Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with Stage IIIB-IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy.

Detailed description:

Arms:
arm 1: Participants will receive atezolizumab plus bevacizumab intravenously on Day 1 of each cycle. Treatment will continue until progressive disease, unacceptable toxicity, or death.

Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Atezolizumab will be administered at a dose of 1200 mg intravenously on Day 1 of each 21-day cycle. intervention 2: Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Single Arm, Phase II Study of Atezolizumab (MPDL3280A, Anti-PD-
L1 Antibody) in Combination With Bevacizumab in Patients With 
EGFR Mutation Positive Stage IIIB-IV Non-Squamous Non-Small Cell 
Lung Cancer Pretreated With Epidermal Growth Factor Receptor 
Tyrosine-Kinase Inhibitors 
NCT Number: 
NCT04426825 
Document Date: 
Protocol Version 3: 11-January-2021 
 
 


PROTOCOL AMENDMENT APPROVAL 
[This space is reserved for the electronic signature] 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
 
 
 
 
PROTOCOL 
TITLE: 
A SINGLE ARM, PHASE II STUDY OF ATEZOLIZUMAB 
(MPDL3280A, ANTI-PD-L1 ANTIBODY) IN COMBINATION WITH 
BEVACIZUMAB IN PATIENTS WITH EGFR MUTATION 
POSITIVE STAGE IIIB-IV NON-SQUAMOUS NON-SMALL CELL 
LUNG CANCER PRETREATED WITH EPIDERMAL GROWTH 
FACTOR RECEPTOR TYROSINE-KINASE INHIBITORS 
PROTOCOL NUMBER: 
ML41256 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab（RO4876646） 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
2021-1-11 




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with stage IIIC NSCLC shared same systemic treatment with stage IIIB and stage IV 
patients. The prognosis of these patients is between stage IIIB and stage IV 
regardless of the molecular type and treatment. 
4. Addition of “severe cutaneous adverse reactions” in Risks associated with 
Atezolizumab (section 5.1.1) and updated related contents in Appendix 6 and 
Appendix 9. 
5. Updated SAE and AESI reporting period from 6 months to 90 days to reflect protocol 
template change (section 5.3.1, section 5.4.2.2, section 5.6 and Appendix 1). 
6. Addition of “Cytokine-Release Syndrome” in section 5.3.5.1 Infusion-Related 
Reactions to align with management guidelines for IRR and CRS inTable 7, 
Appendix 9 and updated content in Table 7 footnote, Appendix 9. 
7. Clarified that all special situations with atezolizumab and bevacizumab should be 
reported to the Sponsor within 30 calendar days (Section 5.3.5.13). 
8. Clarified spontaneous abortions, therapeutic or elective abortion in reporting 
requirements for pregnancies (section 5.4.3.3). 
9. Updated management guidelines for suspected HLH or MAS in Table 14, Appendix 
9. 
 
 
 
 


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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, 
where applicable. 
TITLE:  
A SINGLE ARM, PHASE II STUDY OF ATEZOLIZUMAB (MPDL3280A, ANTI-PD-L1 
ANTIBODY) IN COMBINATION WITH BEVACIZUMAB IN PATIENTS WITH EGFR 
MUTATION POSITIVE STAGE IIIB/-IV NON-SQUAMOUS NON-SMALL CELL LUNG 
CANCER PRETREATED WITH EPIDERMAL GROWTH FACTOR RECEPTOR 
TYROSINE-KINASE INHIBITORS 
2.1.1 Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoint (evaluable 
population:  it includes all enrolled patients who receive any amount of atezolizumab or 
bevacizumab, and have at least one post-baseline efficacy measurement): 
 
PFS rate at 6 months, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 6 months after enrollment, as determined 
by the investigator according to RECIST v1.1.Objective response rate (ORR), defined as 
the proportion of patients with a complete response (CR) or partial response (PR) on two 
consecutive occasions ≥4 weeks apart, as determined by the investigator according to 
RECIST v1.1. 
 
2.1.2 Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoints: 
 
Objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) on two consecutive occasions 
≥4 weeks apart, as determined by the investigator according to RECIST v1.1. 
 
 Duration of objective 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. 
 
Time to response (TTR), defined as the time from the start of the treatment to 
the first objective tumor response observed for patients who achieved CR or 
PR, as determined by the investigator according to RECIST v1.1. 
 
Disease control rate (DCR), defined as the proportion of patients who have a 
best overall response of CR or PR or stable disease (SD), as determined by the 
investigator according to RECIST v1.1 


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 
Overall survival (OS) after enrollment, defined as the time from enrollment to 
death from any cause. 
 
Progression-free survival (PFS), defined as the time from enrollment 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 
 
PFS rate at 6 and 12 months, defined as the proportion of patients who have 
not experienced disease progression or death from any cause at 6 months and 
12 months, as determined by the investigator according to RECIST v1.1. 
 
OS rate at 1 and 2 years, defined as the proportion of patients who have not 
experienced death from any cause at 1 and 2 years.  
 
The above endpoints will also be summarized in PD L1 expression high vs. low 
population. 
 
 The consistency among in SP 142 and SP 263. 
 
 
 Exploratory analyses ORR, DOR, PFS,PFS rate at 12m,by investigator 
according to Modified RECIST V1.1(iRECIST) 
 
 Expression of PD-L1 defined by the SP142 and SP263 assay. 
 
Analyses ORR, DOR, PFS,PFS rate at 12m,by investigator according to 
Modified RECIST V1.1(iRECIST) 
2.2     SAFETY OBJECTIVE 
 
Incidence of serious and non-serious immune-relatedmediated adverse events (irAEs) 
related to atezolizumab treatment 
3.1.1  Overview of Study Design  
This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy 
and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with 
Stage IIIB/ IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy. 
Patients should have received at least one EGFR TKI and have disease progressed before 
enrollment.  
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.  
Figure 1 
Study Schema 
  
IV  intravenous; NSCLC  nonsmall cell lung cancer;  


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3.3.5 Rationale for Objective response rate as Primary Endpoint  
In this study, the primary efficacy endpoint will be investigator-assessed 6m PFS rate confirmed 
objective response rate. Phase II studies are limited because they lack a control arm. Objective 
response rate directly measures the efficacy of initial therapy, unaffected by treatment at 
progression.   
4.1 Patients 
Approximately  60 44 patients with PD-L1-expression ≥1%,Stage IIIB/ -IV Non-Squamous 
NSCLC harbored EGFR mutation after EGFR TKI therapy will be enrolled in this study. 
4.1.1 Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
 
Histologically or cytologically confirmed stage IIIB or -IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
8th edition) 
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, meningoencephalitis, myocarditis, nephritis, and myositis and 
severe cutaneous adverse reactions.  Immune-mediated reactions may involve any organ 
system and may lead to hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome.  Refer to Appendix 9 of the protocol and Section 6 of the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab.   
5.3.1 Adverse Event Reporting Period 
After initiation of study treatment, all adverse events will be reported until 30 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs 
first, and serious adverse events and adverse events of special interest will continue to be 
reported until 6 months 90 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first. 
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, tumor lysis syndrome, early disease 
progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration and are 
judged to be related to study treatment infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "cytokine-release syndrome") on the Adverse Event eCRF.  If 
possible, 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.  If a patient 


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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. 
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 9. 
5.3.5.13 Cases of Accidental Overdose or Medication Error 
In addition, all special situations associated with atezolizumab and bevacizumab, regardless of 
whether they result in an adverse event, should be reported to the Sponsor within 30 calendar 
days and recorded on the Adverse Event eCRF as described below: 
5.4.1 Emergency Medical Contacts   
Medical Monitor Contact Information for  All sites 
Medical Monitor{Roche Medical Responsible}: 
(Primary) 
Telephone No.: 
 
 
Mobile Telephone No.:
 
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 6 months 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 case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF on the electronic data capture (EDC) system, generate, and submit the 
report to Sponsor.   
5.4.3.3 Abortions 
Any 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).  A report should be downloaded from EDC system and sent the report to Sponsor. 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  A therapeutic or elective abortion performed for 
reasons other than an underlying maternal or embryofetal toxicity is not considered an adverse 
event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial Pregnancy 
Reporting Form. 
5.6 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 6 months 90 days) after the final dose of study treatment or until initiation of 


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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. 
 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN. 
This is an open-label, single-arm study. A Simon’s Minimax two-stage design will be used 
(Simon. 1989). 
 
