unless otherwise specified.  The participant acceptability questionnaire will be 
administered following treatment administration per the schedule of activities. 

 
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PRO instruments, translated into the local language as appropriate, will be completed 
through use of an ePRO app downloaded on the patient’s own electronic device.  The 
ePRO app will be independent of the DPM solution.  The ePRO app will enable the 
appropriate instruments to be administered in the correct order at each specified time 
point.  The link to download the app and instructions for completing the instruments 
electronically will be provided by the site staff.  If the patient does not have access to a 
device capable of installing the app, a web link for the electronic completion of PROs 
may be provided.  In the event that a patient does not have access to their own device 
at site visits, the site can provide an electronic device for the completion of PRO 
instruments.  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.  The data will be available for access by appropriate study 
personnel. 
Patients should be given the following instructions for completing PRO instruments at-
home: 
• 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
• 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
During clinic visits and visits conducted by a qualified mobile HCP (Cohort B only), PRO 
instruments should be administered as outlined below: 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for participants to complete the instruments, 
estimated to be ~15 minutes at each specified visit. 
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Patients 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. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 

 
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5.5.8.2 
Description of Clinical Outcome Assessment Instruments 
MD Anderson Symptom Inventory (MDASI) (Cohorts A and B) 
The MDASI is a cancer-related, multisymptomatic, validated, reliable self-report 
questionnaire for clinical and research use (Cleeland et al. 2000).  It consists of 19 items 
over two scales that assess symptom severity and symptom interference with different 
aspects of a patient's life.  For 13 items (pertaining to pain, fatigue, nausea, disturbed 
sleep, distress (emotional), shortness of breath, remembering things, lack of appetite, 
drowsy, dry mouth, sadness, vomiting, and numbness or tingling), patients rate how 
severe the symptoms were when “at their worst” in the last 7 days.  For 6 items, patients 
rate how much the symptoms have interfered with six areas of function (general activity, 
walking, work, mood, relations with other people, and enjoyment of life) in the last 
7 days.  The MDASI items are rated from 0−10, with 0 indicating that the symptom is 
either not present or does not interfere with the patient's activities and 10 indicating that 
the symptom is “as bad as you can imagine” or “interfered completely” with the 
participant's life.  The MDASI takes approximately 5 minutes to complete. 
EORTC Item Library 6 Global Health Status/Quality of Life (IL6 GHS/QoL 
from EORTC QLQ-C30) (Cohorts A and B) 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; Cocks et al. 2011).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, and pain), GHS and quality of life (QoL), 
and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) with a recall period of the previous week.  Scale scores can be 
obtained for the multi-item scales.  The functioning and symptoms items are scored on a 
4-point scale that ranges from "not at all" to "very much," and the GHS and QoL items 
are scored on a 7-point scale that ranges from "very poor" to "excellent." EORTC 
QLQ−C30 module takes approximately 10 minutes to complete.  The EORTC IL6 
GHS/QoL consists of only the GHS and QoL items from the EORTC QLQ-C30 and will 
be used for this study.  The EORTC IL6 GHS/QoL takes approximately 1 minute to 
complete. 
EQ-5D-5L (Cohorts A and B) 
The EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L), is a validated self-report 
health status questionnaire that is used to calculate a health status utility score for use in 
health economic analyses (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; 
Janssen et al. 2013).  There are two components to the EQ-5D-5L:  a five-item health 
state profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale (VAS) that measures health state.  
The EQ-5D-5L is designed to capture the patient's current health status.  Published 
weighting systems allow for creation of a single composite score of the patient's health 
status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It will be used in this 
study for informing pharmacoeconomic evaluations. 

 
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EORTC Satisfaction with Out-Patient Cancer Care (EORTC OUT-PATSAT7) 
(Cohort A) 
EORTC OUT-PATSAT7 is a 7-item complementary module from PATSAT-33, a core 
questionnaire to assess patient satisfaction with cancer care.  OUT-PATSAT7 
specifically assesses aspects of ambulatory care: care convenience (3 items), transition 
(3 items) and care continuity (1 item).  Items are assessed on a 5-point Likert scale 
ranging from Poor to Excellent for the most recent experience of care received by the 
patient (Brédart et al. 2018).  Higher score indicates greater satisfaction with care. 
PRO-CTCAE (Cohorts A and B) 
The PRO Common Terminology Criteria for Adverse Events (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 
PRO-CTCAE contains 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 PRO-CTCAE recall period is the previous 7 days. 
A subset of symptoms deemed most applicable to the current treatments has been 
selected for this study (see Appendix 3).  Symptoms have been selected on the basis of 
expected symptoms due to underlying disease in the patient population or known 
Atezolizumab adverse drug reactions.  Clinical care relevance of the selected symptoms 
has been reviewed, amended and confirmed by HCPs, patients, and 
patient representatives with relevant disease and treatment expertise. 
Participant Acceptability Questionnaire (Cohort B) 
The participant acceptability questionnaire will be used to assess convenience and 
patient satisfaction with the at-home treatment setting as well as patients’ perception of 
safety.  The questions are rated on a 4-points Likert scale ranging from strongly disagree 
to strongly agree.  Concepts related to acceptability include patient preference of 
different locations for the administration of Atezolizumab SC treatment (Appendix 4). 
5.5.9 
Anti-cancer Treatment Associated Adverse Events 
Anti-cancer treatment associated adverse events will be collected as part of the 
secondary efficacy objectives for Cohort A.  Text on the assessment of safety of the 
DPM solution as part of the safety analyses is provided in Section 6.1. 
5.5.9.1 
Safety Plan 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 

 
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myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 7 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for Atezolizumab. 
Management of Patients Who Experience Adverse Events 
Treatment Interruption or Discontinuation 
Interruption or discontinuation of the anti-cancer regimen containing Atezolizumab (IV) 
should be done according to local approval and local SOC practices. 
Management Guidelines 
Management of patients who experience adverse events should be done according to 
the Atezolizumab local approval and local SOC practices. 
5.5.9.2 
Safety parameters and definitions 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.5.9.4. 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 

 
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• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study intervention (e.g., screening invasive 
procedures such as biopsies) 
 
Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
participant or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.9.4 
for reporting instructions). 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.9.4 for reporting instructions).  Adverse events of special interest for this 
study are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.5.9.3) 

 
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• 
Suspected transmission of an infectious agent by an anti-cancer treatment, as 
defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies only 
when a contamination of the anti-cancer treatment is suspected. 
• 
Systemic lupus erythematosus 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, HLH, and MAS 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Grade ≥ 2 cardiac disorders 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
• 
Myelitis 
• 
Facial paresis 
Adverse Events for Exploratory Research 
For the purposes of the study objectives, additional laboratory data will be collected for 
the following selected adverse events: 
• 
Pneumonitis 
• 
Thyroid disorders 
• 
Diarrhea or colitis 
• 
Nephritis 
• 
Rash 
• 
Hepatitis 
 
Injection-Site Reactions (Atezo SC) 
With SC administration, local reactions at site of injection (erythema, pruritus, edema, 
rash, and pain) may occur.  In case of severe injection-site reactions, unscheduled 
photographs will be taken.  Photographs should include a label showing the subject’s 
identification number, date and time of calendar date, and a centimeter ruler to provide 
scale.  Efforts will be made to standardize the photography with regard to parameters 
such as angle, light, distance from body, and settings. 

 
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5.5.9.3 
Methods and Timing for Capturing and Assessing Safety 
Parameters 
The investigator is responsible for ensuring that all events (see Section 5.5.9.2 for 
definitions) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this Section 5.5.9.3 and in 
Sections 5.5.9.4−5.5.9.7.  The investigator is also responsible for reporting medical 
device complaints (see Section 6.1). 
For each event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness, severity, and causality. 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each participant contact.  All 
adverse events, whether reported by the participant or noted by study personnel, will be 
recorded in the participant’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of anti-cancer treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.5.9.4 for instructions for reporting serious adverse events). 
After initiation of anti-cancer treatment, all adverse events will be reported until 90 days 
after the last dose of Atezolizumab and for 30 days after the last dose of an alternative 
cancer therapy that has started prior to the 24-week time point and has continued follow-
up beyond this time point. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.5.9.6. 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation time points.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by 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 5.5.9.4 for reporting instructions), per the definition of serious 
adverse event in Section 5.5.9.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.5.9.4 for 
reporting instructions), per the definition of serious adverse event in Section 5.5.9.2. 
 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the anti-cancer 
treatment, indicating "yes" or "no" accordingly.  The following guidance should be taken 
into consideration (see also Table 4): 
• 
Temporal relationship of event onset to the initiation of anti-cancer treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of anti-cancer treatment, or reintroduction of anti-cancer treatment 
(as applicable) 
• 
Known association of the event with anti-cancer treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 

 
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Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by anti-cancer treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of anti-cancer treatment, and the adverse event cannot be readily 
explained by the participant's clinical state, intercurrent illness, or concomitant 
therapies; and/or the adverse event follows a known pattern of response to anti-cancer 
treatment; and/or the adverse event abates or resolves upon discontinuation of anti-
cancer treatment or dose reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the adverse event has an etiology other than anti-cancer treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of anti-cancer treatment (e.g., cancer diagnosed 2 days 
after first dose of anti-cancer treatment). 
 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
Infusion-Related Reactions and Cytokine Release Syndrome 
There may be significant overlap in signs and symptoms of infusion-related reactions 
(IRRs) and cytokine release syndrome (CRS).  While IRRs occur during or within 
24 hours after treatment administration, time to onset of CRS may vary.  Differential 
diagnosis should be applied, particularly for late-onset CRS (occurring more than 
24 hours after treatment administration), to rule out other etiologies such as delayed 
hypersensitivity reactions, sepsis or infections, HLH, tumor lysis syndrome, early disease 
progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine 
release syndrome").  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine release syndrome" on the Adverse 
Event eCRF.  Associated signs and symptoms of an IRR should be recorded on the 
dedicated Infusion-Related Reaction eCRF. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded as a separate event on the Adverse 
Event eCRF, with associated signs and symptoms of an IRR also recorded separately 
on the dedicated Infusion-Related Reaction eCRF. 

 
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In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 7. 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
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. 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 

 
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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.5.9.4 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in anti-cancer treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 × ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF. 

 
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Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in anti-cancer treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (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. 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see  Section 5.5.9.3 ) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see  Section 5.5.9.4 ). 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.5.9.3 ) that are attributed by the 

 
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investigator solely to progression of 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 anti-cancer treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.5.9.4). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.5.9.6. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
Lack of Efficacy or Worsening of 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 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 carcinoma, 
extensive-stage small-cell lung carcinoma, or hepatocellular carcinoma").  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 investigator assessment according to local standard of care.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  

 
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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. 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.5.9.2), 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 anti-cancer treatment 
administration or performance of an efficacy measurement for the study) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 

 
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Note:  Special situations are not in themselves adverse events, but may result in 
adverse events. 
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
or qualifies as an adverse event of special interest, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.9.4).  For anti-cancer treatment, adverse events associated with special 
situations should be recorded as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
In addition, all special situations associated with anti-cancer treatment, 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:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from symptom reporting within the DPM 
solution, PRO-CTCAE or other PRO data by the Sponsor.  Sites are not expected to 
review the DPM solution, PRO CTCAE or other PRO data for adverse events. 

 
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5.5.9.4 
Immediate Reporting Requirements from Investigator to 
Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study device or procedure: 
• 
Serious adverse events (defined in Section 5.5.9.2; see Section 5.5.9.4 for details 
on reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.5.9.2; see Section 5.5.9.4 
for details on reporting requirements) 
• 
Pregnancies (see Section 5.5.9.4 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, access to Medical Monitors is available 24 hours 
per day, 7 days per week.  Details will be provided separately.  An Emergency Medical 
Call Center will also be available 24 hours per day, 7 days per week.  The Emergency 
Medical Call Center will connect the investigator with an Emergency Medical Contact, 
provide medical translation service if necessary, and track all calls.  Contact information, 
including toll-free numbers for the Emergency Medical Call Center, will be distributed to 
investigators. 
Reporting Requirements for Serious Adverse Events and Adverse Events 
of Special Interest 
Events that Occur prior to Starting Anti-cancer Treatment 
After informed consent has been obtained but prior to initiation of anti-cancer treatment, 
only serious adverse events caused by a protocol-mandated intervention should be 

 
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reported.  The paper Clinical Trial Adverse Event/Special Situations Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
Events that Occur after Starting Anti-cancer Treatment 
After initiation of anti-cancer treatment, serious adverse events and adverse events of 
special interest will be reported until 90 days after the last dose of Atezolizumab and for 
30 days after the last dose of an alternative cancer therapy that has started prior to the 
24-week time point and has continued follow-up beyond this time point (see 
Section 5.5.9.3).  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.5.9.6. 
Reporting Requirements for Pregnancies 
Pregnancies in Female Participants 
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 within 5 months after the final dose of Atezolizumab or within 30 days after the 
last dose of an alternative cancer therapy that has started prior to the 24-week time point 
and has continued follow-up beyond this time point.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue anti-cancer 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/birth defect in 

 
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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. 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event).  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. 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
anti-cancer treatment or the female partner of a male participant exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event). 
5.5.9.5 
Follow-up of Patients after Adverse Events 
Investigator Follow-up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, or the event is assessed as stable by the investigator, or the 
patient is lost to follow-up, or the patient withdraws consent.  Every effort should be 
made to follow all serious adverse events considered to be related to anti-cancer 
treatment or study-related procedures until a final outcome can be reported. 

