A Phase IIIb, Single Arm, Multicenter Study of Atezolizumab in Combination With Bevacizumab to Investigate Safety and Efficacy in Spanish Patients With Unresectable or Unsuitable for Locoregional Treatments Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Sponsor: Hoffmann-La Roche

Official Title: 
NCT Number: 
Document Date: 
A Phase IIIB, Single Arm, Multicenter Study of Atezolizumab in 
Combination with Bevacizumab to Investigate Safety and Efficacy in 
Spanish Patients with Unresectable or Unsuitable for Locoregional 
Treatments Hepatocellular Carcinoma Not Previously Treated with 
Systemic Therapy
NCT04732286
Protocol Version 2: 16-March-2023

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
2/ Protocol ML42600, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol ML42600, Version 2, changes to the protocol Version 1, along with a rationale for each 
change, are summarized below: 
● 
Language regarding Exploratory Efficacy, Exploratory Biomarker Analysis for Tissue and Blood 
biomarker Plan and Exploratory Radiomic Analysis Plan have been updated (Sections 2.2, 2.4, 
3.1.1, 4.1.1 and Appendixes 1, 2 and 3). 
● 
Language of exclusion criteria has been added to indicate that - Patients with vascular invasion 
of the portal or hepatic veins may be enrolled (4.1.2). 
● 
Immunosuppressive medications have been removed from the prohibited therapy section 
(4.4.3) and added to the cautionary therapy section (4.2.2.1) to align with atezolizumab 
management guidelines in Appendix 10 that permit use of immunosuppressive medications for 
the treatment of corticosteroid-refractory immune-mediated adverse events. 
● 
The list of identified risks for atezolizumab has been revised to include pericardial disorders, 
myelitis, and facial paresis (Section 5.1.2). 
● 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an identified 
risk associated with atezolizumab and language has been revised accordingly (Section 5.1.2). 
● 
 The list of adverse events of special interest has been revised to include myelitis and facial 
paresis (Section 5.2.3). 
● 
Emergency Medical Contacts section have been updated (Section 5.4.1). 
● 
Management of study quality has been modified. Establishment of quality tolerance limits has 
been deleted. (Section 9.3). 
● 
Administrative structure from the Sponsor (Roche Farma S.A.) has been modified. (Section 
9.5). 
● 
Appendix 7 has been revised to indicate that caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening skin 
adverse reaction or pericardial disorder while receiving another immunostimulatory anticancer 
agent. 
● 
Appendix 7 has been revised to include autoimmune myelitis and the term “primary biliary 
cirrhosis” has been replaced with “primary biliary cholangitis” as the term “primary biliary 
cirrhosis” is outdated in clinical practice. 
● 
Management guidelines for Bevacizumab have been updated (Appendix 9). 
● 
Risks and management guidelines for atezolizumab have been updated to align with the 
Atezolizumab Investigator’s Brochure Version 19 and addenda (Appendix 10). 
● 
Amylase, lipase and -fetoprotein have been added to section 4.5.6 and Appendix 1 (subtitle 
n) 
Additional minor changes have been made to improve clarity and consistency. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
3/ Protocol ML42600, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IIIB, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB TO INVESTIGATE SAFETY AND 
EFFICACY IN SPANISH PATIENTS WITH 
UNRESECTABLE OR UNSUITABLE FOR 
LOCOREGIONAL TREATMENTS HEPATOCELLULAR 
CARCINOMA NOT PREVIOUSLY TREATED WITH 
SYSTEMIC THERAPY 
ACRONYM: 
ATHECA study 
PROTOCOL NUMBER: 
ML42600 
VERSION NUMBER 
2 
EUDRACT NUMBER: 
2020-005268-71 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04732286 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
PHASE: 
IIIb 
INDICATION: 
Hepatocellular carcinoma 
SPONSOR: 
Roche Farma S.A. 
 
 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
4/ Protocol ML42600, Version 2 
Objectives and Endpoints 
This study will evaluate primarily the safety of Atezolizumab in combination with 
Bevacizumab in patients with unresectable hepatocellular carcinoma who have received no 
prior systemic treatment and are considered unsuitable for locoregional therapy, by 
assessing the incidence and severity of adverse events that lead to discontinuation of any 
study agent. In this protocol, "study treatment" refers to the combination of agents assigned 
to patients as part of this study (i.e., Atezolizumab and Bevacizumab). Efficacy of 
Atezolizumab in combination with Bevacizumab in this study, in contrast with IMbrave150 
study, is considered within secondary and exploratory objectives. 
Primary Objective 
Corresponding Endpoint 
To evaluate the safety of 
Atezolizumab + Bevacizumab 
- Incidence and severity of adverse events of grade ≥ 3. that lead to 
discontinuation of Atezolizumab and/ or Bevacizumab. 
Main Secondary Objective 
Corresponding Endpoint 
To evaluate the efficacy of 
Atezolizumab + Bevacizumab 
OS, defined as the time from initiation of study treatment to death 
from any cause. 
Other Secondary Objectives 
Corresponding Endpoints 
To further evaluate the safety 
of Atezolizumab + 
Bevacizumab 
 
- Adverse Event severity will be determined according to NCI 
CTCAE v5.0 during patient’s treatment. 
- Change from baseline in targeted Vital signs. 
- Change from baseline in targeted Clinical laboratory test results. 
To further evaluate the 
efficacy of Atezolizumab + 
Bevacizumab 
- PFS, defined as the time from initiation of study treatment to the 
first occurrence of disease progression or death from any cause 
(whichever occurs first), as determined by the investigator 
according to RECIST v1.1. 
- Objective response rate (ORR), defined as a complete or partial 
response, on two consecutive occasions ≥ 4 weeks apart, as 
determined by the investigator according to RECIST v1.1. 
- Time to progression (TTP), defined as the time from initiation of 
study treatment to the first occurrence of disease progression, as 
determined by the investigator according to RECIST v1.1 criteria. 
- Duration of Response (DOR), defined as the time from the first 
occurrence of a documented objective response to disease 
progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1. 
- Number/Rate of patients starting second line treatment 
To evaluate deterioration of 
Liver function during the 
treatment 
- Hepatic function assessed according to the following parameter: 
o International normalized ratio (INR). 
o Presence 
or 
absence 
of 
Ascites 
and 
/or 
Hepatic 
Encephalopathy. 
o Albumin-Bilirubin (ALBI) assessment grades of 1 to 3.* 
* ALBI assessment grades 1 to 3 (Johnson et al. 2015) are based on calculated ALBI score (log10 
bilirubin [µmol/L] × 0.66) + (albumin [g/L] × −0.0852) values as follows: ALBI score ≤ −2.60 = ALBI 
grade 1; > −2.60 to ≤ −1.39 =ALBI grade 2); and > −1.39 = ALBI grade 3. 
NCI CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; OS = overall survival; PFS = progression-free survival; RECIST v1.1 = Response 
Evaluation Criteria in Solid Tumours, Version 1.1. 
 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
5/ Protocol ML42600, Version 2 
Exploratory Response 
Objectives 
Corresponding Endpoint 
To further, evaluate whether 
the Tumour Responses 
patters to Atezolizumab + 
Bevacizumab treatment using 
different criteria have a 
different impact on OS and 
PFS 
- Tumour Response will be primarily assessed by RECIST 1.1. 
And the results in efficacy on terms of OS and PFS reported 
accordingly. 
- Additionally, a secondary analysis will include HCC mRECIST, 
EASL and iRECIST criteria, based on the following patterns of 
progression: 
o HCC mRECIST, by measuring for any increase (confirmed in 
follow up visit) in the sum of longest diameter of viable tumour 
(unidimensional measurement). 
o EASL, by measuring for any increase (confirmed in follow up 
visit) 
in 
the 
area 
of 
viable 
tumour 
(bidimensional 
measurement). 
o iRECIST, 
by 
taking 
into 
consideration 
tumour 
pseudoprogression. 
To further evaluate whether 
the patterns of tumour 
progression (growth versus 
new lesion, intrahepatic versus 
extrahepatic) have a different 
impact on OS and PFS 
- Tumour Progression (and the results in efficacy on terms of OS 
and PFS) will be primarily assessed by RECIST v1.1 criteria 
based on the following patterns of progression: 
o > 20% increase in tumour size against a known baseline lesion 
(intrahepatic growth [IHG] or extrahepatic growth [EHG]) 
o new intrahepatic lesion (NIH)  
o new extrahepatic lesion and/or vascular invasion (NEH). 
- Additionally, a secondary analysis for the registration of tumour 
progression will include HCC mRECIST, taking into consideration 
the RECIST modifications described for SHARP (Reig 2015). 
- Exploratory assessment on OS and PFS will be performed based 
on the following patterns of progression: 
o New intrahepatic nodules are considered progression if: 
- They exceed 10 mm in diameter and present arterial 
enhancement at dynamic imaging. 
- Non-specific non-hypervascular nodules ≥ 10 mm (absence 
of the above definitions) present a doubling tumour size 
reaching a diameter > 20 mm since its initial detection or 
showing hyperenhancement during the follow-up. 
- Ascites and pleural effusion reflect progression only if malignant 
cells are pathology (cytology) proven. 
- Vascular invasion may be classified as progression if expansive 
and/or displaying arterial enhancement at dynamic imaging. 
- Hilar lymph nodes will be considered malignant if the smaller 
diameter exceeds 20 mm. Growth of existing nodes uses the 
same cut-offs as other lesions. 
- Lobar or segmental portal invasion with growth of the tumour 
thrombus reaching the main trunk of the portal vein. 
To explore if post-study 
treatments have an impact on 
OS  
- OS will be analysed according to type and duration of each post-
study treatment. 
To evaluate if reasons for 
treatment withdrawal have an 
impact on OS 
- OS based on the following reasons of treatment withdrawal: 
o PD vs AE vs deteriorating liver function based on: 
- INR assessments; 
- presence 
or 
increase 
in 
ascites 
and/or 
hepatic 
encephalopathy; 
- increase in ALBI assessment scores grading.* 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
6/ Protocol ML42600, Version 2 
To analyse the organ-specific 
response rate (OS-RR) using 
RECIST 1.1 and the 
cumulative incidence 
probability of organ-specific 
progression 
- We hypothesized that treatment efficacy varies across different 
metastatic sites. Comparison of OS-RR including target lesions 
from the liver, lungs, lymph nodes and non-target lesions in bones. 
To determine the applicability 
of depth of response as 
surrogate for OS 
- Depth of response (decrease in tumour burden) compared to 
baseline measurement according to: 
o RECIST 1.1 
o EASL 
o mRECIST 
o iRECIST 
Exploratory Biomarker 
Objective 
Corresponding Endpoint 
To identify Tissue & Blood 
based Biomarkers that might 
be associated with response 
patterns to Atezolizumab + 
Bevacizumab and patient 
outcomes under 
Atezolizumab+ Bevacizumab 
treatment 
Tumour biopsy sample if available to characterize: 
(1) Tumour immune-cell infiltrate  
(2) The specificities of T lymphocyte receptors against tumour-
specific antigens. 
(3) Specific expression patterns that may constitute gene signatures 
with prognostic and/or predictive power of response to Atezolizumab 
+ Bevacizumab. 
(4) Specific set of mutations associated with response to 
Atezolizumab + Bevacizumab 
Biomarker (blood, plasma, and serum) samples to evaluate one 
or more of the following: 
(1) Cytokines. 
(2) cfDNA exome sequencing to capture mutations present in 
circulating DNA. 
(3) Sequencing the TCRs of circulating T cells to detect specific 
antigenicity of tumour antigens. 
(4) Characterization of circulating immune populations which 
changes could predict response  to Atezolizumab + Bevacizumab  
* ALBI assessment grades 1 to 3 (Johnson et al. 2015) are based on calculated ALBI score (log10 
bilirubin [µmol/L] × 0.66) + (albumin [g/L] × −0.0852) values as follows: ALBI score ≤ −2.60 = ALBI 
grade 1; > −2.60 to ≤ −1.39 =ALBI grade 2); and > −1.39 = ALBI grade 3. 
ALBI = Albumin-Bilirubin; EASL = European Association for the Study of the Liver; HCC = 
hepatocellular carcinoma; iRECIST = modified Response Evaluation Criteria in Solid Tumours for 
immune therapeutics; mRECIST = modified Response Evaluation Criteria in Solid Tumours; ORR = 
Objective Response Rate; OS = overall survival; PD = progressive disease; PFS = progression-free 
survival; RECIST v1.1 = Response Evaluation Criteria in Solid Tumours, Version 1.1. 
 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
7/ Protocol ML42600, Version 2 
Exploratory Radiomic 
Objective 
Corresponding Endpoint 
CT-radiomics analysis 
towards a more precise 
evaluation of response to 
Atezolizumab and 
Bevacizumab in patients with 
unresectable hepatocellular 
carcinoma included. 
- 
To explore correlation of CT-radiomics signatures (including 
shape, first-order and higher-order texture features) at baseline 
with response to treatment. 
- 
To explore correlation in early changes in CT-radiomics 
signatures with response to treatment. 
- 
To explore inter- and intra- tumour CT-radiomics changes in 
relation to differences in responder/non-responder lesions and 
with the patient clinical outcome. 
- 
To explore correlation of radiomics features with tumour 
mutational status to develop radiogenomics phenotypes. 
- 
To explore correlation of CT-radiomics features with the tumour 
microenvironment including tumour immunophenotype by RNA 
seq 
and 
multiparametric 
immunofluorescence 
and 
vascularisation from tumour samples. 
 
Efficacy Objectives 
Secondary Efficacy Objective 
Efficacy analysis includes both main and other secondary objectives. 
All baseline summaries and efficacy analyses will be based on the ITT (intent-to-treat) 
analysis set defined as all recruited patients. 
Time-dependent variables OS, PFS, TTP and Duration of Response (DOR) will be analysed 
using Kaplan-Meier (K-M) methods and Greewood’s formula. Medians and the quartiles with 
95% confidence interval will be derived from the K-M curves. Kaplan-Meier plots with a 95% 
CI for OS, PFS, PPS and DOR will be prepared. 
ORR will simply be summarized. The ORR will be calculated as the percentage of patients 
who have a CR or PR before any evidence of progression. A 95% CI will be derived for the 
ORR using Wilson score intervals (CIs for a single proportion). 
Following disease progression, patients will be followed for survival to evaluate whether the 
patterns of tumour progression (growth versus new lesion, intrahepatic versus extrahepatic) 
have a different impact on OS and PPS. OS and PPS will be described based on the 
following patterns of progression: 
- 
> 20% increase in tumour size against a known baseline lesion (intrahepatic growth 
[IHG] or extrahepatic growth [EHG]) 
- 
new intrahepatic lesion (NIH)  
- 
new extrahepatic lesion (NEH) and/or vascular invasion 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
8/ Protocol ML42600, Version 2 
To evaluate if post-study treatments have an impact on OS following disease progression, 
patients will be followed for anti-cancer therapies and survival with a descriptive analysis. In 
details, number and rate of patients starting second or further lines of treatment will be 
described indicating time and duration of each post-study treatment. OS based on the type 
and duration of each post-study treatments will be described. 
To evaluate if reason of treatment withdrawal has impact on OS, OS based on the following 
reasons of treatment withdrawal will be described: 
- 
Progressive disease (PD) vs adverse event (AE) vs deteriorating liver 
function/clinical conditions vs radical treatment. 
Missing values will be classified and managed using the methods outlined described above. 
Continuous and count variables: 
- location measures: mean and median; 
- dispersion measures: standard deviation and range; 
- categorical variables: absolute and relative frequency. 
Study Design 
a) Description of the Study 
This is a Phase IIIb, one arm, multicentre, open - label study designed to primarily evaluate 
the safety and efficacy of Atezolizumab + Bevacizumab in patients with locally advanced or 
metastatic HCC who have received no prior systemic treatment. 
The treatment schemed for all patients included in the study will be:  
- Atezolizumab 1200 mg IV infusions Q3W (dosed in 3-week cycles) + Bevacizumab 15 
mg/kg Q3W (dosed in 3-week cycles). 
Patients treated with Atezolizumab + Bevacizumab, who transiently withhold or 
permanently discontinue either Atezolizumab or Bevacizumab, may continue on single-
agent therapy as long as the patients are experiencing clinical benefit in the opinion of the 
investigator and after discussion with the Medical Monitor (i.e., patients transiently withhold 
or permanently discontinue Bevacizumab for adverse effects may continue Atezolizumab 
monotherapy and vice versa).  
Patients will receive Atezolizumab and/ or Bevacizumab until unacceptable toxicity or loss 
of clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data, and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease). 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
9/ Protocol ML42600, Version 2 
The patients who are clinically stable will be allowed to continue on treatment beyond initial 
RECIST v1.1 defined progression, until next assessment (between 4 to 8 weeks later) to 
ensure patient’s suitability for treatment, as recommended by iRECIST criteria. 
In the absence of unacceptable toxicity, patients who meet criteria for disease progression 
per RECIST v1.1 while receiving Atezolizumab and/or Bevacizumab will be permitted to 
continue the study treatment if they meet all of the following criteria: 
- 
Evidence of clinical benefit, as determined by the investigator following a review of all 
available data. 
- 
Absence of symptoms and signs (including laboratory values) indicating unequivocal 
progression of disease. 
- 
Absence of decline in ECOG Performance Status that can be attributed to disease 
progression. 
- 
Absence of tumour progression at critical anatomical sites (e.g., leptomeningeal 
disease or brain metastases) that cannot be managed by protocol-allowed medical 
interventions. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Laboratory safety assessments 
will include the regular monitoring of haematology and blood chemistry. 
Tumour assessments will be performed at baseline and at regular intervals during study 
treatment. Additional scans will be performed as clinically indicated. Tumour assessments 
will continue until disease progression according to RECIST v1.1 criteria and confirmed in 
the patient’s next follow-up (providing there is a further increase of at least 5 mm of target 
tumour burden or new target lesion or any increase in non-target disease), regardless of 
whether treatment has been discontinued (e.g., for toxicity). Patients who meet RECIST 
v1.1 criteria for progression will undergo tumour assessments until loss of clinical benefit. 
In the absence of disease progression, tumour assessments should continue until consent 
is withdrawn, death, or the study is terminated by the Sponsor, whichever occurs first.  
Following disease progression, patients will be followed for survival and subsequent anti-
cancer therapies until death, loss to follow-up, withdrawal of consent, or study termination 
by Sponsor, whichever occurs first. 
Patients my withdraw their consent for study participation but can continue to participate in 
the study survival follow up program should they wish to do so. 
Patient samples, including serum and plasma, will be collected for the exploratory Tissue 
and Blood Biomarker Plan assessments. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
10/ Protocol ML42600, Version 2 
b) Assessment of response and progression 
Registration of Response: Tumour Response will be primarily assessed by RECIST 1.1 
as a main assessment. Since activity may be detected by appearance of necrosis, a 
secondary exploratory analysis will include HCC mRECIST and EASL criteria. HCC 
mRECIST measures the sum of longest diameter of viable tumour and EASL the area of 
viable tumour. 
Registration of response will be also assessed by applying iRECIST rules and compared 
with other response criteria in terms of OS and PFS. 
Bevacizumab induces vasoconstriction and this reduces splanchnic blood flow and thus, 
hepatic artery blood flow. This may reduce the intensity of contrast uptake that should not 
be registered as necrosis. In any case, registration of response or of stable disease will not 
affect in treatment maintenance. 
Registration of progression: Tumour Progression will be primarily assessed by RECIST 
1.1 and the efficacy results in in terms of OS and PFS will be registered based on the 
following patterns of progression:  
- 
> 20% increase in tumour size against a known baseline lesion (intrahepatic growth 
[IHG] or extrahepatic growth [EHG]) 
- 
new intrahepatic lesion (NIH)  
- 
new extrahepatic lesion and/or vascular invasion (NEH) 
Secondary exploratory analysis will include HCC mRECIST, taking into consideration the 
RECIST modifications described for SHARP (Reig 2015) for the capture of tumour 
progression to prevent over registration of progression and improper treatment interruption. 
Exploratory assessment on OS and PFS will be performed based on the following patterns 
of progression:  
 New intrahepatic nodules will be considered progression if:  
- They exceed 10 mm in diameter and present arterial enhancement at dynamic 
imaging. 
- Non-specific non-hypervascular nodules ≥ 10 mm (absence of the above definitions) 
present a doubling tumour size reaching a diameter > 20 mm since its initial detection 
or showing hyperenhancement during the follow-up. 
- Ascites and pleural effusion reflect progression only if malignant cells are pathology 
(cytology) proven. 
- Vascular invasion may be classified as progression if expansive and/or displaying 
arterial enhancement at dynamic imaging. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
11/ Protocol ML42600, Version 2 
- Hilar lymph nodes are considered malignant if the smaller diameter exceeds 20mm 
and/or are hypervascular with these characteristics confirmed on the next follow up. 
Growth of existing nodes uses the same cut-offs as other target lesions. 
 Registration of progression will be also assessed by applying iRECIST rules and 
compared with other response criteria in terms of OS and PFS. 
 Additional exploratory assessment of the depth of response by means of changes in TL 
tumour burden and its association with OS and PFS will be analysed. 
 Finally, based on the hypothesis that treatment efficacy varies across different metastatic 
sites, will carry out a comparison of organ-specific – response rate including target lesions 
from the liver, lungs, lymph nodes and non-target lesions in bones. 
c) Criteria for treatment discontinuation 
Safety events related to treatment discontinuation is the primary endpoint of the study; this 
may be reached through several events. 
● 
Development of SAEs ≥ grade 3 clinically significant considered related to any 
study treatment and irrespective of tumour evolution. 
● 
Tumour progression outside the liver: this includes confirmed growth in 
sequential imaging, and metastasis spread in any location, new lymph nodes, new 
vascular invasion – note that vascular invasion should never be considered a target 
lesion.) assessed by RECIST v1.1 and confirmed by iRECIST 
● 
Tumour progression within the liver: assessed by RECIST v1.1as confirmed by 
iRECIST for target lesions. However, in case of new intrahepatic (NIH) tumour sites, 
treatment should not be interrupted upon detection of new nodules at first time. 
Further growth during follow-up should be registered to decide treatment interruption. 
● 
Liver function deterioration: 
o 
Associated to progression will also represent a criterion for treatment 
interruption as it will also fit into SAEs ≥ 3.  
o 
Associated to appearance of ascites in need of treatment, jaundice or 
encephalopathy will be considered also a criterion for treatment 
discontinuation. 
According to these definitions, treatment may be maintained beyond progression in very 
specific circumstances following the iRECIST and the refinements related to HCC as per 
registration of progression. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
12/ Protocol ML42600, Version 2 
Number of patients 
This study will enrol approximately 100 patients in one arm of treatment. 
a) Target Population Inclusion Criteria 
Patients must meet the following criteria for study entry: 
- 
Signed Informed Consent Form. 
- 
Age ≥ 18 years at time of signing Informed Consent Form. 
- 
Ability to comply with the study protocol, in the investigator's judgment. 
- 
Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by 
histology or radiologically, following the AASLD criteria. 
- 
Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies. 
- 
No prior systemic therapy (including systemic investigational agents) for HCC. 
- 
At least one measurable (per RECIST 1.1) untreated lesion detected by CT scan. 
- 
Patients who received prior local therapy such as radiofrequency ablation, 
percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused 
ultrasound, transarterial chemoembolization, transarterial embolization (excluding 
transarterial radioembolization.) are eligible provided the target lesion(s) have not been 
previously treated with local therapy or the target lesion(s) within the field of local 
therapy have subsequently progressed in accordance with RECIST version 1.1: Those 
patients. 
- 
For those patients who received external beam radiotherapy as prior locoregional 
therapy should be necessary to wait at least 3 months before they could be included in 
this study. 
- 
ECOG Performance Status of 0 or 1 within 7 days prior to recruitment. 
- 
Child-Pugh class A with compensated ascites, within 7 days prior to recruitment. 
- 
Patients should submit a pre-treatment tumour tissue sample. If tumour tissue is not 
available (e.g., depleted for prior diagnostic testing), it is recommendable to take a 
new biopsy if it´s clinically possible. If tumour tissue is available: A formalin-fixed, 
paraffin-embedded (FFPE) tumour specimen in a paraffin block (preferred) or a total of 
28 slides (12 slides for histologic studies and 2x8 slides for genomic studies) containing 
unstained, freshly cut, serial sections should be submitted as detailed in the sample 
manual. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
13/ Protocol ML42600, Version 2 
- 
Adequate haematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to recruitment, unless otherwise specified: 
– 
ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support. 
– 
Lymphocyte count ≥ 0.5 × 109/L (500/μL). 
– 
Platelet count ≥ 75 × 109/L (75,000/μL) without transfusion. 
– 
Haemoglobin ≥ 90 g/L (9 g/dL). 
– 
AST, ALT, and alkaline phosphatase (ALP) ≤ 5 × upper limit of normal (ULN) 
– 
Serum bilirubin ≤ 3 × ULN. 
– 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated 
using the Cockcroft-Gault formula). 
– 
Serum albumin ≥ 28 g/L (2.8 g/dL) without albumin infusion. 
– 
INR ≤ 1.5. 
– 
Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study 
treatment). 
Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate < 1 g of protein 
in 24 hours. 
- 
Resolution of any acute, clinically significant treatment-related toxicity from prior 
therapy to Grade ≤ 1 prior to study entry. 
 