6.1 Determination of Sample Size 
The sample size estimation is based on having sufficient sample in the FAS population to show 
that the ORR is higher than 30%.  Simon’s minimax two-stage design will be used (Simon, 1989).  
The null hypothesis that the true ORR is at least 50% will be tested against a one-sided 
alternative.   
The sample size calculation was based on a Simon two-stage design, and the primary end point 
was ORR (H0 = 30%, H1 = 50%). Two-sided alpha is set to be 0.1 and statistical power is set to 
be 80%. 
19 fully evaluable patients will be included at the first stage.  If there are 6 or fewer responders 
(CR/PR) in these 19 patients, enrollment will be stopped.  Otherwise, additional 20 fully evaluable 
patients will be included into the second stage.  Finally, if we have more than 16 patients in 39 
patients have objective response, the endpoint is reached. Thus, considering a drop-out rate of 
10%, a total number of 22 patients (if stops at the first stage) or 44 patients (if runs into the 
second stage) will need to be finally enrolled in this study. 
Figure 2 presents an overview of the sample size allocation.   


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Figure 2 Sample size allocation 
 
 
The purpose of this study is to estimate the effect of atezolizumab plus bevacizumab on the 
primary endpoint, PFS rate at 6 months. Objective response rate. Point and interval estimates of 
the true underlying hazard rate will be obtained. 
It is assumed that the median duration of PFS in the atezolizumab plus bevacizumab group is 
about 8 months, thus the hazard rate is 0.0866 under the exponential distribution.  At the time of 
6 months after the last patient enrollment, about 40% patients will experience disease 
progression or death. Assuming the percent censoring (includeing those that are lost to follow 
up, and those patient who does not experience disease progression of death at the time of 6 
months after enrollmen) at 6 months is 65%, so the number of events at 6 months is estimated 
to be 21. A total of 21 events produces a two sided 95% confidence interval for hazard rate with 
a width equal to 0.074 when the estimate of λ (the hazard rate) is 0.0866, see the table below. 
Relatively, the 95% CI for the estimate PFS rate at 6 months, 60%, will be (46.6%, 72.5%). The 
estimation accuracy is acceptable clinically. 
 
Numeric Results for Two Sided Confidence Intervals for an Exponential Hazard Rate 
 
           
          
                Expected                         
           
      Number of  
  Sample                     Hazard 
 C.I.      C.I. 
Confidence    Events                Size                       Rate 
Lower 
Upper 
Level                     E 
                 N           Width 
     λ           Limit 
Limit 
0.950 
            21              60       0.074 
 0.0866 0.0536 0.1274 
 
6.2  SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used in evaluating the conduct of the study. 


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Enrollment, study treatment administration and discontinuation (including reasons) from the study 
will be summarized with ITT population. The reasons for study treatment discontinuation will also 
be tabulated. Major protocol deviations, including major deviations with regard to the inclusion 
and exclusion criteria, will be summarized. 
6.4 EFFICACY ANALYSES 
The efficacy analyses will be performed on the FAS population, defined as all enrolled patients 
who receive any amount of study treatment and evaluable for efficacy endpoints. 
The analysis population for the efficacy analyses will consist of all enrolled patients who receive 
any amount of study treatment and evaluable for efficacy endpoints.  ORR and DCR will be 
analyzed using all enrolled patients who have measureable disease at baseline.  DOR will be 
assessed in patients who have an objective response. 
6.4.1Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab on the basis of the following endpoint: 
●          PFS rate at 6 months, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 6 months after enrollment, as determined by the 
investigator according to RECIST v1.1  
The primary efficacy analysis will be performed in FAS population, of which consists all enrolled 
patients who receive any amount of study treatment and evaluable for efficacy endpoints.  
PFS will be summarized descriptively using the Kaplan Meier (KM) product limit method. Median 
values of PFS, if available, along with two sided 95% CIs (based on the log log transformation), 
will also be calculated. The source of progression (death vs. progression) will be summarized.  
The status of subjects who are censored in the PFS Kaplan Meier analysis will be tabulated using 
the following three categories:  
• Received another kind of anti cancer therapy before progression  
• Still on treatment and progression free at the time of analysis  
• Off study: (lost to follow up, withdrew consent, other).  
Patients who are alive and have not experienced disease progression at the time of analysis will 
be censored at the time of the last tumor assessment. Patients with no post baseline tumor 
assessment will be censored at the time of initiation of study treatment plus 1 day.  
KM curve of PFS will be generated. PFS rates 6 and 12 months will be estimated using KM 
estimates on the PFS curve. Associated two sided 95% CIs will be calculated.  
Further detailed discussion will be found in the Statistical Analysis Plan 
 
ORR defined as the proportion of patients with a CR or PR on two consecutive occasions 
 4 weeks apart, as determined by the investigator according to RECIST v1.1.  Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, will 
be excluded from the primary analysis. 
Number and percentage of responders with corresponding Clopper-Pearson 90% and 95% 
confidence intervals will be provided. 
The ORR will be the basis for decision whether the study would be continued when Stage 1 is 
completed.  Refer to section 66.1 Determination of sample size for details. 
6.4.2 Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoints and the analysis 
will be performed in FAS population. : 


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●     Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as 
determined by the investigator according to RECIST v1.1. Patients without any post baseline 
tumor assessments will be considered non responders. An estimate of ORR will be provided 
along with the corresponding 95% CIs calculated using the Clopper Pearson method. ORR will 
be summarized by estimated response rate and its corresponding 95% Pearson Clopper 
confidence interval. 
●     For patients who have experienced an objective response (CR or PR) during the study, 
duration of objective response (DOR) is defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause whichever 
occurs first, as determined by the investigator according to RECIST v1.1. 
       Patients who are alive and who have not experienced disease progression at the time of 
analysis will be censored at the time of the last tumor assessment date. If no tumor assessments 
were performed after the date of the first occurrence of a complete or partial response, DOR will 
be censored at the date of the first occurrence of a complete or partial response plus 1 day. 
       The analysis population will be FAS that have experienced an objective response (CR or 
PR). 
●     Time to response (TTR), defined as the time from the start of the treatment to the first 
objective tumor response observed for patients who achieved CR or PR, as determined by the 
investigator according to RECIST v1.1.  
     Patients who are alive and who have not experienced the response at the time of analysis will 
be censored at the date of data cutoff.        
●     Overall survival (OS) after enrollment, defined as the time from enrollment to death from any 
cause. 
       Patients who do not have post baseline information will be censored at the date of initiation 
of study treatment plus 1 day. 
●     Progression free survival (PFS), defined as the time from enrollment to the first occurrence 
of disease progression or death from any cause, whichever occurs first, as determined by the 
investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
(RECIST v1.1). 
       Patients who are alive and have not experienced disease progression at the time of analysis 
will be censored at the time of the last tumor assessment. Patients with no post baseline tumor 
assessment will be censored at the time of initiation of study treatment plus 1 day. 
●     PFS rate at 12 months, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 12 months, as determined by the investigator 
according to RECIST v1.1. The analysis method is similar with PFS rate at 6 months. 
●          OS rate at 12 and 24 months, defined as the proportion of patients who have not 
experienced death from any cause at 12 and 24 months. The analysis method is similar with PFS 
rate at 6 months. The above endpoints will also be summarized in PD L1 expression high vs. low 
population. 
The consistency among in SP 142 and SP 263. 
Exploratory analyses ORR, DOR, PFS,PFS rate at 12m,by investigator according to Modified 
RECIST V1.1(iRECIST) 
6.4.2.1 Duration of Response 
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time interval from the date of the first 
occurrence of a documented objective response until the first date of disease progression or 


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death from any cause (whichever occurs first), as determined by the investigator according to 
RECIST v1.1.   
Patients who have not progressed and who have not died at the time of analysis will be censored 
at the time of last tumor assessment date.  If no tumor assessments were performed after the 
date of the first occurrence of a documented objective response, DOR will be censored at the 
date of the first occurrence of a documented objective response plus 1 day.  The KM approach 
will be used to estimate median DOR.  The Brookmeyer-Crowley methodology (Brookmeyer and 
Crowley 1982) will be used to construct the 95% CI for the median DOR.   
6.4.2.2 Time to Response  
TTR, defined as the time from the start of the treatment to the first objective tumor response 
observed for patients who achieved CR or PR, as determined by the investigator according to 
RECIST v1.1.  
Patients who are alive and who have not experienced the response at the time of analysis will be 
censored at the date of data cutoff.        
The methodologies detailed for the DOR analysis will be used for the TTR analysis. 
6.4.2.3 Disease Control Rate 
DCR, defined as the proportion of patients who have a best overall response of CR or PR or SD, 
as determined by the investigator according to RECIST v1.1. 
Number and percentage of patients with DCR with corresponding Clopper-Pearson 95% 
confidence intervals will be provided. 
6.4.2.4 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), as determined by the investigator 
according to RECIST v1.1.  Patients who have not experienced disease progression or death at 
the time of analysis will be censored at the time of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored at the date of initiation of study treatment plus 1 
day. 
The methodologies detailed for the DOR analysis will be used for the PFS analysis. 
6.4.2.5 Overall Survival  
OS, defined as the time from initiation of study treatment to death from any cause.  Patients who 
are alive at the time of the analysis data cutoff will be censored at the last date they were known 
to be alive.  Patients with no post-baseline information will be censored at the date of initiation of 
study treatment plus 1 day.  Methods for OS analyses are similar to those described for the DOR 
endpoint. 