 
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During the adverse event reporting period (defined in Section 5.5.9.3), 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. 
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 5.5.9.4. 
Sponsor Follow-up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.5.9.6 
Adverse Events That Occur after the Adverse Event Reporting 
Period 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the last dose of Atezolizumab or 30 days after 
the last dose of an alternative cancer therapy that has started prior to the 24-week time 
point and has continued follow up beyond this time point), all deaths, regardless of 
cause, should be reported through use of the Long-Term Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to anti-cancer treatment, the event should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.5.9.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, And Ethics Committees 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
 

 
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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. 
5.6 INTERVENTION, PARTICIPANT, STUDY, AND SITE DISCONTINUATION 
5.6.1 
Study Intervention Discontinuation 
5.6.1.1 
DPM Discontinuation (Cohort A and Cohort B) 
Patients must permanently discontinue use of the DPM solution if they experience any 
of the following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study intervention 
• 
Investigator or Sponsor determination that intervention discontinuation is in the best 
interest of the patient 
• 
Permanent device malfunction, if patient has access to one usable device only 
• 
Patient treated with a protocol approved study intervention (see Section 5.3.1.1.2 
and Section 5.3.1.2.6) 
 
The primary reason for DPM discontinuation should be documented on the appropriate 
eCRF.  Patients who discontinue use of the DPM will not be replaced. 
5.6.1.2 
Atezolizumab SC Discontinuation (Cohort B) 
Patients in Cohort B must permanently discontinue Atezolizumab SC if they experience 
any of the following: 
• 
Intolerable toxicity related to Atezolizumab SC, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant's safety if he or she continues to receive Atezolizumab SC 
• 
Investigator or Sponsor determination that Atezolizumab SC discontinuation is in the 
best interest of the patient 
• 
Use of another non-protocol anti-cancer therapy 
• 
Pregnancy 
• 
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) 
 

 
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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue Atezolizumab SC prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit ≤30 days after the 
final scheduled treatment.  An earlier visit may be used as the treatment discontinuation 
visit if a local assessment of tumor response indicates a loss of clinical benefit. 
Refer to the schedule of activities for details on follow-up assessments to be performed 
for patients who permanently discontinue Atezolizumab SC.  If a patient requests to be 
withdrawn from treatment or follow-up assessments, this request must be documented in 
the source documents and signed by the investigator. 
5.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any 
time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
• 
Technical reasons related to DPM utilization 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
Patients who withdraw from the study will not be replaced. 
5.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants 
• 
Patient enrollment is unsatisfactory 
 

 
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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
5.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation guidelines for 
Good Clinical Practice 
• 
No study activity (i.e., all participants have completed the study and all obligations 
have been fulfilled) 
 
6. 
ASSESSMENT OF SAFETY 
Text in Section 6.1 refers to the assessment of safety of the DPM solution for Cohorts A 
and B.  Text on the assessment of anti-cancer treatment associated adverse events as 
part of the efficacy analyses for Cohort A is provided in Section 5.5.9 and text on the 
assessment of the safety of Atezolizumab for Cohort B is provided in Section 6.2. 
6.1 
DEVICE SAFETY (COHORTS A AND B) 
6.1.1 
Safety Plan 
The anticipated important safety risks for the DPM solution are outlined below. 
Several measures will be taken to ensure the safety of patients in this study.  Patients 
will undergo safety monitoring during the study, including assessment of the nature, 
frequency, and severity of adverse device incidents.  In addition, guidelines for 
managing adverse device incidents, including criteria for DPM solution discontinuation, 
are provided below. 
6.1.1.1 
Risks Associated with the Kaiku Health DPM Solution 
Kaiku Health is compliant with industry regulations and is a CE-marked Class IIa medical 
device in the European Union, in Australia Kaiku Health is registered in the ARTG via 
its parent company Elekta (ARTG No 337499), and is fully GDPR compliant. 
Potential risks have been assessed according to the manufacturer‘s risk assessment 
processes and categorized by severity and probability of occurrence.  Risks that remain 
after mitigation strategies were put in place are considered residual risks.  The residual 
risks for this study are listed below. 

 
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• 
Non-transmission of information: The intended recipient of information does not 
or cannot view the information in a timely manner.  This may be caused e.g., by the 
user not accessing Kaiku Health in a timely manner despite notifications, availability 
issues with Kaiku Health, technical issues with Kaiku Health in displaying the 
information. 
• 
Incorrect self-management instructions: Self-management instructions 
presented to a user of Kaiku Health may not be applicable to the particular situation, 
e.g., due to misconfiguration of Kaiku Health, participant misinterpretation of the 
given instructions, or erroneous algorithm implementation. 
• 
Misuse of free text field for reporting of listed symptoms: If symptoms listed in 
the questionnaire are reported via the free text field, the participant will not receive 
self-management instructions that are provided with the listed symptom. 
• 
Information security: Various risks that impact the confidentiality, integrity, and/or 
availability of the sensitive personal data processed by Kaiku Health. 
 
Due to the residual risks above, the following warnings are presented to the users of 
Kaiku Health within the application: 
1. 
Kaiku Health is not monitored in real-time by the clinical staff, it is intended only for 
non-urgent communication.  In urgent situations, contact your care unit or 
emergency number by phone. 
2. 
In some special cases the guidance and self-care instructions that Kaiku Health 
provides might not apply to you.  If you have any questions regarding your care, or 
your symptoms and their management, we kindly ask you to contact your care team. 
3. 
If you do not receive a response from your care unit within a reasonable time, 
please contact the care unit via phone. 
4. 
Risks related to confidentiality, integrity, and/or availability of the personal data 
processed by Kaiku Health cannot be completely eliminated.  If you suspect that 
your personal data has been compromised, please contact Kaiku Health support. 
 
If the DPM solution fails, participants will receive local SOC.  At all times, the patient 
may contact their care provider using the means available under the local SOC. 
6.1.1.2 
Management of Patients Who Experience Adverse Device 
Incidents 
DPM Solution Interruption or Discontinuation 
The DPM solution may be temporarily interrupted or permanently discontinued in 
patients who experience adverse device incidents considered to be related to the device 
or associated procedure. 
Management Guidelines 
If a patient experiences an adverse device incident related to one of the residual risks 
mentioned above, medical care should be provided according to the clinician's best 
judgement. 

 
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For patients who experience anxiety which exceeds previously reported levels or occurs 
for the first time and is persistent, medical care should be provided as per clinical 
judgement and treatment may be temporarily interrupted. 
6.1.2 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording adverse device incidents 
including field safety corrective actions (FSCA). 
In this clinical trial, the Kaiku DPM Solution and the Roche modules are used in their 
intended purpose.  Thus, clinical trial medical device safety reporting does not apply. 
To report any medical device adverse incident, the device manufacturers processes are 
used. 
6.1.2.1 
Medical Device Adverse Incident 
An adverse incident is an event that caused, or almost caused, an injury to a patient or 
other person, or a wrong or delayed diagnosis and treatment of a patient.  Adverse 
device event reporting in regard to Kaiku Health will be as per the CE mark and local 
regulations for the reporting of such events.  Per the DPM device’s labelling, no 
adverse device incidents are anticipated. 
6.1.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters 
The investigator is responsible for ensuring that all incidents (see Section 6.1.2 for 
definitions) are reported to the manufacturer in accordance with instructions provided in 
this Section 6.1.3. 
For each incident reported to the manufacturer the investigator will make an 
assessment of seriousness (see Section 6.1.3.2 for adverse device effects) and 
causality (only applicable for adverse device effects, see Section 6.1.3.3). 
6.1.3.1 
Device Incident Reporting Period 
Investigators will seek information on adverse device incidents and device deficiencies 
at each patient contact.  All events, whether reported by the patient or noted by study 
personnel, will be recorded in the patient's medical record and reported to the device 
manufacturer. 
After initiation of study treatment, all adverse device effects will be reported until 30 days 
after study end. 
6.1.3.2 
Assessment of Severity of Adverse Device Incidents 
Guidelines for classifying the severity of adverse device incidents are provided in 
Table 5.  This information is used to determine acceptability thresholds for anticipated 
adverse device incidents. 

 
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Table 5 
Severity Classification for Adverse Device Incidents 
Grade 
Severity 
1 
Negligible 
No impact or at most inconvenience or temporary discomfort 
2 
Moderate 
Results in temporary injury or impairment, not requiring professional 
medical interventiona 
3 
Severe 
Results in temporary injury or impairment requiring professional 
medical intervention 
4 
Critical 
Results in permanent impairment or life-threatening injury  
5 
Catastrophic 
Results in patient death 
a Clinical or diagnostic observations only are not considered an intervention 
 
6.1.3.3 
Assessment of Causality of Adverse Device Incidents 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative cause to determine whether an 
adverse device incident is considered to be related to the device or device-related 
procedure.  The guidelines provided in Table 6 should be used to assess the causality of 
adverse device effects. 

 
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Table 6 
Assessment of Event Relationship to Device or  
Device-Related Procedure 
Relationship 
Criteria for Classification 
Not related a 
 
• Event has no temporal relationship with the use of the device, or the 
procedures related to application of the device; 
• Event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• Discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the event; 
• Event involves a body site or an organ not expected to be affected by the 
device or procedure; 
• Event can be attributed to another cause (e.g., an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other 
risk factors); 
• Event does not depend on a false result given by the device used for 
diagnosis, when applicable. 
Possible 
 
• Relationship with the use of the device or comparator, or the relationship with 
procedures is weak but cannot be ruled out completely.  Alternative causes are 
also possible (e.g., an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment).  Cases where relatedness 
cannot be assessed or no information has been obtained should also be 
classified as possible.   
Probable 
 
• Relationship with the use of the device or comparator, or the relationship with 
procedures seems relevant and/or the event cannot reasonably be explained 
by another cause. 

 
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Table 6 Assessment of Event Relationship to Device or Device-Related Procedure 
(Cont) 
Causal 
relationship 
 
Event is associated with the device or comparator or with procedures beyond 
reasonable doubt when: 
• Event is a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
• Event has a temporal relationship with device use/application or procedures; 
• Event involves a body site or organ that: 
o The device or procedures are applied to; 
o The device or procedures have an effect on; 
• Event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
• Discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the event (when clinically feasible); 
• Other possible causes (e.g., an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
• Harm to the participant is due to error in use; 
• Event depends on a false result given by the device used for diagnosis, when 
applicable. 
a Complications of procedures are considered to be not related if said procedures would have 
also been applied to participants in the absence of medical device use/application. 
 
6.1.3.4 
Procedures for Reporting Adverse Device Incidents 
Investigators should use correct medical terminology/concepts when reporting adverse 
device incidents to the manufacturer.  Avoid colloquialisms and abbreviations.  Only 
one adverse device effect term should be reported per report.  Multiple effects in one 
email/report should be avoided.  As a minimum site number, patient number, reporter 
name, incident description and current outcome are to be reported.  Kaiku Health 
adverse device incidents should be reported to Kaiku Health Oy: 
support+ade@kaikuhealth.com 
Patient-Reported Outcome Data 
Adverse device effect reports will not be derived from symptom reporting within the DPM 
Solution, PRO-CTCAE or other PRO data by the Sponsor. 
6.2 
ATEZOLIZUMAB SAFETY (COHORT B) 
6.2.1 
Safety Plan 
The safety plan for patients in this study is based on clinical experience with 
Atezolizumab and rHuPH20 in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Section 6.2.1.1 and Section 6.2.1.2). 