Negative HIV test at screening. 
- 
Documented virology status of hepatitis, as confirmed by screening HBV and HCV 
serology test.  
- 
For patients with active hepatitis B virus (HBV): 
HBV DNA < 500 IU/mL obtained within 28 days prior to initiation of study treatment, 
and 
Anti-HBV treatment (per local standard of care, e.g., entecavir) for a minimum of 
14 days prior to study entry and willingness to continue treatment for the length of 
the study. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
14/ Protocol ML42600, Version 2 
- 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per 
year during the treatment period and for at least 5 months after the last dose of 
Atezolizumab and 6 months after the last dose of Bevacizumab. Women must refrain 
from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
- 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of < 1% per year during the treatment period and for 6 months after the last dose of 
Bevacizumab. Men must refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the last dose of Bevacizumab to avoid 
exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
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b) Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
- 
Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
⮚ Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone treatment are eligible for the study. 
⮚ Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
⮚ Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
o Rash must cover < 10% of body surface area. 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
o 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. 
- 
Known 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. 
- 
History of congenital long QT syndrome or corrected QT interval > 500 ms (calculated 
with use of the Fridericia method) at screening. 
- 
History of uncorrectable electrolyte disorder affecting serum levels of potassium, 
calcium, or magnesium within the previous 12 months. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
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- 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the study. 
- 
History of malignancy other than HCC within 5 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, ductal carcinoma in situ, Stage I uterine 
cancer or bladder carcinoma in situ. 
- 
Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteraemia, or severe 
pneumonia. 
- 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment. 
⮚ Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) or patients receiving 
Rifaximin as prevention of encephalopathy are eligible for the study. 
- 
Prior allogeneic stem cell or solid organ transplantation. 
- 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications. 
- 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during Atezolizumab treatment or 
within 5 months after the last dose of Atezolizumab. 
- 
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 or Bevacizumab formulation. 
- 
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment 
or within at least 5 months after the last dose of Atezolizumab and 6 months after the 
last dose of Bevacizumab. 
⮚ Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
- 
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
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- 
Untreated or incompletely treated oesophageal and/or gastric varices with bleeding or 
high-risk for bleeding. 
⮚ Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of 
varices (small to large) must be assessed and treated per local standard of care 
prior to enrolment. Patients who have undergone an EGD within 6 months of prior 
to initiation of study treatment do not need to repeat the procedure provided they 
had no active varices or varices at high risk of bleeding. 
⮚ A prior bleeding event due to oesophageal and/or gastric varices within 6 months 
prior to initiation of study treatment. 
- 
Clinically evident moderate or severe ascites that might require any treatment. 
- 
At least one clinically evident episode of encephalopathy in the past three months. 
- 
Co-infection of HBV and HCV. 
⮚ Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV. 
- 
Symptomatic, untreated, or actively progressing central nervous system (CNS) 
metastases. 
- 
Uncontrolled tumour-related pain. 
⮚ Patients requiring pain medication must be on a stable regimen at study entry. 
⮚ Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrolment. Patients should be recovered from the effects of radiation. There is 
no required minimum recovery period. 
⮚ Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrolment. 
- 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently). 
- 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL or corrected serum calcium > ULN). 
- 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment. 

 
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- 
Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study 
treatment, including rifampin (and its analogues) or St. John's wort. 
- 
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 interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (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−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: 
⮚ Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 
48 hours of corticosteroids for a contrast allergy) are eligible for the study after 
Medical Monitor approval has been obtained. 
⮚ Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids (e.g., prednisone 10mg or equivalent) for orthostatic hypotension 
or adrenal insufficiency are eligible for the study. 
- 
Inadequately controlled arterial hypertension (defined as systolic blood pressure 
(BP) ≥ 150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average 
of ≥ 3 BP readings on ≥ 2 sessions. 
⮚ Anti-hypertensive therapy to achieve these parameters is allowable. 
- 
Prior history of hypertensive crisis or hypertensive encephalopathy. 
- 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment. 
- 
History of haemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior 
to initiation of study treatment. 
- 
Evidence of bleeding diathesis or significant coagulopathy. 
- 
Current or recent (within 10 days of first dose of study treatment) use of aspirin 
(> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 

 
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- 
Current or recent (within 10 days prior to study treatment start) use of full-dose oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose. 
⮚ Prophylactic anticoagulation for the patency of venous access devices is allowed 
provided the activity of the agent results in an INR < 1.5 × ULN and aPTT is within 
normal limits within 14 days prior to initiation of study treatment. 
⮚ For prophylactic use of anticoagulants or thrombolytic therapies, local label 
approved dose levels may be used. 
- 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to the first dose of Bevacizumab. 
- 
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or 
intra-abdominal abscess within 6 months prior to initiation of study treatment. 
- 
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction 
including sub-occlusive disease related to the underlying disease or requirement for 
routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of 
study treatment. 
⮚ Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction 
at time of initial diagnosis may be enrolled if they had received definitive 
(surgical) treatment for symptom resolution. 
- 
Evidence of abdominal free air that is not explained by paracentesis or recent surgical 
procedure. 
- 
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture. 
- 
Metastatic disease that involves major airways or blood vessels like vena cava, or 
centrally located mediastinal tumour masses (< 30 mm from the carina) of large volume. 
 Patients with vascular invasion of the portal or hepatic veins may be enrolled. 
- 
History of intra-abdominal inflammatory process within 6 months prior to initiation of 
study treatment, including but not limited to complicated active peptic ulcer disease, 
diverticulitis, or colitis. 
- 
Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to 
initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days 
prior to initiation of study treatment 
- 
Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid 
injection, 
cryoablation, 
high-intensity 
focused 
ultrasound, 
transarterial 
chemoembolization, transarterial embolization, transarterial radioembolization etc.) 

 
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within 28 days prior to initiation of study treatment or non-recovery from side effects of 
any such procedure 
- 
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to initiation of study treatment, or abdominal surgery, abdominal interventions or 
significant abdominal traumatic injury within 60 days prior to initiation of study 
treatment or anticipation of need for major surgical procedure during the course of the 
study or non-recovery from side effects of any such procedure 
- 
Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) 
⮚ Occasional use of NSAIDs for the symptomatic relief of medical conditions such 
as headache or fever is allowed. 
End of Study and Length of Study 
a) End of Study 
The end of study will occur when all enrolled patients have either died, withdrawn consent, 
are lost to follow up, or have been followed for 24 months since the last study patient is 
enrolled, whichever occurs first.  
In addition, the Sponsor may decide to terminate the study at any time. 
b) Length of Study 
The total length of the study, from screening of the first patient to the end of the study is 
approximately 3 years (12 months enrolment). 
Investigational Medicinal Products 
Patients will receive treatment as outlined below until unacceptable toxicity or loss of clinical 
benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease). For those patients clinically stable to continue on treatment beyond 
initial RECIST v1.1 defined progression, will be allowed to continue on treatment until next 
assessment (between 4 to 8 weeks later) to ensure patient’s suitability for treatment, as is 
it recommended by iRECIST criteria. 
Treatment Arm Cycle Length 
Dose, Route, and Regimen (drugs listed in order of 
administration) 
A 
21 days 
Atezolizumab 1200 mg IV on Day 1 
Bevacizumab 15 mg/kg IV on Day 1 
 

 
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Comparator 
Not applicable 
Non-Investigational Medicinal Products 
Not applicable 
Statistical Methods 
This is not a hypothesis testing study but an exploratory study with predefined precision of 
estimates for key safety parameters for sample size determination; there are no formal 
statistical hypotheses tests to be tested, and there will be no adjustments for multiplicity of 
endpoints or within-subgroups comparisons. 
The safety analysis population will consist of all enrolled patients who received at least one 
full or partial dose of study treatment. 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded according 
to NCI CTCAE v5.0. 
Drug exposure will be summarized by descriptive statistics to include treatment duration, 
number of doses, and dose intensity. 
The following events occurring during or after the first dose of study treatment will be 
summarized by NCI CTCAE v5.0: 
 All Adverse Events (AEs). 
 All severe AEs (Grade 3-4). 
 All treatment related AEs. 
 All severe treatment related AEs (Grade 3 -4). 
 All serious AEs. 
 All treatment related serious AEs. 
 Immune-related AEs. 
 All severe immune-mediated AEs (Grade 3-4). 
 All adverse events leading to withdrawal from any component. 
 All adverse events leading to withdrawal from Atezolizumab. 
 All adverse events leading to withdrawal from Bevacizumab. 
 All Grade 5 AEs. 
 All treatment related Grade 5 AE. 
 All adverse event of special interest (AESIs) of Atezolizumab. 

 
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 All severe AESIs of Atezolizumab (Grade 3-4). 
 All adverse events leading to temporary interruption of any component. 
 All adverse events leading to temporary interruption of Atezolizumab. 
 All adverse events leading to temporary interruption of Bevacizumab. 
Multiple occurrences of the same event will be counted once at the maximum severity. 
Laboratory data with values outside the normal ranges will be identified. In addition, 
selected laboratory data will be summarized by grade. 
Descriptive statistics will be used to summarize changes in vital signs. 
Deaths with causes of death reported during the study will be summarized. 
Additional analyses may be performed as indicated. 
Determination of Sample Size 
This is a Phase IIIb, one arm, prospective multicentre, open - label study designed to 
evaluate the safety and efficacy of Atezolizumab + Bevacizumab in patients with untreated 
or unsuitable for locoregional treatments hepatocellular carcinoma who have received no 
prior systemic treatment. 
Approximately 100 patients will be recruited in 12 months, and we estimate 25 sites will 
participate in the study. 
There is no formal statistical hypothesis, hence all safety (primary) endpoints results will be 
presented by 95% confidence intervals and descriptively explained. 
For proportions exceeding 10-20%, estimates of the observed frequencies will have an 
acceptable precision (e.g., 95% confidence limit ± 5-6%) while for rare AE’s, rather 
imprecise estimates will be obtained. For example, with an expected frequency of 1-2% 
(2-3 events in the 100 patients) the 95% CI of the observed proportion will cover a range of 
values compatible with the expected results with a 12-fold or greater of variation. 
For the same reason, a 2-3-fold increase over the expected frequencies might easily be 
observed by chance. As a consequence, for rare AEs the results of this study will have to 
be interpreted with caution. 
Exploratory Biomarker Analysis for Tissue and Blood biomarker 
Plan 
Exploratory biomarker analyses will be performed in an effort to understand the association 
of tissue or blood-based biomarkers with response to Atezolizumab + Bevacizumab and 
increase the understanding of HCC disease evolution under Atezolizumab + Bevacizumab 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
23/ Protocol ML42600, Version 2 
treatment. This may include appropriate multivariate analyses. Blood based samples will 
be obtained at several timepoints of the study: Screening, Cycle 2 (Week 3) and Cycle 3 
(Week 6). 
The exploratory biomarker analyses of the Tissue and Blood Biomarker Plan include the 
following assessments: 
● 
Multiplex Immunofluorescence T/B series & PDL1 (6-Plex+DAPI): S5 Oncomine™ TCR 
Beta-SR Assay Sequencing, NGS-based somatic mutation panel, and RNA 
sequencing, will be performed on tumour biopsy samples to characterize: 
o 
the tumour immune cell infiltrate 
o 
the specificities of T lymphocyte receptors against tumour-specific antigens 
o 
Specific expression patterns that may constitute gene signatures with prognostic 
and/or predictive power of response to Atezolizumab + Bevacizumab 
o 
Specific set of mutations associated with response to Atezolizumab + Bevacizumab  
● 
Primer Extension Assay (PEA) identification of plasma cytokines and chemokines (384-
plex, Olink), cfTNA Whole Exome Sequencing, Euroflow Panel, Whole Blood RNA 
sequencing andS5 Oncomine™ TCR Beta-SR Assay Sequencing to evaluate potential 
non-invasive biomarkers on blood, plasma or serum samples, such us:  
o 
Cytokines 
o 
cfDNA exome sequencing to capture mutations present in circulating DNA  
o 
 Flow Cytometry and whole blood cell RNAseq to characterize circulating immune 
populations which changes could predict response  to Atezolizumab + Bevacizumab  
o 
sequencing the TCRs of circulating T cells to detect specific antigenicity of tumour 
antigens 
Exploratory Radiomic Analysis Plan 
An exploratory Radiomic Analysis Plan will be performed to obtain a more precise evaluation 
of response to Atezolizumab + Bevacizumab in patients with unresectable hepatocellular 
carcinoma to correlate early changes in CT-radiomics signatures with PFS and OS. The 
Radiomic Analysis Plan will also evaluate the use of radiomics features for non-invasive 
prediction of immuno-oncologic characteristics based on biopsied lesions. 
Target lesions corresponding to the primary tumour and metastases will be selected for 
radiomics features extraction. Target lesions will be selected based on size (≥ 1cm in large 
diameter for solid lesions and ≥ 1.5 cm in short diameter for nodes), preferably well-defined 
and avoiding for cystic changes and cavitation.  

 
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Multiple radiomics features from the target lesions will be extracted, including: 
1. First order features (energy, entropy, minimum, percentiles, maximum, mean, median, 
interquartile range, range, standard deviation, skewness, kurtosis, among others). 
2. Shape Features (volume, surface area, sphericity, among others). 
3. Different filters for texture analysis will be applied for higher order statistics texture 
analysis, including: Gray Level Co-occurrence Matrix (GLCM) and Gray Level Run Length 
Matrix (GLRLM) features among others. 
Interim Analyses 
One interim analysis of safety is planned at the time of 50 recruited patients. This analysis 
is estimated to occur at approximately 6 months after the first patient was included in the 
study. The primary intent of the interim analysis is to allow the study to stop early if signs of 
safety risks for the patients are detected. 

 
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TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES 
Table of Contents 
PROTOCOL SYNOPSIS ................................................................................................. 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM ...................................................... 30 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 31 
1. 
BACKGROUND ON HEPATOCELLULAR CARCINOMA ...................................... 34 
1.1 
Current Systemic Treatment for Advanced 
Hepatocellular Carcinoma .............................................................. 34 
1.2 
Background on Atezolizumab ......................................................... 36 
1.3 
Background on Bevacizumab ......................................................... 36 
1.4 
Overview of Clinical Development Program of 
Atezolizumab and Bevacizumab as Monotherapies in 
Hepatocellular Carcinoma .............................................................. 37 
1.4.1 
Atezolizumab Monotherapy ............................................................ 37 
1.4.2 
Bevacizumab Monotherapy ............................................................ 38 
1.5 
Study Rationale and Benefit-risk Assessment ................................ 40 
1.5.1 
Rationale for the Combination of Anti-PD-L1 and Anti-
VEGF Therapy in Hepatocellular Carcinoma ...................................................... 40 
1.5.2 
Clinical Data of Atezolizumab in Combination with 
Bevacizumab in Hepatocellular Carcinoma ........................................................ 41 
1.5.3 
Benefit-risk Assessment ................................................................. 43 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................... 44 
2.1 
Main Objectives .............................................................................. 44 
2.2 
Exploratory Efficacy Objectives ...................................................... 45 
2.3 
Safety Objective ............................................................................. 47 
2.4 
Biomarker and Radiomic Objectives ............................................... 47 
3. 
STUDY DESIGN ................................................................................................... 48 
3.1 
Description of the Study ................................................................. 48 
3.1.1 
Overview of Study Design .............................................................. 48 
3.2 
End of Study and Length of Study .................................................. 53 
3.2.1 
End of Study ................................................................................... 53 
3.2.2 
Length of Study .............................................................................. 54 
3.3 
Rationale for Study Design ............................................................. 54 
3.3.1 
Rationale for Atezolizumab Dose and Schedule ............................. 54 
3.3.2 
Rationale for Bevacizumab Dose and Schedule ............................. 54 

 
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3.3.3 
Rationale for Patient Population ..................................................... 54 
3.3.4 
Rationale for Open-Label Study ..................................................... 55 
3.3.5 
Rationale for Primary Safety Endpoint ............................................ 55 
3.3.6 
Rationale for Atezolizumab + Bevacizumab Treatment 
beyond Initial Radiographic Progression ............................................................ 56 
3.3.7 
Rationale for the Use of iRECIST Criteria to Evaluate 
Tumour Response ............................................................................................. 56 
3.3.8 
Rationale for the Use of HCC mRECIST Criteria to 
Evaluate Tumour Progression and Tumour Response ....................................... 57 
3.3.9 
Rationale for the Use of EASL Criteria to Evaluate 
Tumour Response ............................................................................................. 57 
3.3.10 
Rationale for Biomarker Assessments ............................................ 58 
3.3.11 
Rationale for Non-Standard Clinical Outcome 
Assessments ..................................................................................................... 58 
4. 
MATERIALS AND METHODS ............................................................................... 58 
4.1 
Patients .......................................................................................... 58 
4.1.1 
Inclusion Criteria ............................................................................ 58 
4.1.2 
Exclusion Criteria ........................................................................... 61 
4.2 
Method of Treatment Assignment and Blinding .............................. 67 
4.2.1 
Treatment Assignment ................................................................... 67 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design .................................................................................. 67 
4.3.1 
Study Treatment Formulation and Packaging ................................. 67 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance 67 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ..................................................................................................... 70 
4.3.4 
Continued Access to Atezolizumab and Bevacizumab ................... 71 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .................................................................................... 72 
4.4.1 
Permitted Therapy .......................................................................... 72 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients.................. 74 
4.4.3 
Prohibited Therapy ......................................................................... 74 
4.4.4 
Prohibited Food .............................................................................. 75 
4.5 
Study Assessments ........................................................................ 75 
4.5.1 
Informed Consent Forms and Screening Log ................................. 76 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ................................................................... 76 

 
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4.5.3 
Physical Examinations ................................................................... 76 
4.5.4 
Vital Signs ...................................................................................... 77 
4.5.5 
Tumour and Response Evaluations ................................................ 77 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ................... 78 
4.5.7 
Electrocardiograms ........................................................................ 79 
4.5.8 
Blood and Tissue Samples for Exploratory Tissue and 
Blood Biomarker Plan Study .............................................................................. 80 
4.5.9 
Exploratory Radiomic Analysis Plan ............................................... 80 
4.6 
Treatment, Patient, Study, and Site Discontinuation ....................... 81 
4.6.1 
Study Treatment Discontinuation .................................................... 81 
4.6.2 
Patient Discontinuation from the Study ........................................... 82 
4.6.3 
Study Discontinuation ..................................................................... 82 
4.6.4 
Site Discontinuation ........................................................................ 83 
5. 
ASSESSMENT OF SAFETY ................................................................................. 83 
5.1 
Safety Plan ..................................................................................... 83 
5.1.1 
Risks Associated with Atezolizumab .............................................. 84 
5.1.2 
Risks Associated with Bevacizumab............................................... 84 
5.1.3 
Risks Associated with Combination Use of 
Atezolizumab and Bevacizumab ........................................................................ 84 
5.2 
Safety Parameters and Definitions ................................................. 85 
5.2.1 
Adverse Events .............................................................................. 85 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
85 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ................................................................................ 86 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters .......................................................................... 87 
5.3.1 
Adverse Event Reporting Period .................................................... 87 
5.3.2 
Eliciting Adverse Event Information ................................................ 88 
5.3.3 
Assessment of Severity of Adverse Events .................................... 88 
5.3.4 
Assessment of Causality of Adverse Events ................................... 89 
5.3.5 
Procedures for Recording Adverse Events ..................................... 90 
5.4 
Immediate Reporting Requirements From Investigator 
To Sponsor..................................................................................... 97 
5.4.1 
Medical Monitors and Emergency Medical Contacts ...................... 98 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest .............................................................. 98 

 
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5.4.3 
Reporting Requirements for Pregnancies ....................................... 99 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................ 102 
6.1 
Determination of Sample Size ...................................................... 102 
6.2 
Summaries of Conduct of Study ................................................... 103 
6.3 
Summaries of Demographic and Baseline 
Characteristics ............................................................................. 103 
6.4 
Safety Analyses ........................................................................... 103 
6.4.1 
Primary Analysis .......................................................................... 103 
6.4.2 
Other Safety Analyses Including Analyses of Exposure, 
Adverse Event Severity, Laboratory, Vital Sign, and Hepatic 
Function Data .................................................................................................. 104 
6.5 
Efficacy Analyses ......................................................................... 105 
6.5.1 
Primary Efficacy Endpoints ........................................................... 105 
6.5.2 
Exploratory Efficacy Endpoints ..................................................... 106 
6.6 
Biomarker and radiomic Analyses ................................................ 106 
6.7 
Interim Analysis ............................................................................ 107 
6.7.1 
Planned Interim Analysis .............................................................. 107 
7. 
DATA COLLECTION AND MANAGEMENT ........................................................ 107 
7.1 
Data Quality Assurance ................................................................ 107 
7.2 
Electronic Case Report Forms...................................................... 108 
7.3 
Source Data Documentation ........................................................ 108 
7.4 
Use of Computerized Systems ..................................................... 109 
7.5 
Retention of Records .................................................................... 109 
8. 
ETHICAL CONSIDERATIONS ............................................................................ 109 
8.1 
Compliance with Laws and Regulations ....................................... 109 
8.2 
Informed Consent ......................................................................... 110 
8.3 
Institutional Review Board (IRB) or Ethics Committee 
(EC).............................................................................................. 111 
8.4 
Confidentiality ............................................................................... 111 
8.5 
Financial Disclosure ..................................................................... 112 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .............. 112 
9.1 
Study Documentation ................................................................... 112 
9.2 
Protocol Deviations ...................................................................... 112 
9.3 
Management of Study Quality ...................................................... 112 
9.4 
Administrative Structure ............................................................... 113 
9.5 
Dissemination of Data and Protection of Trade Secrets ............... 113 

 
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9.6 
Protocol Amendments .................................................................. 114 
10. REFERENCES .................................................................................................... 114 
 
– SCHEDULE OF ACTIVITIES ..................................................... 119 
 
– SCHEDULE OF SAMPLES FOR TISSUE AND 
BIOMARKER PLAN ............................................................................................ 124 
 
– RADIOMIC ANALYSIS PLAN .................................................... 125 
 
– RESPONSE EVALUATION CRITERIA IN SOLID 
TUMOURS, VERSION 1.1 (RECIST V1.1) .......................................................... 131 
 
– MODIFIED RECIST (MRECIST) ASSESSMENT FOR 
HEPATOCELLULAR CARCINOMA ..................................................................... 140 
 
– EASL GUIDELINES FOR THE CLINICAL 
MANAGEMENT OF HEPATOCELLULAR CARCINOMA .................................... 141 
 
– PREEXISTING AUTOIMMUNE DISEASES AND 
IMMUNE DEFICIENCIES .................................................................................... 142 
 
– ANAPHYLAXIS PRECAUTIONS ............................................... 144 
 
– GUIDELINES FOR MANAGEMENT OF ADVERSE 
EVENTS ASSOCIATED WITH BEVACIZUMAB .................................................. 145 
 
– RISKS ASSOCIATED WITH ATEZOLIZUMAB AND 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS 
ASSOCIATED WITH ATEZOLIZUMAB ............................................................... 150 
 
LIST OF TABLES AND FIGURES 
Table 1- Study GO30140: Overall Efficacy Summary .................................................... 42 
Table 2 - Study YO40245: Overall Efficacy Summary: ................................................... 43 
Figure 1 
 Study Schema ..................................................................................... 50 
Table 3 - Study Treatment regimens ............................................................................. 68 
Table 4 - Administration of First and Subsequent Atezolizumab Infusions ..................... 69 
Table 5 - Administration of First and Subsequent Bevacizumab Infusions ..................... 70 
Table 6 - Timing for Vital Sign Measurements for First and Subsequent Infusions ........ 77 
Table 7 - Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE .......................................................................................... 89 
Table 8 - Causal Attribution Guidance ........................................................................... 90 
 

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIIB, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB 
IN 
COMBINATION 
WITH 
BEVACIZUMAB 
TO 
INVESTIGATE 
SAFETY 
AND 
EFFICACY 
IN 
SPANISH 
PATIENTS 
WITH 
UNRESECTABLE 
OR 
UNSUITABLE 
FOR 
LOCOREGIONAL TREATMENTS HEPATOCELLULAR 
CARCINOMA 
NOT 
PREVIOUSLY 
TREATED 
WITH 
SYSTEMIC THERAPY 
ACRONYM: 
ATHECA study 
PROTOCOL NUMBER: 
ML42600 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2020-005268-71 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04732286 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
MEDICAL MONITOR: 
 
SPONSOR: 
Roche Farma S.A. 
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 to 
the Sponsor or their designee. Contact details will be provided to the investigator prior to 
study start. 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
ALBI 
Albumin-Bilirubin 
AP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BID 
twice a day 
CD80 
cluster of differentiation 80 
CI 
confidence interval 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
Covid-19 
Coronavirus Disease 2019 
CR 
complete response 
CRC 
colorectal cancer 
CRS 
cytokine-release syndrome 
CRO 
contract research organization 
CT 
computerized tomography 
CTC 
circulating tumour cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EHG 
extrahepatic growth 
EOC 
epithelial ovarian cancer 