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6.4.2.6 Landmark Analysis on Progression-free Survival and Overall 
Survival 
PFS rate at 6 months and 1 year, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 6 months and 1 year separately, as determined 
by the investigator according to RECIST v1.1.  OS rate at 1 year and 2 years, defined as the 
proportion of patients who have not experienced death from any cause at 1 year and 2 years. 
The PFS rates at 6 months and 1 year after initiation of treatment will be estimated using Kaplan-
Meier methodology, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula.  
Similar analyses will be performed for the OS rates at 1 year and 2 years after initiation of 
treatment. 
6.4.2.7 ORR, DCR, DOR, and PFS per Modified RECIST 
Analyses using modified RECIST criteria (see Appendix 5) for ORR, DCR, DOR, and PFS as 
determined by the investigator will be conducted. The methods outlined for the primary and 
secondary efficacy endpoint analyses will be used for these analyses. 
6.4.2.8 Expression of PD-L1 defined by the SP142 and SP263 IHC Assay  
Expression of PD-L1 defined by the SP142 and SP263 IHC assay will be investigated. The 
proportions of the patients with PD-L1+ tested by SP142 and SP263 in all patients will be 
presented respectively, with their 95% Clopper-Pearson CI. The consistency between SP142 and 
SP263 IHC assay will be investigated using Chisq-square Test if applicable. 
6.4.2.9 Patent-Reported Outcomes (PROs) 
TTD using EORTC is defined as the time from baseline to the first time the patient’s score shows 
a ≥10 points increase above baseline in any of the following EORTC-transformed symptom 
subscale scores (whichever occurs first): cough, dyspnea (single item), dyspnea (multi-item 
subscale), chest pain, or arm/shoulder pain, whichever occurs first. The linear transformation 
gives each individual symptom subscale a possible score of 0-100. In order for the symptoms to 
be considered “deteriorated”, acore increase of ≥ 10 points above baseline must be held for at 
least two consecutive assessment or an initial score increase of ≥ 10 points is followed by death 
within 3 weeks from the last assessment. A “≥10 point” change in the symptoms subscale score 
is perceived by patients as clinically significant (Osoba et al. 1998). Patients will be censored at 
the last time when they complete an assessment if they have not deteriorated. If no post-baseline 
assessment is performed, patients will be censored at the randomization date plus 1 day. TTD 
using the EORTC scale will be analyzed using the same methods as for PFS. The analysis 
populations for TTD will be all randomized patients with a non-missing baseline PRO 
assessment. 
PROs of HRQoL, lung cancer related symptoms, and health status will be measured using the 
EORTC QLQ-C30 and EORTC QLQ-LC3. Summary statistics (mean, SD, median, 25th and 75th 
percentiles, minimum and maximum) and mean change from baseline of linear-transformed 
scores will be reported for all of the items and subscales of EORTC QLQ-C30 questionnaire and 
the QLQ-LC13 according to the EORTC scoring manual guidelines. Completion and compliance 


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rates will be summarized at each timepoint by treatment arm. The analysis populations for PRO 
changes will be all randomized patients with a non-missing baseline assessment and at least one 
non-missing post-baseline assessment. 
6.5 Safety Analyses 
The safety objective for this study is to evaluate the safety of atezolizumab plus bevacizumab on  
the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0 
• 
Incidence of serious and non serious immune related adverse events (irAEs) related to 
atezolizumab treatment 
These safety endpoints will be summarized by incidence rates and 95% Pearson Clopper  
confidence intervals if applicable. 
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. 
The safety analysis population will consist of all enrolled patients who received at least one dose 
of study treatment.  
Safety will be assessed through summaries of exposure to study treatment, adverse events, 
changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number of cycles 
and dose modifications) will be summarized with descriptive statistics. 
All 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.  All adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, and adverse events leading to study treatment discontinuation that 
occur on or after the first dose of study treatment (i.e., treatment-emergent adverse events) will 
be summarized by mapped term, appropriate thesaurus level, and severity grade.  For events of 
varying severity, the highest grade will be used in the summaries.  Deaths and cause of death will 
be summarized. 
Relevant laboratory, vital sign (respiratory rate, pulse rate, systolic and diastolic blood pressure, 
and temperature), physical examination and ECG data will be displayed by time, with grades 
identified where appropriate.  Changes from baseline in vital signs and ECGs will be summarized. 
6.6 BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be performed, data may be 
analyzed in the context of this study and in aggregate with data from other studies. 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
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6.67 INTERIM ANALYSES  
No interim analyses were planned for efficacy endpoints in this study. However, to address 
information that may emerge during the course of this study, the Sponsor may choose to 
conduct one interim analysis for reporting of safety and efficacy result.  
One interim analysis is planned. The interim analysis will be performed for futility at the time of 19 
patients completing ORR evaluation. According to preplanned stopping rules of Simon 2-stage 
design, further testing of Atezolizumab and Bevacizumab would be halted if the number of 
patients that respond in the first evaluable 19 patients (stage 1) is less or equal than 6. This study 
has probability of 66.6% terminate at the first stage. 
When the study runs into the second stage, in the end of the study, if more than 16 patients out of 
39 patients have responses, we can recommend this treatment in IIIB-IV Non-squamous NSCLC 
to go to the next step in the clinical trial phase, otherwise, the treatment is rejected. 
9.4 Administrative Structure 
Approximately 8 sites globally will participate to randomize Approximately 60 44 patients from 
China will be enrolled into this study.  
Central facilities will be used for certain study assessments throughout the study (e.g., specified 
laboratory tests, biomarker analyses, and PK analyses), as specified in Section 4.5.6.  Accredited 
local laboratories will be used for routine monitoring; local laboratory ranges will be collected. 
Appendix 1 Schedule of Activities 
Footnote “u”: 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. 
After initiation of study treatment, all adverse events will be reported until 30 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs 
first, and serious adverse events and adverse events of special interest, regardless of relationship 
to study treatment, will be reported until 6 months 90 days after the last dose of study treatment 
or initiation of new non-protocol systemic anti-cancer therapy after the last dose of study 
treatment, whichever occurs first. After this period, all deaths, regardless of cause, should be 
reported.  In addition, the investigator should report any serious adverse event or adverse events 
of special interest that is believed to be related to prior exposure to study treatment. 
 
Appendix 6 
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias 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 


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atezolizumab for patients who have previously experienced a severe or lifethreatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  
Contact the Medical Monitor regarding any uncertainty over autoimmune exclusions. 
Appendix 9 
 
Table 7 Management Guidelines for Infusion-Related Reactions and Cytokine-Release 
Syndrome (cont.) 
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established. 
fe Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the 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.  For subsequent infusions, administer oral premedication with antihistamines, 
anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication with 
corticosteroids and extending the infusion time may also be considered after consulting the 
Medical Monitor and considering the benefitrisk ratio. 
gf Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self limited, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab. A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in Table 9.  


Atezolizumab—F. Hoffmann-La Roche Ltd 
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Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
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), and, if indicated, biopsy. 
• 
Follow the applicable treatment and management guidelines above. 
• 
Permanently discontinue atezolizumab for confirmed 
Stevens-Johnson syndrome or toxic epidermal necrolysis. 
 