 
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Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of Atezolizumab SC will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  Atezolizumab SC 
administration in the at-home treatment setting will be performed by a qualified mobile 
HCP with access to adequate equipment to manage adverse events (AEs).   A phone or 
video call will be established between the qualified mobile HCP and the treating clinic 
HCPs during Atezolizumab SC administration in the at-home treatment setting.  
Additional risk mitigation strategies for administration in the at-home treatment setting 
are outlined in Section 1.7.  Guidelines for managing patients who experience 
anticipated adverse events, including criteria for treatment interruption or 
discontinuation, are provided in Appendix 7.  Refer to Sections 6.2.2−6.2.7 for details on 
safety reporting (e.g., adverse events, pregnancies) for this study. 
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  If a 
participant develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
6.2.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, facial paresis, myelitis 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 7 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for Atezolizumab. 
Guidelines for managing patients who experience anticipated adverse events are 
provided in Appendix 7. 

 
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6.2.1.2 
Risks Associated with rHuPH20 
rHuPH20 is co-formulated with Atezolizumab.  rHuPH20 should not be injected into 
or around an infected or acutely inflamed area because of the danger of spreading a 
localized infection.  Refer to the rHuPH20 U.S. Package Insert for more details 
regarding the full safety profile of rHuPH20, including boxed warnings and 
contraindications (HYLENEX® recombinant (hyaluronidase human injection) U.S. 
Package Insert, Halozyme, Inc.).   
Refer to Appendix 7 for adverse event management guidelines for Atezolizumab. 
6.2.2 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 6.2.4. 
6.2.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 6.2.3.5.9 
and 6.2.3.5.10 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 

 
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6.2.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 6.2.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 6.2.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 6.2.4.2 
for reporting instructions). 
6.2.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 6.2.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 6.2.3.5.7) 
• 
Suspected transmission of an infectious agent by a study treatment, as 
defined below: 

 
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Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study treatment is suspected. 
• 
Systemic lupus erythematosus 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, hemophagocytic lymphohistiocytosis (HLH), and macrophage activation 
syndrome (MAS) 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Grade ≥ 2 cardiac disorders 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
• 
Myelitis 
• 
Facial paresis 
 
6.2.2.4 
Selected Adverse Events 
Injection-Site Reactions 
With SC administration, local reactions at site of injection (erythema, pruritus, edema, 
rash, and pain) may occur.  In case of severe injection-site reactions, unscheduled 
photographs will be taken.  Photographs should include a label showing the patient’s 
identification number, date and time of calendar date, and a centimeter ruler to provide 
scale.  Efforts will be made to standardize the photography with regard to parameters 
such as angle, light, distance from body, and settings. 
See Section 6.2.3.5.1 for instructions on reporting injection-related reactions and 
infusion related reactions. 
6.2.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters 
The investigator is responsible for ensuring that all adverse events (see Section 6.2.2.1 
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 6.2.4−6.2.6.  The 
investigator is also responsible for reporting medical device complaints 
(see Section 6.1). 

 
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For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 6.2.2.2 for seriousness criteria), severity 
(see Section 6.2.3.3), and causality (see Section 6.2.3.4). 
6.2.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 6.2.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest 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. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 6.2.6. 
6.2.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation timepoints.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
6.2.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. 

 
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Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention 
not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, 
using the toilet, and taking medications, as performed by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
(see Section 6.2.4.2 for reporting instructions), per the definition of serious adverse event in 
Section 6.2.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6.2.4.2 for reporting 
instructions), per the definition of serious adverse event in Section 6.2.2.2. 
 
6.2.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to study treatment, 
indicating "yes" or "no" accordingly.  The following guidance should be taken into 
consideration (see also Table 8): 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment 
(as applicable) 
• 
Known association of the event with study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 

 
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Table 8 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
6.2.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
6.2.3.5.1 
Infusion-Related Reactions and Cytokine Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine release 
syndrome (CRS).  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be applied, 
particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, HLH, tumor lysis syndrome, early disease progression, or other 
manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine 
release syndrome").  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine release syndrome" on the Adverse 
Event eCRF.  Associated signs and symptoms of an IRR should be recorded on the 
dedicated Infusion-Related Reaction eCRF. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded as a separate event on the Adverse 
Event eCRF, with associated signs and symptoms of an IRR also recorded separately 
on the dedicated Infusion-Related Reaction eCRF. 

 
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In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 7. 
6.2.3.5.2 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
6.2.3.5.3 
Adverse Events That are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
6.2.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 

 
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Section 6.2.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
6.2.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 × ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 6.2.3.5.4 for 
details on recording persistent adverse events). 

 
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6.2.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (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 6.2.3.5.4 for 
details on recording persistent adverse events). 
6.2.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF 
(see Section 6.2.3.5.2) and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event), either as a serious adverse event or an adverse 
event of special interest (see Section 6.2.4.2). 
6.2.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 6.2.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded on the Death Attributed 
to Progressive Disease eCRF.  All other deaths that occur during the adverse event 

 
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reporting period, regardless of relationship to study treatment, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 6.2.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 6.2.6. 
6.2.3.5.9 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
6.2.3.5.10 
Lack of Efficacy or Worsening of NSCLC 
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 NSCLC 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 investigator assessment according to local SOC.  In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event. 

 
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6.2.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 6.2.2.2), except as 
outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The participant has not experienced an adverse event. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
• 
Hospitalization that was necessary because of participant requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
6.2.3.5.12 
Cases Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
• 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
• 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 

 
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In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the 
participant. 
 
Note:  Special situations are not in themselves adverse events, but may result in 
adverse events. 
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
or qualifies as an adverse event of special interest, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 6.2.4.2).  For Atezolizumab, adverse events associated with special situations 
should be recorded as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
• 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
• 
 Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
• 
 Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
In addition, all special situations associated Atezolizumab, 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. 

 
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• 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
• 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
• 
 Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
• 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
• 
 Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the participant:  Enter the drug name and 
"participant supplied drug to third party" as the event term.  Check the "Drug 
misuse" box. 
 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from symptom reporting within the DPM 
solution, PRO-CTCAE or other PRO data by the Sponsor.  In addition, the Sponsor will 
make no attempt to reconcile participant reports of treatment-related symptoms (via 
PRO-CTCAE) with investigator reports of adverse events.  Sites are not expected to 
review the DPM solution, PRO-CTCAE or other PRO data for adverse events. 
6.2.4 
Immediate Reporting Requirements from Investigator to 
Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 

 
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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
• 
Serious adverse events (defined in Section 6.2.2.2; see Section 6.2.4.2 for details 
on reporting requirements) 
• 
Adverse events of special interest (defined in Section 6.2.2.3; see Section 6.2.4.2 
for details on reporting requirements) 
• 
Pregnancies (see Section 6.2.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
6.2.4.1 
Medical Monitors and Emergency Medical Contacts 
 
To ensure the safety of study patients, an access to Medical Monitor is available 
24 hours per day, 7 days per week.  Details will be provided separately.  An Emergency 
Medical Call Center will also be available 24 hours per day, 7 days per week.  The 
Emergency Medical Call Center will connect the investigator with an Emergency Medical 
Contact, provide medical translation service if necessary, and track all calls.  Contact 
information, including toll-free numbers for the Emergency Medical Call Center, will be 
distributed to investigators. 
6.2.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
6.2.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
6.2.4.2.2 
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 or until 

 
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initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 6.2.6. 
6.2.4.3 
Reporting Requirements for Pregnancies 
6.2.4.3.1 
Pregnancies in Female Participants 
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 within 5 months after the final dose of Atezolizumab.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
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. 

 
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6.2.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 6.2.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 6.2.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
6.2.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male participant exposed to study treatment should 
be classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 6.2.4.2). 
6.2.5 
Follow-Up of Patients after Adverse Events 
6.2.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, or the event is assessed as stable by the investigator, or the patient is lost 
to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 6.2.3.1), 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. 
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 6.2.4.3. 
6.2.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 

 
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summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
6.2.6 
Adverse Events That Occur after the Adverse Event Reporting 
Period 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the 
Long- Term Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
6.2.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
7. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
7.1 
COHORT A 
The Full Analysis Set will consist of all randomized participants, in line with the intent-to-
treat (ITT) principle.  Randomized patients who receive incorrect assignment of DPM 

 
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from that intended will be summarized in the group according to their planned 
randomization. 
The primary analysis population for safety is the Safety Analysis Population defined as 
all participants who received at least one dose of the anti-cancer regimen containing 
Atezolizumab (IV) and/or used the DPM solution.  All patients who were given access to 
the DPM solution will be included in the DPM arm. 
 
 
 
OS will be analysed at the time of the primary analysis. If less than 50% of patients have 
been followed up for 12 months at the time of the primary analysis, an OS follow-up 
analysis may take place.  The study is not powered to demonstrate a statistically 
significant difference in OS and this is for the purpose of assessing the exploratory 
efficacy objective of OS. 
Hypothesis tests will be 
 with a significance level of
%. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of the anti-cancer regimen containing Atezolizumab (IV) 
and the Roche DPM Atezolizumab Module. 
Further details of all analyses will be provided in the Statistical Analysis Plan (SAP). 
7.2 
COHORT B 
The Full Analysis Set will consist of all enrolled patients. 
The Evaluable Population is defined as patients who completed three cycles of 
Atezolizumab SC in the hospital setting. 
The primary analysis population for safety is the Safety Analysis Population defined as 
all patients who received at least one dose of Atezolizumab SC and/or used the DPM 
solution. 
 
 
 

 
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7.3 
DETERMINATION OF SAMPLE SIZE 
7.3.1 
Cohort A 
The focus of this cohort is hypothesis testing, and the primary endpoint of change of 
Week 12 value from baseline in the patient-reported Symptom Interference Score from 
the MDASI Core Items was used to determine the sample size of the study.  A mean 
difference of 8 points is assumed to be clinically meaningful (Cocks et al. 2011). 
A sample size of 400 randomized participants 
 provides 
% power to detect a difference in means between study arms in the change from 
baseline at Week 12 in the MDASI Total Interference Score of at least 8 points, 
assuming a 
 and a standard deviation (SD) of 
approximately 25 points. 
The assumption for mean change and SD is based on both the responsiveness of the 
MDASI Total Interference Score reported by Shi et al. 2016 and analyses of historical 
data from pivotal trials from GHS scale from EORTC QLQ-C30. 
Shi et al. reported a moderate effect size of 0.65 in patients that received 
Chemoradiation with mean change from baseline of 12 and SD of 24 points 
(Shi et al. 2016). In total 110 patients completed MDASI at baseline and after the 
Chemoradiotherapy.  Considering the small sample size reported in the study and the 
fact those reflect intra-participant comparison we also took into account historical data 
from GHS scale from EORTC QLQ-C30 as the EORTC IL6 GHS/QoL scale will be 
included as a PRO in this study. 
The assumption for the SD is based on analyses of historical data from pivotal trials of 
Atezolizumab in the same indications to be studied (IMpower110 [mNSCLC], 
IMpower133 [ES-SCLC], and IMbrave150 [HCC]).  Based on this data, the SD of the 
change from baseline to Week 12 scores range from 17.6 to 24.2.  For the purpose of 
this sample size calculation, 25 points is used as a conservative estimate.  This also 
corresponds to published sample size assumptions relating to the EORTC QLQ-C30 
questionnaire scores which typically power to target an effect size of 0.4 for these PRO 
endpoints, corresponding to a mean difference of 10 points divided by a SD of 
25 (10/25=0.4) (Basch et al. 2016; Basch et al. 2014). 
Table 9 summarizes the reference data from the pivotal trials for the 
EORTC QLQ-C30 GHS scale score for patients treated with an Atezolizumab regimen 
(and the respective combination partners as applicable) with available data at cycles 
corresponding to the Week 12 time point. 

 
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Table 9 
Analysis of EORTC QLQ-C30 Global Health Status Score from 
Historical Atezolizumab Pivotal Trails 
Trial Name 
Indication 
Baseline Score 
(SD) 
Mean Week 12a 
Score (SD) 
Mean Change from 
Baseline to Week 
12a Score (SD) 
IMpower110 
mNSCLC  
n=267 
63.7 (20.0) 
n=54 
67.9 (23.3) 
n=51 
2.0 (21.2) 
IMpower133 
ES-SCLC   
n=238 
54.1 (23.3) 
n=188 
64.9 (18.5) 
n=180 
10.6 (24.2) 
IMbrave150 
HCC  
n=316 
70.6 (21.1) 
n=260 
69.8 (19.8) 
n=253 
-3.3 (17.6) 
ES-SCLC = extensive-stage small-cell lung carcinoma; mNSCLC = metastatic non-small cell 
lung cancer; HCC = hepatocellular carcinoma; SD = standard deviation. 
aIMpower110, IMpower133 and IMbrave150: Week 12 corresponds to pre-Cycle 5 PRO 
assessment. 
 