 
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FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FoxP3 
forkhead box P3 
FTC 
fallopian tube cancer  
5-FU 
5-fluorouracil 
GBM 
glioblastoma multiforme 
GI 
Gastrointestinal 
GIDEON 
Global 
Investigation 
of 
therapeutic 
DEcisions 
in 
hepatocellular carcinoma and Of its treatment with 
sorafeNib 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HLH 
hemophagocytic lymphohistiocytosis 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgG1 
immunoglobulin G1 
IHG 
intrahepatic growth 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
iRECIST 
immunotherapy Response Evaluation Criteria in Solid 
Tumours 
IL-2 
interleukin 2 
IRF 
independent review facility 
IRR 
infusion related reaction 
ITT 
intent to treat 
IxRS 
Interactive Voice/Web Response System 
IV 
Intravenous 
K-M 
Kaplan Meier 
LMWH 
low molecular weight heparin 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
NAFLD 
non-alcoholic fatty liver disease 
NCI 
National Cancer Institute 

 
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NE 
not estimable 
NSCLC 
non-small-cell lung carcinoma 
ORR 
objective response rate 
OS 
overall survival 
OS-RR 
organ-specific response rate 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-L1 
programmed death-ligand 1  
PET 
positron emission tomography 
PFS 
progression-free survival 
PIVKA II 
Protein induced by vitamin K absence-II 
PK 
Pharmacokinetic 
PMBC 
peripheral blood mononuclear cells 
PPC 
primary peritoneal cancer (PPC) 
PPS 
post progression survival 
PR 
partial response 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
RBC 
red blood cell 
RBR 
Research Biosample Repository 
RCC 
renal cell cancer 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
16W-DCR 
disease-control rate at 16 weeks 
SHARP 
Sorafenib HCC Assessment Randomized Protocol 
SD 
stable disease 
T4 
Thyroxine 
T3 
Triiodothyronine 
TNF-α 
tumour necrosis factor alpha 
TTP 
time to progression 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 

 
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WBC 
white blood cell 
 
1. 
BACKGROUND ON HEPATOCELLULAR CARCINOMA  
Liver cancer is the fifth most common cancer, accounting for 7% of all cancers, and the 
second most frequent cause of cancer-related death globally, with 854,000 new cases and 
810,000 deaths per year. Hepatocellular carcinoma (HCC) represents approximately 90% 
of primary liver cancers and thus represents a significant global public health issue. On the 
basis of annual projections, the World Health Organization estimates that in excess of 1 
million people will die from liver cancer in 2030 (Villanueva 2019). 
The majority of HCCs occur in patients with underlying liver disease, mostly due to hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infection or alcohol abuse. HBV infection accounts 
for the majority of HCC cases worldwide; however, in Western countries and Japan, HCV is 
the main cause of HCC (Villanueva 2019). Universal HBV vaccination and wide 
implementation of direct-acting antiviral agents against HCV are likely to change the 
etiologic landscape of HCC. However, the incidence of non-alcoholic fatty liver disease 
(NAFLD), which is a risk factor for HCC, is increasing worldwide and NAFLD will soon 
become a leading cause of liver cancer in Western countries (Villanueva 2019). 
1.1 
CURRENT 
SYSTEMIC 
TREATMENT 
FOR 
ADVANCED 
HEPATOCELLULAR 
CARCINOMA 
Prior to the approval of sorafenib (Nexavar®), there was no globally approved systemic 
treatment for patients presenting with unresectable advanced or metastatic HCC. 
Doxorubicin was the most widely used cytotoxic agent and is reported to have an 11% to 
15% response rate (Mok et al. 1999; Zhu 2006; Lind et al. 2007). More aggressive 
combinations of cytotoxic chemotherapy have not been shown to increase overall survival 
(OS) rates and have been associated with considerable toxicity (Yeo et al. 2005). 
Sorafenib, an oral multikinase inhibitor, was first approved in 2007 by the U.S. Food and 
Drug Administration (FDA) and is currently considered the global standard of care for the 
first-line treatment of patients with advanced HCC. The efficacy of sorafenib has been 
demonstrated in two large multicentre, randomized, double-blind, placebo-controlled Phase 
III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a trial 
conducted in the Asia-Pacific region. Both studies demonstrated a survival benefit of 
sorafenib versus placebo. In the SHARP trial, median OS was 10.7 months with sorafenib 
versus 7.9 months with placebo (hazard ratio [HR] = 0.69 [95% CI: 0.55, 0.87]); in the Asia 
Pacific trial, median OS was 6.5 months versus 4.2 months (HR = 0.68 [95% CI: 0.50, 0.93]). 
Benefit in median time to radiographic progression was also demonstrated: 5.5 months 
versus 2.8 months in the SHARP trial (HR = 0.58 [95% CI: 0.5, 0.7]) and 2.8 months versus 
1.4 months in the Asia Pacific trial (HR = 0.6 [95% CI: 0.4, 0.8]). 

 
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The objective response rate per Response Evaluation Criteria in Solid Tumours (RECIST) 
version 1.0 was 2.3% (7 of 299 patients) in the SHARP trial and 3.3% (5 of 150 patients) in 
the Asia Pacific trial. The numerically shorter OS and duration of benefit in the Asia-Pacific 
trial may be largely attributed to the fact that patients had more advanced disease at the 
time of recruitment, and potentially also to the regional difference in aetiology and supportive 
care (Llovet et al. 2008; Cheng et al. 2009). 
Despite the survival benefit reported from these two Phase III studies, the overall benefit-
risk ratio of sorafenib is modest given the known toxicity. Adverse events commonly reported 
across both sorafenib studies included hand-foot skin reaction, diarrhoea, hypertension, 
weight loss, fatigue, anorexia, alopecia, nausea, and rash/desquamation. Drug-related 
adverse events reported were predominantly Grade 1 or 2 in severity. Drug discontinuation 
rate in patients receiving sorafenib was 38% in the SHARP trial compared with 20% in the 
Asia-Pacific trial. The frequency of dose reductions due to adverse events was similar 
between the two studies (26% in SHARP and 30.9% in the Asia-Pacific trial) (Llovet et al. 
2008; Cheng et al. 2009). 
Despite additional clinical experience with the use of sorafenib, the Global Investigation of 
therapeutic Decisions in hepatocellular carcinoma and Of its treatment with sorafeNib 
(GIDEON) study, which evaluated sorafenib in the real-world setting, showed the drug 
discontinuation rates due to adverse events in patients starting at the label recommended 
dose of 800 mg was 27%, indicating that tolerability has not improved. Moreover, GIDEON 
showed that in real-life practice, the starting dose of 800 mg daily (400 mg twice a day [BID]) 
was halved to 400 mg daily in over 22% of patients (Lencioni et al. 2014). 
Since the approval of sorafenib, there have been a number of Phase III trial failures in first-
line HCC in head-to-head comparisons with sorafenib, including sunitinib, brivanib, and 
linifanib (Cheng et al. 2013; Johnson et al. 2013; Cainap et al. 2015). Recently, frontline 
treatment with lenvatinib, a multi-targeted receptor tyrosine kinase inhibitor, was shown to 
be non-inferior to sorafenib in terms of OS (lenvatinib vs. sorafenib: median OS 13.6 months 
vs. 12.3 months; HR = 0.92, 95% CI: 0.79, 1.06) in the phase III non-inferiority REFLECT 
trial (Kudo et al. 2018). In addition, lenvatinib showed statistically significant superiority 
compared to sorafenib in terms of PFS, time to progression (TTP), and objective response 
rate (ORR), as determined by the local investigator tumour assessments per mRECIST. Of 
note, patients with ≥ 50% liver involvement, clear invasion of the bile duct, or main portal 
vein invasion were excluded from the trial. Lenvatinib had a generally manageable 
tolerability profile, with the most common treatment-emergent adverse events being 
hypertension, diarrhoea, decreased appetite and decreased weight. The findings from the 
REFLECT trial were the basis for approval of lenvatinib in Japan, the US (July 2018) and 
the EU (October 2018). However, there remains an ongoing high unmet medical need for 
patients with advanced unresectable HCC, requiring further evaluation of treatment with 
novel, more efficacious, and less toxic agents. 
 

 
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1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets 
programmed death-ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its 
receptors, PD-1 and B7-1 (also known as cluster of differentiation 80 [CD80]), both of which 
function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding 
by Atezolizumab enhances the magnitude and quality of tumour-specific T-cell responses, 
resulting in improved anti-tumour 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 anti-tumour activity in nonclinical models. In the clinical setting, 
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. Targeting the PD-L1 pathway with Atezolizumab has demonstrated activity 
in patients with advanced malignancies who have failed standard-of-care therapies. 
Objective responses have been observed across a broad range of malignancies, including 
non-small-cell lung carcinoma (NSCLC), urothelial carcinoma, RCC, melanoma, colorectal 
cancer, head and neck cancer, gastric cancer, breast cancer, and sarcoma. Atezolizumab 
is currently approved for the treatment of urothelial carcinoma, NSCLC, small-cell lung 
cancer, hepatocellular carcinoma, and triple-negative breast cancer. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.3 
BACKGROUND ON BEVACIZUMAB 
Avastin (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds 
to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in-
vitro and in-vivo assay systems. Bevacizumab contains human framework regions and the 
complementarity-determining regions of a murine antibody that binds to VEGF and has an 
approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian 
Chinese hamster ovary cell line. 
Bevacizumab was first granted marketing approval in the United States on 26 February 2004 
(international birth date) in combination with intravenous (IV) 5-fluorouracil (5-FU)-based 
chemotherapy for the first-line treatment of patients with metastatic colorectal cancer (CRC). 
As of November 2016, Bevacizumab has been approved for use in over a 100 countries 
worldwide in a variety of indications, including locally recurrent or metastatic breast cancer; 
advanced, metastatic, or recurrent NSCLC; advanced and/or metastatic renal cell cancer 
(RCC); newly diagnosed glioblastoma multiforme (GBM) and GBM after relapse or disease 
progression; persistent, recurrent, or metastatic cervical cancer; front-line treatment of 
epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer 
(FTC); and treatment of platinum-sensitive and platinum-resistant recurrent EOC, PPC, or 
FTC. 

 
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1.4 
OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM OF ATEZOLIZUMAB AND 
BEVACIZUMAB AS MONOTHERAPIES IN HEPATOCELLULAR CARCINOMA 
1.4.1 
Atezolizumab Monotherapy 
A comprehensive overview of Atezolizumab efficacy across all indications is provided in the 
Atezolizumab Investigator's Brochure. This section provides an overview of the available 
efficacy data in patients with HCC treated with Atezolizumab as monotherapy. 
To date, Atezolizumab as single agent has shown minimal activity in the treatment of HCC 
patients with similar characteristics as those that would be included in this study. 
Safety findings in the HCC cohort are in line with expectations for an HCC population and 
with the Atezolizumab safety profile observed in the overall study population across multiple 
tumour types. No new safety signals related to Atezolizumab monotherapy were observed 
in the HCC population. 
Study PCD4989g 
Study PCD4989g is a Phase Ia, multicentre, first-in-human, open-label, dose-escalation 
study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of Atezolizumab 
administered as a single agent by IV infusion every 3 weeks (Q3W) to patients with locally 
advanced or metastatic solid malignancies or hematologic malignancies. 
The largest cohorts enrolled into this trial consisted of patients with NSCLC, RCC, and UC. 
Expansion cohorts have included patients with CRC, melanoma, NSCLC, pancreatic cancer, 
UC, breast cancer, oesophageal cancer, prostate cancer, small-cell lung cancer, malignant 
lymphoma, multiple myeloma, HCC, and other less common tumour types. 
In the analysis of Study PCD4989g (clinical cut-off date of 31 December 2016) conducted 
in 15 patients with first- and later-line HCC, the median duration of treatment was 2.0 months 
(range: 0.7-6.3 months). At the time of the clinical cut-off date, 1 patient remained on 
treatment, 12 patients had discontinued treatment due to disease progression, 1 patient 
discontinued because of an adverse event, and 1 patient was discontinued as per the 
physician's decision. 
Of the 15 response-evaluable patients, none had an objective response (confirmed 
complete response (CR) or partial response (PR) as assessed by investigator per Response 
Evaluation Criteria in Solid Tumours [RECIST] v1.1). Four patients (33.3%) had stable 
disease (SD) < 24 weeks. No patients had SD ≥ 24 weeks. Median progression-free survival 
(PFS) per investigator assessment per RECIST v1.1 was 2.3 (95% confidence interval [CI]: 
1.3, 3.4) months and median OS was 5.3 (95% CI: 2.4, not estimable [NE]) months. 

 
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Study YO29233 
Study YO29233 is a Phase I, open-label, multicentre study evaluating the pharmacokinetics, 
safety, and preliminary anti-tumour activity of Atezolizumab as monotherapy in Chinese 
patients with locally advanced or metastatic gastric cancer, nasopharyngeal carcinoma, 
oesophageal cancer, HCC and other solid tumours, and the safety and preliminary anti-
tumour activity of Atezolizumab in combination with gemcitabine and cisplatin in Chinese 
patients with Stage IV, treatment-naive NSCLC. 
For monotherapy cohorts, Atezolizumab is administered as a single agent at a dose of 
1200 mg IV Q3W.  
Based on a clinical cut-off date of 1 April 2018, 21 patients with HCC had received 
Atezolizumab monotherapy. At the time of the clinical cut-off date, 7 patients remained on 
treatment (3 first-line HCC patients), while 7 patients had discontinued treatment due to 
disease progression, 2 patients discontinued treatment due to an adverse event, 2 patients 
discontinued treatment due to non-compliance with study drug, and 1 patient each 
discontinued treatment due to a protocol deviation, physician decision, and death due to 
progression of disease. 
Of the 21 efficacy-evaluable patients (first-line and second-line or greater), 2 patients (9.5% 
[95% CI: 1.17%, 30.38%]) had a confirmed objective response and 11 patients (52.4% [95% 
CI: 29.78%, 74.29%]) had a best response of SD. Median PFS was 2.8 months (95% CI: 
1.4, 7.8 months) and median OS was 11.1 months (95% CI: 4.7 months, NE). 
1.4.2 
Bevacizumab Monotherapy 
A comprehensive overview of Bevacizumab efficacy across all indications is provided in the 
Bevacizumab Investigator's Brochure. This section provides an overview of the available 
efficacy data in patients with HCC treated with Bevacizumab as monotherapy. 
Overall, Bevacizumab as a single agent demonstrated minimal activity in HCC and is unlikely 
to demonstrate a meaningful clinical benefit over current standard of care (sorafenib) based 
on the survival data observed. Bevacizumab monotherapy was generally safe and well 
tolerated in the HCC population, and safety findings were consistent with the HCC 
population and established safety profile of Bevacizumab. No new safety signals related to 
Bevacizumab monotherapy were observed in this patient population. 
Phase II Study of Bevacizumab in Unresectable Hepatocellular Carcinoma 
This study was a Phase II, single centre, single arm trial designed to evaluate the clinical 
and biological effects of Bevacizumab in unresectable HCC (Siegel et al. 2008). Adult 
patients with organ-confined HCC, Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0-2, and compensated liver function (Child-Pugh class A or B7), 

 
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received Bevacizumab 5 mg/kg or 10 mg/kg every 2 weeks (Q2W) until disease progression 
or treatment-limiting toxicity. 
Of note, patients with extrahepatic disease, tumour invasion of the main portal vein or inferior 
vena cava were excluded. Given the known prognostic value of these factors, the study 
likely enrolled a population with a more favourable prognosis and treatment outcome 
compared with a population that would typically be enrolled in a first-line HCC study. The 
primary objective was to determine whether Bevacizumab improved the 6-month PFS rate 
from 40% to at least 60%. Overall, 46 patents were enrolled, including 12 patients who 
received Bevacizumab 5 mg/kg and 34 patients who received Bevacizumab 10 mg/kg Q2W. 
Clinical activity of Bevacizumab was observed in patients with non-metastatic HCC. Of the 
46 patients, 6 patients (13%) had objective responses (95% CI: 3%, 23%), and 65% (95% 
CI: 51%, 79%) of patients were progression free at 6 months. Median PFS was 6.9 months 
(95% CI: 6.5, 9.1) and median OS was 12.4 months (95% CI: 9.4, 19.9). 
No significant changes were seen with respect to dose and outcome. The response rates 
for the 5 mg/kg and 10 mg/kg groups were 8.3% and 14.7%, respectively (p = 0.99 by 
Fisher's exact test). Median OS times for patients receiving 5 mg/kg and 10 mg/kg were 15.1 
months and 12.2 months, respectively (p = 0.64 by the log-rank test) (Siegel et al. 2008). 
Phase II Study of Bevacizumab in Advanced Hepatocellular Carcinoma 
This study was a Phase II, single-centre, single-arm trial designed to evaluate the efficacy, 
safety, and potential biomarkers of activity of Bevacizumab in patients with advanced HCC 
(Boige et al. 2012). Patients with histologically confirmed advanced HCC that was not 
amenable to curative-intent therapies (e.g., resection, liver transplantation, or percutaneous 
ablation) received Bevacizumab 5 mg/kg or 10 mg/kg Q2W until disease progression or 
unacceptable toxicity. The primary objective was to determine the disease-control rate at 16 
weeks (16W-DCR) defined as the proportion of patients with a CR, PR, or SD at 16 weeks 
after study entry, according to RECIST v1.0. 
Overall, 48 patients were enrolled, of which 25 patients were planned to receive 
Bevacizumab 5 mg/kg and 23 patients were planned to receive Bevacizumab 10 mg/kg, 
Q2W. Of the 48 patients enrolled, 43 patients received at least one dose of Bevacizumab. 
Among the 38 response-evaluable patients, six patients achieved a PR (intent to treat [ITT] 
group ORR, 14%; 95% CI: 4%, 24%), median duration of response (DOR) was 148 days 
(range, 55-362 days), 18 patients had SD (DCR, 56%), including 12 patients who 
experienced SD for ≥ 16 weeks. The 16W-DCR was 42% (95% CI: 27%, 57%) in the overall 
population, 39% (95% CI: 19%, 59%) in patients treated with 5 mg/kg Bevacizumab, and 
45% (95% CI: 23%, 67%) in those treated at the 10 mg/kg dose. In the overall population (n 
= 43), median PFS was 3 months (95% CI: 2, 4); median OS was 8 months (95% CI: 4, 9) 
(Boige et al. 2012). 

 
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1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.5.1 
Rationale for the Combination of Anti-PD-L1 and Anti-VEGF Therapy in 
Hepatocellular Carcinoma 
Strong scientific rationale and emerging clinical data suggest that the combined PD-
L1/VEGF blockade may be clinically beneficial in a number of tumour types including HCC. 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer. PD-
L1 is an extracellular protein that downregulates immune responses through binding to its 
two receptors, programmed cell death protein 1 (PD-1) and B7-1. PD-1 is an inhibitory 
receptor expressed on T cells following T-cell activation, and expression is sustained in 
states of chronic stimulation (Blank et al. 2005; Keir et al. 2008). B7-1 is a molecule 
expressed on antigen-presenting cells and activated T cells. Binding of PD-L1 to PD-1 and 
B7-1 inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011). Overexpression of PD-L1 on tumour cells has been reported to impede 
anti-tumour immunity, resulting in immune evasion (Blank and Mackensen 2007). Therefore, 
interruption of the PD-L1 pathway represents an attractive strategy for restoring tumour-
specific T-cell immunity. In patients with advanced malignancies, therapies focused on 
enhancing T cell responses against cancer have been shown to give a significant survival 
benefit (Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
HCC itself is a highly vascularised tumour type and several proangiogenic factors play a role 
in HCC pathogenesis. For example, in HCC, increased VEGF correlates with vascular 
density, tumour invasiveness and metastasis, and poor prognosis (Boige et al. 2012; 
Frenette 2012). The VEGF pathway also plays a crucial role in exerting and maintaining an 
immunosuppressive tumour microenvironment through several mechanisms. For instance, 
VEGF-A has been shown to induce FasL expression on endothelial cells, which have the 
ability to kill effector CD8+ T cells, but not T-reg cells. Administration of anti-VEGF-A 
attenuated tumour endothelial FasL expression and produced a significant increase in the 
influx of tumour-rejecting CD8+ over forkhead box P3 (FoxP3)+ T cells, which was FasL-
dependent, and led to CD8-dependent tumour growth suppression (Motz et al. 2014). 
Furthermore, Bevacizumab can restore and/or maintain the antigen presentation capacity 
of dendritic cells, leading to enhanced T-cell infiltration in tumours (Oelkrug and Ramage 
2014; Wallin et al. 2016). In addition to increased trafficking of T cells into tumours (Manning 
et al. 2007), several publications have illustrated that anti-VEGF therapies can also reduce 
frequency of myeloid-derived suppressor cells, decrease production of suppressive 
cytokines, and lower expression of inhibitory checkpoints on CD8+ T cells in tumours 
(Roland et al. 2009; Voron et al. 2015).  
The immunomodulatory effect of Bevacizumab is thus expected to enhance the effects of 
Atezolizumab by increasing CD8+ T-cell recruitment and relieving intratumoural 
immunosuppression. 

 
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1.5.2 
Clinical Data of Atezolizumab in Combination with Bevacizumab in 
Hepatocellular Carcinoma 
The efficacy and safety of Atezolizumab + Bevacizumab combination therapy as first-line 
treatment of non-resectable or metastatic HCC is currently being assessed in two studies: 
GO30140 and YO40245 (IMbrave150). 
Study GO30140 
Study GO30140 was a Phase Ib, multicentre, open-label study of Atezolizumab in 
combination with Bevacizumab and/or chemotherapy as first-line therapy in patients with 
various metastatic cancers. Arms A and F of GO30140 were specific to unresectable or 
advanced HCC. Arm A was designed to evaluate the combination of Atezolizumab + 
Bevacizumab in 104 patients with locally advanced or metastatic HCC who have not 
received prior systemic therapy. Arm F was later added to the study to compare combination 
treatment with Atezolizumab + Bevacizumab to Atezolizumab alone, in which 119 patients 
with locally advanced or metastatic HCC were randomized 1:1 to Atezolizumab + 
Bevacizumab (60 patients) or Atezolizumab (59 patients) monotherapy. Results for Arm A 
and Arm F have been recently published (Lee et al. 2020). 
Arm A 
As of the clinical cut-off date of 14 June 2019, the efficacy data for Arm A showed clinically 
meaningful and durable objective responses. The confirmed ORR based on Independent-
Review Facility (IRF) assessment per Response Evaluation Criteria in Solid Tumours, 
Version 1.1 (RECIST v1.1) was 35.6% (37 of 104 patients; Table 1). Among the 37 
responders, 12 patients (11.5%) achieved a CR and the remaining 25 patients (24.0%) 
achieved a PR. Median DOR was not reached at the time of this analysis. 
Arm F 
At the same clinical cut-off date of 14 June 2019, Arm F met its primary efficacy endpoint by 
demonstrating a statistically significant and clinically meaningful improvement in PFS with 
the combination compared to Atezolizumab monotherapy. 
Median PFS for the combination was 5.6 months compared to 3.4 months for the 
combination resulting in an HR of 0.55 and a stratified p-value of 0.0108 (Table 1). 
These results demonstrate the need for combination therapy rather than checkpoint 
inhibition alone to effectively increase progression free survival in patients with HCC. 
 

 
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Table 1- Study GO30140: Overall Efficacy Summary 
Arm 
Median 
Duration 
of 
Follow-Up  
Key Efficacy Endpoint  
Arm A 
12.4 m  
ORR (95% CI): 35.6% (26.4-45.6%)  
Median DOR: Not reached with 76% ongoing responders  
Arm F 
6.6 m  
Median PFS: 5.6 m (Atezo - Bev) vs. 3.4 m (Atezo) Stratified HR 
(80% CI): 0.55 (0.40-0.74)  
Stratified p-value: 0.0108  
Abbreviations: Atezo = atezolizumab; Bev = bevacizumab; DOR = duration of response; HR = hazard 
ratio; m = month; ORR = objective response rate; PFS = progression-free survival. 
The combination of Atezolizumab + Bevacizumab was generally well tolerated; no new 
safety signals related to the combination therapy were identified beyond the established 
safety profile for each individual agent. Furthermore, no unexpected adverse events were 
observed. The most common adverse events were proteinuria, decreased appetite, fatigue, 
pyrexia, and rash. 
Study YO40245 (IMbrave150) 
Study YO40245 (IMbrave150) is a Phase III, multicentre, randomized, open-label study 
designed to evaluate the efficacy and safety of Atezolizumab + Bevacizumab versus 
sorafenib in patients with advanced or metastatic HCC who have received no prior systemic 
treatment. The study enrolled 501 patients randomized in a 2:1 ratio to one of the following 
treatment arms: 
- 
Arm A (experimental arm): Atezolizumab 1200 mg IV every 3 weeks (Q3W) + 
Bevacizumab 15 mg/kg IV Q3W (336 patients) 
- 
Arm B (control arm): sorafenib 400 mg by mouth, twice per day, continuously (165 
patients) 
The co-primary efficacy endpoints were OS and IRF-assessed PFS by RECIST v1.1. 
The last patient was enrolled in April 2019. Based on a clinical cut-off date of 
29 August 2019, the primary analysis of Study YO40245 demonstrated statistically 
significant and clinically meaningful improvements with Atezolizumab + Bevacizumab 
compared with sorafenib in the co-primary endpoints of OS and IRF-assessed PFS per 
RECIST v1.1 in the ITT population (Table 2; Finn et al. 2020). 
- 
The co-primary endpoint of OS demonstrated a statistically significant and clinically 
meaningful improvement for Atezolizumab + Bevacizumab over sorafenib. The 
observed OS translated into a reduction in the risk of death by 42% in the 
Atezolizumab + Bevacizumab arm compared with sorafenib (HR = 0.58 [95% CI: 
0.42, 0.79], p = 0.0006, median OS: NE vs. 13.24 months). 