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation 
Syndrome 
 If event does not improve within 48 hours after initating corticosteroids, consider 
adding an immunosuppressive agent 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).  
 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM ...................................................................................... 21 
PROTOCOL SYNOPSIS ............................................................................................................................. 22 
SAFETY OBJECTIVE ......................................................................................................................................... 23 
1. 
BACKGROUND ............................................................................................................................... 32 
1.1 
BACKGROUND ON LUNG CANCER ........................................................................................................ 32 
1.2 
FIRST-LINE TREATMENT FOR NON-SQUAMOUS NSCLC ............................................................................... 32 
1.2.1 
Patients with an EGFR Mutation ........................................................................................... 32 
1.3 
BACKGROUND ON ATEZOLIZUMAB ........................................................................................................... 33 
1.4 
BACKGROUND ON BEVACIZUMAB ............................................................................................................ 33 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT .................................................................................... 34 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................................................ 36 
2.1 
EFFICACY OBJECTIVES ........................................................................................................................... 36 
2.1.1 
Primary Efficacy Objective ..................................................................................................... 36 
2.1.2 
Secondary Efficacy Objective ................................................................................................. 36 
2.2 
SAFETY OBJECTIVE ................................................................................................................................ 37 
2.3 
HEALTH STATUS UTILITY OBJECTIVE ......................................................................................................... 37 
3. 
STUDY DESIGN .............................................................................................................................. 37 
3.1 
DESCRIPTION OF THE STUDY ................................................................................................................... 37 
3.1.1 
Overview of Study Design ...................................................................................................... 37 
3.2 
END OF STUDY AND LENGTH OF STUDY..................................................................................................... 39 
3.3 
RATIONALE FOR STUDY DESIGN............................................................................................................... 39 
3.3.1 
Rationale for Atezolizumab Dose and Schedule .................................................................... 39 
3.3.2 
Rationale for bevacizumab Dose and Schedule ..................................................................... 39 
3.3.3 
Rationale for Patient Population ........................................................................................... 40 
3.3.4 
Rationale for Open-Label Study ............................................................................................. 40 
3.3.5 
Rationale for Objective response rate as Primary Endpoint .................................................. 41 
3.3.6 
Rationale for Atezolizumab Treatment beyond Initial Radiographic Progression ................. 41 
3.3.7 
Rationale for the Use of Modified Response Criteria ............................................................. 41 
3.3.8 
Rationale for Biomarker Assessments ................................................................................... 42 
3.3.9 
Rationale for Patient-Reported Outcome Assessments ......................................................... 42 
4. 
MATERIALS AND METHODS .......................................................................................................... 42 
4.1 
PATIENTS............................................................................................................................................ 42 
4.1.1 
Inclusion Criteria .................................................................................................................... 42 
4.1.2 
Exclusion Criteria ................................................................................................................... 44 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING ............................................................................... 47 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE STUDY DESIGN .............................................. 48 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ...................................................... 48 
4.3.1.1 
Atezolizumab.............................................................................................................................. 48 
4.3.1.2 
Bevacizumab .............................................................................................................................. 48 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .................................................. 48 
4.3.2.1 
Atezolizumab.............................................................................................................................. 48 
4.3.2.2 
Bevacizumab .............................................................................................................................. 49 
4.3.3 
Investigational Medicinal Product Accountability ................................................................. 50 
4.3.4 
Continued Access to Atezolizumab ........................................................................................ 50 
4.4 
CONCOMITANT THERAPY ....................................................................................................................... 51 


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4.4.1 
Permitted Therapy ................................................................................................................. 51 
4.4.2 
Cautionary Therapy ............................................................................................................... 52 
4.4.2.1 
Corticosteroids and TNF- Inhibitors for Atezolizumab-Treated Patients ................................. 52 
4.4.2.2 
Cautionary Therapy Specific to Bevacizumab ............................................................................ 52 
4.4.2.3 
Herbal Therapies ........................................................................................................................ 52 
4.4.3 
Prohibited Therapy ................................................................................................................ 53 
4.5 
STUDY ASSESSMENTS ............................................................................................................................ 53 
4.5.1 
Informed Consent Forms and Screening Log ......................................................................... 53 
4.5.2 
Medical History, Concomitant Medication, and Demographic Data ..................................... 54 
4.5.3 
Physical Examinations ........................................................................................................... 54 
4.5.4 
Vital Signs .............................................................................................................................. 54 
4.5.5 
Tumor and Response Evaluations .......................................................................................... 54 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples .......................................................... 55 
4.5.7 
Electrocardiograms ................................................................................................................ 57 
4.5.8 
Patient-Reported Outcomes .................................................................................................. 57 
4.5.8.1 
EORTC QLQ-C30 ......................................................................................................................... 58 
4.5.8.2 
EORTC QLQ-LC13 ........................................................................................................................ 58 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION ........................................................................ 58 
4.6.1 
Study Treatment Discontinuation .......................................................................................... 58 
4.6.2 
Patient Discontinuation from Study....................................................................................... 59 
4.6.3 
Study Discontinuation ............................................................................................................ 60 
4.6.4 
Site Discontinuation ............................................................................................................... 60 
5. 
ASSESSMENT OF SAFETY ............................................................................................................... 60 
5.1 
SAFETY PLAN ....................................................................................................................................... 60 
5.1.1 
Risks Associated with Atezolizumab ...................................................................................... 61 
5.1.2 
Risks Associated with Bevacizumab ....................................................................................... 61 
5.1.3 
Risks Associated with Atezolimab with Bevacizumab ........................................................... 61 
5.2 
SAFETY PARAMETERS AND DEFINITIONS .................................................................................................... 61 
5.2.1 
Adverse Events ....................................................................................................................... 62 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) ........................................ 62 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor) ....................... 63 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY PARAMETERS ............................................... 64 
5.3.1 
Adverse Event Reporting Period ............................................................................................ 64 
5.3.2 
Eliciting Adverse Event Information ....................................................................................... 65 
5.3.3 
Assessment of Severity of Adverse Events ............................................................................. 65 
5.3.4 
Assessment of Causality of Adverse Events ........................................................................... 66 
5.3.5 
Procedures for Recording Adverse Events ............................................................................. 66 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release Syndrome .................................................... 67 
5.3.5.2 
Diagnosis versus Signs and Symptoms ....................................................................................... 67 
5.3.5.3 
Adverse Events That Are Secondary to Other Events................................................................. 67 
5.3.5.4 
Persistent or Recurrent Adverse Events ..................................................................................... 68 
5.3.5.5 
Abnormal Laboratory Values...................................................................................................... 68 
5.3.5.6 
Abnormal Vital Sign Values ........................................................................................................ 69 
5.3.5.7 
Abnormal Liver Function Tests ................................................................................................... 69 
5.3.5.8 
Deaths ........................................................................................................................................ 70 
5.3.5.9 
Preexisting Medical Conditions .................................................................................................. 70 
5.3.5.10 
Lack of Efficacy or Worsening of NSCLC ..................................................................................... 70 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................................................................. 71 
5.3.5.12 
Patient-Reported Outcome Data ............................................................................................... 71 
5.3.5.13 
Cases of Accidental Overdose or Medication Error .................................................................... 71 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO SPONSOR .................................................... 72 
5.4.1 
Emergency Medical Contacts ................................................................................................ 73 
Medical Monitor Contact Information for  All sites ................................................................................... 73 


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5.4.2 
Reporting Requirements for Serious Adverse Events and Adverse Events of Special Interest
 
73 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation .............................................................. 73 
5.4.2.2 
Events That Occur after Study Treatment Initiation .................................................................. 73 
5.4.3 
Reporting Requirements for Pregnancies .............................................................................. 74 
5.4.3.1 
Pregnancies in Female Patients.................................................................................................. 74 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ...................................................................... 74 
5.4.3.3 
Abortions .................................................................................................................................... 75 
5.4.3.4 
Congenital Anomalies/Birth Defects .......................................................................................... 75 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS .................................................................................... 75 
5.5.1 
Investigator Follow-Up .......................................................................................................... 75 
5.5.2 
Sponsor Follow-Up ................................................................................................................. 75 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT REPORTING PERIOD .............................................. 76 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES ................................................................................................................................................ 76 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN. ................................................................... 76 
6.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................................... 77 
6.2 
SUMMARIES OF CONDUCT OF STUDY ....................................................................................................... 78 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................................................. 78 
6.4 
EFFICACY ANALYSES .............................................................................................................................. 78 
6.4.1 
Primary Efficacy Endpoint ...................................................................................................... 78 
6.4.2 
Secondary Efficacy Endpoints ................................................................................................ 79 
6.4.2.1 
Duration of Response ................................................................................................................. 79 
6.4.2.2 
Time to Response ....................................................................................................................... 79 
6.4.2.3 
Disease Control Rate .................................................................................................................. 79 
6.4.2.4 
Progression-free Survival ........................................................................................................... 79 
6.4.2.5 
Overall Survival .......................................................................................................................... 80 
6.4.2.6 
Landmark Analysis on Progression-free Survival and Overall Survival ....................................... 80 
6.4.2.7 
ORR, DCR, DOR, and PFS per Modified RECIST ........................................................................... 80 
6.4.2.8 
Expression of PD-L1 defined by the SP142 and SP263 IHC Assay ............................................... 80 
6.4.2.9 
Patent-Reported Outcomes (PROs) ............................................................................................ 80 
6.5 
SAFETY ANALYSES ................................................................................................................................ 81 
6.6 
INTERIM ANALYSES ............................................................................................................................... 81 
7. 
DATA COLLECTION AND MANAGEMENT ....................................................................................... 82 
7.1 
DATA QUALITY ASSURANCE ................................................................................................................... 82 
7.2 
ELECTRONIC CASE REPORT FORMS .......................................................................................................... 82 
7.3 
SOURCE DATA DOCUMENTATION ............................................................................................................ 82 
7.4 
USE OF COMPUTERIZED SYSTEMS ............................................................................................................ 83 
7.5 
RETENTION OF RECORDS ....................................................................................................................... 83 
8. 
ETHICAL CONSIDERATIONS ........................................................................................................... 83 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS ............................................................................................ 83 
8.2 
INFORMED CONSENT ............................................................................................................................ 84 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE .............................................................................. 85 
8.4 
CONFIDENTIALITY ................................................................................................................................. 85 
8.5 
FINANCIAL DISCLOSURE ......................................................................................................................... 86 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ............................................... 86 
9.1 
STUDY DOCUMENTATION ...................................................................................................................... 86 
9.2 
PROTOCOL DEVIATIONS ......................................................................................................................... 86 
9.3 
SITE INSPECTIONS ................................................................................................................................. 86 
9.4 
ADMINISTRATIVE STRUCTURE ................................................................................................................. 86 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE SECRETS .................................................................... 87 