In order to ensure that the study population includes a representation of patients across 
all three disease indications, enrollment will be capped for any one indication exceeding 
 i.e., once 
 patients of any one indication 
are enrolled, enrollment into strata corresponding to that disease indication will close 
and the study will continue to enroll participants from the remaining indications. 
7.3.2 
Cohort B 
For this cohort, 
 participants will be enrolled.  Since this cohort is intended to be an 
exploratory pilot study, no formal sample size calculation was performed.  Therefore, no 
formal hypothesis testing will be performed on the primary endpoint of at-home 
treatment adoption at Cycle 6. 
7.4 
SUMMARIES OF CONDUCT OF STUDY (ALL COHORTS) 
Enrollment and reasons for discontinuation from the study will be summarized by study 
arm for the ITT population.  Major protocol deviations, including major deviations of 
inclusion and/or exclusion criteria, will be summarized by study arm and evaluated for 
their potential effects on the interpretation of study results. 
Anti-cancer treatment administration and DPM administration, and reasons for 
discontinuation from study intervention or DPM usage will be summarized. 
7.5 
SUMMARIES OF STUDY GROUP COMPARABILITY (ALL 
COHORTS) 
Summaries of study group comparability will be based on the ITT population. 

 
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Demographic characteristics (such as age, sex, race/ethnicity), baseline disease 
characteristics (such as ECOG performance status, PD-L1 status) will be summarized 
by study arm for the ITT population, including the randomization stratification factors.  
Descriptive baseline summaries of continuous data will present the group mean, 
standard deviation, median and range.  Descriptive summaries of categorical data will 
present frequencies and percentages. 
Subsequent anti-cancer therapy will also be summarized.  Previous and concurrent 
diseases and medications will also be summarized. 
7.6 
EFFICACY ANALYSES 
7.6.1 
Cohort A 
The primary population for all primary and secondary efficacy endpoints will be the ITT 
population (Full Analysis Set).  Subgroup analyses will be performed for important 
baseline covariates to be specified in the SAP.  These will include separate analyses of 
each disease indication subgroup. 
7.6.1.1 
Primary Efficacy Endpoint 
The primary estimand corresponding to the primary cohort objective is defined as 
follows: 
Population 
Participants who have not received prior systemic therapy with the following indications 
will be included:  mNSCLC, ES-SCLC, and HCC.  The study population will comprise a 
maximum of
% from each of these cancer indications. 
Primary endpoint (variable) 
Total Interference Score from MDASI.  The score corresponds to the mean of six 
interference items (Questions 14 to 19 referring to interference in general activity, mood, 
work, relations with other people, walking and enjoyment of life), the mean is then 
linearly transformed so the score ranges from 0 to 100. 
Treatments 
Cohort A: 
Experimental: Local SOC support with use of a DPM solution plus treatment with a 
locally approved anti-cancer regimen containing Atezolizumab (IV) as in Table 1 for each 
indication. 
Control: Local SOC support without use of a DPM solution plus treatment with a locally 
approved anti-cancer regimen containing Atezolizumab (IV) as in Table 1 for each 
indication. 

 
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Intercurrent events 
• 
Atezolizumab (IV) regimen discontinuation prior to Week 12 
• 
New anti-cancer therapy prior to Week 12 
• 
Termination of use of DPM solution prior to Week 12 
• 
Non-treatment/DPM related study discontinuations prior to Week 12 
• 
Death prior to Week 12 
 
Handling of intercurrent events 
• 
Atezolizumab (IV) regimen discontinuation prior to Week 12: treatment-policy 
• 
New anti-cancer therapy prior to Week 12: treatment policy 
• 
Termination of use of DPM solution prior to Week 12: treatment policy 
• 
Non-treatment/DPM related study discontinuations prior to Week 12: hypothetical 
• 
Death prior to Week 12: while alive (last score before death) 
 
Summary measure: Mean difference in change of Week 12 value from baseline 
The Full Analysis Set will consist of all randomized participants (in line with the ITT 
principle).  Randomized participants who receive incorrect assignment of DPM from that 
intended will be summarized in the arm according to their planned randomization. 
The primary comparison of interest is the mean difference in change of the Week 12 
value from baseline of the Total Symptom Interference score from the MDASI core 
items.  The primary efficacy analysis for this cohort will compare the Roche DPM 
Atezolizumab Module plus local SOC support and a locally approved anti-cancer 
regimen containing Atezolizumab (IV) with local SOC support and a locally approved 
anti-cancer regimen containing Atezolizumab (IV) only at Week 12.  The following null 
and alternative hypotheses will be tested at a 
: 
• 
H0: μDPM = μSOC  versus 
• 
Ha: μDPM ≠ μSOC 
 
for which the μDPM and μSOC refer to the mean change from baseline for Roche DPM 
Atezolizumab Module and local SOC support and local SOC support only, respectively. 
The primary study objective is to demonstrate superiority of the experimental over the 
control treatment. 
Primary analysis 
A mixed model repeated measures (MMRM) analysis adjusting for baseline Total 
Symptom Interference score, disease indication and ECOG performance status will be 
used to estimate the mean change from baseline to Week 12 for the primary endpoint.  

 
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The model will include the change from baseline in Total Symptom Interference score as 
the dependent variable.  The effects in the model will include baseline Total Symptom 
Interference score, disease indication, ECOG performance status, treatment arm, visit, 
and treatment-by-visit interaction.  Visit week will be treated as the repeated variable 
within a participant. 
The difference in the change from baseline of the participants randomized to the DPM 
arm from participants randomized to the comparator arm will be estimated at each time 
point.  The 95% CI and p-value for treatment difference will be determined. 
All efforts will be made to minimize missing data.  For those participants with an 
intercurrent event handled by treatment policy, efficacy data including PRO assessments 
will still be collected for the primary and secondary endpoints until Week 24.  For 
participants who die prior to the Week 12 assessment, the last score before death will be 
used.  This may include the baseline value. 
Data affected by intercurrent events following a hypothetical strategy 
(i.e.,  non-treatment/DPM related study discontinuations prior to Week 12), as well as 
purely missing Week 12 PRO assessments which are considered to be missing at 
random, the following imputation strategy will be used: 
1. 
Imputation step: Hypothetical values will be imputed m times based on statistical 
modeling that will consider the Total Symptom Interference baseline score, disease 
indication and ECOG performance status as predictor variables. 
2. 
Analysis step: Each of the resulting m data sets will be analyzed using the statistical 
model above, which will provide an estimate of treatment difference. 
3. 
Pooling step: The results from the m data sets will be combined leading to an overall 
estimate of the treatment effect and associated 95% confidence intervals and p-
values. 
 
More details, including m and further details of the multiple imputation strategy, will be 
specified in the statistical analysis plan. 
7.6.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will not be formally tested; therefore, no multiplicity 
adjustment is performed.  P-values may be presented for descriptive purposes only. 
7.6.1.2.1 
Hospitalizations 
The number and percentage of participants who are hospitalized due to an AE will be 
summarized overall and over time by treatment arm for the ITT population.  Reason for 
hospitalization will be based on information documented in the eCRF.  The number of 
cumulative days hospitalized due to SAEs will also be summarized overall and by 
treatment arm for the ITT population.  Summaries may be presented by country or by 
pre-defined groupings of countries.  More details will be provided in the SAP. 

 
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In order to account for competing events of death before observation of a hospitalization, 
as well as the varying follow-up for hospitalizations of participants, hospitalization 
probability estimates will be based on the cumulative incidence function.  This will be 
estimated using the non-parametric Aalen-Johansen estimator. 
A plot of the cumulative incidence function (CIF) will be produced to display the 
probability of a hospitalization over time.  In order to compare treatment groups, the 
relative risk at Week 6, Week 12, Week 18 and Week 24 will be calculated based on 
these estimated probabilities. 
To assess the effect of DPM solution on estimated probabilities over the entire time-
span, subdistribution hazards corresponding to the cumulative incidence functions will 
be compared using a Gray’s test.  To assess the effect of the DPM solution on the 
hazard of hospitalization, the event-specific hazard ratio for hospitalization will be 
presented. 
Descriptive summaries will also be provided for hospitalizations for any reason. 
7.6.1.2.2 
Unscheduled visits to the ER or clinic visits for symptom 
management 
The number and percentage of participants who have unscheduled visits to the ER or 
unscheduled clinic visits for non-administrative reasons (e.g., symptom management) 
will be summarized overall and over time by treatment arm for the ITT population.  This 
will be based on information documented in the eCRF.  Summaries may be presented 
by country or by pre-defined groupings of countries.  More details will be provided in the 
SAP. 
In order to account for competing events of death before unscheduled ER or clinic visits, 
as well as the varying follow-up of participants, this endpoint will be analyzed using the 
same methodology as specified for hospitalizations (see Section 7.6.1.2.1). 
7.6.1.2.3 
Incidence, nature, and severity of anti-cancer treatment 
associated AEs 
Anti-cancer treatment associated AEs will be coded using MedDRA and summarized by 
mapped term and appropriate thesaurus level.  All AEs and routine laboratory 
parameters will be assessed according to the NCI-CTCAE v 5.0 grading system. 
The following safety parameters will be summarized in tables to evaluate and compare 
the safety profile of participants treated with a locally approved anti-cancer regimen 
containing Atezolizumab (IV) in combination with the Roche DPM Atezolizumab Module 
plus local SOC support versus a locally approved anti-cancer regimen containing 
Atezolizumab (IV) with local SOC support only in terms of: 
• 
AEs including AEs leading to dose modifications or interruptions, or withdrawal of 
anti-cancer treatment, and death 

 
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• 
AEs related to anti-cancer treatment and adverse events related to study device 
• 
Severe, serious, and selected immune-related adverse events (pneumonitis, thyroid 
disorders, diarrhea or colitis, nephritis, rash, and hepatitis) 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 
 
AEs will generally be reported according to the most extreme severity; however 
summaries will also be produced to present changes in the severity of selected adverse 
events.  More details will be provided in the SAP. 
7.6.1.2.4 
Grade ≥ 3 AEs 
The number and percentage of participants who have Grade ≥ 3 AEs will be 
summarized overall and over time by treatment arm. 
In order to compare rates between study arms and to account for competing events of 
death before observation of a Grade ≥ 3 AE, as well as the varying follow-up for AEs of 
participants, this endpoint will be analyzed using the same methodology as specified for 
hospitalizations (see Section 7.6.1.2.1). 
7.6.1.2.5 
SAEs 
The number and percentage of participants who have SAEs will be summarized overall 
and over time by study arm. 
In order to compare rates between study arms and to account for competing events of 
death before observation of a SAE, as well as the varying follow-up for AEs of 
participants, this endpoint will be analyzed using the same methodology as specified for 
hospitalizations (see Section 7.6.1.2.1). 
7.6.1.2.6 
Weighted Toxicity Score 
The weighted toxicity score (WTS) was first defined by Carbini et al. in ‘A Method to 
Summarize Toxicity in Cancer Randomized Clinical Trials’ (Carbini et al. 2018). 
The WTS is defined as the sum of the proportion of participants with toxicities (Grade 1 
to 4) weighted by a severity index, which increases from Grade 1 to Grade 4 for a 
specific toxicity.  The weight for each toxicity grade is multiplied by the proportion of 
participants with that toxicity grade, and all products are added to yield a toxicity score 
for a particular adverse event.  The WTS for a treatment arm is the sum of all individual 
toxicity scores for that arm.  Adverse event weighting will be pre-specified in the SAP, 
with pre-specified adverse events of interest potentially being more heavily weighted. 
The WTS will be summarized by study arm using descriptive statistics, i.e., mean, 
standard deviation, median, minimum and maximum.  The WTS will be compared across 
study arms using a t-test for descriptive purposes. 

 
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7.6.1.2.7 
Interruption, Modification, or Discontinuation due to AEs 
The number and percentage of participants who have anti-cancer treatment dose 
interruptions, modifications or discontinuations due to AEs will be summarized overall 
and over time by study arm. 
In order to compare rates of anti-cancer treatment discontinuation due to AEs between 
study arms and to account for competing events of death or discontinuation of anti-
cancer treatment due to any other reason, as well as the varying follow-up for AEs of 
participants, this endpoint will be analyzed using the same methodology as specified for 
hospitalizations (see Section 7.6.1.2.1). 
7.6.1.2.8 
Selected Immune-Related Adverse Events 
The number and percentage of participants who have selected immune-related AEs will 
be summarized overall and over time by study arm.  Selected immune-related AEs are 
listed in Section 3.1.1.2. 
7.6.1.2.9 
EORTC IL6 GHS/QoL 
Change from baseline in EORTC IL6 GHS/QoL score will be analyzed. 
EORTC IL6 GHS/QoL scores and change from baseline will be summarized 
descriptively using means, standard deviations, medians, and range, by treatment arm 
at baseline and across time. 
7.6.1.2.10 
Patient-reported health status utility (EQ-5D-5L) 
Change from baseline in EQ-5D-5L VAS score will be analyzed. 
EQ-5D-5L VAS scores and change from baseline will be summarized descriptively using 
means, standard deviations, medians, and range, by treatment arm at baseline and 
across time 
7.6.1.2.11 
MDASI Symptom Severity Score 
Change from baseline in MDASI Symptom Severity Score will be analyzed. 
MDASI Symptom Severity scores and change from baseline will be summarized 
descriptively using means, standard deviations, medians, and range, by treatment arm 
at baseline and across time. 
7.6.1.3 
Exploratory Efficacy Endpoints 
7.6.1.3.1 
Patient-reported satisfaction of healthcare treatment 
Change from baseline in the scores of care convenience and transition will be analyzed 
using EORTC specific complementary outpatient module (EORTC OUT-PATSAT7). 
Care convenience and transition scores and change from baseline will be summarized 
descriptively using means, standard deviations, medians, and range, by treatment arm 
at baseline and across time. 