 
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- 
OS benefits were generally consistent across predefined subgroups. 
- 
The co-primary endpoint of IRF-assessed PFS per RECIST v1.1 demonstrated a 
statistically significant and clinically meaningful improvement for Atezolizumab + 
Bevacizumab over sorafenib (HR = 0.59 [95% CI: 0.47, 0.76]; p = 0.0001; median 
PFS: 6.83 vs. 4.27 months). 
These PFS benefits were generally consistent across predefined subgroups. 
Similar to Study GO30140, the safety of the combination was consistent with the known 
safety profile of each agent and no new safety signals were identified. 
Table 2 - Study YO40245: Overall Efficacy Summary: 
Co-primary 
Efficacy 
Endpoints 
Median Duration 
of Follow-up 
 
Sorafenib 
(n = 165) 
Atezo + Bev 
(n = 336) 
OS 
8.6 months 
Median (months) 
(95% CI) 
13.2 (10.4, NE) 
NE 
Stratified HR (95% CI) 
0.58 (0.42, 0.79) 
Stratified log-rank p-value 
0.0006 
IRF-PFS 
8.6 months 
Median (months) 
(95% CI) 
4.3 (4.0-5.6) 
6.8 (5.7-8.3) 
Stratified HR (95% CI) 
0.59 (0.47-0.76) 
Stratified log-rank p-value 
<0.0001 
Abbreviations: Atezo = atezolizumab; Bev = bevacizumab; HR = hazard ratio; IRF = Independent 
Review Facility; NE = Not Estimable; OS = Overall Survival; PFS = progression-free survival. 
1.5.3 
Benefit-risk Assessment 
Atezolizumab has been combined with Bevacizumab in patients with a range of different 
tumour types in Phase I-III studies. Overall, the adverse events observed with Atezolizumab 
in combination with Bevacizumab are consistent with the known risks of each individual 
study treatment across tumour types including HCC (Socinski et al. 2018; Rini et al. 2019).  
This trial will enrol patients with unresectable or unsuitable for locoregional treatments HCC 
not previously treated with systemic therapy. Given the poor prognosis and limited treatment 
options for these patients, this population is considered amenable for treatment with 
combined PD-L1 and VEGF antagonists. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving Atezolizumab in combination with 
chemotherapy. 

 
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In the setting of the 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 COVID-19. However, it is unclear whether or how systemic cancer 
therapies such as chemotherapy, targeted therapy, or immunotherapy impact the incidence 
or severity of COVID-19. 
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 defences. 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 COVID-19 is altered by cancer immunotherapy. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-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 COVID-19. 
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 
COVID-19−related interstitial pneumonia. Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
The benefit-risk profile for Atezolizumab in combination with Bevacizumab in this patient 
population is expected to be favourable. 
2. 
OBJECTIVES AND ENDPOINTS 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., Atezolizumab and Bevacizumab).  
Specific details on the study objectives and their corresponding endpoints are outlined 
below. 
2.1 
MAIN OBJECTIVES 
This study is designed to evaluate the safety of Atezolizumab in combination with 
Bevacizumab in patients with unresectable HCC who have received no prior systemic 
treatment and are considered unsuitable for locoregional therapy. The primary endpoint is 
the incidence and severity of adverse events of grade ≥ 3 that lead to discontinuation of 

 
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study treatment. To further evaluate the safety of Atezolizumab in combination with 
Bevacizumab, secondary endpoints of severity of AEs (determined according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 [NCI CTCAE 
v5.0]), as well as changes from baseline in targeted vital signs and clinical laboratory test 
results will be evaluated during the patients’ treatment. 
As part of the secondary objectives of this study, the efficacy of Atezolizumab and 
Bevacizumab will be evaluated using the endpoint of overall survival ([OS] defined as the 
time from initiation of study treatment to death from any cause). Efficacy will also be 
examined using the following endpoints evaluated by RECIST v1.1 criteria (See 
Appendix 4): progression free survival ([PFS] defined as the time from initiation of study 
treatment to the first occurrence of disease progression or death from any cause, whichever 
occurs first); objective response rate ([ORR], defined as a complete or partial response, on 
two consecutive occasions ≥ 4 weeks apart; time to progression ([TTP], defined as the time 
from initiation of study treatment to the first occurrence of disease progression) and duration 
of response ([DOR], defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause, whichever occurs first). The 
endpoints of the number/rate of patients starting second line treatment and the changes 
from baseline in targeted vital signs and targeted clinical laboratory test results will also be 
used to further evaluate treatment efficacy. 
During the study, deterioration in hepatic function will be monitored using the endpoints of:  
- 
Changes in international normalized ratio (INR)  
- 
Presence or absence of Ascites and /or Hepatic Encephalopathy 
- 
Albumin-Bilirubin (ALBI) assessment grades of 1 to 3 (Johnson et al. 2015) based 
on calculated ALBI score (log10 bilirubin [µmol/L] × 0.66) + (albumin [g/L] × −0.0852) 
values as follows: ALBI score ≤ −2.60 = ALBI grade 1; > −2.60 to ≤ −1.39 =ALBI 
grade 2); and > −1.39 = ALBI grade 3 
2.2 
EXPLORATORY EFFICACY OBJECTIVES 
This study also has exploratory objectives based on evaluating how patients’ responses to 
study treatment influence survival from HCC. Tumour response will be primarily assessed 
by each investigational site, using RESIST 1.1 criteria and the efficacy findings by response 
in terms of OS and PFS will be reported accordingly. Tumour response will also be evaluated 
as additional exploratory objective over four different timepoints of the study (screening, 
week 6, week 12 and end of treatment) by a centralized assessment using the following 
criteria: HCC mRECIST, by measuring the sum of longest diameter of viable tumour 
(unidimensional measurement); the European Association for the Study of the Liver (EASL), 
by measuring the area of viable tumour (bidimensional measurement); and immunotherapy 
RECIST 
criteria 
(IRECIST), 
confirmed 
by 
taking 
into 
consideration 
tumour 
pseudoprogression. The patterns of tumour responses to Atezolizumab and Bevacizumab 

 
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treatment using these different criteria will be evaluated to analyze their exploratory impact 
on OS and PFS. 
Another exploratory objective of this study is to evaluate whether the patterns of tumour 
progression (growth versus new lesion, intrahepatic versus extrahepatic) have different 
impacts on OS and PFS. Tumour Progression will be primarily assessed by RECIST 1.1 
criteria (Appendix 4) and classified into three categories of progression which should all be 
confirmed at the next follow up visit:  
i. 
> 20% increase in tumour size against a known baseline lesion (intrahepatic growth 
[IHG] or extrahepatic growth [EHG]) 
ii. 
New intrahepatic lesion (NIH)  
iii. 
New extrahepatic lesion and/or vascular invasion (NEH) 
Within these three categories, OS and PFS will be evaluated. 
In a secondary analysis, which will use HCC mRECIST criteria —taking into consideration 
the RECIST modifications described for SHARP (Reig et al. 2014)— the registration of 
tumour progression will also be categorized as follows: 
i. 
New intrahepatic nodules will be considered progression if: 
a. They exceed 10 mm in diameter and present arterial enhancement at 
dynamic imaging.  
b. Non-specific non-hypervascular nodules ≥ 10 mm (absence of the above 
definitions) present a doubling tumour size reaching a diameter > 20 mm 
since its initial detection or showing hyperenhancement during the follow-up. 
ii. 
Ascites and pleural effusion reflect progression only if malignant cells are pathology 
(cytology) proven. 
iii. 
Vascular invasion may be classified as progression if expansive and/or displaying 
arterial enhancement at dynamic imaging. 
iv. 
Hilar lymph nodes will be considered malignant if the smaller diameter exceeds 
20mm and/or are hypervascular. Growth of existing nodes uses the same cut-offs as 
other lesions. 
v. 
Lobar or segmental portal invasion with growth of the tumour thrombus reaching the 
main trunk of the portal vein or reaching the contralateral lobe. 
OS and PFS will be evaluated within each of these five categories. 

 
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This study will explore how the factors underlying treatment withdrawal and post-study 
treatments impact patients by analysing OS according to the reason for treatment withdrawal 
(progressive disease [PD] versus AE versus deteriorating liver function/clinical conditions) 
and according to the type and duration of each post-study treatment given. This study will 
be performed over the same CT images used for the Radiomic exploratory analysis: Basal, 
week 6, week 12 and progression scan. 
To investigate whether treatment efficacy varies across different metastatic sites, the organ-
specific response rate (OS-RR) using RECIST 1.1 criteria, and the cumulative incidence 
probability of organ-specific progression will be measured. Comparison of OS-RR will be 
compared for target lesions including in the liver, lungs, and lymph-nodes as well as for non-
target lesions in bones. 
The final exploratory efficacy objective of the study will be to determine the applicability of 
depth of response (decrease in tumour burden) as a surrogate for OS. Tumour response 
according to RECIST 1.1, EASL, mRECIST and iRECIST criteria will be compared to 
baseline evaluations. 
2.3 
SAFETY OBJECTIVE 
As described in Section 2.1, this study will primarily evaluate the safety of Atezolizumab in 
combination with Bevacizumab in patients with unresectable hepatocellular carcinoma who 
have received no prior systemic treatment and they are consider unsuitable for locoregional 
therapy. 
This will be done by assessing the incidence and severity of adverse events grade ≥ 3 that 
lead to discontinuation of study treatment. 
2.4 
BIOMARKER AND RADIOMIC OBJECTIVES 
In the Tissue & Blood Biomarker Plan, patients will have samples taken to identify Tissue 
and Blood based Biomarkers that might be associated with response patterns to 
Atezolizumab + Bevacizumab and patient outcomes under Atezolizumab+ Bevacizumab 
treatment. These samples will be obtained at three different study time points: Screening, 
Cycle 2 (week 3), Cycle 3 (week 6t 
The following analyses will be conducted on blood, plasma, serum, and tumour biopsy 
samples taken from patients included in the project: 
i. 
Multiplex Immunofluorescence T/B series & PDL1 (6-Plex+DAPI): S5 Oncomine™ 
TCR Beta-SR Assay Sequencing and RNA sequencing, will be performed on tumour 
biopsy samples to characterize: 
a. the tumour immune cell infiltrate 
b. the specificities of T lymphocyte receptors against tumour-specific antigens 

 
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c. Specific expression patterns that may constitute gene signatures with prognostic 
and/or predictive power of response to Atezolizumab + Bevacizumab 
ii. ELISA Luminex HCYTA-60K-26 Human Cyto Panel A (48 cytokines), cfTNA Whole 
Exome Sequencing, Euroflow Panel, Whole Blood RNA sequencing andS5 
Oncomine™ TCR Beta-SR Assay Sequencing to evaluate potential non-invasive 
biomarkers on blood, plasma or serum samples, such us: 
a. 
 Cytokines  
b. 
cfDNA exome sequencing to capture mutations present in circulating DNA  
c. 
sequencing the TCRs of circulating T cells to detect specific antigenicity of 
tumour antigens characterization of leukocyte subpopulations that could predict 
response 
 
In addition, an exploratory Radiomic Analysis Plan will be performed and will aim to gain a 
more precise evaluation of response to Atezolizumab and Bevacizumab in patients with 
unresectable hepatocellular carcinoma. This Radiomic Analysis will be performed over the 
following CT images: Basal, week 6, week 12 and progression scan. The Radiomic Analysis 
Plan will also evaluate the use of radiomics features as a means of noninvasive prediction 
of immuno-oncologic characteristics based on biopsied lesions. To this end, the following 
analyses will be performed: 
i. 
CT-radiomics signatures (including shape, first-order and higher-order texture 
features) at baseline will be correlated with the response to study treatment. 
ii. 
Any early changes in CT-radiomics signatures during the study will be correlated with 
the response to study treatment. 
iii. 
Any changes in inter- and intra- tumour CT-radiomics will be explored in relation to 
any differences in responder/non-responder lesions and to the patient clinical 
outcome. 
iv. 
Any CT-radiomics features will be correlated with tumour mutational status in order 
to develop radiogenomic phenotypes. 
v. 
Any CT-radiomics features will also be correlated with the tumour microenvironment 
on biopsied lesions including the tumour immunophenotype, RNA sequences, and 
vascularization. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase IIIb, one arm, multicentre, open-label study primarily designed to evaluate 
the safety of Atezolizumab + Bevacizumab in patients with unresectable or unsuitable for 
locoregional treatments for metastatic HCC not previously treated with systemic therapy. 

 
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As part of its secondary objectives, this study is also designed to evaluate the efficacy of 
Atezolizumab and Bevacizumab in these patients.  
The treatment schemed for all patients included in the study will be:  
- Atezolizumab 1200 mg IV infusions Q3W (dosed in 3-week cycles) + Bevacizumab 15 
mg/kg Q3W (dosed in 3-week cycles)  
This study will enrol approximately 100 patients from 26 sites throughout Spain in one arm 
of treatment; Figure 1 presents an overview of the study design. A schedule of activities is 
provided in Appendix 1. 
 
 

 
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Figure 1  Study Schema 
 
 
 
 
 
 
 
Patients treated with Atezolizumab + Bevacizumab, who transiently withhold or 
permanently discontinue either Atezolizumab or Bevacizumab, may continue on single-
agent therapy as long as the patients are experiencing clinical benefit in the opinion of the 
investigator and after discussion with the Medical Monitor (i.e., patients transiently withhold 
or permanently discontinue Bevacizumab for adverse effects may continue Atezolizumab 
monotherapy and vice versa). 
Patients will receive Atezolizumab and/ or Bevacizumab until unacceptable toxicity or loss 
of clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data, and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease). 
For those patients clinically stable to continue on treatment beyond initial RECIST v1.1 
defined progression, will be allowed to continue on treatment until next assessment 
(between 4 to 8 weeks later) to ensure patient’s suitability for treatment, as is it 
recommended by immunotherapy (iRECIST) criteria. 
In the absence of unacceptable toxicity, patients who meet criteria for disease progression 
per RECIST v1.1 while receiving Atezolizumab and/or Bevacizumab will be permitted to 
continue the study treatment if they meet all of the following criteria: 
- 
Evidence of clinical benefit, as determined by the investigator following a review of 
all available data. 
- 
Absence of symptoms and signs (including laboratory values) indicating unequivocal 
progression of disease. 
- 
Absence of decline in ECOG Performance Status that can be attributed to disease 
progression. 
- 
Absence of tumour progression at critical anatomical sites (e.g., leptomeningeal 
disease or brain metastases) that cannot be managed by protocol-allowed medical 
interventions. 
End of treatment 
Treatment given until 
unacceptable toxicity or 
loss of clinical benefit 
Patient population 
Patients with unresectable or 
unsuitable for locoregional 
treatments HCC not previously 
treated with systemic therapy 
(N = 100) 
Study treatment 
Atezolizumab 1200 mg IV on 
Day 1 of each 21-day cycle 
+ 
Bevacizumab 15 mg/kg IV on 
Day 1 of each 21-day cycle 

 
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Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Laboratory safety assessments 
will include the regular monitoring of haematology and blood chemistry. 
Tumour assessments will be performed at baseline and at regular intervals during study 
treatment. Additional scans will be performed as clinically indicated. Tumour assessments 
will continue until disease progression, regardless of whether treatment has been 
discontinued (e.g., for toxicity). Patients who meet RECIST v1.1 criteria for progression will 
undergo tumour assessments until loss of clinical benefit, whichever occurs later. In the 
absence of disease progression, tumour assessments should continue until consent is 
withdrawn, death, or the study is terminated by the Sponsor, whichever occurs first. 
Following disease progression, patients will be followed for survival and subsequent anti-
cancer therapies until death, loss to follow-up, withdrawal of consent, or study termination 
by Sponsor, whichever occurs first. 
Patient samples, including serum and plasma, will be collected for the exploratory biomarker 
assessments for the Tissue and Blood Biomarker Plan. 
The regular tumour assessments will be performed at baseline, then every 6 weeks for the 
first 54 weeks and every 12 weeks thereafter. The CT images used for the Radiomic 
Analysis Plan will be the same as those for the regular tumour assessments performed at 
baseline, week 6, week 12 and patient’s progression. The same images will be used for the 
exploratory efficacy analysis (see section 2.2). In these images, target lesions corresponding 
to the primary tumour and metastases will be selected for extraction of radiomic features 
and the exploratory efficacy analysis. 
Assessment of response and progression 
Registration of Response: Tumour Response will be primarily assessed locally by the 
study investigators using RECIST 1.1 criteria (Appendix 4) as a main assessment. Since 
activity may be detected by appearance of necrosis, an exploratory secondary analysis will 
include HCC mRECIST and EASL criteria. HCC mRECIST to measure the sum of longest 
diameter of viable tumour and EASL the area of viable tumour. This exploratory analysis will 
be performed over those scans shipped for the radiomic analysis: Screening, week 6, week 
12 and progression scan (see section 2.2). 
Registration of response will be also assessed by applying iRECIST rules and compared 
with other response criteria in terms of OS and PFS. 
Bevacizumab induces vasoconstriction and this reduces splanchnic blood flow and thus, 
hepatic artery blood flow. This may reduce the intensity of contrast uptake that should not 
be registered as necrosis. In any case, registration of response or of stable disease will not 
affect in treatment maintenance. 

 
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Registration of progression: Tumour Progression will be primary assessed by RECIST 
1.1 and the results in efficacy on terms of OS and PFS based on the following Patterns of 
progression:  
- > 20% increase in tumour size against a known baseline lesion (intrahepatic growth 
[IHG] or extrahepatic growth [EHG]) 
- new intrahepatic lesion (NIH)  
- new extrahepatic lesion and/or vascular invasion (NEH) 
Secondary exploratory analysis will include HCC mRECIST, taking into consideration the 
RECIST modifications described for SHARP (Reig et al. 2014) for the capture of tumour 
progression to prevent over registration of progression and improper treatment interruption. 
Exploratory assessment on OS and PFS will be performed based on the following patterns 
of progression:  
- 
New intrahepatic nodules will be considered progression if:  
⮚ They exceed 10 mm in diameter and present arterial enhancement at dynamic 
imaging. 
⮚ Non-specific non-hypervascular nodules ≥ 10 mm (absence of the above 
definitions) present a doubling tumour size reaching a diameter > 20 mm since its 
initial detection or showing hyperenhancement during the follow-up. 
⮚ Ascites and pleural effusion reflect progression only if malignant cells are pathology 
(cytology) proven. 
⮚ Vascular invasion may be classified as progression if expansive and/or displaying 
arterial enhancement at dynamic imaging. 
⮚ Hilar lymph nodes are considered malignant if the smaller diameter exceeds 20mm 
and/or are hypervascular. Growth of existing nodes uses the same cut-offs as other 
lesions. 
- 
Registration of progression will be also assessed by applying iRECIST rules and 
compared with other response criteria in terms of OS and PFS. 
- 
Additional exploratory assessment of the depth of response by means of changes in TL 
tumour burden and its association with OS and PFS will be analysed. 
- 
Finally, based on the hypothesis that treatment efficacy varies across different metastatic 
sites, a comparison of organ-specific response rates will be performed, including target 
lesions from the liver, lungs, lymph-nodes and non-target lesions in bones. 

 
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Criteria for treatment discontinuation 
Safety events > grade 3 related to treatment discontinuation is the primary endpoint of the 
study thus may be reached through several events. 
- 
Development of AEs or SAEs > grade 3 clinically significant considered related to 
any study treatment and irrespective of tumour evolution. 
- 
Tumour progression outside the liver: this includes confirmed growth in 
sequential imaging, and metastasis spread in any location, new lymph nodes, new 
vascular invasion – note that vascular invasion should never be considered a target 
lesion.) assessed by RECIST v1.1 and confirmed by iRECIST. 
- 
Tumour progression within the liver: assessed by RECIST v1.1as confirmed by 
iRECIST for target lesions. However, in case of new intrahepatic (NIH) tumour sites, 
treatment should not be interrupted upon detection of new nodules at first time. 
Further growth during follow-up should be registered to decide treatment interruption. 
- 
Liver function deterioration: 
⮚ Associated with progression will also represent a criterion for treatment 
interruption as it will also fit into SAEs > 3.  
⮚ Associated with the appearance of ascites in need of treatment, jaundice or 
encephalopathy will be considered also a criterion for treatment 
discontinuation.  
According to these definitions, treatment may be maintained beyond progression under very 
specific circumstances following the iRECIST criteria and the refinements related to HCC 
per registration of progression and following confirmation with the medical monitor of the 
study. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
3.2.1 
End of Study 
The end of study will occur when all enrolled patients have either died, withdrawn consent, 
are lost to follow up, or have been followed for 24 months since the last study patient is 
enrolled, whichever occurs first. 
In addition, the Sponsor may decide to terminate the study due to low recruitment at any 
time. 

 
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3.2.2 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study is 
approximately 3 years (12 months enrolment). 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of 
each 21-day cycle), which is an approved dosage for Atezolizumab, as outlined in the 
prescribing information. Anti-tumour activity has been observed across doses ranging from 
1 mg/kg to 20 mg/kg Q3W. In Study PCD4989g, the maximum tolerated dose of 
Atezolizumab was not reached and no DLTs were observed at any dose. The fixed dose of 
1200 mg Q3W (equivalent to an average body weight−based dose of 15 mg/kg Q3W) was 
selected on the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's Brochure 
for details). 
Moreover, both the above-mentioned dose and schedule of Atezolizumab in combination 
with Bevacizumab were indicated as generally safe and well tolerated by the results of 
GO30140 (Lee et al. 2020) and YO40245 (IMbrave150) (Finn et al. 2020) trials. In addition, 
no new safety signals related to the combination therapy were identified beyond the 
established safety profile for each individual agent. 
3.3.2 
Rationale for Bevacizumab Dose and Schedule 
Bevacizumab will be administered at a fixed dose of 15 mg/kg Q3W on Day 1 of each 21-
day cycle which is one of the approved dosages for Bevacizumab (Avastin® local labels). 
This dose schedule aligns with the Atezolizumab dose schedule used in combination with 
Atezolizumab in Study GO30140 and YO40245 (IMbrave150). 
3.3.3 
Rationale for Patient Population 
This study will enrol patients with unresectable or unsuitable for locoregional treatments 
metastatic HCC not previously treated with systemic therapy. Given the poor prognosis and 
limited treatment options for these patients, this population is considered amenable for 
treatment with combined PD-L1 and VEGF antagonists. 
The broad patient population selected is similar to that enrolled in Study YO40245, the initial 
study testing this combination in first-line HCC patients. 

 
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Although sorafenib and lenvatinib are approved for the first-line treatment of patients with 
advanced HCC, the prognosis of these patients remains poor with a median OS reported of 
10.7 – 14.7 months for sorafenib (Llovet et al. 2008; Yau et al. 2019) and 13.6 months for 
lenvatinib (Kudo et al. 2018). 
Therefore, there is a continuing need for more efficacious, better tolerated treatments for the 
first line treatment of patients with locally advanced or metastatic HCC. 
3.3.4 
Rationale for Open-Label Study  
The primary objective of this study is to assess the safety profile of Atezolizumab + 
Bevacizumab in a non-comparative fashion. Thus, as all patients are pre-specified to receive 
active treatment, the study will have an open-label and non-randomized design. 
3.3.5 
Rationale for Primary Safety Endpoint 
In this study, incidence and severity of safety events> grade 3 related to any study treatment 
discontinuation is the primary endpoint of the study. 
In the YO40245 (IMbrave150) phase III trial (Finn et al. 2020), treatment-related events 
occurred in at least 10% of patients. The percentage of patients who discontinued any 
treatment component because of adverse events was 15.5% in the Atezolizumab–
Bevacizumab group (7% discontinued both components) and 10.3% in the sorafenib group. 
In the context of this protocol study, the safety events that will lead to any study treatment 
discontinuation may be reached through the occurrence of the following events: 
- 
Development of AEs or SAEs > grade 3 clinically significant considered related to 
any study treatment and irrespective of tumour evolution. 
- 
Tumour progression outside the liver: this includes confirmed growth in 
sequential imaging, and metastasis spread in any location, new lymph nodes, new 
vascular invasion – note that vascular invasion should never be considered a target 
lesion.) assessed by RECIST v1.1 and confirmed by iRECIST. 
- 
Tumour progression within the liver: assessed by RECIST v1.1as confirmed by 
iRECIST for target lesions. However, in case of new intrahepatic (NIH) tumour sites, 
treatment should not be interrupted upon detection of new nodules at first time. 
Further growth during follow-up should be registered to decide treatment interruption. 
- 
Liver function deterioration: 
⮚ Associated to progression will also represent a criterion for treatment 
interruption as it will also fit into SAEs > 3. 