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9.6 
PROTOCOL AMENDMENTS ..................................................................................................................... 88 
10. 
REFERENCES .................................................................................................................................. 89 
 
 
LIST OF TABLES 
Table 1  Administration of First and Subsequent Atezolizumab Infusions .......... 49 
Table 2 Administration of First and Subsequent Bevacizumab Infusions ........... 50 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 65 
Table 4 
Causal Attribution Guidance ....................................................... 66 
Table 12 
Management Guidelines for Renal Events ................................ 143 
 
LIST OF FIGURES 
 
Figure 1 
Study Schema ............................................................................. 38 
Figure 2 
Sample size allocation ................................................................ 78 
 
LIST OF APPENDICES 
 
Appendix 1 
 Schedule of Activities ................................................................. 94 
Appendix 2 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1).......................................................... 99 
Appendix 3 
 Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST).................................................................................. 108 
Appendix 4 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ- LC 13 .... 111 
Appendix 5 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 ........ 112 
Appendix 6 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 114 
Appendix 7 
 Anaphylaxis Precautions .......................................................... 115 
Appendix 8      Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
and bevacizumab. ..................................................................... 116 
Appendix 9     Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab .
 .................................................................................................. 122 
Appendix 10 
 Overall Guidelines for Management of Patients Who Experience 
Adverse Events ......................................................................... 149 
Appendix 11 Instructions for Preparation, Administration, and Disposal of 
Bevacizumab ............................................................................ 150 


Atezolizumab—F. Hoffmann-La Roche Ltd 
21/Protocol ML41256 Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A SINGLE ARM, PHASE II STUDY OF ATEZOLIZUMAB 
(MPDL3280A, ANTI-PD-L1 ANTIBODY) IN COMBINATION 
WITH BEVACIZUMAB IN PATIENTS WITH EGFR MUTATION 
POSITIVE STAGE IIIB-IV NON-SQUAMOUS NON-SMALL CELL 
LUNG CANCER PRETREATED WITH EPIDERMAL GROWTH 
FACTOR RECEPTOR TYROSINE-KINASE INHIBITORS 
PROTOCOL NUMBER: ML41256 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
NA 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab（RO4876646） 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
22/Protocol ML41256 Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A SINGLE ARM, PHASE II STUDY OF ATEZOLIZUMAB 
(MPDL3280A, ANTI-PD-L1 ANTIBODY) IN COMBINATION WITH 
BEVACIZUMAB IN PATIENTS WITH EGFR MUTATION POSITIVE 
STAGE IIIB-IV NON-SQUAMOUS NON-SMALL CELL LUNG 
CANCER PRETREATED WITH EPIDERMAL GROWTH FACTOR 
RECEPTOR TYROSINE-KINASE INHIBITORS 
PROTOCOL NUMBER: 
ML41256 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Bevacizumab（RO4876646） 
PHASE: 
Phase  II 
INDICATION: 
Non-squamous NSCLC 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab in patients with stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer 
(NSCLC) harbored EGFR mutation after treatment failure of EGFR TKI. All patients will be 
selected on the basis of PD-L1 expression ≥ 1% on tumor cells (TC) and/or immune cells (ICs) 
using a centrally performed immunohistochemistry (IHC) test. Specific objectives and 
corresponding endpoints for the study are outlined below. 
In this protocol, "study treatment" refers to the combination of atezolizumab and bevacizumab 
assigned to patients as part of this study. 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoint (evaluable 
population:  it includes all enrolled patients who receive any amount of atezolizumab or 
bevacizumab, and have at least one post-baseline efficacy measurement): 
 
Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as 
determined by the investigator according to RECIST v1.1. 
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoints: 
• 
Duration of objective 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. 
• 
Time to response (TTR), defined as the time from the start of the treatment to the first 
objective tumor response observed for patients who achieved CR or PR, as determined 
by the investigator according to RECIST v1.1. 
• 
Disease control rate (DCR), defined as the proportion of patients who have a best 
overall response of CR or PR or stable disease (SD), as determined by the investigator 
according to RECIST v1.1 


 
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23/Protocol ML41256 Version 3 
• 
Overall survival (OS) after enrollment, defined as the time from enrollment to death from 
any cause. 
• 
Progression-free survival (PFS), defined as the time from enrollment 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 
• 
PFS rate at 6 and 12 months, defined as the proportion of patients who have not 
experienced disease progression or death from any cause at 6 months and 12 months, 
as determined by the investigator according to RECIST v1.1. 
• 
OS rate at 1 and 2 years, defined as the proportion of patients who have not 
experienced death from any cause at 1 and 2 years.  
• 
Expression of PD-L1 defined by the SP142 and SP263 assay. 
• 
Analyses ORR, DOR, PFS,PFS rate at 12m,by investigator according to Modified 
RECIST V1.1(iRECIST) 
Safety Objective 
The safety objective for this study is to evaluate the safety of atezolizumab plus bevacizumab on 
the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0 
 
Incidence of serious and non-serious immune-mediated adverse events related to 
atezolizumab treatment 
 
Study Design 
Description of Study 
This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy 
and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with 
Stage IIIB-IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy. 
Patients should have received at least one EGFR TKI and have disease progressed before 
enrollment.  
This study will consist of a screening period (Day -28 to Day -1), a treatment period, a treatment 
discontinuation visit period (≤30 days after last dose) and a follow-up period. It is anticipated 
that this study will enroll about 60 patients at multiple sites in China. 
At screening, tumor specimens (either fresh or archival) from each potentially eligible patient will 
be tested for PD-L1 expression by a central laboratory using an IHC assay. The patients will be 
tested T790M by blood or re-biospy tissue sample. 
All eligible enrollees will receive atezolizumab by intravenous (IV) infusion at a fixed dose of 
1200 mg on Day 1 of each 21-day cycle.  Bevacizumab will be administered by IV infusion at 15 
mg/kg on Day 1 of each 21-day cycle. Patients will continue treatment until progressive disease, 
unacceptable toxicity, or death. Patients may continue treatment beyond radiographic 
progression by RECIST v1.1, provided they are experiencing clinical benefit as assessed by 
investigator (i.e., in the absence of unacceptable toxicity or symptomatic deterioration attributed 
to disease progression as determined by the investigator after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status (see below). Patients who 
temporarily or permanently discontinue either atezolizumab or bevacizumab may continue on 
single-agent therapy until disease progression (i.e., patients temporarily withdrawn from 
bevacizumab due to adverse events may continue atezolizumab monotherapy and vice versa).  
Because of the possibility of an initial increase in tumor burden caused by immune-cell 
infiltration in the setting of a T-cell response (termed pseudoprogression) with atezolizumab 
treatment, radiographic progression per RECIST v1.1 may not be indicative of true disease 
progression.  In the absence of unacceptable toxicity, patients who meet criteria for disease 
progression per RECIST v1.1 while receiving atezolizumab will be permitted to continue 
atezolizumab if they meet all of the following criteria: 
 
Evidence of clinical benefit, as determined by the investigator following a review of all 
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 
Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease 
 
Absence of decline in ECOG Performance Status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 
weeks following Cycle 1, Day 1, regardless of dose delays.  After 36 weeks, tumor assessment 
will be required every 9 weeks (±7days).  Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab 
treated patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs 
first.  Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) will continue scheduled tumor assessments until radiographic 
disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab treated 
patients who continue treatment after radiographic disease progression according to RECIST 
v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs first, 
even if patient starts another anti-cancer therapy after study treatment discontinuation, unless 
consent is withdrawn. 
Number of Patients 
Approximately 44 patients will be enrolled in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Male or female, Age ≥ 18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Life expectancy ≥ 10 months 
 
Histologically or cytologically confirmed stage IIIB, IIIC, IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
8th edition) 
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible if 
the major histological component appears to be non-squamous. 
 