 
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7.6.1.3.2 
Time to discontinuation of treatment 
TTD is defined as the time from the date of randomization to the date of discontinuation 
of Atezolizumab (IV) regimen for any reason.  Patients who are still ongoing treatment 
with an Atezolizumab (IV) regimen at the time of analysis will be censored at the date of 
last administration of the last administered component of the Atezolizumab (IV) regimen.  
The comparison of TTD will be made regardless of whether a patient progresses or 
receives a new anti-cancer therapy prior to discontinuation of the Atezolizumab (IV) 
regimen. 
The Kaplan-Meier method will be used to estimate the median TTD for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the study arms.  A stratified Cox 
proportional regression model will be used including study arm in order to provide an 
estimate of the treatment effect of DPM expressed as a HR, as well as a 95% CI. 
 
 
In this analysis, intercurrent events and their handling are defined as follows: 
• 
Disease progression prior to treatment discontinuation: treatment policy 
• 
New anti-cancer therapy prior to treatment discontinuation: treatment policy 
• 
Death while on treatment: composite strategy (death on treatment will be classed as 
a treatment discontinuation). 
 
In addition, a time to event analysis of time to discontinuation of the first component of 
the treatment regimen for any reason, including premature discontinuation of induction 
chemotherapy, if applicable, will be performed using the same methodology. 
7.6.1.3.3 
Time to clinical progression or death (PFS) 
PFS is defined as the time from the date of randomization to the date of clinical 
progression or death due to any cause.  Investigators will be asked whether the 
participant has clinically progressed since the last visit and this will be documented by 
the investigator on the eCRF.  Patients who are not reported as having progressed or 
died at the time of analysis will be censored at the date when they were last assessed to 
be clinically stable / progression free. Participants who do not have post-baseline 
information will be censored at the date of randomization.  PFS will be analyzed using 
the same methodology as specified for TTD (see Section 7.6.1.3.2). 
In this analysis, intercurrent events and their handling are defined as follows: 
• 
Discontinuation of treatment prior to clinical or symptomatic progression: treatment 
policy 
• 
New anti-cancer therapy prior to clinical or symptomatic progression: treatment 
policy 

 
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7.6.1.3.4 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Participants who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Participants who do not 
have post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for TTD (see Section 7.6.1.3.2).  A 
survival follow-up analysis may be performed based on more mature data. 
In this analysis, intercurrent events and their handling are defined as follows: 
• 
Discontinuation of treatment prior to death: treatment policy 
• 
Disease progression prior to death: treatment policy 
• 
New anti-cancer therapy prior to death: treatment policy 
 
7.6.1.3.5 
Utilization of concomitant medication of special interest for 
management of AEs (e.g., steroids for immune-related adverse 
events (irAEs); diarrhea medication) 
Concomitant medications will be summarized by study group.  Baskets of medications of 
interest will be pre-defined and summaries will be produced to present the number and 
percentage of participants administered these medications due to specific AEs such as 
irAEs and diarrhea.  More details will be provided in the SAP. 
7.6.1.3.6 
Anti-cancer treatment dose intensity and exposure 
Anti-cancer treatment administration will be summarized by duration of treatment and 
cumulative dose.  In addition, treatment exposure will be summarized including the 
number of doses received, dose intensity, and the percentage of planned dose. 
7.6.1.3.7 
Utilization 
Summaries will be produced to describe the utilization of Roche DPM Atezolizumab 
Module, and DPM platform, and/or local SOC support. 
Descriptive baseline summaries of continuous data will present the group mean, 
standard deviation, median and range.  Descriptive summaries of categorical data will 
present frequencies and percentages.  Summaries will be produced overall and over 
time. 
The following variables will be summarized for the DPM arm only: 
• 
DPM Utilization: 
– 
Percentage of enrolled patients using DPM weekly 
– 
Duration of use for each participant or on average by all participants (in weeks) 
 
The following endpoints will be summarized over time by weeks referenced to treatment 
start/DPM assignment, i.e., Week 1, Week 2, etc.: 
• 
Time spent by patients vs. care teams on the platform (in minutes) 

 
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Number of logins 
• 
Time spent by patients on completing the symptom questionnaire (in minutes) 
• 
Time spent by patients on self-management or educational materials; ranking of 
most accessed materials 
• 
Number of symptom questionnaires filled in by patients 
• 
Number of patients for which a symptom alert was triggered.  Time (in hours) until 
an alerted vs. non-alerted symptom questionnaire was reviewed by care teams 
• 
Number of messages sent between care teams and patients 
 
7.6.2 
Cohort B 
7.6.2.1 
Primary Efficacy Endpoint 
The primary estimand corresponding to the primary cohort objective is defined as 
follows: 
Population 
Participants with resected Stage IIB-IIIB (early-stage) NSCLC who have had a complete 
resection of NSCLC, are adequately recovered from surgery and who have completed 
up to four cycles of adjuvant platinum-based chemotherapy without evidence of disease 
relapse/recurrence will be included. 
For efficacy analysis the Evaluable Population as defined in Section 7.2 will be used. 
Primary endpoint (variable) 
Binary assessment of at-home treatment adoption at Cycle 6 in patients who are 
continuing to receive Atezolizumab SC treatment (1 = adoption; 0 = non adoption). 
Adoption is defined as a decision by the investigator and the participant to continue to 
receive Atezolizumab SC in the at-home treatment setting rather than Atezolizumab SC 
in the hospital setting. 
If a patient or investigator decides to terminate the Atezolizumab SC in the at-home 
treatment setting while continuing Atezolizumab SC in the hospital setting before Cycle 
6, they will be classified as not adopting (0). 
Treatments 
Cohort B: 
Experimental: Three cycles of Atezolizumab SC in the hospital setting followed by 13 
cycles of Atezolizumab SC in the at-home treatment setting 

 
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Intercurrent events and handling 
The following intercurrent events will be summarized descriptively: 
• 
Atezolizumab SC discontinuation at a time after the last dose of Atezolizumab SC 
administered in the hospital setting and prior to Cycle 6 
• 
Death at a time after the last dose of Atezolizumab SC administered in the hospital 
setting and prior to Cycle 6 
For the primary endpoint these participants will not be included in the denominator. 
Summary measure: Percentage of at-home treatment adoption at Cycle 6. 
The primary endpoint of interest is at-home treatment adoption at Cycle 6.  No 
hypothesis testing for this endpoint will be performed. 
7.6.2.2 
Exploratory Endpoints 
7.6.2.2.1 
At-home treatment adherence 
At-home treatment adherence at Cycles 9, 12, and 15 will be calculated. 
Adherence is defined as receiving Atezolizumab SC in the at-home treatment setting at 
certain cycle given that patient received Atezolizumab SC in the at-home treatment 
setting at Cycle 6. 
7.6.2.2.2 
Unscheduled visits to the ER or clinic visits for symptom 
management 
The number and percentage of patients who have unscheduled visits to the ER or 
unscheduled clinic visits for non-administrative reasons (e.g., symptom management) 
within one day of SC administration will be summarized overall and over time for the ITT 
population.  This will be based on information documented in the eCRF. 
7.6.2.2.3 
Number of hospitalizations within 1 day of SC administration 
due to SAEs 
The number and percentage of patients who are hospitalized due to an SAE will be 
summarized overall and over time for the safety population.  Reason for hospitalization 
will be based on information documented in the eCRF.  The number of cumulative days 
hospitalized due to SAEs will also be summarized overall. 
7.6.2.2.4 
Interruption, modification, or discontinuation of Atezolizumab 
due to AEs occurring within 1 day of SC administration 
The number and percentage of patients who have Atezolizumab dose interruptions, 
modifications or discontinuations due to AEs occurring within 1 day of SC administration 
will be summarized. 

 
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7.6.2.2.5 
Incidence, nature, and severity of Atezolizumab SC associated 
AEs graded per-CTCAE v5.0 with particular focus on Grade ≥ 3 
AEs and SAEs 
Atezolizumab SC associated AEs will be coded using MedDRA and summarized by 
mapped term and appropriate thesaurus level.  All AEs and routine laboratory 
parameters will be assessed according to the NCI-CTCAE v 5.0 grading system. 
Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be summarized.  A shift table of selected 
laboratory tests will be produced to summarize the baseline and maximum post-baseline 
severity grade. 
7.6.2.2.6 
Reasons for not continuing in at-home treatment setting 
(questionnaire for participants / HCPs) 
Reasons for not continuing in at-home treatment setting will be asked at the time of 
drop-out. 
7.6.2.2.7 
Anti-cancer treatment dose intensity and exposure 
Anti-cancer treatment administration will be summarized by duration of treatment and 
cumulative dose.  In addition, treatment exposure will be summarized including the 
number of doses received, dose intensity, and the percentage of planned dose. 
7.6.2.2.8 
Patient-Reported Outcomes 
Change from baseline in EORTC IL6 GHS/QoL, EQ-5D-5L VAS, and MDASI Symptom 
Severity scores will be analyzed. 
Scores and change from baseline will be summarized descriptively using means, 
standard deviations, medians, and range at baseline and across time. 
7.7 
SAFETY ANALYSES 
7.7.1 
Cohort A 
The primary analysis population for safety is the Safety Analysis Population as described 
in Section Section 7.  All adverse device effects occurring on or after the date of 
administration of the DPM solution, will be included in analyses. 
Safety will be assessed through summaries of exposure to study device and adverse 
device effects. 
Study device exposure (such as device use duration) will be summarized with 
descriptive statistics. 
All adverse device effects, serious adverse device effects, and device deficiencies that 
could have led to a serious adverse device effect will be summarized. 

 
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7.7.2 
Cohort B 
The primary analysis population for safety is the Safety Analysis Population as described 
in Section 7.  All adverse device effects occurring on or after the date of administration of 
the DPM solution, will be included in analyses. 
Safety will be assessed through summaries of exposure to study device and adverse 
device effects. 
Study device exposure (such as device use duration) will be summarized with 
descriptive statistics. 
All adverse device effects, serious adverse device effects, and device deficiencies that 
could have led to a serious adverse device effect will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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8. 
DATA COLLECTION AND MANAGEMENT 
8.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via EDC through use of eCRFs.  Sites will be responsible for data entry into the 
EDC system.  In the event of discrepant data, the CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will perform oversight of the data management of this study.  The Sponsor 
will produce an EDC Study Specification document that describes the quality checking to 
be performed on the data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
8.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive participant data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
8.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
An app downloaded onto an electronic device will be used to capture PRO data.  The 
app is designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. Food and Drug Administration (FDA) regulations for electronic 
records (21 CFR Part 11).  The data will be transmitted to a centralized database 
maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 

 
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Once the study is complete, the data, audit trail, and study and system documentation 
will be archived.  The investigator will receive participant data for the site in both human- 
and machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
8.4 
DEVICE DATA 
For a full description of the medical device used in this study, refer to Section 2.3.  Data 
will be collected within a cloud-based platform(s), for processing, analysis and storage, 
managed by the Device Manufacturer.  Only identified and trained users access this 
system. 
Device data may be analyzed on an ongoing basis for the purpose of device changes 
(refer to Section 7.8.3).  Relevant data, as specified in the appropriate study plans and 
specifications, will be transmitted to the sponsor. 
8.5 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review according to the 
Trial Monitoring Plan to confirm that critical protocol data (i.e., source data) entered into 
the eCRFs by authorized site personnel are accurate, complete, and verifiable from 
source documents. 
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 8.7. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
study-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 

 
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8.6 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
8.7 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
devices, including eCRFs, electronic or paper PRO data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche 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. 
9. 
ETHICAL CONSIDERATIONS 
9.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States will comply with U.S. 
FDA regulations and applicable local, state, and federal laws.  Studies conducted in the 
European Union or European Economic Area will comply with E.U. Clinical Trials 
Directive (2001/20/EC) or Clinical Trials Regulation (536/2014) and applicable local, 
regional, and national laws. 
9.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 