 
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⮚ Associated to appearance of ascites in need of treatment, jaundice or 
encephalopathy will be considered also a criterion for treatment 
discontinuation.  
Even though the safety profiles of Atezolizumab and Bevacizumab are well established, the 
additional information collected, using this endpoint will have the potential to reinforce the 
safety data already available for these treatments in the context of patients in Spain with 
unresectable or unsuitable for locoregional treatment HCC. 
3.3.6 
Rationale for Atezolizumab + Bevacizumab Treatment beyond Initial 
Radiographic Progression 
In studies of immunotherapeutic agents, complete response, partial response, and stable 
disease have each been shown to occur after radiographic evidence of an apparent increase 
in tumour burden. This initial increase in tumour burden caused by immune-cell infiltration 
in the setting of a T-cell response has been termed pseudoprogression (Hales et al. 2010). 
In Study PCD4989g, evidence of tumour growth followed by a response was observed in 
several tumour types. In addition, in some responding patients with radiographic evidence 
of progression, biopsies of new lesions or areas of new growth in existing lesions revealed 
immune cells and no viable cancer cells. Therefore, this study will allow all patients to 
continue their assigned treatment after apparent radiographic progression per RECIST v1.1, 
provided the benefit-risk ratio is judged to be favourable by the investigator (see criteria in 
Section 3.1). Patients should be discontinued for unacceptable toxicity or loss of clinical 
benefit as determined by the investigator after an integrated assessment of radiographic and 
biochemical data, and clinical status (see Section 3.1.1 for details). 
3.3.7 
Rationale for the Use of iRECIST Criteria to Evaluate Tumour Response 
Increasing clinical experience indicates that traditional response criteria (e.g., RECIST v1.1) 
may not adequately assess the activity of immunotherapeutic agents because initial 
radiographic evidence of disease progression does not necessarily reflect therapeutic 
failure. Patients can experience a response in the presence of new lesions or after an 
increase in tumour burden. Thus, this study will also employ iRECIST tumour response 
criteria (Seymour et al. 2017) that have been modified for unconventional tumour change 
patterns associated with cancer immunotherapy. 
iRECIST was developed by the RECIST working group in an effort to create a common set 
of criteria that the cancer immunotherapy field could apply to clinical trials (Seymour et al. 
2017). iRECIST accounts for responses that may occur following transient radiographic 
progression caused by immune-cell infiltration in tumours (leading to a transient increase in 
the size of existing lesions, including those that were previously undetectable and 
consequently appear as new lesions). iRECIST relies on collection of tumour assessment 
data after initial disease progression per RECIST v1.1. 

 
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Given the proposed immunomodulatory mechanism of action of Atezolizumab and the 
possibility of observing delayed responses, exploratory efficacy endpoints will include 
analyses based on iRECIST. These analyses will allow for exploratory analysis, the 
evaluation of iRECIST as an improved measure of the efficacy of immunotherapies relative 
to standard RECIST v1.1. 
3.3.8 
Rationale for the Use of HCC mRECIST Criteria to Evaluate Tumour 
Progression and Tumour Response 
Increasing clinical experience indicates that traditional response criteria (e.g., RECIST 
v1.1) do have some limitations with regard to the evaluation of tumour response in 
hepatocellular carcinoma (HCC) treated with locoregional therapies and new targeted 
chemotherapy agents. For advanced hepatocellular carcinoma, the standard RECIST v1.1 
criteria correlated poorly with the clinical benefits demonstrated in the SHARP trial for 
sorafeninb (Nexavar, a multikinase inhibitor of the vascular endothelial growth factor and 
platelet derived growth factor receptors) (Llovet JM 2008). Similar findings were seen after 
locoregional therapies for HCC such as radiofrequency ablation and chemoembolization 
(Forner A 2008). This is likely because these therapies reduce the vascularity of the 
tumour, producing necrosis which does not always reduce the overall tumour size. In 
addition, as HCC tumours enlarge, they show intranodular variability in their enhancement 
pattern on imaging which further complicates the evaluation of tumour size. 
To address these issues and to provide a common framework for the design of clinical 
trials in HCC the American Association for the Study of Liver Diseases has proposed 
modified criteria (mRECIST), which quantify only the viable portions (characterized as 
arterially enhancing on imaging) of the tumour to provide an improved endpoint for 
assessment (Llovet JM, Di Bisceglie AM et al. 2008, Lencioni R 2012). 
Secondary exploratory analyses in this study will therefore also include HCC mRECIST, 
taking into consideration the RECIST modifications described for SHARP (Reig et al. 
2014) for the capture of tumour progression to prevent over registration of progression and 
improper treatment interruption. Further information on the HCC mRECIST criteria used to 
evaluate tumour progression can be found in Appendix 5. 
3.3.9 
Rationale for the Use of EASL Criteria to Evaluate Tumour Response 
When specifically assessing tumour response in HCC lesions, the European Association of 
the Study of the Liver (EASL) guidelines were first developed in 2001 in order to account for 
the intranodular variability seen in imaging of HCC tumours. The EASL guidelines 
recommend measuring the viable and necrotic portions of the treated nodules and have 
been shown to allow early detection (within 1 to 2 months) of tumour necrosis (Riaz, A.,2009 
Riaz A, Lewandowski RJ et al. 2009). Furthermore, the EASL guidelines recommend that 
only nodules exhibiting the typical characteristics of arterial wash-in followed by wash-out 
can be considered as new lesions. This recommendation addresses the peculiar 

 
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characteristic of the cirrhotic liver, in which a wide range of non-neoplastic lesions (such as 
large regenerative nodules) can develop during patient follow-up. 
Secondary exploratory analyses in this study will therefore also include EASL guidelines 
(EASL 2018) for the evaluation of HCC response on imaging. Further information on the 
EASL criteria used to evaluate HCC response are provided in Appendix 6. 
3.3.10 
Rationale for Biomarker Assessments  
In this study, exploratory biomarkers will be evaluated. This is part of the Tissue & Blood 
Biomarker Plan for patients included in translational research, to identify biomarkers that 
might be potentially associated with response patterns to Atezolizumab + Bevacizumab or 
the HCC disease evolution under Atezolizumab+ Bevacizumab treatment. Section 2.4 
presents the details of the biomarkers that will be evaluated. 
3.3.11 
Rationale for Non-Standard Clinical Outcome Assessments 
This study will include a Radiomic Analysis Plan aimed at providing a more precise 
evaluation of the response to Atezolizumab and Bevacizumab in patients with unresectable 
hepatocellular carcinoma. The CT-radiomic signatures identified will be correlated to various 
clinical outcomes of the study treatment. Details on the endpoints assessed in this Radiomic 
Analysis Plan are provided in Section 2.4. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 100 patients with unresectable or unsuitable for locoregional treatments 
metastatic HCC not previously treated with systemic therapy will be enrolled in 
approximately 25 Spanish sites. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
- 
Signed Informed Consent Form. 
- 
Age ≥ 18 years at time of signing Informed Consent Form. 
- 
Ability to comply with the study protocol, in the investigator's judgment. 
- 
Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by 
histology or radiologically, following the American Association for the Study of Liver 
Diseases (AASLD) criteria. 

 
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- 
Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies. 
- 
No prior systemic therapy (including systemic investigational agents) for HCC. 
- 
At least one measurable (per RECIST 1.1) untreated lesion detected by computerized 
tomography (CT) scan. 
- 
Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous 
ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, 
transarterial 
chemoembolization, 
transarterial 
embolization, 
transarterial 
radioembolization, etc.) are eligible provided the target lesion(s) have not been 
previously treated with local therapy or the target lesion(s) within the field of local 
therapy have subsequently progressed in accordance with RECIST version 1.1. 
- 
For those patients who received radioembolization as prior locoregional therapy should 
be necessary to wait at least 3 months before they could be included in this study. 
- 
ECOG Performance Status of 0 or 1 within 7 days prior to recruitment. 
- 
Child-Pugh class A with compensated ascites, within 7 days prior to recruitment. 
- 
Patients should submit a pre-treatment tumour tissue sample. If tumour tissue is not 
available (e.g., depleted for prior diagnostic testing), it is recommendable to take a new 
biopsy if it´s clinically possible. If tumour tissue is available: A formalin-fixed, paraffin-
embedded (FFPE) tumour specimen in a paraffin block (preferred) or a total of 28 slides 
(12 slides for histologic studies and 2x8 slides for genomic studies) containing 
unstained, freshly cut, serial sections should be submitted. 
- 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to recruitment, unless otherwise specified: 
– 
ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support 
– 
Lymphocyte count ≥ 0.5 × 109/L (500/μL) 
– 
Platelet count ≥ 75 × 109/L (75,000/μL) without transfusion 
– 
Haemoglobin ≥ 90 g/L (9 g/dL).  
– 
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase (ALP) ≤ 5 × upper limit of normal (ULN) 
– 
Serum bilirubin ≤ 3 × ULN  
– 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated using 
the Cockcroft-Gault formula) 

 
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– 
Serum albumin ≥ 28 g/L (2.8 g/dL) without transfusion 
– 
INR ≤ 1.5 
– 
Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study treatment) 
Patients discovered to have < 2+ proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate < 1 g of 
protein in 24 hours. 
- 
Resolution of any acute, clinically significant treatment-related toxicity from prior therapy 
to Grade ≤ 1 prior to study entry, with the exception of alopecia 
- 
Negative HIV test at screening 
- 
Documented virology status of hepatitis, as confirmed by screening HBV and HCV 
serology test  
- 
For patients with active hepatitis B virus (HBV):  
HBV DNA < 500 IU/mL obtained within 28 days prior to initiation of study treatment, 
and 
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 
days prior to study entry and willingness to continue treatment for the length of the 
study 
- 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per 
year during the treatment period and for at least 5 months after the last dose of 
Atezolizumab and 6 months after the last dose of Bevacizumab. Women must refrain 
from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 

 
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- 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of < 1% per year during the treatment period and for 6 months after the last dose of 
Bevacizumab. Men must refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the last dose of Bevacizumab to avoid 
exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
- 
- Active or history of autoimmune disease or immune deficiency, including, but not 
limited to (full list of conditions presented in Appendix 7), myasthenia gravis, myositis, 
autoimmune 
hepatitis, 
systemic 
lupus 
erythematosus, 
rheumatoid 
arthritis, 
inflammatory bowel disease, 
antiphospholipid antibody syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with 
the following exceptions: 
⮚ Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone treatment are eligible for the study. 
⮚ Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
⮚ Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of the following conditions are 
met: 
o Rash must cover < 10% of body surface area. 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 

 
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o 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 CT scan. 
⮚ History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
- 
Known 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. 
- 
History of congenital long QT syndrome or corrected QT interval > 500 ms (calculated 
with use of the Fridericia method) at screening. 
- 
History of uncorrectable electrolyte disorder affecting serum levels of potassium, 
calcium, or magnesium within the previous 12 months. 
- 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the study. 
- 
History of malignancy other than HCC within 5 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, ductal carcinoma in situ, Stage I uterine 
cancer or bladder carcinoma in situ. 
- 
Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteraemia, or severe 
pneumonia. 
- 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment. 
⮚ Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) or patients receiving 
Rifaximin as prevention of encephalopathy 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 

 
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interpretation of the results, or may render the patient at high risk from treatment 
complications. 
- 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during Atezolizumab treatment or 
within 5 months after the last dose of Atezolizumab. 
- 
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 or Bevacizumab formulation. 
- 
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment 
or within at least 5 months after the last dose of Atezolizumab and 6 months after the 
last dose of Bevacizumab. 
⮚ Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
- 
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 
- 
Untreated or incompletely treated oesophageal and/or gastric varices with bleeding or 
high-risk for bleeding. 
⮚ Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of 
varices (small to large) must be assessed and treated per local standard of care 
prior to enrolment. Patients who have undergone an EGD within 6 months of prior 
to initiation of study treatment do not need to repeat the procedure provided they 
had no active varices or varices at risk of bleeding. 
⮚ A prior bleeding event due to oesophageal and/or gastric varices within 6 months 
prior to initiation of study treatment. 
- 
Clinically evident moderate or severe ascites that might require any treatment. 
- 
At least one clinically evident episode of encephalopathy in the past three months. 
- 
Co-infection of HBV and HCV. 
⮚ Patients with a history of HCV infection but who are negative for HCV RNA by 
polymerase chain reaction (PCR) will be considered non-infected with HCV. 
- 
Symptomatic, untreated, or actively progressing central nervous system (CNS) 
metastases. 

 
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- 
Uncontrolled tumour-related pain. 
⮚ Patients requiring pain medication must be on a stable regimen at study entry. 
⮚ Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrolment. Patients should be recovered from the effects of radiation. There is 
no required minimum recovery period. 
⮚ Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrolment. 
- 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently). 
- 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL or corrected serum calcium > ULN). 
- 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment. 
- 
Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study 
treatment, including rifampin (and its analogues) or St. John's wort. 
- 
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 interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (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−tumour necrosis factor alpha [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: 
⮚ Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 
48 hours of corticosteroids for a contrast allergy) are eligible for the study after 
Medical Monitor approval has been obtained. 
⮚ Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 

 
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corticosteroids (e.g., prednisone 10mg or equivalent) for orthostatic hypotension 
or adrenal insufficiency are eligible for the study. 
- 
Inadequately controlled arterial hypertension (defined as systolic blood pressure 
(BP) ≥ 150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average 
of ≥ 3 BP readings on ≥ 2 sessions. 
⮚ Anti-hypertensive therapy to achieve these parameters is allowable. 
- 
Prior history of hypertensive crisis or hypertensive encephalopathy. 
- 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment. 
- 
History of haemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior 
to initiation of study treatment. 
- 
Evidence of bleeding diathesis or significant coagulopathy. 
- 
Current or recent (within 10 days of first dose of study treatment) use of aspirin 
(> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 
- 
Current or recent (within 10 days prior to study treatment start) use of full-dose oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose. 
⮚ Prophylactic anticoagulation for the patency of venous access devices is allowed 
provided the activity of the agent results in an INR < 1.5 × ULN and activated 
partial thromboplastin time (aPTT) is within normal limits within 14 days prior to 
initiation of study treatment. 
⮚ For prophylactic use of anticoagulants or thrombolytic therapies, local label 
approved dose levels may be used. 
- 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to the first dose of Bevacizumab. 
- 
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or 
intra-abdominal abscess within 6 months prior to initiation of study treatment. 

 
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- 
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction 
including sub-occlusive disease related to the underlying disease or requirement for 
routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of 
study treatment. 
⮚ Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction 
at time of initial diagnosis may be enrolled if they had received definitive 
(surgical) treatment for symptom resolution. 
- 
Evidence of abdominal free air that is not explained by paracentesis or recent surgical 
procedure. 
- 
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture. 
- 
Metastatic disease that involves major airways or blood vessels like vena cava, or 
centrally located mediastinal tumour masses (< 30 mm from the carina) of large volume. 
 Patients with vascular invasion of the portal or hepatic veins may be enrolled. 
- 
History of intra-abdominal inflammatory process within 6 months prior to initiation of 
study treatment, including but not limited to complicated active peptic ulcer disease, 
diverticulitis, or colitis. 
- 
Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to 
initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days 
prior to initiation of study treatment. 
- 
Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid 
injection, 
cryoablation, 
high-intensity 
focused 
ultrasound, 
transarterial 
chemoembolization, transarterial embolization, transarterial radioembolization etc.) 
within 28 days prior to initiation of study treatment or non-recovery from side effects of 
any such procedure. 
- 
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to initiation of study treatment, or abdominal surgery, abdominal interventions or 
significant abdominal traumatic injury within 60 days prior to initiation of study 
treatment or anticipation of need for major surgical procedure during the course of the 
study or non-recovery from side effects of any such procedure. 
- 
Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID). 
⮚ Occasional use of NSAIDs for the symptomatic relief of medical conditions such 
as headache or fever is allowed. 
- 
If a diagnosis of COVID-19 infection is confirmed in a patient or if a patient has been in 
direct contact with a confirmed COVID-19 case within 2 weeks prior to the planned start 
of the study, the patient is excluded from the study. 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1 
Treatment Assignment 
This is an open-label single-arm study. After written informed consent has been obtained, 
the study site will obtain the patient's identification number from the electronic Case Report 
Form (eCRF). 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE STUDY DESIGN 
The investigational medicinal products (IMP) for this study are Atezolizumab & 
Bevacizumab. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Atezolizumab 
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL glass 
vial. The vial contains approximately 20 mL (1200 mg) of Atezolizumab solution. 
For information on the Atezolizumab formulation, see the pharmacy manual and the 
Atezolizumab Investigator's Brochure. 
4.3.1.2 
Bevacizumab 
Bevacizumab will be supplied by the Sponsor as a sterile liquid in single-use 100-mg and 
400 mg preservative-free glass vials to deliver 4 mL or 16 mL Bevacizumab (25 mg/mL). 
The vial contains approximately 4 mL or 16 mL of Bevacizumab solution. 
For information on the Bevacizumab formulation, see the pharmacy manual and the 
Bevacizumab Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Patients will receive treatment as outlined in Table 3 until unacceptable toxicity or loss of 
clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data, and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease). 

 
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Table 3 - Study Treatment Regimens 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
Atezolizumab 1200 mg IV on Day 1 
Bevacizumab 15 mg/kg IV on Day 1 
 
Atezolizumab will be administered first followed by Bevacizumab, with a minimum of 5 
minutes between dosing. 
If scheduled dosing and study assessments are precluded because of a holiday, weekend, 
or other event, then dosing may be postponed to the soonest following date, with subsequent 
dosing continuing on a 21-day schedule. If treatment is postponed for fewer than 3 days, the 
patient can resume the original schedule. 
After six complete cycles, one of three cycles may be delayed by 1 week (28 days instead 
of 21 days for one cycle) to allow for vacations/holidays. Following the delay, the next cycle 
visit must be 21 days from the previous Day 1 Visit: two consecutive 28 cycles are not 
permitted. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the Study 
Drug Administration eCRF. Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience adverse 
events are provided in Appendix 10 (Atezolizumab) and Appendix 9 (Bevacizumab). 
4.3.2.1 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available or applicable by clinical practice), and clinical status (see 
Section 3.1.1 for details). 
Administration of Atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. For anaphylaxis precautions, see Appendix 8. Atezolizumab 
infusions will be administered per the instructions outlined in Table 4. 

 
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Table 4 - Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
● No premedication is permitted prior to the 
Atezolizumab infusion. 
● Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
measured within 60 minutes prior to the 
infusion. 
● Atezolizumab should be infused over 
60 (± 15) minutes. 
● If clinically indicated, vital signs should be 
measured every 15 (± 5) minutes during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
● Patients should be informed about the 
possibility 
of 
delayed 
post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
● If the patient experienced an infusion-
related 
reaction 
with 
any 
previous 
infusion, 
premedication 
with 
antihistamines, 
antipyretics, 
and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
● Vital signs should be measured within 
60 minutes prior to the infusion. 
● Atezolizumab should be infused over 
30 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (± 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
● If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be measured during the infusion and at 
30 (± 10) minutes after the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 9 and Appendix 10. 
No dose modification for Atezolizumab is allowed. 
4.3.2.2 
Bevacizumab 
Bevacizumab will be administered by IV infusion at a fixed dose of 15 mg/kg on Day 1 of 
each 21-day Cycle (see Table 3). 
Administration of Bevacizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. For anaphylaxis precautions, see Appendix 8. 
Bevacizumab infusions will be administered per the instructions outlined in Table 5. 

 
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Table 5 - Administration of First and Subsequent Bevacizumab Infusions 
First Infusion 
Subsequent Infusions 
● No premedication is permitted prior to the 
Bevacizumab infusion. 
● Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
measured within 60 minutes prior to the 
infusion. 
● Bevacizumab should be infused over 
90 (± 15) minutes. 
● Vital signs should be measured at the end 
of infusion and 2 (± 1) hours after the 
infusion. 
● Patients should be informed about the 
possibility 
of 
delayed 
post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
● If the patient experienced an infusion-
related 
reaction 
with 
any 
previous 
infusion, 
premedication 
with 
antihistamines, 
antipyretics, 
and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
● Vital signs should be measured within 
60 minutes prior to the infusion. 
● Bevacizumab should be infused over 
60 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 90 (± 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. If the 60-minute 
infusion was well tolerated, bevacizumab 
may be infused over 30 (± 15) minutes 
thereafter. 
● Vital signs should be measured at the end 
of infusion and 2 (± 1) hours after the 
infusion. 
Guidelines for dosage modification and treatment interruption or discontinuation because of 
toxicities are provided in Appendix 9. 
No dose modification for Bevacizumab is allowed. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor (Roche Farma 
S.A) The study site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, IMP 
use by each 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 IMPs supplied by the Sponsor, using the interactive 
Voice/Web Response System (IxRS) to confirm the shipment condition and content. Any 
damaged shipments will be replaced. The investigator or designee must confirm that 
appropriate temperature conditions have been maintained during transit for all IMPs received 
and that any discrepancies have been reported and resolved before use of the IMPs. All IMPs 
must be stored in a secure, environmentally controlled, and monitored (manual or automated) 

 
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area in accordance with the labelled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may supply 
or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) with 
the appropriate documentation. The site's method of destroying Sponsor-supplied IMPs must 
be agreed to by the Sponsor. The site must obtain written authorization from the Sponsor 
before any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the drug accountability log. 
4.3.4 
Continued Access to Atezolizumab and Bevacizumab 
The Sponsor will offer continued access to Roche IMPs (Atezolizumab and Bevacizumab) 
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 IMPs (Atezolizumab and Bevacizumab) 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 IMPs (atezolizumab and bevacizumab) 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 metastatic HCC that is unresectable or unsuitable for locoregional 
treatments;  
- The Sponsor has reasonable safety concerns regarding the IMP as treatment for HCC 
that is unresectable or unsuitable for locoregional treatments; 

 
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- Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the 
treatment discontinuation visit. All such medications should be reported to the investigator 
and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
- 
Oral contraceptives with a failure rate of < 1% per year (see Section 4.1.1). 
- 
Hormone-replacement therapy. 
- 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose 
or low-molecular-weight heparin [LMWH]). 
- 
Vaccinations (such as influenza, COVID-19). 
Live, attenuated vaccines are not permitted (see Section 4.4.3); 
- 
Megestrol acetate administered as an appetite stimulant. 
- 
Mineralocorticoids (e.g., fludrocortisone). 
- 
Inhaled or low-dose corticosteroids administered for COPD or asthma. 
- 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency. 
- 
Low-dose aspirin (< 325 mg/day) is permitted. Co-administration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage. 

 
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- 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief 
of pain) as outlined below: 
⮚ Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumour target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease). Treatment with Atezolizumab may be 
continued during palliative radiotherapy. Treatment with Bevacizumab should be 
suspended during palliative radiotherapy. 
- 
Radiotherapy to the brain as outlined below: 
⮚ Patients whose extracranial tumour burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
i. 
The patient has no evidence of progression or haemorrhage after completion 
of CNS-directed therapy. 
ii. 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. 
iii. 
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment. 
iv. 
Anti-convulsant therapy, if required, is administered at a stable dose. 
Note: Treatment with Atezolizumab and Bevacizumab should be withheld during 
CNS-directed radiation therapy. 
- 
Other 
local 
therapy 
(e.g., 
surgery, 
stereotactic 
radiosurgery, 
radiotherapy, 
radiofrequency ablation); patients experiencing a mixed response requiring local therapy 
for control of three or fewer non-target lesions may still be eligible to continue study 
treatment after Medical Monitor approval has been obtained. 
- 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent Atezolizumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient's care (including pre-existing conditions) 
with supportive therapies other than those defined as cautionary or prohibited therapies (see 
Section 4.4.2 and Section 4.4.3) as clinically indicated, per local standard practice. Patients 
who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., 
famotidine, cimetidine), or equivalent medications per local standard practice. Serious 

 
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infusion-associated 
events 
manifested 
by 
dyspnoea, 
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 8. 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
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 10 for details). 
4.4.2.2 
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 4.4.3) may be used 
during the study at the discretion of the investigator. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
- 
Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether health authority−approved or experimental, is prohibited for various time periods 
prior to starting study treatment, depending on the agent (see Section 4.1.2), and during 
study treatment, until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy, radiotherapy 
to the brain and local therapy under certain circumstances (see Section 4.4.1 for details); 
- 
Investigational therapy is prohibited within 28 days prior to initiation of study treatment 
and during study treatment; 

 
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- 
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; 
- 
Current use of full dose anticoagulants, thrombolytic therapy at therapeutic doses, or 
anti-platelet therapy are prohibited. 
⮚ Local label recommended doses for prophylactic use of anticoagulants or 
thrombolytic therapies is allowed. 
⮚ Low-dose aspirin (< 325 mg/day) is permitted. Co-administration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage. 
⮚ If a patient experiences a venous thromboembolism (VTE) event while still 
receiving study drug treatment, it may still be possible for the patient to remain 
on study medication despite anticoagulation treatment (see Section 4.1.2). 
- 
Use of warfarin or Coumadin-like products (includes for prophylactic use) is prohibited. 
⮚ Prophylactic use of low dose anticoagulation, unfractionated heparin or LMWH 
is permitted. The preferred choice for anticoagulation treatment should be 
LMWH as per ASCO guidelines (Lyman et al. 2015). 
- Concomitant chronic use of NSAIDs while receiving study drugs is prohibited, with the 
exception of chronic low-dose aspirin (< 325 mg/day). However, for the symptomatic relief 
of medical conditions (e.g., headache, fever) intermittent or short-term intake of oral NSAIDs 
is allowed, when co-administered with proton pump inhibitors to reduce potential GI damage. 
4.4.4 
Prohibited Food 
Use of the following foods is prohibited as described below: 
Consumption of grapefruit juice, a potent CYP3A4 enzyme inhibitor, is prohibited during the 
study and for 30 days after the final dose of study treatment. 
4.5 
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. 
If scheduled dosing and study assessments are precluded because of a holiday, weekend, 
or other event, then dosing may be postponed to the soonest following date, with subsequent 
dosing continuing on a 21-day schedule. If treatment is postponed for fewer than 3 days, the 
patient can resume the original schedule. 