No prior treatment for Stage IIIB,IIIC, IV non-squamous NSCLC, with the following 
exceptions: 
Patients with a sensitizing mutation in the EGFR gene must have experienced disease 
progression (during or after treatment) or were intolerant to treatment with one or more 
EGFR TKIs, such as erlotinib, gefitinib, icotinib, afatinib, osimertinib, or another EGFR TKI 
appropriate for the treatment of EGFR-mutant NSCLC. 
Patients who have progressed on or were intolerant to first-line osimertinib or other third-
generation EGFR TKIs are eligible. 
Patients who have progressed on or were intolerant to first- or second-generation EGFR 
TKIs, such as erlotinib, gefitinib, afatinib, dacomitinib, and who have no evidence of the 
EGFR T790M mutation after TKI therapy are eligible. 
Patients who have progressed on or were intolerant to first- or second-generation EGFR 
TKIs and who have evidence of the T790M mutation must have also progressed on or were 
intolerant to osimertinib to be eligible. 
 
TKIs approved for treatment of NSCLC discontinued ＞7 days prior to enrollment. 
 
Measurable disease per RECIST v1.1 
PD-L1 expression of ≥1% as documented through central testing of a representative tumor 
tissue specimen either from previously obtained archival tumor tissue or tissue obtained 
from a biopsy at screening (see Section 4.5.6 for details ) 
 
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 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment: 
- ANC 1.5  109/L (1500/L) without granulocyte colony-stimulating factor support 
- Lymphocyte count 0.5 109/L (500/L) 
- Platelet count 100  109/L (100,000/L) without transfusion  
- Hemoglobin 90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5  upper limit of normal (ULN), with the 
following exceptions: 
Patients with documented liver metastases:  AST and ALT ≤5  ULN 
Patients with documented liver or bone metastases:  ALP ≤5 ULN 
- Bilirubin ≤1.5 ULN with the following exception: 
Patients with known Gilbert disease:   bilirubin level ≤3 ULN 
- Creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula) 
- Albumin  25 g/L (2.5 g/dL) 
- For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤1.5 ULN 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
 
Negative HIV test at screening 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening 
The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.  
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of ＜
1% per year during the treatment period and for 5 months after the final dose of 
atezolizumab and/or 6 months after the last dose of bevacizumab, whichever is later. 
Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of ＜ 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile 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 


 
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treatment period and for 6 months after the final dose of bevacizumab.  Men must 
refrain from donating sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final 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 preventing drug exposure. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases 
as determined by CT or MRI evaluation during screening and prior radiographic 
assessments 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met: 
- Measurable disease, per RECIST v1.1, must be present outside the CNS. 
- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
- The patient has not undergone stereotactic radiotherapy within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment. 
- The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease. Anticonvulsant therapy at a stable dose is permitted. 
- Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord). 
- There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment.  
Asymptomatic patients with CNS metastases newly detected at screening are eligible 
for the study after receiving radiotherapy or surgery, with no need to repeat the 
screening brain 
 
History of leptomeningeal disease 
 
Prior chemotherapy or other systemic therapy for stage IIIB/IV disease 
 
Uncontrolled tumor-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 
enrollment.  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 enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium 12 
mg/dL or corrected calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis 


 
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(see Appendix 6 for a more comprehensive list of autoimmune diseases and immune 
deficiencies), with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
- Rash must cover   10% of body surface area 
- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
- No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to 
initiation of study treatment, unstable arrhythmia, or unstable angina  
Patients with known coronary artery disease, arrhythmias, congestive heart failure not 
meeting the above criteria must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate. 
Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for 
all patients, especially in those with cardiac risk factors and/or history of coronary 
artery disease or where low LVEF is suspected  
Patients with known LVEF < 40% 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study 
 
History of malignancy other than NSCLC within 5 years prior to 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, or Stage I uterine cancer 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.  
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, or may render the patient at high risk from treatment complications 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 
5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for HBV 
 
Treatment with investigational therapy within 28 days prior to initiation of study treatment 


 
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 
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-
 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 
for orthostatic hypotension or adrenal insufficiency are eligible for the study. 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or bevacizumab formulations  
 
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within 5 months after the final dose of atezolizumab, 6 months after the final dose of 
bevacizumab   
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
 
Inadequately controlled hypertension (defined as systolic blood pressure ＞150 mmHg 
and/or diastolic blood pressure ＞100 mmHg) 
Anti-hypertensive therapy to achieve these parameters is allowable. 
 
Prior history of hypertensive crisis or hypertensive encephalopathy 
 
Patients with a baseline ECG demonstrating a QTc > 460 msec 
 
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 Grade ≥ 2 hemoptysis (defined as ≥ one-half teaspoon of bright red blood per 
episode (approximately 2.5ml)) within 1 month prior to enrollment 
 
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation) Current or recent (within 10 days of initiation of study treatment) use of 
aspirin (＞ 325 mg/day), clopidogrel (＞ 75mg/day) or treatment with dipyramidole, 
ticlopidine,  or cilostazol 
 
Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable for ＞ 2 weeks prior to enrollment 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR 
or aPTT is within therapeutic limits (according to the medical standard of the enrolling 
institution) and the patient has been on a stable dose of anticoagulants for at least 2 
weeks prior to enro 
llment 
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 enrollment. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted. 
 
History of stroke or transient ischemic attack within 6 months prior to enrollment  


 
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 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of bevacizumab 
 
History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 
months prior to enrollment 
 
History of intra-abdominal inflammatory process within 6 months prior to initiation of study 
treatment, including but not limited to active peptic ulcer disease, diverticulitis,or colitis 
 
Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding  
 
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure 
 
Serious, non-healing wound, active ulcer, or untreated bone fracture 
 
Proteinuria, as demonstrated by urinalysis or ＞1.0 g of protein in a 24-hour urine collection 
All patients with ≥ 2 ＋ protein on urinalysis at baseline must undergo a 24 hour urine 
collection and must demonstrate ≤ 1 g of protein in 24 hours. 
 
Clear tumor infiltration into the thoracic great vessels is seen on imaging 
 
Clear cavitation of pulmonary lesions is seen on imaging 
End of Study 
The end of this study is defined as the date when all the patients have either died, withdraw 
from study, are lost to follow up, or have been followed for 24 months since the last patient is 
enrolled, whichever occurs first. 
Length of Study 
The total length of the study, from first patients recruited to the end of the study, is expected to 
be approximately 3 years. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Atezolizumab (1200 mg IV) will be administered by IV infusion on Day 1 of each 21–day cycle.   
Bevacizumab (15 mg/kg IV) will be administered by IV infusion on Day 1 of each 21-day 
Statistical Methods 
Primary Analysis 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab on the 
basis of the following endpoint: 
 
ORR defined as the proportion of patients with a CR or PR on two consecutive occasions 
 4 weeks apart, as determined by the investigator according to RECIST v1.1.  Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, will 
be excluded from the primary analysis. 
Number and percentage of responders with corresponding Clopper-Pearson 90% and 95% 
confidence intervals will be provided. 
The ORR will be the basis for decision whether the study would be continued when Stage 1 is 
completed.  Refer to section 6.1 Determination of sample size for details. 
Determination of Sample Size   
The sample size estimation is based on having sufficient sample in the FAS population to show 
that the ORR is higher than 30%.  Simon’s minimax two-stage design will be used (Simon, 1989).  
The null hypothesis that the true ORR is at least 50% will be tested against a one-sided 
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The sample size calculation was based on a Simon two-stage design, and the primary end point 
was ORR (H0 = 30%, H1 = 50%). Two-sided alpha is set to be 0.1 and statistical power is set to 
be 80%. 
19 fully evaluable patients will be included at the first stage.  If there are 6 for fewer responders 
(CR/PR) in these 19 patients, enrollment will be stopped.  Otherwise, additional 20 fully 
evaluable patients will be included in the second stage.  Finally, if we have more than 16 patients 
in 39 patients have objective response, the endpoint is reached. Thus, considering a drop-out 
rate of 10%, a total number of 22 patients (if stops at the first stage) or 44 patients (if runs into 
the second stage) will need to be finally enrolled in this study. 
Interim Analyses  
One interim analysis is planned. The interim analysis will be performed for futility at the time of 19 
patients completing ORR evaluation. According to preplanned stopping rules of Simon 2-stage 
design, further testing of Atezolizumab and Bevacizumab would be halted if the number of 
patients that respond in the first evaluable 19 patients (stage 1) is less or equal than 6. This study 
has probability of 66.6% terminate at the first stage. 
When the study runs into the second stage, in the end of the study, if more than 16 patients out of 
39 patients have responses, we can recommend this treatment in IIIB-IV Non-squamous NSCLC 
to go to the next step in the clinical trial phase, otherwise, the treatment is rejected. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
BFI 
Brief Fatigue Inventory 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-level version 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
IC 
tumor-infiltrating immune cell 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRF 
independent review facility 
IV 
intravenous 
LPLV 
last patient, last visit 
MDASI 
MD Anderson Symptom Inventory 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
QLQ-C30 
quality-of-life questionnaire for cancer 
RBR 
Research Biosample Repository 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 