 
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will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/IEC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient’s agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before their participation in the study.  The case history or 
clinical records for each participant shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
patient to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient’s willingness to continue in the 
study, the participant or a legally authorized representative must re-consent by signing 
the most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC requirements.  For any updated or revised Consent Forms, 
the case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the participant or the 
participant's legally authorized representative.  All signed and dated Consent Forms 
must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time. 
9.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the 
participant, and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 

 
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initiated.  In addition, any patient recruitment materials must be approved by the 
IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 10.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
9.4 
CONFIDENTIALITY 
Information technology systems used to collect, process and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. In 
the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique participant identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the participant's welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data 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, 

 
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development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 10.6). 
9.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 4.2). 
10. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
10.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the participant data, including an audit trail containing a complete record of all changes 
to data. 
10.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on 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. 
10.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity.  
Prior to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.  
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  

 
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Details on the establishment and monitoring of quality tolerance limits are provided in a 
Quality Tolerance Limit Management Plan. 
10.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
10.5 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 40 sites globally will participate to enroll approximately 400 participants in 
Cohort A and
participants in Cohort B.  Enrollment will occur through an IxRS. 
10.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical study registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 9.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Studies Data at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 

 
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monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
10.7 
PROTOCOL AMENDMENTS 
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) E6 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, Clinical Trials Directive (2001/20/EC) or Clinical Trials 
Regulation (536/2014) (EEA sites only), and all other applicable local regulations 
 
 

 
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11. 
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Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
150/Protocol MO42720, Version 2 
Appendix 1: Schedule of Activities 
Schedule of activities for Cohort A 
 
Screening 
(Days -28 to 
0) 
Baseline a 
(Cycle 1, 
Day 1) 
Treatment period b 
Post-last treatment safety 
follow-up visit 
(28 days) c 
Follow-up telephone call 
(90 days) d 
Approximate visit frequency (as per local 
standard): 
 
 
 
 
 
mNSCLC 
Once 
Once 
~Every 2–4 weeks 
Once 
Once 
ES-SCLC 
Once 
Once 
~Every 3 weeks 
Once 
Once 
HCC  
Once 
Once 
~Every 3 weeks 
Once 
Once 
Informed consent e 
x 
 
 
 
 
Diagnosis confirmation f 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
Randomization 
 
x (-3 days) 
 
 
 
Medical history, participant characteristics, 
socioeconomic status, and demographical 
data 
x 
 
 
 
 
Cancer treatment history 
x 
 
 
 
 
Documentation of PD-L1-positivity 
status by local testx 
x 
 
 
 
 
Concomitant medications/treatments 
x 
 
x 
x 
 
Vital signs g 
 
x 
x 
x 
 
Hematology h  
 
x 
x 
x 
 
Chemistry i 
 
x 
x 
x 
 
Coagulation j 
 
x 
x 
x 
 
Thyroid function testing k 
 
x 
x 
x 
 
Urinalysis l 
 
x 
x 
x 
 
Complete physical examination m 
x 
 
 
 
 
Limited physical examination n 
 
 
x 
x 
 
Height 
x 
 
 
 
 
Weight o 
x 
x 
x 
 
 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
151/Protocol MO42720, Version 2 
 
Screening 
(Days -28 to 
0) 
Baseline a 
(Cycle 1, 
Day 1) 
Treatment period b 
Post-last treatment safety 
follow-up visit 
(28 days) c 
Follow-up telephone call 
(90 days) d 
Assessment of disease progression p 
 
As per local standard of care 
MDASI q 
 
x 
Weeks 6, 12, 18, 
24 (± 3days) 
 
x 
HRQoL – EORTC IL6 GHS/QoL and EQ-
5D-5L q 
 
x 
Weeks 6, 12, 18, 
24 (±3days) 
 
x 
EORTC OUT-PATSAT7b q 
 
x 
Week 9 (±3days) 
 
x 
DPM participant training  r, s 
 
x 
 
 
 
DPM completion by participant r 
 
x t 
x u 
ADEs/SADEs and AEs/SAEs v 
 
x 
x 
x 
x 
Anti-cancer treatment administration w 
 
x 
x 
 
 
Survival status  
 
 
x 
x 
x 
ADE = adverse device effect; AE = adverse event; DPM = Digital Patient Monitoring; EQ-5D-5L = EuroQoL 5 Dimension, 5-Level Questionnaire; 
EORTC = European Organisation for Research and Treatment of Cancer; ES-SCLC = extensive-stage small-cell lung carcinoma; GHS = global 
health status; HCC = hepatocellular carcinoma; HRQoL = health-related quality of life; IL6 = item library 6; m = metastatic; NSCLC = non-small cell 
lung cancer; OUT-PATSAT7 = out-patient satisfaction with cancer care questionnaire; QoL = Quality of Life scale; SADE = serious adverse device 
effect; SAE = serious adverse event. 
 
Notes: 
- Available data as per SOC will be collected; no additional diagnostic or monitoring procedures shall be requested outside of local routine clinical practice. 
- Participant data collection will continue until the end of the follow up period, or until death, loss to follow-up, or withdrawal of consent. 
 
a 
Baseline visit will occur on Cycle 1, Day 1. Baseline assessments should be conducted prior to the administration of anti-cancer treatment. Laboratory 
assessments must be performed within 72 hours of first study treatment (Day 1 of Cycle 1). 
b 
Visits for each indication will be repeated as necessary as per SOC. Treatment regimens per indications are outlined in Section 5.1. 
c 
Follow-up visit will occur 28 days after the patient discontinues their anti-cancer treatment (i.e., 28 days after the last dose of the last administered component 
of the regimen, which may or may not be Atezolizumab). 
d 
Follow-up telephone call will occur 90 days after the participant receives the last dose of Atezolizumab (IV) treatment or discontinues Atezolizumab treatment. 
e 
Informed consent must be documented before any study-specific procedures are performed. 
f  
Diagnosis confirmation via histology or radiological report, except for HCC where ultrasound and alpha-fetoprotein (AFP) may be sufficient for diagnosis 
confirmation and a tissue biopsy may not be required and for mNSCLC or ES-SCLC where cytology may be sufficient for diagnosis. 
g 
Vital signs will be carried out locally as per local SOC. 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
152/Protocol MO42720, Version 2 
h 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells). Only standard of care measurements are required. 
i 
Chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH. Only standard of care measurements are required. 
j 
Coagulation includes INR, aPTT, and PT. Only standard of care measurements are required. 
k 
Thyroid function testing includes thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), and free T4. Only standard of care 
measurements are required. 
l 
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood); dipstick permitted. Only standard of care measurements are required. 
m  
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems. Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF. 
n 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. Changes from baseline abnormalities 
should be recorded in participant notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
o 
Weight is to be measured at Day 1 of each cycle, or whenever the investigator considers there is a substantial change from baseline. 
p 
Radiologic confirmation per RECIST is not mandated. 
q 
PRO instruments should be conducted by the participant at-home or at the clinic.  At the clinic, instruments 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 anti-cancer treatment, unless otherwise 
specified. 
r 
Only for participants randomized to the DPM arm. 
s 
Participants randomized to the DPM arm will receive training on use of the DPM solution at the baseline visit. DPM participant training will include setting up an 
account for the participant. 
t 
The participant will complete the baseline assessment of symptoms that occurred over the previous 7 days at the end of the DPM participant training session, 
under the supervision of the trainer. 
u 
Participants can report symptoms in real-time throughout the course of the study using the DPM solution. Participants will receive weekly messages to remind 
them that they must report symptoms at least every 7 days. 
v 
Includes adverse events due to the device and adverse events due to the treatment regimen. 
w 
All the above assessments should be conducted before anti-cancer treatment is administered. 
x 
Documented PD-L1 positivity (PD-L1 expression on ≥  1% of tumor cells) must have been determined locally using a Health-Authority approved 
immunohistochemistry assay. Documentation of PD-L1-positivity with a full pathology report of the local testing results is required to be submitted to the 
Sponsor. 
 
 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
153/Protocol MO42720, Version 2 
Schedule of activities for Cohort B 
 
Screening 
Hospital Treatment Period 
Disease 
control and 
safety visit cc 
At-home Treatment 
Visits b 
End of 
treatment 
visit c 
Follow-up telephone 
call 
Cycle 
 
1 a 
2 
3 
4 to 15 
4 to 16 
 
 
Day 
-28 to -1 
1 (±3 days) 
every 12 
weeks after 
the first at-
home 
treatment 
visit (± 5 
days) 
7 to 3 
days 
prior to 
each 
cycle 
day 1 
1 (±3 
days) of 
each 21-
day 
cycle 
≤ 30 days 
from last 
study 
treatment 
90 days from last 
study treatment 
Informed consent d 
x 
 
 
 
 
 
 
 
 
Diagnosis 
confirmation e 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
PD-L1 expression and 
EGFR and ALK 
mutational status f 
x 
 
 
 
 
 
 
 
 
Medical history, 
participant 
characteristics, 
socioeconomic status, 
time required to 
travel to the site and 
demographical data 
x 
 
 
 
 
 
 
 
 
Cancer treatment 
history 
x 
 
 
 
 
 
 
 
 
Concomitant 
medications/ 
treatments 
x 
 
Collected on an ongoing basis 
 
 
Vital signs g 
x 
x 
x 
x 
x 
 
x h 
x 
 
Weight i 
x 
x 
x 
x 
x 
 
 
x 
 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
154/Protocol MO42720, Version 2 
 
Screening 
Hospital Treatment Period 
Disease 
control and 
safety visit cc 
At-home Treatment 
Visits b 
End of 
treatment 
visit c 
Follow-up telephone 
call 
Cycle 
 
1 a 
2 
3 
4 to 15 
4 to 16 
 
 
Day 
-28 to -1 
1 (±3 days) 
every 12 
weeks after 
the first at-
home 
treatment 
visit (± 5 
days) 
7 to 3 
days 
prior to 
each 
cycle 
day 1 
1 (±3 
days) of 
each 21-
day 
cycle 
≤ 30 days 
from last 
study 
treatment 
90 days from last 
study treatment 
Height 
x 
 
 
 
x 
 
 
 
 
Complete physical 
examination j 
x 
 
 
 
 
 
 
 
 
Limited physical 
examination k 
 
x 
x 
x 
x 
 
x h 
x 
 
ECOG Performance 
Status 
x 
x 
 
x 
x 
 
 
x 
 
Hematology l  
x 
x 
x 
x 
x 
x h 
 
x 
 
Chemistry m 
x 
x 
x 
x 
x 
x h 
 
x 
 
Coagulation n 
x 
x 
 
 
x 
 
 
x 
 
Thyroid function 
testing o 
x 
x 
 
 
x 
x h 
 
x 
 
Urinalysis p 
x 
x 
 
 
 
 
 
 
 
HIV/HBV/HCV 
Serology bb 
x 
 
 
 
 
 
 
 
 
Pregnancy test q 
x 
x 
x 
x 
x 
  
x h 
x 
(x) r 
Phone/Video HCP 
contact s 
 
 
 
 
 
 
x 
 
 
MDASI t 
 
x 
 
x 
 
 
x 
(Cycles 
6, 9, and 
12) 
x 
 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
155/Protocol MO42720, Version 2 
 
Screening 
Hospital Treatment Period 
Disease 
control and 
safety visit cc 
At-home Treatment 
Visits b 
End of 
treatment 
visit c 
Follow-up telephone 
call 
Cycle 
 
1 a 
2 
3 
4 to 15 
4 to 16 
 
 
Day 
-28 to -1 
1 (±3 days) 
every 12 
weeks after 
the first at-
home 
treatment 
visit (± 5 
days) 
7 to 3 
days 
prior to 
each 
cycle 
day 1 
1 (±3 
days) of 
each 21-
day 
cycle 
≤ 30 days 
from last 
study 
treatment 
90 days from last 
study treatment 
HRQoL – EORTC IL6 
GHS/QoL,EQ-5D-5L, t 
 
x 
 
x 
 
 
x 
(Cycles 
6, 9, and 
12) 
x 
 
Participant 
acceptability 
questionnaire t 
 
 
 
 
 
 
x 
(Cycles 
4, 6, and 
8) 
x 
 
DPM patient training  
u 
 
x 
 
 
 
 
 
 
 