 
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After six complete cycles, one of three cycles may be delayed by 1 week (28 days instead 
of 21 days for one cycle) to allow for vacations/holidays. Following the delay, the next cycle 
visit must be 21 days from the previous Day 1 visit: two consecutive 28 cycles are not 
permitted. 
Patients will be closely monitored for safety and tolerability throughout the study. Patients 
should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before performing 
any study-related procedures (including screening evaluations). Informed consent forms 
(ICFs) for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrolment. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, and 
Demographic Data 
Medical history, including clinically significant diseases, assessment of oesophageal and/or 
gastric varices per local standard procedures, treatment for these assessed oesophageal 
and/or gastric varices, surgeries, cancer history (including prior cancer therapies and 
procedures), reproductive status, smoking history, and use of alcohol and drugs of abuse, 
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 patient 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. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, should 
include an evaluation of the head, eyes, ears, nose, and throat, 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. 

 
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Limited, symptom-directed physical examinations should be performed at specified post-
baseline visits and as clinically indicated. Changes from baseline abnormalities should be 
recorded in patient notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
As part of the tumour assessment, physical examinations should include the evaluation of 
the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic 
blood pressure, 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. 
Vital signs are to be measured before, during, and after infusions as outlined in Table 6, and 
at other specified timepoints as outlined in the schedule of activities (see Appendix 1). 
Table 6 - Timing for Vital Sign Measurements for First and Subsequent Infusions 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Atezolizumab 
● Within 60 minutes prior to the 
Atezolizumab infusion 
● Record patient's vital signs during or 
after the infusion. If clinically 
indicated, vital signs should be 
measured 
every 
15 (± 5) minutes 
during 
the 
infusion 
and 
at 
30 (± 10) minutes after the infusion. 
● Within 
60 
minutes 
prior 
to 
the 
Atezolizumab infusion 
● Record patient's vital signs during or 
after the infusion if clinically indicated 
Bevacizumab 
● Within 60 minutes prior to the 
Bevacizumab infusion 
● At the end of infusion and 2 (± 1) 
hours after the infusion 
● Within 
60 
minutes 
prior 
to 
the 
Bevacizumab infusion 
● At the end of infusion and 2 (± 1) hours 
after the infusion 
 
4.5.5 
Tumour and Response Evaluations 
Patients will undergo tumour assessments at baseline, every 6 weeks (± 1 week) for the first 
54 weeks following treatment initiation, and every 12 weeks (± 1 week) thereafter, regardless 
of dose delays, until radiographic disease progression per RECIST v1.1 criteria (see 
Appendix 4) or (for patients who continue treatment after radiographic disease progression) 
loss of clinical benefit as determined by the investigator (see Section 3.1.1 for details). Thus, 

 
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tumour assessments are to continue according to schedule in patients who discontinue 
treatment for reasons other than disease progression or loss of clinical benefit, even if they 
start new anti-cancer therapy. At the investigator's discretion, tumour assessments may be 
repeated at any time if progressive disease is suspected. 
All measurable and evaluable lesions should be assessed and documented at screening. 
Tumour 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. 
Screening assessments must include CT scans (with oral or IV contrast) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, and pelvis. 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 of the chest may 
be performed, and MRI scans of the abdomen and pelvis should be performed. A CT scan 
with contrast or MRI scan of the head 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 head 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 as per RECIST v1.1 may be used. 
If a CT scan for tumour 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. 
All measurable and evaluable lesions identified at baseline should be re-assessed at each 
subsequent tumour evaluation. The same radiographic procedures used to assess disease 
sites at screening should be used for subsequent tumour assessments (e.g., the same 
contrast protocol for CT scans).  
Objective response at a single timepoint will be determined by the Investigator according to 
RECIST v1.1 (see Appendix 4). Assessments should be performed by the same evaluator, 
if possible, to ensure internal consistency across visits. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests, outlined in the schedule of activities (see 
Appendix 1), will be sent to the study site's local laboratory for analysis: 
- 
Haematology: white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin, 
haematocrit, 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, magnesium, chloride, glucose, 

 
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BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
alkaline phosphatase, ALT, AST, LDH, amylase, lipase and -fetoprotein.  
- 
Coagulation: INR, and aPTT. 
- 
Thyroid function testing: thyroid-stimulating hormone (TSH), free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4). 
- 
HIV serology: HIV-1 antibody. 
- 
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 and (if HCV antibody test is positive) HCV RNA. 
- 
Pregnancy test: 
⮚ All women of childbearing potential will have a serum pregnancy test at 
screening. Urine pregnancy tests will be performed at specified subsequent 
visits. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
⮚ A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and 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). 
- 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted. 
4.5.7 
Electrocardiograms 
An electrocardiogram (ECG) is required at screening and when clinically indicated. ECGs 
for each patient should be obtained from the same machine wherever possible. Lead 
placement should be as consistent as possible. ECG recordings must be performed after 
the patient has been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF. 

 
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4.5.8 
Blood and Tissue Samples for Exploratory Tissue and Blood Biomarker 
Plan Study 
The main ICF will contain information about the Tissue and Blood Biomarker plan. 
The following samples will be stored locally, until shipment to a central laboratory identified 
by the Sponsor, for the exploratory Tissue and Blood Biomarker Plan: 
- Blood samples for exploratory research on biomarkers. 
- Tumour biopsy samples from screening (if available) to characterize the tumour 
immune cell infiltrate by multiparametric immunofluorescence. 
For sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual. 
For more details on the Tissue and Blood Biomarker Plan for patients included in the 
translational research, see Section 2.4. For a summary of the schedule for blood and tissue 
biomarker samples to be taken from patients, see Appendix 2. 
Blood and tumour biopsy samples collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analysed, unless the patient specifically requests that the samples be destroyed, 
or local laws require destruction of the samples. However, if samples have been tested prior 
to withdrawal, results from those tests will remain as part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards described 
in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data derived 
from these analyses will generally not be provided to study investigators or patients unless 
required by law. The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.9 
Exploratory Radiomic Analysis Plan 
The Informed Consent Form will contain information about the Radiomic Analysis Plan of 
the patient’s CT scans. Patients with any contraindication to intravenous contrasts cannot 
be included in the Radiomic Analysis Plan. 
The Radiomic Analysis Plan will not require additional CT Scans for patients who agreed to 
participate. All the radiomic analyses will be performed on the same images acquired for 
tumour assessment during the study treatment. 

 
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For collecting CT Scans procedures, storage conditions, and shipment instructions, see the 
Radiomic Analysis Plan protocol (Appendix 3). 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (Atezolizumab + Bevacizumab) if 
they experience any of the following: 
- Intolerable toxicity related to study treatment, 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 may jeopardize the patient's safety if he or she continues 
study treatment. 
- Investigator or Sponsor determination that treatment 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). 
See Section 3.1.1 for details. 
If one component of study treatment (Atezolizumab or Bevacizumab) is discontinued 
permanently because of tolerability concerns, the patient may continue with the other 
components of study treatment until loss of clinical benefit as long as the patients are 
experiencing clinical benefit in the opinion of the investigator and after discussion with the 
Medical Monitor if agreed upon by the investigator and patient. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit ≤ 30 days after the final 
dose of study treatment. The visit at which response assessment shows progressive disease 
may be used as the treatment discontinuation visit. Patients who discontinue study treatment 
for any reason other than progressive disease or loss of clinical benefit will continue to 
undergo tumour response assessments (see Appendix 1). 

 
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After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent, or the 
Sponsor terminates the study). 
4.6.2 
Patient Discontinuation from 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. 
Every effort should be made to obtain a reason for patient discontinuation from the study. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF. If a patient requests to be withdrawn from the study, this request must 
be documented in the source documents and signed by the investigator. Patients who 
withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 
- The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 
- Patient enrolment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 

 
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4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may include, 
but are not limited to, the following: 
- 
Excessively slow recruitment. 
- 
Poor protocol adherence. 
- 
Inaccurate or incomplete data recording. 
- 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice. 
- 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled). 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with Atezolizumab 
and Bevacizumab in completed and ongoing studies. The anticipated important safety risks 
are outlined below (see Section 5.1.1 and Section 5.1.2). 
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 and Bevacizumab 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. Guidelines for managing 
patients who experience anticipated adverse events, including criteria for treatment 
interruption or discontinuation, are provided in Appendix 9 (Bevacizumab) and Appendix 10 
(Atezolizumab). Refer to Section 5.2, Section 5.3, Section 5.4, Section 5.5, and Section 5.6 
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 COVID-19 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 patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, which 
should be confirmed or refuted through assessment of exposure history, appropriate 
laboratory testing, and clinical or radiologic evaluations per investigator judgment. If a 

 
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diagnosis of COVID-19 is confirmed, the disease should be managed as per local or 
institutional guidelines. 
5.1.1 
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, 
severe cutaneous adverse reactions, pericardial disorders, nephritis, and myositis. In 
addition, immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH). Refer to Appendix 10 of the protocol and 
Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for Atezolizumab. 
5.1.2 
Risks Associated with Bevacizumab 
Bevacizumab has been associated with risks such as the following: GI perforations, 
haemorrhage, arterial thromboembolic events, fistulae, wound-healing complications, 
hypertension, venous thromboembolism, and proteinuria. 
Refer to Appendix 9 of the protocol and Section 6 of the Bevacizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for Bevacizumab. 
5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Bevacizumab  
The risk of overlapping toxicities between Atezolizumab and Bevacizumab is anticipated to 
be minimal. Nevertheless, the attribution and management of certain adverse events that 
have been associated with each agent separately (e.g., haemorrhage, hypothyroidism, and 
GI toxicity) may not be unambiguous when the agents are administered together. It is 
theoretically possible that allergic or inflammatory adverse events associated with 
Bevacizumab could be exacerbated by the immunostimulatory activity of Atezolizumab. 
Toxicities should initially be managed according to the recommendations in Appendix 9 
(Bevacizumab) and Appendix 10 (Atezolizumab) with dose holds and modifications (if 
applicable) applied to the component of the study treatment judged to be the primary cause. 
If individual component causality for the toxicity cannot be adequately determined, then the 
most conservative management recommendation should be applied, refer to adverse event 
management guidelines in Appendix 9 (Bevacizumab) and Appendix 10 (Atezolizumab) and 
in the most recent version of the Atezolizumab and Bevacizumab Investigator's Brochures. 

 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing protocol-specified 
safety laboratory assessments, measuring protocol-specified vital signs, and conducting 
other protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An AE can therefore be any of the following: 
- Any unfavourable 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 Section 5.3.5.9 and Section 5.3.5.10 
for more information. 
- Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
- Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study 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). 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
- 
Is fatal (i.e., the adverse event actually causes or leads to death). 
- 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death). 
⮚ This does not include any adverse event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death. 

 
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- 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11). 
- 
Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient's ability to conduct normal life functions). 
- 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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  5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). Adverse events of special interest for this study are 
as follows: 
- 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7). 
- 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
o 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 study treatment is suspected. 

 
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- 
Systemic lupus erythematosus. 
- 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome (CRS), HLH and MAS. 
- 
Nephritis. 
- 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis). 
- 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis); 
- 
Vasculitis. 
- 
Autoimmune haemolytic anaemia. 
- 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis). 
- 
Myelitis. 
- 
Facial paresis. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in the 
patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study 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 5.4.2 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 

 
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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 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints. Examples of non-directive 
questions include the following: 
- 
"How have you felt since your last clinic visit?". 
- 
"Have you had any new or changed health problems since you were last here?". 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 7 will be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. 

 
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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 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to 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 patient or use of concomitant medications known to 
increase the occurrence of the event. 

 
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- 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
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 fulfils the criteria specified below. 
Evidence exists that the adverse event has an aetiology other than study 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 study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
The health care resources consumed for managing all Grade 3 and Grade 4 AEs will be 
identified and quantified in a dedicated section of the Adverse Event eCRF. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
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, tumour lysis 
syndrome, early disease progression, or other manifestations of systemic inflammation. 

 
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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 should be recorded on the dedicated Infusion-Related Reaction eCRF 
or Cytokine Release Syndrome eCRF, as appropriate. If a patient experiences both a local 
and systemic reaction to the same dose of study treatment, each reaction should be 
recorded separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF or Cytokine Release 
Syndrome eCRF. 
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 8. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases). However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF. If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom of 
the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of severe 
or serious secondary events. A medically significant secondary adverse event that is 
separated in time from the initiating event should be recorded as an independent event on 
the Adverse Event eCRF. For example: 
- If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
- If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
- If a severe gastrointestinal haemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 

 
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- If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF. 
- If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is unclear 
as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported. If a persistent adverse event becomes more severe, the most 
extreme severity should also be recorded on the Adverse Event eCRF. If the event becomes 
serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions). The 
Adverse Event eCRF should be updated by changing the event from "non-serious" to 
"serious," providing the date that the event became serious, and completing all data fields 
related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation time points and 
subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must 
be reported as an adverse event if it meets any of the following criteria: 
- Is accompanied by clinical symptoms. 
- Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
- Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) 
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. 

 
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It is the investigator's responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., "elevated 
potassium" as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalaemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on 
recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
- Is accompanied by clinical symptoms. 
- Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
- Results in a medical intervention or a change in concomitant therapy. 
- Is clinically significant in the investigator's judgment. 
It is the investigator's responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on 
recording persistent adverse events). 

 
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5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either an 
elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
- Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin). 
- Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event), 
either as a serious adverse event or an adverse event of special interest (see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of metastatic HCC should be recorded on the Death 
Attributed to Progressive Disease eCRF. All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered as an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of death 
later becomes available (e.g., after autopsy), "unexplained death" should be replaced by the 
established cause of death. The term "sudden death" should not be used unless combined 
with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as described 
in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline Conditions 
eCRF. 

 
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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When recording 
such events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more frequent 
headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of metastatic 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 
RECIST v1.1 criteria. In rare cases, the determination of clinical progression will be based 
on symptomatic deterioration. However, every effort should be made to document 
progression through use of objective criteria. If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) or 
prolonged hospitalization should be documented and reported as a serious adverse event 
(per the definition of serious adverse event in Section 5.2.2), except as outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
- 
Hospitalization for respite care. 
- 
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 patient has not experienced an adverse event. 
- 
Hospitalization due solely to progression of the underlying cancer. 

 
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An event that leads to hospitalization under the following circumstances is not considered 
to be a serious adverse event, but should be reported as an adverse event instead: 
- 
Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours. 
5.3.5.12 
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. 
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. Special situations and non serious AEs associated with special 
situations need to be reported to Roche within 30 calendar days. If the associated adverse 
event fulfils seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). For Atezolizumab 
and Bevacizumab, adverse events associated with special situations should be recorded as 
described below for each situation: 
- 
Accidental overdose: Enter the adverse event term. Check the "Accidental overdose" 
and "Medication error" boxes. 
- 
Medication error that does not qualify as an overdose: Enter the adverse event term. 
Check the "Medication error" box. 
- 
Medication error that qualifies as an overdose: Enter the adverse event term. Check the 
"Accidental overdose" and "Medication error" boxes. 
In addition, all special situations associated with Atezolizumab and Bevacizumab, 
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 

 
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dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
- Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication error" 
boxes. Enter a description of the error in the additional case details. 
- Intercepted medication error: Enter the drug name and "intercepted medication error" 
as the event term. Check the "Medication error" box. Enter a description of the error in 
the additional case details. 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache. The "Accidental overdose" and "Medication error" boxes would 
need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data 
There will be no patient reported outcomes (PROs) collected in this study. Adverse event 
reports will therefore not be derived from PRO data by the Sponsor. In addition, the Sponsor 
will make no attempt to reconcile patient reports of treatment-related symptoms with 
investigator reports of adverse events. 
5.3.5.14 
Biomarker Data 
Adverse event reports will not be derived from biomarker data by the Sponsor, and safety 
biomarker data will not be included in the formal safety analyses for this study. In addition, 
safety biomarker data will not inform decisions on patient management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list of 
events that the investigator must report to the Sponsor within 24 hours after learning of the 
event, regardless of relationship to study treatment: 
- Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
- Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
- Pregnancies (see Section 5.4.3 for details on reporting requirements) 

 
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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. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Centre will be available 
24 hours per day, 7 days per week, in case the above-listed contacts cannot be reached. 
The Emergency Medical Call Centre 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 Centre, will be 
distributed to investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest 
5.4.2.1 
Events that Occur Prior to Study 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 Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the event), either by 
faxing or by scanning and emailing the form using the fax number or email address provided 
to investigators. 
5.4.2.2 
Events that Occur after Study 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 initiation 
of new systemic anti-cancer therapy, whichever occurs first. Investigators should record all 

 
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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 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last dose 
of Atezolizumab or 6 months after the last dose of Bevacizumab.  
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 foetus. 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 foetus, an event in the mother during 
or after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported 
on the Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform 
the investigator if their partner becomes pregnant during the study or within 6 months after 
the last dose of Bevacizumab. 
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 

 
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email address provided to investigators. Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient exposed 
to study treatment. When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow-up 
on her pregnancy. If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available. An investigator who is contacted by the male 
patient or his pregnant partner may provide information on the risks of the pregnancy and 
the possible effects on the foetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofoetal toxicity, the toxicity should be classified as a serious adverse event, recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). A therapeutic or elective abortion 
performed for reasons other than an underlying maternal or embryofoetal toxicity is not 
considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient 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 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-
up, or the patient withdraws consent. Every effort should be made to follow all serious adverse 
events considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported. 

 
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During the study period, resolution of adverse events (with dates) should be documented on 
the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT REPORTING 
PERIOD 
After the end of the 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 drug, the event should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Special Situations Form 
using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS 
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, 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 documents listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
Bevacizumab 
Bevacizumab 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. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is not a hypothesis testing study but an exploratory study with predefined precision of 
estimates for key safety parameters for sample size determination; there are no formal 
statistical hypotheses tests to be tested, and there will be no adjustments for multiplicity of 
endpoints or within-subgroups comparisons. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study will enrol approximately a sample of convenience (Lohr 2010) of 100 patients 
across approximately 20 Spanish sites, possibly according to a competitive enrolment 
scheme (Kim et al. 2017). Approximately 100 patients will be recruited in 12 months and 
estimated 25 sites will participate in the study. 
With this sample size, estimates of the observed frequencies exceeding 10-20% will have 
an acceptable precision (e.g., 95% confidence limit ± 5-6%), while for rare AE’s, rather 
imprecise estimates will be obtained. For example, with an expected frequency of 1-2% (2-
3 events in the 100 patients) the 95% CI of the observed proportion will cover a range of 
values compatible with the expected results with a 12-fold or greater of variation. For the 
same reason, a 2 to 3-fold increase over the expected frequencies might easily be observed 
by chance. As a consequence, the results for rare AEs in this study will have to be 
interpreted with caution. 
The table below displays the confidence level and the width at observed frequencies of 10%, 
15% and 20%. As shown, a sample size of 100 produces a two-sided 87% confidence 
interval with a width equal to 0.1 when the sample proportion is 10%, an 80% confidence 
interval with a width equal to 0.1 when the sample proportion is 15% and a 74% confidence 
interval with a width equal to 0.1 when the sample proportion is 20%. 
Confidence 
Level 
Sample 
size (N) 
Target 
Width 
Actual 
width 
Proportion 
(P) 
Lower 
limit 
Upper 
limit 
Width if 
p=0.5 
0.866 
100 
0.1 
0.1 
0.1 
0.05 
0.15 
0.16 
0.792 
100 
0.1 
0.1 
0.15 
0.1 
0.2 
0.136 
0.739 
100 
0.1 
0.1 
0.2 
0.15 
0.25 
0.123 

 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrolment, study drug administration, and discontinuation from the study will be summarized 
for the ITT population, defined as all recruited patients. The reasons for study drug 
discontinuation will also be tabulated. Major protocol deviations, including major deviations 
with regard to the inclusion and exclusion criteria, will be summarized for the ITT population. 
All safety analyses will be conducted in the SAS, defined as all enrolled patients who had at 
least one administration of Atezolizumab + Bevacizumab. 
All efficacy analyses will be conducted on the ITT population. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, self-reported race/ethnicity) 
will be summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate. Missing values will also 
be displayed, and they will be classified and managed using the methods outlined in the 
statistical analysis plan (SAP). Reproductive status and smoking history should also be 
captured. Summaries of patient’s baseline cancer history will include stage, date of 
diagnosis, and any prior anti-tumour treatment. Demographic information includes age and 
self-reported race/ethnicity. 
Missing values will be classified according to their underlying missing mechanism (missing 
completely at random; missing at random; missing not at random) and pattern (monotonic; 
generalized; univariate) (van Buuren et al. 1999; Little and Rubin 2002; van Buuren 2018). 
If necessary, missing data will be dealt with via one or more multiple imputation regression 
models and/or other statistical methods consistent with their underlying missing mechanism 
(Van Buuren et al., 1999; Little & Rubin 2002; Van Buuren 2018). 
6.4 
SAFETY ANALYSES 
This study is primarily a safety study. The safety analysis population of this single-arm study 
will consist of all enrolled patients who received at least one full or partial dose of study 
treatment. 
6.4.1 
Primary Analysis 
The primary safety analysis will evaluate the incidence of treatment discontinuations of 
Atezolizumab and/or Bevacizumab due to adverse events of grade ≥ 3. Verbatim adverse 
event terms will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus terms. Adverse event severity will be graded according to NCI CTCAE v5.0. 
Multiple occurrences of the same event will be counted once at the maximum severity. 

 
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6.4.2 
Other Safety Analyses Including Analyses of Exposure, Adverse Event 
Severity, Laboratory, Vital Sign, and Hepatic Function Data 
Drug exposure will be summarized by descriptive statistics to include treatment duration, 
number of doses, and dose intensity. The following events occurring during or after the first 
dose of study treatment will be summarized by NCI CTCAE v5.0: 
- 
All Adverse Events (AEs). 
- 
All severe AEs (Grade 3-4). 
- 
All treatment related AEs. 
- 
All severe treatment related AEs (Grade 3 -4). 
- 
All serious AEs. 
- 
All treatment related serious AEs. 
- 
Immune-related AEs. 
- 
All severe immune-mediated AEs (Grade 3-4). 
- 
All adverse events leading to withdrawal from any component. 
- 
All adverse events leading to withdrawal from Atezolizumab. 
- 
All adverse events leading to withdrawal from Bevacizumab. 
- 
All Grade 5 AEs. 
- 
All treatment related Grade 5 AE. 
- 
All adverse event of special interest (AESIs) of Atezolizumab. 
- 
All severe AESIs of Atezolizumab (Grade 3-4). 
- 
All adverse events leading to temporary interruption of any component. 
- 
All adverse events leading to temporary interruption of Atezolizumab. 
- 
All adverse events leading to temporary interruption of Bevacizumab. 
Laboratory data with values outside the normal ranges will be identified. In addition, selected 
laboratory data will be summarized by grade. 
Descriptive statistics will be used to summarize changes in vital signs. 

 
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Additional analyses may be performed as indicated. 
Missing data for items and patients will be summarized to improve results interpretation. 
6.5 
EFFICACY ANALYSES 
6.5.1 
Primary Efficacy Endpoints 
This study is not designed to primarily evaluate efficacy. All baseline summaries and efficacy 
analyses will be based on the ITT analysis set defined as all recruited patients. 
The main analysis of efficacy will be an analysis of OS, defined as the time from initiation of 
study treatment to death from any cause. Deaths with causes of death reported during the 
study will also be summarized. 
Other efficacy endpoints for the study are as follows: 
- 
PFS, defined as the time from initiation of study treatment to the first occurrence of 
disease progression or death from any cause (whichever occurs first), as determined 
by the investigator according to RECIST v1.1 
- 
ORR, defined as a complete or partial response, on two consecutive occasions, 4 
weeks apart, as determined by the investigator according to RECIST v1.1  
- 
TTP, defined as the time from initiation of study treatment to the first occurrence of 
disease progression, as determined by the investigator according to RECIST v1.1 
- 
DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1.  
- 
Number/Rate of patients starting second line treatment. 
Time-dependent variables OS, PFS, TTP, DOR and PPS will be analysed using Kaplan-
Meier (K-M) methods (Kaplan and Meier 1958) and Greenwood’s formula (Greenwood 
1926). Medians and quartiles with 95% confidence interval (CI) will be derived from the K-
M curves. K-M plots with a 95% CI for OS, PFS, TTP, DOR and PPS will be prepared. 
To evaluate whether post-study treatment has an impact on OS following disease 
progression, patients will be followed up with a descriptive analysis for anti-cancer therapies 
and survival. In detail, the number and rate of patients starting second or further lines of 
treatment will be described indicating the time and duration of each post-study treatment. 
OS based on type and duration of each post-study treatment will be described. 