 
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TC 
tumor cell 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON LUNG CANCER 
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most common 
cancer in both men and women and accounted for approximately 13% of all new cancers in 2008 
(Jemal et al. 2011).  In 2012, it was estimated that there were 313,000 new cases of lung cancer 
and 268,000 lung cancer deaths in Europe (GLOBOCAN 2012).  In the United States, there were 
an estimated 221,200 new cases of lung cancer and 158,040 lung cancer deaths in 2015 (Siegel 
et al. 2015). 
Nonsmall cell lung cancer (NSCLC) is the predominant subtype of lung cancer, accounting for 
approximately 85% of all cases (Howlader et al. 2015).  NSCLC can be divided into two major 
histologic types:  adenocarcinoma and squamous cell carcinoma (Travis et al. 2011).  
Adenocarcinoma histology accounts for more than half of all NSCLC, while squamous cell 
histology accounts for approximately 25% of NSCLC (Langer et al. 2010).  The remaining cases 
of NSCLC are represented by large cell carcinoma, neuroendocrine tumors, sarcomatoid 
carcinoma, and poorly differentiated histology. 
The overall 5-year survival rate for advanced disease is 2%4%, depending on geographic 
location (Cetin et al. 2011).  Poor prognostic factors for survival in patients with NSCLC include 
advanced stage of disease at the time of initial diagnosis, poor performance status, and a history 
of unintentional weight loss.  More than half of the patients with NSCLC are diagnosed with 
distant disease, which directly contributes to poor survival prospects. 
Genetic changes that have prognostic and/or predictive significance in NSCLC include mutations in 
the EGFR gene and rearrangement in the ALK gene.  The rates of these mutations differ between 
squamous cell carcinoma and adenocarcinoma.  For example, EGFR mutations have been 
reported in 10%40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
squamous NSCLC (Herbst et al. 2008).  Rearrangement in the ALK gene is very rare in the 
squamous histology but observed in approximately 7% of patients with adenocarcinoma 
(Herbst et al. 2008; Langer et al. 2010). 
1.2 
FIRST-LINE TREATMENT FOR NON-SQUAMOUS NSCLC 
1.2.1 
Patients with an EGFR Mutation 
Genotype-directed therapy has the potential to dramatically improve the balance of benefit and 
toxicity for selected patients with NSCLC (mainly non-squamous histology) characterized by 
alterations of driver oncogenes, including sensitizing EGFR mutations and ALK rearrangements.  
Randomized Phase III trials of the EGFR inhibitors gefitinib, erlotinib, and afatinib showed 


 
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significant improvement of PFS and objective response rate (ORR) compared with platinum 
doublet chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; Yang et al. 2012).   
Despite the high initial response rate, patients treated with first line EGFR TKIs develop acquired 
resistance after 9–14 months. About half of these resistance conditions are caused by EGFR 
T790M mutation (8) and respond well to third-generation EGFR TKIs such as osimertinib 
targeting EGFR T790M (Janne PA et al 2015). Unfortunately, almost all patients treated with 
EGFR TKIs ultimately develop resistance to targeted therapies. Salvage treatment with platinum-
based doublet chemotherapy gives response rate of ~10-20% only(Yang CJ et al 2016, Tseng Y-
H et al 2016). Hence novel treatment strategies are urgently warranted. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which 
function as inhibitory receptors expressed on T cells.  Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell 
responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 
2016).  Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies.  Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, the treatment of nonsmall 
cell lung cancer ,the treatment of Triple-Negative Breast Cancer and for small cell lung cancer. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical studies. 
1.4 
BACKGROUND ON BEVACIZUMAB 
Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor and a key 
regulator of physiological angiogenesis. It is also implicated in pathological angiogenesis such as 
that associated with tumor growth. Increased levels of VEGF have been found in most tumors 
examined to date, including tumors of the lung where, in addition, overexpression is associated 
with a poorer prognosis (Giatromanolaki 2001;Brattstrom et al. 2004). 
AVASTIN® (bevacizumab) is a recombinant humanized monoclonal antibody to VEGF that 
recognizes all isoforms of VEGF. It may exert a direct anti-angiogenic effect by binding to and 
clearing VEGF from the tumor environment. Additional anti-tumor activity may be on tumor 
vasculature, interstitial pressure, and blood vessel permeability, providing for enhanced 
chemotherapy delivery to tumor cells (Jain 2001).Bevacizumab has been tested in Phase II and 
III studies in a variety of solid tumors in combination with chemotherapy. Bevacizumab is 
registered in over 40 countries worldwide for the first-line treatment of metastatic colorectal 


 
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cancer (CRC) in combination with chemotherapy, as second-line CRC treatment, and first-line 
treatment of advanced NSCLC, metastatic breast cancer, advanced renal cell carcinoma (RCC), 
ovarian cancer, and glioblastoma (Reck and Crino 2009). 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a significant 
survival benefit in patients with advanced malignancies (Hodi et al. 2010; Kantoff et al. 2010; 
Chen et al. 2012). 
The PD-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, 
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 tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1 pathway represents an attractive strategy for restoring tumor-specific 
T-cell immunity. 
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 NSCLC, urothelial carcinoma, 
RCC, melanoma, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma (see Atezolizumab Investigator's Brochure for detailed efficacy results).   
Atezolizumab has been generally well tolerated.  Adverse events with potentially immune-related 
causes consistent with an immunotherapeutic agent, including rash, influenza-like illness 
endocrinopathies, hepatitis or transaminitis, pneumonitis colitis, and myasthenia gravis, have 
been observed (see Atezolizumab Investigator's Brochure for detailed safety results).  To date, 
these events have been manageable with treatment or interruption of atezolizumab treatment. 
Bevacizumab is a recombinant, humanized therapeutic antibody directed against VEGF. In 
addition to promoting tumor angiogenesis, there is increasing evidence that VEGF plays a role in 
cancer immune evasion through several different mechanisms. For example, experiments with 
activated endothelial cells suggest that in the tumor microenvironment, VEGF may reduce 
lymphocyte adhesion to vessel walls, thus contributing to decreased immune-cell recruitment to 
the tumor site (Bouzin et al. 2007).  
Some immunosuppressive activities of VEGF can be reversed by inhibition of VEGF signaling. 
Thus, mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell function, 