DPM completion by 
patient  
 
 x v 
x w 
 
 
ADEs/SADEs and 
AEs/SAEs x 
 
Collected on an ongoing basis 
x 
Atezolizumab SC 
administration y 
 
x 
x 
x 
 
 
x h 
 
 
Tumor assessment  
x z 
x aa 
 
 
ADE = adverse device effect; AE = adverse event; DPM = Digital Patient Monitoring; ECOG = Eastern Cooperative Oncology Group; eCRF = 
electronic Case Report Form; EQ-5D-5L = EuroQoL 5 Dimension, 5-Level Questionnaire; EORTC = European Organisation for Research and 
Treatment of Cancer; GHS = Global Health Score; HCP = Healthcare Professional; HRQoL = health-related quality of life; IL6 = item library 6; 
IRR = injection related reaction; MDASI = MD Anderson Symptom Interference; NSCLC = non-small cell lung cancer; OUT-PATSAT7 = out-patient 
satisfaction with cancer care questionnaire; PRO = patient-reported outcome; QoL = quality of life; SADE = serious adverse device effect; SAE = 
serious adverse event; SC = subcutaneous; IL6 = EORTC Global Health Status/Quality of Life scale 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
156/Protocol MO42720, Version 2 
a 
Baseline visit will occur on Cycle 1, Day 1. Baseline assessments should be conducted prior to the administration of Atezolizumab SC. 
Laboratory assessments must be performed within 72 hours of first study treatment (Day 1 of Cycle 1). 
b  
For participants who develop IRRs (or symptoms suggestive of IRR that require immediate medical intervention during infusion) during the first 
three cycles of Atezolizumab SC administration or that stop to receive the treatment at-home for any other reason, all subsequent 
Atezolizumab SC administration will be done in the hospital setting only. For low grade (Grade 1–2) IRR events during the first three cycles, 
administration in the at-home treatment setting may be considered with premedication. 
c 
Participants who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after their final 
dose of study treatment. The visit at which response assessment shows progressive disease may be used as the treatment discontinuation 
visit. 
d 
Informed consent must be documented before any study-specific procedures are performed. 
e  
Participants must have a complete resection of a histologically or cytologically confirmed Stage IIB-IIIB (T3-N2) NSCLC (per the UICC/AJCC 
staging system, 8th edition; Detterbeck et al. 2018). Participants must have completed adjuvant chemotherapy at least 4 weeks and up to 12 
weeks prior to randomization and must be adequately recovered from chemotherapy treatment. 
f 
Results of PD-L1 expression tests and EGFR and ALK mutational status performed prior to obtaining informed consent and within 28 days prior 
to may be used for screening assessments rather than repeating such tests, providing that these tests meet protocol requirements. 
g 
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature. See Section 5.5.4.2 for details of the timings of vital 
sign assessments. 
h 
Samples will be collected by a qualified mobile HCP within 3 to 7 days prior to treatment administration and sent to the central laboratory 
for analysis. This is not required if there are valid local laboratory results available for that time window. Central laboratory results will be 
shared with the investigator prior to each planned drug administration at-home. 
i 
Weight is to be measured at Day 1 of each cycle, or whenever the investigator considers there is a substantial change from baseline. 
j  
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems. Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
k 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. Changes from baseline 
abnormalities should be recorded in participant notes.  New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. In the at-home treatment setting findings are to be reported to the study site. 
l 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). Assessments to be performed by the local laboratory in the hospital setting and central laboratory 
during the treatment at-home phase. 
m 
Chemistry includes   bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH. Assessments to be performed by 
the local laboratory in the hospital setting and central laboratory during the treatment at-home phase. 
n 
Coagulation includes INR, aPTT, and PT. 
o 
Thyroid function testing includes thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), and free T4. 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
157/Protocol MO42720, Version 2 
p 
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood); dipstick permitted. 
q 
All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study Atezolizumab SC.  
Urine pregnancy tests (or serum, if urine is not feasible) will be performed at specified subsequent visits during treatment, at the treatment 
discontinuation visit, and may be required beyond Atezolizumab SC discontinuation, monthly for 5 months after the final dose of Atezolizumab 
SC. Pregnancy tests after Atezolizumab SC discontinuation can be performed at-home.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
r 
In accordance with country-specific health authority mandates, pregnancy tests may be required beyond treatment discontinuation, monthly for 
5 months after the final dose of Atezolizumab. Pregnancy tests after study treatment discontinuation can be performed at-home. If a home urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test and if confirmed, immediately communicated to the treating 
physician. 
s 
During Atezolizumab SC administration in the at-home treatment setting, a phone or video connection between the qualified mobile HCP and 
the treating clinic HCPs will be established. 
t 
PRO instruments should be conducted by the participant at-home or at the clinic. MDASI, EORTC IL6 GHS/QoL, EQ-5D-5L, and EORTC OUT-
PATSAT7 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 Atezolizumab SC, unless otherwise specified. The participant acceptability questionnaire will be 
administered following treatment administration. 
u  
Participants will receive training on use of the DPM solution at the baseline visit. DPM participant training will include setting up an account for 
the participant. 
v 
The participant will complete the baseline assessment of symptoms that occurred over the previous 7 days at the end of the DPM participant 
training session, under the supervision of the trainer. 
w 
Participants can report symptoms in real-time throughout the course of the study using the DPM solution. Participants will receive weekly 
messages to remind them that they must report symptoms at least every 7 days as well as 24 hours after each Atezolizumab SC administration 
in the at-home treatment setting. 
x  
Includes adverse events due to the device and adverse events due to the treatment regimen. 
y 
All the above assessments should be conducted before Atezolizumab SC is administered. 
z 
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 in Section 5.5.5. Screening assessments must include CT scans with contrast or MRI scans of the chest, 
abdomen, pelvis, and brain. A spiral CT scan of the chest may be obtained but is not a requirement. If a CT scan with contrast is 
contraindicated (e.g., in participants with impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans of 
the abdomen, pelvis, and brain should be performed. A CT scan with contrast or MRI scan of the brain must be done at screening to 
evaluate CNS metastasis in all participants (MRI scan must be performed if CT scan is contraindicated). An MRI scan of the brain is required 
to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT scan. Bone scans and CT scans of the 
neck should also be performed if clinically indicated. At the investigator's discretion, other methods of assessment of measurable disease may 
be used. 

Appendix 1: Schedule of Activities 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
158/Protocol MO42720, Version 2 
aa  
Patients will undergo tumor assessments as per local standard of care. 
bb 
 HIV serology, HBV serology (HBsAg, HBsAb, and total HBcAb for all patients; HBV DNA for patients with negative HBsAg and HBsAb 
tests and a positive total HBcAb test), HCV serology (HCV antibody for all patients; HCV RNA for patients with a positive HCV antibody 
test) 
cc 
Disease control visits are site visits and only take place while the patient is in the at-home treatment setting. If the patient receives the 
study drug administrations in the hospital, no disease control visits are required. Local laboratory results from the disease control visits 
can be used to confirm the next study drug administration. 
 
 
 

 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
159/Protocol MO42720, Version 2 
Appendix 2  
Eastern Cooperative Oncology Group Performance Status Scale 
 
GRADE 
PERFORMANCE STATUS -  WHO CLASSIFICATION 
0 
Fully active, able to carry out all normal activity 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 more than 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair more 
than 50% of waking hours 
4 
Completely disabled; cannot carry out any self-care; totally 
confined to bed and chair 

 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
160/Protocol MO42720, Version 2 
Appendix 3  
Selected PRO-CTCAE and Other Symptoms 
Category 
Symptom / AE 
PRO CTCAE term 
Cohort A: 
mNSCLC/ ES-
SCLC 
Cohort B: 
eNSCLC 
Cohort 
A: HCC 
Sleep/Wake 
Fatigue / Tiredness / 
Asthenia 
53. PRO-CTCAE™ Symptom 
Term: Fatigue 
X 
X 
X 
Pain 
Abdominal pain 
17. PRO-CTCAE™ Symptom 
Term: Abdominal pain 
X 
X 
X 
Pain 
Chest Pain 
N/A 
X 
X 
 
Pain 
Headache 
49. PRO-CTCAE™ Symptom 
Term: Headache 
X 
X 
 
Pain 
Musculoskeletal pain, 
bone/joint pain 
51. PRO-CTCAE™ Symptom 
Term: Joint pain 
X 
X 
X 
Respiratory 
Cough 
20. PRO-CTCAE™ Symptom 
Term: Cough 
X 
X 
 
Respiratory 
Shortness of breath 
(Dyspnea) 
19. PRO-CTCAE™ Symptom 
Term: Shortness of breath 
X 
X 
 
Cardiologic 
Pounding or Racing 
Heartbeat (Palpitations) 
23. PRO-CTCAE™ Symptom 
Term: Heart palpitations 
X 
X 
 
Cardiologic 
Swelling of arms and legs 22. PRO-CTCAE™ Symptom 
Term: Swelling 
 
X 
X 
Cutaneous 
Itching (Pruritus) 
28. PRO-CTCAE™ Symptom 
Term: Itching 
X 
X (alert for 
any 
increase) 
X 
Cutaneous 
Rash, Urticaria 
24. PRO-CTCAE™ Symptom 
Term: Rash 
X 
X (alert for 
any 
increase) 
X 
Cutaneous 
Infusion or injection site 
reaction 
79. PRO-CTCAE™ Symptom 
Term: Pain, redness, 
inflammation, rash or swelling 
at injection site' 
X 
X (alert for 
any 
increase) 
 
Gastrointestinal Decreased appetite 
(Anorexia) 
8. PRO-CTCAE™ Symptom 
Term: Decreased appetite 
X 
X 
X 
Gastrointestinal Diarrhea 
16. PRO-CTCAE™ Symptom 
Term: Diarrhea 
X 
X 
X 
Gastrointestinal Nausea 
9. PRO-CTCAE™ Symptom 
Term: Nausea 
X 
X 
X 
Gastrointestinal Vomiting 
10. PRO-CTCAE™ Symptom 
Term: Vomiting 
X 
X 
 
Gastrointestinal Constipation 
15. PRO-CTCAE™ Symptom 
Term: Constipation 
 
 
X 
Gastrointestinal Taste Changes (e.g., bad 
taste in mouth) 
7. PRO-CTCAE™ Symptom 
Term: Taste changes 
x 
x 
 
Mood 
Cognitive or psychological 
(anxiety, fear, depression) 
54. PRO-CTCAE™ Symptom 
Term: Anxious 
x 
x 
 
Neurological 
Peripheral neuropathy 
39. PRO-CTCAE™ Symptom 
Term: Numbness & tingling 
x 
x 
 
Miscellaneous 
Fever 
N/A 
x 
x 
x 

 
Appendix 3: Selected PRO-CTCAE and other Symptoms 
 
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Miscellaneous 
Haemorrhage / Bleeds 
(blood in urine, nose 
bleed, blood in cough) 
N/A 
x 
x 
x 
Miscellaneous 
Weight loss 
N/A 
x 
x 
x 
Other 
symptoms 
Other symptoms 
(free text field) 
N/A 
x 
x 
x 
AE = adverse event; ESSCLC =  ES-SCLC = extensive-stage small-cell lung carcinoma; HCC = hepatocellular 
carcinoma; mNSCLC = metastatic non-small cell lung cancer; N/A = not applicable;  PRO CTCAE = patient-reported 
outcomes common terminology criteria for adverse Events; 
 

 
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Appendix 4 
Participant Acceptability Questionnaire 
You previously received Atezolizumab delivered through subcutaneous (SC) injection at 
a clinic, and have now received Atezolizumab through SC injection at-home. 
We are interested in understanding your experiences and preferences as they relate to 
SC administration of Atezolizumab treatment in the clinic versus treatment at-home. 
Please answer the following questions about your experience.  There are no right or 
wrong answers. 
1. Were you satisfied with the care you received at-home? 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 
 
2. Would you describe the type care you received as convenient? 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 
 
3. Did you prefer to receive your treatment in the clinic or at-home? 
 In the clinic 
 
  
At-home  
 
  
No preference (Go to question 6) 
 
4. If you have a preference for one of the locations, how strong is this preference? 
 Very strong 
 
 
Fairly strong  
  
 Not very strong 
 
5. If you have a preference for one of the locations, what are the TWO main reasons for 
your preference? 
□ Feels less emotionally distressing 
□ Reduces my risk of infection 
□ Provides more time to interact with a health care provider 
□ It’s generally more convenient 
□ Other reason; please specify: 
 
6. Please use the space below for any other comments you would like to add: 
 
 

 
Appendix 4: Participant Acceptability Questionnaire 
 
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7. During my treatment at-home I felt supported by the treatment team 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 
 
8. The nurses were very well informed about my history and current medical condition 
and treatment 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 
 
9. I always knew who was responsible for my treatment and care 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 
 
10. There was always qualified staff available if I had questions 
Strongly disagree 
Somewhat disagree  
Somewhat agree  
Strongly agree 

 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
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Appendix 5  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Those 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 people with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
Atezolizumab for people who have previously experienced a severe or life−threatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
• Acute disseminated 
encephalomyelitis 
• Addison disease 
• Ankylosing spondylitis 
• Anti-phospholipid antibody 
syndrome 
• Aplastic anemia 
• Autoimmune hemolytic 
anemia 
• Autoimmune hepatitis 
• Autoimmune 
hypoparathyroidism 
• Autoimmune hypophysitis 
• Autoimmune myelitis 
• Autoimmune myocarditis 
• Autoimmune oophoritis 
• Autoimmune orchitis 
• Autoimmune 
thrombocytopenic purpura 
• Behçet disease 
• Bullous pemphigoid 
• Chronic fatigue syndrome 
• Chronic inflammatory 
demyelinating 
polyneuropathy 
• Churg-Strauss syndrome 
• Crohn’s 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 6  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment administration in a clinical setting: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, or 
endotracheal administration in accordance with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
In the at-home treatment setting, emergency medical services are to be called 
immediately and the provided rescue medication (epinephrine) is to be used as 
applicable to stabilize the patient until emergency medical services arrive. 
 