 
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To evaluate whether the reason for treatment withdrawal has an impact on OS, OS based 
on the following reasons for treatment withdrawal will be described: 
- 
Progressive disease (PD) vs AE vs deteriorating liver function/clinical conditions. 
Missing values will be classified and managed using the methods outlined in the SAP. 
6.5.2 
Exploratory Efficacy Endpoints 
Exploratory efficacy analyses will be as follows: 
- 
To further, evaluate whether the patterns of tumour responses to Atezolizumab + 
Bevacizumab treatment using different criteria have a different impact on OS and 
PFS. The different criteria for evaluation of tumour responses that will be compared 
are as follows: RECIST 1.1, HCC mRECIST, EASL and iRECIST criteria. Further 
details on the patterns of progression measured by these criteria are given in 
Section 2.2. 
- 
- To further evaluate whether the patterns of tumour progression (growth versus new 
lesion, intrahepatic versus extrahepatic) have a different impact on OS and PFS. 
RECIST 1.1 criteria will be used to evaluate of tumour progression. Additionally, a 
secondary analysis for the registration of tumour progression will include HCC 
mRECIST, taking into consideration the RECIST modifications described for SHARP 
(Reig 2014). Further details on the patterns of progression measured by both these 
criteria are given in Section 2.2. 
- 
To explore whether post-study treatments have an impact on OS. OS will be 
analysed according to type and duration of each post-study treatments. 
- 
To evaluate whether reasons for treatment withdrawal (progressive disease or AE) 
have an impact on OS. 
- 
To analyse the organ-specific response rate (OS-RR) using RECIST 1.1 and the 
cumulative incidence probability of organ-specific progression RR including target 
lesions from the liver, lungs, lymph-nodes and non-target lesions in bones. 
- 
To determine the applicability of depth of response (decrease in tumour burden) as 
a surrogate for OS when compared to baseline measurement according to RECIST 
1.1, EASL mRECIST and iRECIST criteria. 
6.6 
BIOMARKER AND RADIOMIC ANALYSES 
The Tissue & Blood Biomarker Plan for patients included from the study included in 
translational research aims to identify biomarkers that might be potentially associated with 
response patterns to Atezolizumab + Bevacizumab or the HCC disease evolution under 

 
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Atezolizumab + Bevacizumab treatment. Further details of the exploratory biomarkers to be 
investigated are given in Section 2.6. 
Although no formal statistical analysis of these exploratory biomarkers will be performed, 
data may be analysed in the context of this study and in aggregate with data from other 
studies. 
This study includes CT Radiomic Analysis Plan designed to more precisely evaluate the 
tumour response to Atezolizumab and Bevacizumab in patients with unresectable HCC. 
Further details of the parameters to be evaluated in the CT Radiomic Analysis Plan are given 
in Section 2.6. Although no formal statistical analysis of these exploratory biomarkers will be 
performed, data may be analysed in the context of this study and in aggregate with data 
from other studies. 
6.7 
INTERIM ANALYSIS 
6.7.1 
Planned Interim Analysis 
One interim analysis of safety will be performed at the time of 50 recruited patients, 
estimated to occur at approximately 6 months after first patient in. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study. A contract research organization 
(CRO) will be responsible for data management of this study, including quality checking of 
the data. Data entered manually will be collected via EDC through use of eCRFs. Sites will 
be responsible for data entry into the EDC system. In the event of discrepant data, the CRO 
will request data clarification from the sites, which the sites will resolve electronically in the 
EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. 
The Sponsor will perform oversight of the data management of this study, including approval 
of the CRO's data management plans and specifications. Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor's standard 
procedures will be used to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail. 
System backups for data stored at the CRO and records retention for the study data will be 
consistent with the CRO's standard procedures. 

 
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7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs will 
be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be reviewed 
and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records. Acknowledgement of receipt of 
the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) is entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly 
into the eCRFs (i.e., no prior written or electronic record of the data) and considered source 
data. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-
related monitoring, Sponsor audits, and IRB/EC review. The study site must also allow 
inspection by applicable health authorities. 

 
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7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve as 
the source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research. An acceptable 
computerized data collection system allows preservation of the original entry of data. If 
original data are modified, the system should maintain a viewable audit trail that shows the 
original data as well as the reason for the change, name of the person making the change, 
and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the applicable laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the individual. The study will comply with the requirements of the ICH E2A 
guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting). Studies conducted in the United States or under a U.S. Investigational New Drug 
(IND) Application will comply with U.S. FDA regulations and applicable local, state, and 
federal laws. Studies conducted in the European Union or European Economic Area will 
comply with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws. 

 
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8.2 
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) will 
be provided to each site. If applicable, it will be provided in a certified translation of the local 
language. The Sponsor or its designee must review and approve any proposed deviations 
from the Sponsor's sample Informed Consent Forms or any alternate consent forms 
proposed by the site (collectively, the "Consent Forms") before IRB/EC submission. The 
final IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. Patients 
will be told that they are free to refuse to participate and may withdraw their consent at any 
time for any reason. A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures. Patients who decline to participate will not 
provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or 
when new information becomes available that may affect the willingness of the patient to 
participate. The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a patient 
is participating in the study, the patient 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 policy. For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's legally 
authorized representative. All signed and dated Consent Forms must remain in each 
patient's study file or in the site file and must be available for verification by study monitors 
at any time. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
111/Protocol ML42600, Version 2 
8.3 
INSTITUTIONAL REVIEW BOARD (IRB) OR ETHICS COMMITTEE (EC) 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.7). 
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 IND safety reports or other safety-
related communications from the Sponsor. Investigators are responsible for ensuring that 
such reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC and archived in the site's study 
file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient 
names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless permitted 
or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker and radiomic 
analyses, data derived from these analyses will generally not be provided to study 
investigators or patients unless required by law. The aggregate results of any conducted 
research will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.6). 
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. 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
112/Protocol ML42600, Version 2 
Study data, which may include data on genomic variants, may be submitted to government 
or other health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study. These data may be 
combined with or linked to other data and used for research purposes, to advance science 
and public health, or for analysis, development, and commercialization of products to treat 
and diagnose disease. In addition, redacted Clinical Study Reports and other summary 
reports will be provided upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of study 
in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
including an audit trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and data 
integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies 
and procedures. The Sponsor will review all protocol deviations and assess whether any 
represent a serious breach of Good Clinical Practice guidelines and require reporting to 
health authorities. As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility criteria, 
are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. Prior to 
study initiation, the Sponsor will identify potential risks associated with critical trial processes 
and data and will implement plans for evaluating and controlling these risks. Risk evaluation 

 
Atezolizumab and bevacizumab — Roche Farma S.A. 
113/Protocol ML42600, Version 2 
and control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate).  
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for inspection 
of study data, patients' medical records, and eCRFs. The investigator will permit national 
and local health authorities; Sponsor monitors, representatives, and collaborators; and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Roche Farma, S.A. (C/ Ribera del Loira 50, 
28042 Madrid, Spain). 
The Sponsor will provide clinical operations management, data management, and medical 
monitoring. 
26 sites in Spain will participate in the study to enrol approximately 100 patients. Screening 
and enrolment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., biomarker analyses). Accredited local laboratories will be used for routine monitoring; 
local laboratory ranges will be collected. 
The SC will monitor and evaluate patient safety throughout the study. Tumour response and 
progression will be evaluated by an IRC. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details) and redacted 
Clinical Study Reports and other summary reports will be made available upon request. 
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data at 
the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application has 
been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within 6 months after the availability of the respective 

 
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114/Protocol ML42600, Version 2 
Clinical Study Report. In addition, for all clinical trials in patients involving an IMP for which 
a marketing authorization application has been filed or approved in any country, the Sponsor 
aims to publish results from analyses of additional endpoints and exploratory data that are 
clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not 
yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre trials only in their entirety and not as individual centre data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. Any formal publication of the study in 
which contribution of Sponsor personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information). 
10. 
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Appendix 1. Schedule of Activities 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
120/Protocol ML42600, Version 2 
TSH, free T3, free T4  
x 
 
 
Cycles 5, 9, 13, etc. 
(every 4 cycles) 
x 
 
Pregnancy test  
 
x r 
 
x s 
x 
 
Concomitant medications t  
 
x 
 
x 
x 
 
Adverse events u  
x 
 
 
x 
x 
 
Identification and quantification of 
health care resources consumed 
for managing Grade 3 and 4 AEs 
 
 
 
x 
x 
 
Study treatment infusion v  
 
 
 
x 
 
 
Survival and anti-cancer therapy 
follow-up w 
 
 
 
 
 
x 
Tumour 
biopsy 
sample 
(if 
available) for biomarker plan 
x 
 
 
 
 
 
Blood samples for biomarker plan 
x 
 
 
Day 1 of Cycle 2 
and then Day 1 of 
Cycle 3 
 
 
CT Scan for Radiomic plan 
x 
 
 
Week 6 (prior cycle 
3) & week 12 (prior 
cycle 5) 
xx 
 
CT = computed tomography; EGD = esophagogastroduodenoscopy; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; MRI = magnetic resonance imaging; PET = 
positron emission tomography; Q3W = every 3 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumours, Version 1.1; T3 = 
triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
Note: Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. Each 
cycle is 21 days in length. 
a All visits and infusions may be administered with a window of ± 3 days. 
b Written informed consent can be obtained up to 30 days prior to study entry and is required before performing any study-specific tests or 
procedures. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and per protocol relevant 
window may be used for screening assessments rather than repeating such tests. Screening local laboratory assessments obtained ≤ 96 
hours prior to the initiation of study treatment do not have to be repeated for Cycle 1. Test results should be reviewed prior to administration 
of study treatment. 
c Patients will be asked to return to the clinic 30 days after the last dose of study treatment for an end-of-treatment visit. After this visit, serious 
adverse events and protocol defined adverse events of special interest, regardless of attribution, will be recorded until 90 days after the last 
dose of study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first. Ongoing adverse events thought to 
be related to study treatment will be followed until the event has resolved to baseline grade or better, the event is assessed by the 

Appendix 1. Schedule of Activities 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
121/Protocol ML42600, Version 2 
investigator as stable, new anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it is 
determined that the study treatment or participation is not the cause of the adverse event. Scans performed within 6 weeks prior to the 
treatment discontinuation visit do not need to be repeated. 
d Cancer history includes stage, date of diagnosis, and prior anti-tumour treatment. Demographic information includes age and self-reported 
race/ethnicity. Reproductive status and smoking history should also be captured. 
e A complete physical examination at screening should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. Changes in abnormalities noted at 
baseline should be recorded at the end of the visit. New or worsened abnormalities should be recorded as adverse events if appropriate. 
f A limited physical examination will be performed at other visits to assess changes from baseline abnormalities and any new abnormalities and 
to evaluate patient reported symptoms. New or worsened abnormalities should be recorded as adverse events if appropriate. 
g ECOG Performance Status at screening must be recorded between day -7 and day -1 before Day 1 of Cycle 1. ECOG Performance Status, 
limited physical examination and local laboratory assessments may be obtained ≤ 96 hours before Day 1 of each cycle. 
h All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic imaging performed during the 
screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis and brain, 2) bone scan or PET scan as clinically 
indicated, and 3) any other imaging studies (CT scan of the neck, plain films, etc.) as clinically indicated by the treating physician. The same 
radiographic procedures and technique must be used throughout the study for each patient (e.g., if the patient had CT 
chest/abdomen/pelvis performer during screening, then she should subsequently undergo CT performed using the same radiologic protocol 
throughout the remainder of the study). Results must be reviewed by the investigator before dosing at the next cycle. Tumour assessments 
will be performed at baseline, every 6 weeks (± 1 week) for the first 54 weeks following the initiation of study treatment, and every 12 weeks 
(± 1 week) thereafter, with additional scans as clinically indicated. All known sites of disease documented at screening should be re-
assessed at each subsequent tumour evaluation. Tumour response will be evaluated by the investigator using RECIST Version 1.1. In the 
absence of disease progression, tumour assessments should continue regardless of whether patients discontinue study treatment or start 
new anti-cancer treatment, unless the patient dies, withdraws consent, or the study is terminated by the Sponsor, whichever occurs first. 
i Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection. 
j Vital signs include heart rate, respiratory rate, blood pressure, and temperature. On days of study treatment administration (Atezolizumab 
and Bevacizumab), the patient's vital signs should be determined up to 60 minutes before all infusions. Vital signs will be measured at the 
end of Bevacizumab infusion and 2 (± 1) hours after end of the infusion and will also be collected during and after every infusion of 
Atezolizumab if clinically indicated. 
k The dose of Bevacizumab will be based on the patient's weight (in kilograms) measured ≤ 14 days prior to baseline (the initiation of study 
treatment) and will remain the same throughout the study unless there is a weight change of > 10% from baseline. If re-baseline is needed 
the latest baseline weight should always be used to calculate percent change in weight for all subsequent doses. 
l All patients must undergo an EGD within 6 months of starting the study and all size of varices (small to large) must be assessed and treated 
per local standard of care prior to enrolment. 
m Haematology consists of CBC, including RBC count, haemoglobin, haematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count. A manual differential can be done if clinically indicated. 

Appendix 1. Schedule of Activities 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
122/Protocol ML42600, Version 2 
n Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, 
ALT, AST, LDH, amylase and lipase. 
o All patients will be tested for HIV locally prior to the inclusion into the study and if not in contradiction with local legislation; HIV-positive 
patients will be excluded from the clinical study. HBsAg, HBsAb, and total HBcAb should be collected during screening and tested locally. 
HBV DNA must be collected prior to Cycle 1, Day 1 in patients who have negative serology for HBsAg and HBsAb tests and a total 
HBcAb. 
p Only if patient tests serologically positive for HBsAg, HBcAb, quantitative HBsAg and HBV DNA will be tested during screening; Cycle 5, 
Day 1; Cycle 9, Day 1; and at treatment discontinuation. Quantitative HBsAg will be tested locally. If a patient tests positive for HCV 
antibody at screening, quantitative HCV RNA must be tested locally at screening, Cycle 5 Day 1, Cycle 9 Day 1, and at treatment 
discontinuation. 
q Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood and should be repeated before every cycle during 
treatment. Urine dipstick for proteinuria must be < 2+ within 7 days prior to initiation of study treatment. Patients discovered to have ≥ 2+ 
proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours. 
r Serum pregnancy test within 14 days before Cycle 1, Day 1. 
s Urine pregnancy test: if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications the patient 
has used within the 7 days prior to initiation of study treatment should be documented. At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded. 
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first. Serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, 
whichever occurs first. After this period, investigators should report any serious adverse events and adverse events of special interest that 
are believed to be related to prior treatment with study drug. The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, new systemic anti-cancer treatment is initiated, 
the patient is lost to follow-up, the patient withdraws consent, or it is determined that the study treatment or participation is not the cause of 
the adverse event. Every effort should be made to follow all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported. 
v The initial dose of Atezolizumab will be delivered over 60 (± 15) minutes. If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions 
may be delivered over 30 (± 10) minutes. The initial dose of Bevacizumab will be delivered over 90 (± 15) minutes. If the first infusion is 
tolerated without infusion-associated adverse events, the second infusion may be delivered over 60 (± 10) minutes. If the 60-minute 
infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes. Atezolizumab will be administered first 

Appendix 1. Schedule of Activities 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
123/Protocol ML42600, Version 2 
followed by Bevacizumab, with a minimum of 5 minutes between dosing. In the absence of unacceptable toxicity, patients may continue 
the study treatment until there is evidence of disease progression or lack of clinical benefit. 
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(± 21 days) until death, loss to follow-up, or until study termination by the Sponsor. All patients will be followed for survival and new anti-
cancer therapy (including targeted therapy and immunotherapy) information unless the patient requests to be withdrawn from follow-up; 
this request must be documented in the source documents and signed by the investigator. If the patient withdraws from study, the study 
staff may use a public information source (e.g., county records) to obtain information about survival status. 
X Progression Scan. 
y Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle. 
 

Appendix 2. Schedule of Samples for Tissue and Biomarker Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
124/Protocol ML42600, Version 2 
 – SCHEDULE OF SAMPLES FOR TISSUE AND BIOMARKER PLAN 
Visit 
Timepoint 
Sample Type 
Screening 
(Day −28 to Day –1) 
Prior to first 
infusion of 
Atezolizumab 
Tumour biopsy sample if available to characterize: 
(1) Tumour immune cells infiltrate by immunofluorescence. 
(2) The specificities of T lymphocyte receptors against 
tumour-specific antigens. 
(3) Specific expression patterns that may constitute gene 
signatures with prognostic and/or predictive power of 
response to Atezolizumab + Bevacizumab. 
● Screening 
(Day −28 to Day –1) 
 
● Cycle 2 (week 3) 
 
● Cycle 3 (week 6) 
Prior to first 
infusion of 
Atezolizumab 
Biomarker (blood, plasma, and serum) sample to evaluate: 
(1) Cytokines. 
(2) cfDNA exome sequencing to capture mutations present in 
circulating DNA. 
(3) Sequencing the TCRs of circulating T cells to detect 
specific antigenicity of tumour antigens. 
(4) Flow cytometry to see leukocyte subpopulations that can 
predict response. 
 
 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
125/Protocol ML42600, Version 2 
 – RADIOMIC ANALYSIS PLAN 
 
Table of Contents 
 
1. BACKGROUND AND RATIONALE ........................................................................ 126 
2. OBJECTIVES OF THE ANALYSIS ......................................................................... 126 
3. IMAGING PROTOCOL ............................................................................................ 127 
4. HEALTH AND SAFETY CONSIDERATIONS ......................................................... 128 
5. IMAGING DATA COLLECTION .............................................................................. 128 
6. QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 129 
7. IMAGING ANALYSES ............................................................................................ 129 
8. REFERENCES ........................................................................................................ 129 
 
 
 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
126/Protocol ML42600, Version 2 
1. Background and rationale 
Medical imaging allows for non-invasive oncologic diagnosis and treatment guidance. Radiomics 
converts imaging data into large number of quantifiable features from tumour tissue using 
automatically extracted data-characterization algorithms. Radiomics can i) facilitate a deeper 
understanding of tumour biology, ii) capture tumour heterogeneity and iii) monitor tumour evolution 
and response to therapy (1-3). Moreover, with the development of high-throughput methods to extract 
and correlate multiple imaging parameters with genomics data, a new opportunity in medical research 
has emerged. Radiogenomics aims to correlate imaging features (i.e., the imaging phenotype) with 
gene expression patterns, gene mutations, and other genome-related data. Radiogenomics can be 
used to develop imaging surrogates for specific genetic signatures to predict outcome and assess 
response to anticancer targeted therapy such antiangiogenics and immunotherapy in 
hepatocarcinoma (HCC) towards a more precise patient care (4, 5). 
The most widely used medical imaging modality in oncology is computed tomography (CT), which 
assesses tissue density. CT is performed as standard of care in the vast majority of patients with 
HCC before starting treatment and routinely for assessing response (6). Due to the non-invasive 
nature of CT, its capacity of study the whole body in just a few seconds and its broad use in clinical 
practice, CT-radiomics is a promising tool for radiogenomics signatures development and the 
identification of novel predictive and response biomarkers to immunotherapy and anti-angiogenic 
treatments (7-9). 
2. Objectives of the analysis 
i. 
To explore the correlation CT-radiomics signatures (including shape, first-order and higher-
order texture features) at baseline with response to atezolizumab and bevacizumab, in 
patients with untreated unresectable hepatocellular carcinoma included in the study 
(ML42600). 
ii. 
To explore early changes in CT-radiomics signatures as response to atezolizumab and 
bevacizumab, in patients with untreated unresectable hepatocellular carcinoma included in 
the study (ML42600). 
iii. 
To explore inter- and intra-tumour heterogeneity changes in CT-radiomics signatures in 
relation to differences in responder/non-responder lesions to atezolizumab and 
bevacizumab, in patients with untreated unresectable hepatocellular carcinoma included in 
the study (ML42600). 
iv. 
To evaluate the correlation of radiomics features with tumour mutational status to develop 
radiogenomics phenotypes, in patients with untreated unresectable hepatocellular carcinoma 
included in the study (ML42600). 
v. 
To evaluate the correlation of CT-radiomics features with the tumour microenvironment on 
biopsied lesions including tumour immunophenotype by RNA seq and vascularisation from 
tumour samples in patients with untreated unresectable hepatocellular carcinoma included 
in the study (ML42600). 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
127/Protocol ML42600, Version 2 
3. Imaging protocol 
Patients included in the study ML42600 will have a CT scan at baseline, before starting treatment 
with Atezolizumab and Bevacizumab (within 28 days of Cycle 1, Day 1), and every 6 weeks (± 1 
week) during the first 54 weeks of treatment with Atezolizumab and Bevacizumab and every 12 weeks 
(± 1 week) thereafter. This will continue until PD defined by RECIST 1.1/iRECIST criteria, or loss of 
clinical benefit defined by the response criteria defined in the main study protocol, whichever occurs 
last, even if starting a new anticancer therapy. If disease progression is documented prior to week 6, 
CT will be done at this point. 
For the Radiomic plan, no additional scans are required. Only the CT scans performed at baseline, 
week 6, week 12 and at disease progression will be required to ship for central radiomic evaluation.  
The CT acquisition protocol will include: 
Scan phase/delay 
Pre-contrast 
Post 
contrast 
chest 
Arterial 
phase 
(late arterial 
phase 
strongly 
preferred) 
Portal 
venous 
phase 
Delayed 
venous 
phase 
Scan 
Locations/Coverage: 
Abdomen and pelvis 
performed 
in 
one 
breathhold 
Chest  
 
Entire liver 
performed in 
one 
breathhold 
Abdomen 
and Pelvis 
in one 
breath-hold 
entire liver 
performed in 
one 
breathhold 
FOV 
Large 
Slice thickness 
5 mm or lower 
Reconstruction 
interval 
(distance 
between 
slice 
locations) 
5 mm 
 
Gap (slice spacing) 
No 
Contrast media 
Oral contrast 
Not required 
Iv contrast 
Required 100 - 150 mL Non-ionic only 
150-300 mg/mL 
Dose 
1.5-2mL/kg body weight 
Rate of injection 
4 
cc / sec (power injector) 
Reconstruction 
algorithm 
- 
Convolution kernels B20f, B20s, B30f and B30s from Siemens (Erlangen, 
Germany) 
- 
B from Philips Electronics (Eindhoven, Netherlands) 
- 
Soft from General Electric (Boston, USA) 
 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
128/Protocol ML42600, Version 2 
Timing of multiphase sequences for the chest and liver 
Multiphase 
acquisitions 
Phase 
Specifications 
Fixed time delay 
Chest 
CT 
scan  
25 seconds after starting injection at 3 mL/s 
Arterial 
phase 
45 seconds after starting injection at 3 mL/s 
Portal 
venous 
phase 
60-80 s after the start of injection at 3 mL/s 
Delayed 
venous 
phase 
4-5 minutes after the start of injection 
Bolus 
tracking 
(recommended) 
Chest 
CT 
scan 
Aortic triggering is performed at ascending aorta. 
After threshold aortic enhancement of 100-120 HU is 
reached, a scan delay of 6 seconds is suggested for 
chest CT scan. 
Arterial 
phase 
After the chest CT scan had been acquired, a scan delay 
of 10 seconds is suggested for late arterial phase 
acquisition. 
Portal 
venous 
phase 
30-35 seconds after late arterial phase acquisition 
Delayed 
phase 
4-5 minutes after the start of injection 
 
4. Health and Safety considerations 
Local health and safety requirements should be followed at all times. 
CT images will be acquired after intravenous contrast administration, the procedure is almost entirely 
safe. The CT scans will be reviewed by radiology staff and made available to the clinical units in the 
standard way, so the CT scans will contribute to patient management. 
5. Imaging data collection 
Acquisition and analysis CT data will be collected at each centre and uploaded into a server after 
anonymization and linked to an alphanumeric code assigned in the protocol ML42600 Anonymization 
will be performed on-site by the owner of the information, and to make it feasible to trace it back). 
Defined investigators at each of the recruiting centres will be in charge of the scans upload into the 
server. The clinical investigator team at each clinical centre will compromise to keep the identity of 
the subjects’ confidential code. The link between the anonymization code and real personal data will 
be safely stored at the clinical centre, and only the local investigator will have access to it. The 
collection and processing of CT scans from enrolled subjects will be limited to those data that are 
necessary to fulfil the objectives of the study. These data will be collected and processed with 
adequate precautions to ensure confidentiality and compliance with applicable data protection 
European and National regulations. Appropriate technical and organizational measures to protect the 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
129/Protocol ML42600, Version 2 
personal data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration will be put in place. Given the complexity and exploratory nature of the 
exploratory analyses, data derived from these analyses will generally not be provided to study 
investigators or patients unless required by law. The aggregate results of any conducted research 
will be available in accordance with the effective Roche’s policy on study data publication. 
6. Quality control and quality assurance 
The overall monitoring of safety issues related to the Radiomic Analysis Plan will be performed by 
the study management group CT acquisition and post-processing are subject to internal validation 
and standardization processes. It is the responsibility of the participating centres to inform the 
Radiomic Analysis Plan team of any upgrades to the CT scanner hardware or software. 
7. Imaging analyses 
Target lesions corresponding to the primary tumour and metastases will be selected for radiomics 
features extraction. Target lesions will be selected based on size (≥ 1 cm in large diameter for solid 
lesions and ≥ 1.5 cm in short diameter for nodes), preferably well-defined and avoiding for cystic 
changes and cavitation.  
Multiple radiomics features from the target lesions will be extracted, including: 
i) First order features (energy, entropy, minimum, percentiles, maximum, mean, median, 
interquartile range, range, standard deviation, skewness, kurtosis, among others). 
ii) Shape Features (volume, surface area, sphericity, among others). 
iii) Different filters for texture analysis will be applied for higher order statistics texture analysis, 
including Gray Level Co-occurrence Matrix (GLCM) and Gray Level Run Length Matrix (GLRLM) 
features among others. 
8. References 
1. Lambin P, Leijenaar RTH, Deist TM, Peerlings J, de Jong EEC, van Timmeren J, Sanduleanu S, 
Larue R, Even AJG, Jochems A, van Wijk Y, Woodruff H, van Soest J, Lustberg T, Roelofs E, van 
Elmpt W, Dekker A, Mottaghy FM, Wildberger JE, Walsh S. Radiomics: the bridge between medical 
imaging 
and 
personalized 
medicine. 
Nat 
Rev 
Clin 
Oncol 
2017;14(12):749-762. 
doi: 
10.1038/nrclinonc.2017.141 
2. Beckers RCJ, Trebeschi S, Maas M, Schnerr RS, Sijmons JML, Beets GL, Houwers JB, Beets-
Tan RGH, Lambregts DMJ. CT texture analysis in colorectal liver metastases and the surrounding 
liver parenchyma and its potential as an imaging biomarker of disease aggressiveness, response and 
survival. Eur J Radiol 2018;102:15-21. doi: 10.1016/j.ejrad.2018.02.031 
3. Vargas HA, Veeraraghavan H, Micco M, Nougaret S, Lakhman Y, Meier AA, Sosa R, Soslow RA, 
Levine DA, Weigelt B, Aghajanian C, Hricak H, Deasy J, Snyder A, Sala E. A novel representation of 
inter-site tumour heterogeneity from pre-treatment computed tomography textures classifies ovarian 
cancers by clinical outcome. Eur Radiol 2017;27(9):3991-4001. doi: 10.1007/s00330-017-4779-y 

Appendix 3. Radiomic Analysis Plan 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
130/Protocol ML42600, Version 2 
4. Zhou Y, He L, Huang Y, Chen S, Wu P, Ye W, Liu Z, Liang C. CT-based radiomics signature: a 
potential biomarker for preoperative prediction of early recurrence in hepatocellular carcinoma. 
Abdom Radiol (NY) 2017;42(6):1695-1704. doi: 10.1007/s00261-017-1072-0 
5. Saini A, Breen I, Pershad Y, Naidu S, Knuttinen MG, Alzubaidi S, Sheth R, Albadawi H, Kuo M, 
Oklu R. Radiogenomics and Radiomics in Liver Cancers. Diagnostics (Basel) 2018;9(1). doi: 
10.3390/diagnostics9010004 
6. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-247. doi: 10.1016/j.ejca.2008.10.026 
7. Limkin EJ, Sun R, Dercle L, Zacharaki EI, Robert C, Reuze S, Schernberg A, Paragios N, Deutsch 
E, Ferte C. Promises and challenges for the implementation of computational medical imaging 
(radiomics) in oncology. Ann Oncol 2017;28(6):1191-1206. doi: 10.1093/annonc/mdx034 
8. Pinker K, Shitano F, Sala E, Do RK, Young RJ, Wibmer AG, Hricak H, Sutton EJ, Morris EA. 
Background, current role, and potential applications of radiogenomics. J Magn Reson Imaging 
2018;47(3):604-620. doi: 10.1002/jmri.25870 
9. Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, Carvalho S, Bussink J, 
Monshouwer R, Haibe-Kains B, Rietveld D, Hoebers F, Rietbergen MM, Leemans CR, Dekker A, 
Quackenbush J, Gillies RJ, Lambin P. Decoding tumour phenotype by noninvasive imaging using a 
quantitative radiomics approach. Nat Commun 2014;5:4006. doi: 10.1038/ncomms5006 
 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
131/Protocol ML42600, Version 2 
 – RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS, VERSION 1.1 (RECIST 
V1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumours, Version 1.1 
(RECIST v1.1, Eisenhauer et al. 2009) are presented below, with slight modifications from 
the original publication and the addition of explanatory text as needed for clarity.1 
TUMOUR MEASURABILITY 
At baseline, tumour lesions/lymph nodes will be categorized as measurable or non-
measurable as described below. All measurable and non-measurable lesions should be 
assessed at screening and at subsequent protocol-specified tumour assessment timepoints. 
Additional assessments may be performed as clinically indicated for suspicion of 
progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumour Lesions 
Tumour lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
- 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ≤ 5 mm) 
- 
10-mm calliper measurement by clinical examination (lesions that cannot be accurately 
measured with callipers should be recorded as non-measurable) 
- 
20 mm by chest X-ray 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm 
in the short axis when assessed by CT scan (CT scan slice thickness recommended to be 
≤ 5 mm). At baseline and follow-up, only the short axis will be measured and followed. 
Additional information on lymph node measurement is provided below (see "Identification of 
Target and Non-Target Lesions" and "Calculation of Sum of Diameters"). 
                                               
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
132/Protocol ML42600, Version 2 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumour lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 mm but < 15 mm) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, peritoneal spread, and abdominal mass/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
- 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
- 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
- 
Blastic bone lesions are non-measurable. 
Cystic Lesions: 
- 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
- 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with Prior Local Treatment: 
- 
Tumour lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
133/Protocol ML42600, Version 2 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using callipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during the study. Imaging-based 
evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm 
in diameter as assessed using callipers (e.g., skin nodules). For the case of skin lesions, 
documentation by colour photography, including a ruler to estimate the size of the lesion, is 
suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. In this guideline, the definition of measurability of lesions on CT scan 
is based on the assumption that CT slice thickness is ≤ 5 mm. When CT scans have slice 
thickness of > 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable.  
If prior to enrolment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and 
during the study should be guided by the tumour type under investigation and the anatomic 
location of the disease. For patients who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) will be performed should also be based on the tumour type and the anatomic 
location of the disease and should be optimized to allow for comparison with the prior studies 
if possible. Each case should be discussed with the radiologist to determine if substitution 
of these other approaches is possible and, if not, the patient should be considered not 
evaluable from that point forward. Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality, since the same 
lesion may appear to have a different size using a new modality. 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
134/Protocol ML42600, Version 2 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOUR MARKERS, CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumour markers, cytology, and histology cannot be 
used for objective tumour evaluation. 
ASSESSMENT OF TUMOUR BURDEN 
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means that, for instances in which patients have only one or two organ sites involved, 
a maximum of two lesions (one site) and four lesions (two sites), respectively, will be 
recorded. Other lesions (albeit measurable) in those organs will be considered non-target 
lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement, in which circumstance 
the next largest lesion that can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may 
be visible by imaging even if not involved by tumour. As noted above, pathological nodes 
that are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumour. Lymph node size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT, this is almost 
always the axial plane; for MRI, the plane of acquisition may be axial, sagittal, or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node that is 
reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the node measurement. 
All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis of < 10 mm are considered non-
pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-
measurable), including pathological lymph nodes, should be identified as non-target lesions 
and should also be recorded at baseline. Measurements are not required. It is possible to 
record multiple non-target lesions involving the same organ as a single item on the Case 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
135/Protocol ML42600, Version 2 
Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver 
metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for lymph 
node lesions) will be calculated for all target lesions at baseline and at each subsequent 
tumour assessment as a measure of tumour burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to < 10 mm during the study. Thus, when lymph 
nodes are included as target lesions, the sum of diameters may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non−lymph node) recorded at baseline 
should have their actual measurements recorded at each subsequent evaluation, even when 
very small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small to 
measure. When this occurs, it is important that a value be recorded on the CRF, as follows: 
- 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
- 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be ticked. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have 
a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and "too small to measure" should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, that should 
be recorded, even if it is < 5 mm, and in that case "too small to measure" should not be 
ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non-lymph node lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the sum of diameters. Similarly, as lesions coalesce, 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
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a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the 
maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to < 10 mm in short axis. Non-target 
lesions should be noted at baseline and should be identified as "present" or "absent" and (in 
rare cases) may be noted as "indicative of progression" at subsequent evaluations. In 
addition, if a lymph node lesion shrinks to a non-malignant size (short axis < 10 mm), this 
should be captured on the CRF as part of the assessment of non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumour response for target lesions are 
provided below: 
- 
Complete response (CR): Disappearance of all target lesions. 
Any pathological lymph nodes must have reduction in short axis to < 10 mm. 
- 
Partial response (PR): At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR. 
- 
Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints (including 
baseline). 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥ 5 mm. 
- 
Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor sufficient 
increase to qualify for PD. 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
137/Protocol ML42600, Version 2 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumour response for the group of non-target 
lesions are provided below. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the 
timepoints specified in the schedule of activities. 
- 
CR: Disappearance of all non-target lesions and (if applicable) normalization of tumour 
marker level. 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
- 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumour marker level above the normal limits. 
- 
PD: Unequivocal progression of existing non-target lesions. 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of SD 
or PR in target lesions, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target lesions in the face of SD or 
PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumour (for example, some 
"new" bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the patient's baseline lesions show PR or CR. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a "new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
138/Protocol ML42600, Version 2 
there is definitely a new lesion, progression should be declared using the date of the initial 
scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table A4-1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table A4-1  Criteria for Overall Response at a Single Timepoint: Patients with Target 
Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If measurements are made on only a subset of target lesions at 
a timepoint, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesions 
would not change the assigned timepoint response. This would be most likely to happen in 
the case of PD. For example, if a patient had a baseline sum of 50 mm with three measured 
lesions and during the study only two lesions were assessed, but those gave a sum of 80 
mm, the patient will have achieved PD status, regardless of the contribution of the missing 
lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration." Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 

Appendix 4. Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST V1.1) 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
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objective response; it is a reason for stopping study therapy. The objective response status 
of such patients is to be determined by evaluation of target and non-target lesions as shown 
in Table A4-1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47. 
 

Appendix 5. Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
140/Protocol ML42600, Version 2 
 – MODIFIED RECIST (mRECIST) ASSESSMENT FOR HEPATOCELLULAR 
CARCINOMA 
The Modiﬁed RECIST (mRECIST) Assessment for Hepatocellular Carcinoma can be 
found at the following website: 
 
https://imaging.cancer.gov/clinical trials/docs/mRECIST%20for%20HCC%202010.pdf 

Appendix 6. EASL Guidelines for the Clinical Management of Hepatocellular Carcinoma 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
141/Protocol ML42600, Version 2 
 – EASL GUIDELINES FOR THE CLINICAL MANAGEMENT OF HEPATOCELLULAR 
CARCINOMA 
The EASL guidelines for the clinical management of hepatocellular carcinoma, including 
imaging assessments to evaluate for disease progression can be found at the following 
website: 
 
https://www.sciencedirect.com/science/article/pii/S0168827818302150 
 
 

Appendix 7. Preexisting Autoimmune Diseases and Immune Deficiencies 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
142/Protocol ML42600, Version 2 
 – PREEXISTING AUTOIMMUNE DISEASES AND IMMUNE DEFICIENCIES 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease. Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from participating 
in the study. Possible exceptions to this exclusion could be patients with a medical history 
of such entities as atopic disease or childhood arthralgias 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 patients 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. 

Appendix 7. Preexisting Autoimmune Diseases and Immune Deficiencies 
 
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143/Protocol ML42600, Version 2 
Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anaemia 
 Autoimmune haemolytic 
anaemia 
 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 disease  
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel 
disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anaemia 
 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 
 Wegener granulomatosis 
 
 

Appendix 8. Anaphylaxis Precautions 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
144/Protocol ML42600, Version 2 
 – ANAPHYLAXIS PRECAUTIONS 
These guidelines are intended as a reference and should not supersede pertinent local or 
institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation monitor, 
and thermometer 
 Oxygen 
 Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 Antihistamines 
 Corticosteroids 
 Intravenous infusion solutions, tubing, catheters, and tape 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as required 
by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
7. 
Collect serum and plasma samples for immunogenicity testing. 
8. 
Ask the patient to return for immunogenicity sample collection at the time of washout, if 
appropriate. 
 

Appendix 9. Guidelines for Management of Adverse Events Associated with Bevacizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
145/Protocol ML42600, Version 2 
 – GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS ASSOCIATED WITH 
BEVACIZUMAB 
1. Dose Modifications 
There will be no dose modifications for Bevacizumab in this study. 
2. Treatment Interruption 
Bevacizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If the event resolves to Grade ≤ 1, Bevacizumab 
may be restarted at the same dose level. If Bevacizumab is delayed due to toxicity 
for > 42 days beyond when the next dose should have been given, the patient must be 
permanently discontinued from Bevacizumab. Bevacizumab can be resumed after being 
withheld for > 42 days if the Medical Monitor agrees that the patient is likely to derive clinical 
benefit. 
Bevacizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures), with Medical Monitor approval. The investigator and the Medical Monitor will 
determine the acceptable length of treatment interruption. 
If Bevacizumab treatment is withheld or discontinued, Atezolizumab can be continued as 
long as the patient is experiencing clinical benefit, as determined by the investigator per 
medical judgment. 
3. Management Guidelines 
Guidelines for management of patients who experience adverse events associated with 
atezolizumab are provided in Appendix 10. 
For cases in which management guidelines are not covered in the bevacizumab Investigator 
Brochure or this protocol, patients should be managed as deemed appropriate by the 
investigator according to their best medical judgment. 
Table A9-1 provides guidelines for the management of patients who experience adverse 
events associated with Bevacizumab. 
 
 
 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
150/Protocol ML42600, Version 2 
 
– RISKS ASSOCIATED WITH ATEZOLIZUMAB AND GUIDELINES FOR 
MANAGEMENT OF ADVERSE EVENTS ASSOCIATED WITH ATEZOLIZUMAB 
 
Table of Contents 
1. BACKGROUND ....................................................................................................... 151 
2. DOSE MODIFICATIONS ......................................................................................... 152 
3. TREATMENT INTERRUPTION ............................................................................... 152 
4. MANAGEMENT GUIDELINES ................................................................................ 152 
4.1 Pulmonary Events ................................................................................................ 152 
4.2 Hepatic Events ..................................................................................................... 154 
4.3 Gastrointestinal Events ........................................................................................ 155 
4.4 Endocrine Events ................................................................................................. 157 
4.5 Ocular Events ...................................................................................................... 159 
4.6 Immune-mediated Cardiac Events ....................................................................... 160 
4.6.1 Immune-Mediated Myocarditis ...................................................................... 160 
4.6.2 Immune-mediated Pericardial Disorders ....................................................... 161 
4.7 Infusion-Related Reactions and Cytokine-Release Syndrome ............................. 162 
4.8 Pancreatic Events ................................................................................................ 165 
4.9 Dermatologic Events ............................................................................................ 167 
4.10 Neurologic Disorders .......................................................................................... 168 
4.11 Immune-Mediated Meningoencephalitis ............................................................. 171 
4.12 Renal Events ...................................................................................................... 172 
4.13 Immune-Mediated Myositis ................................................................................ 173 
4.14 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome ... 174 
5. REFERENCES ........................................................................................................ 176 
 
 
 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
151/Protocol ML42600, Version 2 
1. Background 
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 aetiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications. Discontinuation of 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 a given patient may be 
experiencing prior to further administration of Atezolizumab. Resumption of Atezolizumab 
may be considered in patients who are deriving benefit and have fully recovered from the 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
152/Protocol ML42600, Version 2 
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. 
2. Dose Modifications 
There will be no dose modification for Atezolizumab in this study. 
3. Treatment Interruption 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment. If corticosteroids are initiated for treatment of 
the toxicity, they must be tapered over ≥ 1 month to 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. 
4. Management Guidelines 
4.1 Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnoea 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed tomography 
(CT) scans of the chest performed at every tumour assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
aetiologies 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 A10-1. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
153/Protocol ML42600, Version 2 
Table A10-1  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 patients 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 Medical 
Monitor. c, d 
 For recurrent events, with no improvement after 48–72 hours of 
corticosteroids, treat as treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue Atezolizumab and contact the Medical Monitor. c 
 Oral or IV broad-spectrum antibiotics should be administered in parallel to 
the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day 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. 
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 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 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
154/Protocol ML42600, Version 2 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 
4.2 Hepatic Events 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment. Management guidelines for hepatic events are 
provided in Table A10-2. 
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 aetiologies should be considered and addressed, as appropriate. 
 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
155/Protocol ML42600, Version 2 
Table  2  Management Guidelines for Hepatic Events 
Event 
Management 
AST/ALT is within normal limits 
at baseline and increases to 
 3 × ULN to  10 × ULN 
or 
AST/ALT is  ULN to  3 × ULN 
at baseline and increases to 
 5 × ULN to  10 × ULN 
or 
AST/ALT is  3 × ULN to 
 5 × ULN at baseline and 
increases to  8 × ULN to 
 10 × ULN  
 Withhold atezolizumab for up to 12 weeks after event 
onset. a 
 Monitor LFTs more frequently until return to baseline 
values. 
 For events of  5 days' duration, consider initiating 
treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to baseline or to Grade 1 or better, 
resume atezolizumab. b 
 If event does not resolve to baseline or to Grade 1 or 
better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the Medical 
Monitor. c 
AST or ALT increases to 
 10 × ULN or total bilirubin 
increases to  3 × ULN 
 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish aetiology 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 baseline, taper corticosteroids over 
 1 month. 
LFT  liver function test; ULN  upper limit of normal. 
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. 
 
4.3 Gastrointestinal Events 
Management guidelines for diarrhoea or colitis are provided in Table A10-3. 
All events of diarrhoea or colitis should be thoroughly evaluated for other more common 
aetiologies. For events of significant duration or magnitude or associated with signs of 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
156/Protocol ML42600, Version 2 
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. 
 
Table 3  Management Guidelines for Gastrointestinal Events (Diarrhoea or Colitis) 
Diarrhoea 
or 
colitis, Grade 1 
 Continue Atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for > 7 days. 
 Monitor closely. 
Diarrhoea 
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 
Medical Monitor. c 
Diarrhoea 
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 resolves to Grade 1 or better, resume Atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact 
Medical Monitor. c 
Diarrhoea 
or 
colitis, Grade 4 
 Permanently discontinue Atezolizumab and contact Medical Monitor. c 
 Refer patient to GI specialist for evaluation and confirmation biopsy. 
 Initiate treatment with 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 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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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. 
 
4.4 Endocrine Events 
Management guidelines for endocrine events are provided in Table A10-4. 
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. Thyroid-stimulating hormone (TSH) and free 
triiodothyronine and thyroxine levels should be measured to determine whether thyroid 
abnormalities are present. Pituitary hormone levels and function tests (e.g., TSH, growth 
hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and magnetic 
resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
Table  4  Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue Atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume Atezolizumab when symptoms are controlled, and thyroid 
function is improving. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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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 myxoedema (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 patient referral to endocrinologist. 
 TSH < 0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding Atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume Atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer to an 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 
Symptomatic 
adrenal 
insufficiency, 
Grade 2−4  
 Withhold Atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with 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 patient is stable on 
replacement therapy, resume Atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy while withholding Atezolizumab, permanently 
discontinue Atezolizumab and contact Medical Monitor. c 
Hyperglycaemia, 
Grade 1 or 2  
 Continue Atezolizumab. 
 Investigate for diabetes. If patient has Type 1 diabetes, treat as a Grade 
3 event. If patient does not have Type 1 diabetes, treat as per 
institutional guidelines. 
 Monitor for glucose control. 

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Hyperglycaemia, 
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. 
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 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 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. 
 
4.5 Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in Table A10-5. 

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Adverse Events Associated with Atezolizumab 
 
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Table  5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular 
event, 
Grade 1  
 Continue Atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular 
event, 
Grade 2 
 Withhold Atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume Atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact 
Medical Monitor. c 
Ocular 
event, 
Grade 3 or 4 
 Permanently discontinue Atezolizumab and contact Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with 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 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. 
 
4.6 Immune-mediated Cardiac Events 
Management guidelines for cardiac events are provided in Table A10-6. 
4.6.1 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, dyspnoea, 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 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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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 
aetiology, should be treated according to the guidelines in Table A10-6. 
4.6.2 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 dyspnoea or hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury 
related (post myocardial infarction or iatrogenic), and autoimmune disorders, and should 
be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if clinically 
indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate aetiology, should be treated 
according to the guidelines in Table A10-6. Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the aetiology 
and manage accordingly. 
 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table A10-6 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 
antiarrhythmic 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. 
 
4.7 Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of Atezolizumab. However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome 
(CRS) with Atezolizumab may receive premedication with antihistamines, antipyretics, 
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 
(Reigler et al. 2019). CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported with 
immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and Feldman 2019), 
including 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 the medical management of IRRs and CRS are provided in Table A10-7. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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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 patient 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. 
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 A10-7. 
Table A10-7 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 patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretics, and/or analgesics, and monitor closely for 
IRRs and/or CRS. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
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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. e 
 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 Medical Monitor. 
 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, 
antipyretics, 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 Medical Monitor. 
Grade 3 a 
Fever 
b 
with 
hypotension 
requiring 
a 
vasopressor 
(with or without 
vasopressin) 
and/or 
Hypoxia 
requiring 
high-
flow oxygen d by 
nasal 
cannula, 
face mask, non-
rebreather 
mask, or Venturi 
mask 
 Permanently discontinue Atezolizumab and contact Medical Monitor. f 
 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. e 
 Hospitalize patient 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. 

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Adverse Events Associated with Atezolizumab 
 
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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 Medical Monitor. f 
 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. e For patients who are refractory to anti-
cytokine therapy, experimental treatments g may be considered at the 
discretion of the investigator and in consultation with the Medical Monitor. 
 Hospitalize patient until complete resolution of symptoms. 
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: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading 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, antipyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnoea, 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 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, antipyretics, 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) for information on experimental treatments for CRS. 
 
4.8 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 

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lipase tests. Management guidelines for pancreatic events, including pancreatitis, are 
provided in Table A10-8. 
 
Table A10-8 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 Medical Monitor. c 
 For recurrent events, permanently discontinue Atezolizumab 
and contact Medical Monitor. c 
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 Medical Monitor. c 
 For recurrent events, permanently discontinue Atezolizumab 
and contact Medical Monitor. c  

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Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue Atezolizumab and contact 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 an 
assessment of benefit- risk 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 investigator’s assessment of benefit-risk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 
 
4.9 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 A10-9. 
Table A10-9 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. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
168/Protocol ML42600, Version 2 
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 Medical 
Monitor. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue Atezolizumab and contact 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 patient 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 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. 
 
4.10 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 aetiologies. Management guidelines for neurologic disorders, with specific 
guidelines for myelitis are provided in Table A10-10. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
169/Protocol ML42600, Version 2 
Table A10-10 Management Guidelines for Neurologic Disorders 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
170/Protocol ML42600, Version 2 
Event 
Management 
Immune-
mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate aetiology. 
 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 aetiology 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.  
 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. Patients can be re-challenged with 
Atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 
 
 
 
Table A10-11 Management Guidelines for Immune-Mediated Myelitis 
 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
171/Protocol ML42600, Version 2 
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 tiragolumab/placebo and 
atezolizumab/placebo 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 tiragolumab/placebo and 
atezolizumab/placebo and contact the Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
4.12 Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis should be suspected in any patient presenting with 
signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, 
headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with a 
CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or oedema. 
If deemed safe by the treating physician, a lumbar puncture should be performed, and a 
neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate aetiology, should be treated according to the guidelines in Table A10-12. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
172/Protocol ML42600, Version 2 
Table A10-12 Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact Medical Monitor.  
 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. 
 
 
4.13 Renal Events 
Eligible patients 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 aetiologies (including 
prerenal and postrenal causes, and concomitant medications such as non-steroidal anti-
inflammatory drugs). Refer the patient to a renal specialist if clinically indicated. A renal 
biopsy may be required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
aetiology, should be treated according to the guidelines in Table A10-13. 
Table A10-13 Management Guidelines for Renal Events 
Event 
Management 
Renal 
event, 
Grade 1 
 Continue Atezolizumab. 
 Monitor kidney function, including creatinine, closely until values resolve 
to within normal limits or to baseline values.  
Renal 
event, 
Grade 2 
 Withhold Atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume Atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and contact 
Medical Monitor. c 
Renal 
event, 
Grade 3 or 4 
 Permanently discontinue Atezolizumab and contact Medical Monitor.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. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
173/Protocol ML42600, Version 2 
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. 
4.14 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. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
aetiology, should be treated according to the guidelines in Table A10-14. 
Table A10-14 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 
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 
Medical Monitor. c 
Immune-
mediated 
myositis, Grade 3 
 Withhold Atezolizumab for up to 12 weeks after event onset a and contact 
Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
174/Protocol ML42600, Version 2 
 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 patient 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 Medical 
Monitor. c 
 For recurrent events, treat as a Grade 4 event. Permanently discontinue 
atezolizumab and contact the Medical Monitor. 
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue Atezolizumab and contact 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 patient 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 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. 
 
4.15 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.  

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
175/Protocol ML42600, Version 2 
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: 
– 
Haemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 x 109/L (100,000/μL) 
– 
ANC < 1.0 x 109/L (1000/μL) 
- 
Fasting 
triglycerides 
> 2.992 
mmol/L 
(265 mg/dL) and/or fibrinogen 
< 1.5 g/L 
(150 mg/dL) 
- 
Haemophagocytosis 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 patient 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 x 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 guidelines in 
Table A10-14. 

Appendix 10. Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab and bevacizumab — Roche Farma S.A. 
176/Protocol ML42600, Version 2 
Table A10-15 Management 
Guidelines 
for 
Suspected 
Haemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected 
HLH 
or MAS 
 Permanently discontinue Atezolizumab and contact Medical Monitor. 
 Consider patient referral to haematologist. 
 Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact Medical 
Monitor and initiate treatment as appropriate according to published 
guidelines (La Rosée 2015; Schram and Berliner 2015; La Rosée et al. 
2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
5. 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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