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 (as applicable). 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.  In the treatment at-home setting this will be 
provided by the emergency medical services. 
5. 
Administer epinephrine (antihistamines or other medications and IV fluids in the 
hospital setting) as required by participant status and as directed by the physician 
in charge. 
6. 
Continue to observe the patient and document observations.

 
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Appendix 7  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
 
Toxicities associated or possibly associated with Atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated. 
Although most immune-mediated adverse events observed with Atezolizumab have 
been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications.  Discontinuation of Atezolizumab may not have 
an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The 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, Atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
• 
Consider holding Atezolizumab 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 Atezolizumab 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 
Atezolizumab 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 Atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefit−risk balance for a given patient prior 
to further administration of Atezolizumab.  Resumption of Atezolizumab may be 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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considered in patients who are deriving benefit and have fully recovered from the 
immune−mediated event.  The decision to re-challenge patients with Atezolizumab 
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. 
DOSE MODIFICATIONS 
There will be no dose modifications for Atezolizumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in participants experiencing 
toxicity considered to be related to study treatment.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over ≥1 month to the equivalent of 
≤ 10 mg/day oral prednisone before Atezolizumab can be resumed.  If Atezolizumab is 
withheld for > 12 weeks after event onset, the patient will be discontinued from 
Atezolizumab.  However, Atezolizumab may be withheld for > 12 weeks to allow for 
patients to taper off corticosteroids prior to resuming treatment.  Atezolizumab can be 
resumed after being withheld for > 12 weeks the patient is likely to derive clinical benefit.  
The decision to re-challenge patients with Atezolizumab should be based on the 
investigator’s benefit−risk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.  Atezolizumab treatment may be suspended 
for reasons other than toxicity (e.g., surgical procedures).  The acceptable length of 
treatment interruption must be based on the investigator’s benefit-risk assessment 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. 
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 according to local standard of 
care. 
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 1. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
• Continue Atezolizumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• For Grade 1 pneumonitis, consider withholding Atezolizumab. 
Pulmonary 
event, Grade 2 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
• For recurrent events or events with no improvement after 48–72 hours 
of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. c, d 
• 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 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on 
the investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
participants with Atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to advise 
as needed. 
d In case of pneumonitis, Atezolizumab should not be resumed after permanent 
discontinuation. 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
• Continue Atezolizumab. 
• Monitor LFTs until values resolve to within normal limits 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 Atezolizumab 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (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 benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. c 
• Consider patient 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. 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (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 benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 

 
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue Atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
• Patient 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 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, resume Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
• Permanently discontinue Atezolizumab 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 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on of the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with Atezolizumab should be based on the investigator’s benefit−risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  Patients should be referred to an 
endocrinologist if an endocrinopathy is suspected.  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

 
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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
• Continue Atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
Grade 2 
hypothyroidism 
• Consider withholding Atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Consider patient referral to endocrinologist. 
• Resume Atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Grade 3 and 4 
hypothyroidism 
• Withhold Atezolizumab. 
• 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 Atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue Atezolizumab. 
• Monitor TSH every 4 weeks. 
• Consider participant referral to endocrinologist. 
TSH < 0.1 mU/L: 
• Follow guidelines for Grade 2 hyperthyroidism. 
• Consider participant referral to endocrinologist. 
Grade 2 
hyperthyroidism 
• Consider withholding Atezolizumab. 
• Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
• Consider participant referral to endocrinologist. 
• Resume Atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Grade 3 and 4 
hyperthyroidism 
• Withhold Atezolizumab. 
• Initiate treatment with anti-thyroid drugs such as methimazole 
or carbimazole as needed. 
• Refer to endocrinologist. 
• Resume Atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c 
 
 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
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MRI = magnetic resonance imaging 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c 
Resumption of Atezolizumab 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 Atezolizumab should be based on the investigator’s benefit−risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 

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Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 2−4  
• Withhold Atezolizumab 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better or participant is not 
stable on replacement therapy while withholding Atezolizumab, 
permanently discontinue Atezolizumab and contact the Medical 
Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
• Continue Atezolizumab. 
• 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 Atezolizumab. 
• Initiate treatment with insulin. 
• Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
• Monitor for glucose control. 
• Resume Atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI = magnetic resonance imaging. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on 
the investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab 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 Atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to advise 
as needed. 

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Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact 
the Medical Monitor. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. c 
• Refer patient 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. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on 
the investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab 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 Atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to advise 
as needed. 

 
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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• Continue Atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue Atezolizumab and contact the Medical Monitor. 
c 
• Refer patient 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 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab 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 Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., 
B-type natriuretic peptide) or cardiac imaging abnormalities, 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 patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
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 echocardio−gram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 

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Events Associated with Atezolizumab 
 
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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 6.  Withhold treatment with Atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 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 Atezolizumab and contact the Medical 
Monitor. 
• Refer patient 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. 
 
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of Atezolizumab.  
However, participants who experience an infusion-related reaction (IRR) or cytokine 
release syndrome (CRS) with Atezolizumab may receive premedication with 
antihistamines, antipyretic medications, and/or analgesics (e.g., acetaminophen) for 
subsequent infusions.  Metamizole (dipyrone) is prohibited in treating Atezolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with Atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
Atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T-cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including Atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  
If a participant develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 

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Events Associated with Atezolizumab 
 
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome 
Event 
Management 
Grade 1 a 
fever b with or 
without 
constitutional 
symptoms  
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in 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 IRRs and/or CRS. 
Grade 2 a 
fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
hypoxia requiring 
low-flow oxygen d 
by nasal cannula 
or blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. 
• Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
Atezolizumab, and contact the Medical Monitor. e 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of Atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
antipyretic medications, and/or analgesics and monitor closely for IRRs 
and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Medical Monitor. 

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Events Associated with Atezolizumab 
 
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
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, 
nonrebreather 
mask, or 
Venturi-mask 
• Permanently discontinue Atezolizumab and contact the 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 
the ICU is recommended.  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per institutional 
practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 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 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients who 
are refractory to anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator and in consultation with 
the Medical Monitor. 
Grade 4 a 
fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• Permanently discontinue Atezolizumab and contact the Medical Monitor. e 
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  For patients 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 patient until complete resolution of symptoms. 

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Events Associated with Atezolizumab 
 
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.) 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive 
airway pressure; CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; 
CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; 
eCRF = electronic Case Report Form; HLH = hemophagocytic lymphohistiocytosis; 
ICU = intensive care unit; IRR = infusion-related reaction; MAS = macrophage activation 
syndrome; NCCN = National Cancer Comprehensive Network; NCI = National Cancer Institute. 
Note:  These management guidelines have been adapted from the NCCN guidelines for the 
management of CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for these management guidelines is based on ASTCT Consensus Grading 
Scale for CRS.  NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or 
organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, 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 Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with Atezolizumab should be based on the investigator’s benefit−risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.  For 
subsequent infusions, administer oral premedication with antihistamines, anti pyretic 
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 assessing 
the benefit−risk ratio. 
f Refer to Riegler et al. (2019). 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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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 8. 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• Continue Atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment 
with 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 Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact the Medical Monitor. c 
• For recurrent events, permanently discontinue Atezolizumab 
and contact the Medical Monitor. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 

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Events Associated with Atezolizumab 
 
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Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with 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 
Atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact the Medical Monitor. c 
• For recurrent events, permanently discontinue Atezolizumab 
and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
• Permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
• Refer patient 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. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of Atezolizumab 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 Atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, 
Grade 1  
• Continue Atezolizumab. 
• Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2  
• Continue Atezolizumab. 
• Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
• If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic event, 
Grade 3  
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
• Initiate treatment with 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact 
the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 

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Events Associated with Atezolizumab 
 
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Table 9 
Management Guidelines for Dermatologic Events (cont.) 
Dermatologic event, 
Grade 4 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor.  c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• Withhold Atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis. 
• Confirm diagnosis by referring 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 Atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
NEUROLOGIC DISORDERS 
Patients 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 10, with specific guidelines for myelitis provided in Table 11. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue Atezolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy 
– 
If event resolves to Grade 1 or better, resume Atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and 
contact the Medical Monitor. c 
• For facial paresis: 
– 
If event resolves fully, resume Atezolizumab b 
– 
If event does not resolve fully while withholding 
Atezolizumab, permanently discontinue Atezolizumab 
and contact the Medical Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 
4 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral 
or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue Atezolizumab unless symptoms worsen or do 
not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue Atezolizumab and contact the 
Medical Monitor. 
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue Atezolizumab and contact the 
Medical Monitor. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
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 patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Participants with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 12 Management Guidelines for Immune-Mediated Meningocephalitis 
Event 
Management 
Immune-mediated meningoencephalitis, all grades 
• Permanently discontinue Atezolizumab 
and contact the Medical Monitor. a 
• Refer patient to neurologist. 
• 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. 
 
RENAL EVENTS 
Eligible participants must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common 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. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table13  . 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 13 Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
• Continue Atezolizumab. 
• Monitor kidney function, including creatinine and urine protein, closely 
until values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
• Withhold Atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue Atezolizumab and contact the Medical Monitor. 
c 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (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 benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
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/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the below guidelines in Table 14. 
Table 14  Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue Atezolizumab. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold Atezolizumab for up to 12 weeks after event onset a and 
contact the Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment 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 Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with Atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
Digital Patient Monitoring—F. Hoffmann-La Roche Ltd 
193/Protocol MO42720, Version 2 
Table 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
• Withhold Atezolizumab for up to 12 weeks after event onset a and contact 
the Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if 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 Atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact the 
Medical Monitor. c 
• For recurrent events, treat as a Grade 4 event.  Permanently discontinue 
Atezolizumab and contact the Medical Monitor. c 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue Atezolizumab and contact the Medical Monitor. c 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if 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 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
Atezolizumab should be based on the investigator’s benefit−risk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 
 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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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 prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
• 
Fever ≥ 38.5°C 
• 
Splenomegaly 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 × 109/L (< 100,000/µL) 
– 
ANC < 1.0 × 109/L (< 1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(< 150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (> 500 ng/mL) 
• 
Soluble IL-2 receptor (soluble CD25) elevated ≥ 2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile participant should 
be classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (> 684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (≤ 181,000/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (> 156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (≤ 360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the below 
guidelines in Table 15 . 

Appendix 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• Permanently discontinue Atezolizumab and contact the Medical 
Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if indicated 
per institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact the 
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 7:Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
 
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REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti−programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:502−4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:190−6. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465−77. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:625−38. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:355−62. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:481−9. 
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. 

  
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Appendix 8  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations  
(for Use in European Economic Area) 
 
Product Name 
IMP/NIMP Designation 
Marketing 
Authorization Status 
in EEA 
Used within 
Marketing 
Authorization 
Atezolizumab SC 
(RO5541267) 
IMP (test product) a 
Unauthorized 
No b 
Atezolizumab IV 
(RO5541267) 
NIMP (other) 
Authorized 
Yes 
Bevacizumab 
(RO4876646) 
NIMP (other) 
Authorized 
Yes 
Carboplatin 
NIMP (other) 
Authorized 
Yes 
Nab-paclitaxel 
NIMP (other) 
Authorized 
Yes 
Epinephrine 
NIMP (other) 
Authorized 
Yes 
EEA = European Economic Area; IMP = investigational medicinal product; NIMP = non-investigational 
medicinal product. 
a Atezolizumab SC is considered to be an IMP test product in Cohort B. 
b Atezolizumab IV is approved within the EEA.  Atezolizumab is used in a different form from the 
marketing authorization. 
 

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