 
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which could be restored by blockade of VEGFR2 (Huang et al. 2007). In a murine melanoma 
model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by improved anti-
tumor activity, prolonged survival, and increased trafficking of T cells into tumors (Shrimali et al. 
2010). 
Synergistic effects have also been observed in a clinical study of melanoma patients combining 
an immunomodulatory antibody (anti−CTLA-4; ipilimumab) and bevacizumab (Hodi et al. 2011). 
In this study of an immunomodulatory agent and bevacizumab, best overall responses were PR 
in 8 of 22 patients (35%) and stable disease in 6 of 22 patients (27%). All responses were durable 
for > 6 months. Therefore, the combined treatment with atezolizumab and bevacizumab may 
augment the antitumor immune response, resulting in improved and more durable clinical benefit. 
In phase III trial IMpower 150, stage IV NSCLC patients received atezolizumab plus carboplatin 
plus paclitaxel(ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus 
BCP(ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with 
atezolizumab, bevacizumab, or both. The ABCP followed by maintenance therapy group showed 
mPFS 8.3m, mOS 19.2m, ORR 63.5%. （Socinski MA et al. 2018） 
The IMmotion 151 was the front-line, phase III trail of the atezolizumab combination with 
bevacizumab in RCC. The result of IMmotion 151 showed atezolizumab + bevacizumab 
demonstrated a clinically meaningful and statistically significant improvement in PFS (as 
evaluated by the investigators) versus sunitinib in the PD-L1+ population (HR = 0.74 [95% CI: 
0.57, 0.96]). This significant improvement in HR translated into improved median PFS values of 
11.2 months for atezolizumab + bevacizumab compared to 7.7 months for sunitinib. In the ITT 
population, median PFS was 11.2 versus 8.4 months, respectively (HR = 0.83 [95% CI: 0.70, 
0.97]).( Brian I Rini et al. 2019) 
In the analysis of safety data from Study GO30140 (clinical cutoff date of 7 June 2017) in 20 
patients with HCC (median treatment duration of 2.8 months [range: 1-11 months]), the 
combination of atezolizumab +bevacizumab was generally safe and well tolerated; no new safety 
signals related to the combination therapy were identified beyond the established safety profile for 
each individual agent. There is a global phase III YO40245 is on going, which evaluate the 
efficacy and safety of atezolizumab + bevacizumab versus sorafenib in patients with locally 
advanced or metastatic HCC who have received no prior systemic treatment. 
Several steps will be taken to ensure the safety of participants in ML41256. First, administration 
of atezolizumab and bevacizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies (Section 4.3). 
Second, identified and potential risks associated with study treatment will continue to be closely 
monitored throughout this study (Section 5.1.1 and Section 5.1.2). Third, the study contains 
protocol-specified study treatment interruption criteria designed to ensure safety. 
This trial will enroll patients with stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer 
(NSCLC) harbored EGFR mutation after treatment failure of EGFR TKI. All patients will be 
selected on the basis of PD-L1 expression ≥ 1%.  Given the relatively poor prognosis and limited 


 
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treatment options for these patients, this population is considered appropriate for trials of novel 
therapeutic candidates.   
With the above safety precautions in place, combined with the efficacy, safety evidence from 
previous studies, the current assessment of the expected benefits of atezolizumab + 
bevacizumab combination therapy outweigh the risks in this study, especially given the potential 
of the combination in this setting. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab 
in patients with stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) harbored 
EGFR mutation after treatment failure of EGFR TKI. All patients will be selected on the basis of 
PD-L1 expression ≥ 1% on tumor cells (TC) and/or immune cells (ICs) using a centrally 
performed immunohistochemistry (IHC) test. Specific objectives and corresponding endpoints for 
the study are outlined below. 
In this protocol, "study treatment" refers to the combination of atezolizumab and bevacizumab 
assigned to patients as part of this study. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoint (evaluable 
population: it includes all enrolled patients who receive any amount of atezolizumab or 
bevacizumab, and have at least one post-baseline efficacy measurement): 
 
Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as 
determined by the investigator according to RECIST v1.1. 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoints: 
 
Duration of objective 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. 
 
Time to response (TTR), defined as the time from the start of the treatment to the first 
objective tumor response observed for patients who achieved CR or PR, as determined 
by the investigator according to RECIST v1.1. 
 
Disease control rate (DCR), defined as the proportion of patients who have a best 
overall response of CR or PR or stable disease (SD), as determined by the investigator 
according to RECIST v1.1 


 
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 
Overall survival (OS) after enrollment, defined as the time from enrollment to death from 
any cause. 
 
Progression-free survival (PFS), defined as the time from enrollment 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 
 
PFS rate at 6 and 12 months, defined as the proportion of patients who have not 
experienced disease progression or death from any cause at 6 months and 12 months, 
as determined by the investigator according to RECIST v1.1. 
 
OS rate at 1 and 2 years, defined as the proportion of patients who have not 
experienced death from any cause at 1 and 2 years.  
 
Expression of PD-L1 defined by the SP142 and SP263 assay. 
 
Analyses ORR, DOR, PFS,PFS rate at 12m,by investigator according to Modified 
RECIST V1.1(iRECIST) 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of atezolizumab plus bevacizumab on 
the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0 
 
Incidence of serious and non-serious immune-mediated adverse events related to 
atezolizumab treatment 
2.3 
HEALTH STATUS UTILITY OBJECTIVE 
The patient-reported outcome (PRO) objectives are to evaluate the impact of atezolizumab plus 
bevacizumab from the patient's perspective, on the basis of the following endpoints: 
 
PROs of lung cancer symptoms, patient functioning, and health-related quality of life 
(HRQoL) as measured by the European Organization for Research and treatment of 
Cancer (EORTC) Quality-of-life Questionnaire Core 30 (QLQ C30) and its Lung Cancer 
Module (QLQ LC13). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design  
This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy 
and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with 
Stage IIIB-IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy. Patients 
should have received at least one EGFR TKI and have disease progressed before enrollment.  
This study will consist of a screening period (Day -28 to Day -1), a treatment period, a treatment 
discontinuation visit period (≤30 days after last dose) and a follow-up period. It is anticipated that 
this study will enroll about 60 patients at multiple sites in China. 


 
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At screening, tumor specimens (either fresh or archival) from each potentially eligible patient will 
be tested for PD-L1 expression by a central laboratory using an IHC assay. The specimens will 
be tested PD-L1 expression by Ventana SP142 and SP 263.The patients will be tested T790M by 
blood or re-biospy tissue sample. Tumor EGFR mutation status will also be confirmed by central 
laboratory using either tissue or blood samples. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.  
Figure 1 
Study Schema 
  
IV  intravenous; NSCLC  nonsmall cell lung cancer;  
All eligible enrollees will receive atezolizumab by intravenous (IV) infusion at a fixed dose of 1200 
mg on Day 1 of each 21-day cycle.  Bevacizumab will be administered by IV infusion at 15 mg/kg 
on Day 1 of each 21-day cycle. Patients will continue treatment until progressive disease, 
unacceptable toxicity, or death. Patients may continue treatment beyond radiographic 
progression by RECIST v1.1, provided they are experiencing clinical benefit as assessed by 
investigator (i.e., in the absence of unacceptable toxicity or symptomatic deterioration attributed 
to disease progression as determined by the investigator after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status (see below). Patients who 
temporarily or permanently discontinue either atezolizumab or bevacizumab may continue on 
single-agent therapy until disease progression (i.e., patients temporarily withdrawn from 
bevacizumab due to adverse effects may continue atezolizumab monotherapy and vice versa). 
Because of the possibility of an initial increase in tumor burden caused by immune-cell infiltration 
in the setting of a T-cell response (termed pseudoprogression) with atezolizumab treatment, 
radiographic progression per RECIST v1.1 may not be indicative of true disease progression.  In 
the absence of unacceptable toxicity, patients who meet criteria for disease progression per 
RECIST v1.1 while receiving atezolizumab will be permitted to continue atezolizumab if they meet 
all of the following criteria: 
 
Evidence of clinical benefit, as determined by the investigator following a review of all 
available data 
 
Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease 


 
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 
Absence of decline in ECOG Performance Status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 
weeks following Cycle 1, Day 1, regardless of dose delays.  After 36 weeks, tumor assessment 
will be required every 9 weeks (±7days).  Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab 
treated patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs 
first.  Patients who discontinue treatment for reasons other than radiographic disease progression 
(e.g., toxicity) will continue scheduled tumor assessments until radiographic disease progression 
per RECIST v1.1 or loss of clinical benefit (for atezolizumab treated patients who continue 
treatment after radiographic disease progression according to RECIST v1.1), withdrawal of 
consent, study termination by Sponsor, or death, whichever occurs first, even if patient starts 
another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when all the patients have either died, withdraw from 
study, are lost to follow up, or have been followed for 24 months since the last patient is enrolled, 
whichever occurs first. In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 3 years. 
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 the approved dosage for atezolizumab (Tecentriq U.S. Package Insert).  
Anti-tumor 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). 
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 the approved dosage for bevacizumab. This dose schedule aligns with the 
atezolizumab dose schedule highlighted above and is the dose used in combination with 
atezolizumab in Study GO30140. In this study, the combination of atezolizumab and 


 
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bevacizumab was generally safe and well tolerated and no new safety signals related to the 
combination therapy were identified beyond the established safety profile for each individual 
agent. 
3.3.3 
Rationale for Patient Population 
This study will enroll patients with advanced NSCLC who have PD-L1 expression defined as PD-
L1 ≥1% expression, determined by SP142 and SP 263 IHC assay . 
Phase II trial BIRCH was designed to assess the efficacy and safety of single-agent atezolizumab 
in patients with PD-L1–selected stage IIIB/IV NSCLC, across multiple lines of therapy. In the 
EGFR mutation subgroup analyses, ORR 23%, PFS 5.5m 95%CI (2.6-8.3), OS 20.1m 95%CI 
(NE-NE). The safetyprofile was similar across cohorts and consistent with previous atezolizumab 
monotherapy trials (Solange Peters et al 2017). 
PD-L1 prevalence in IMpower150 using the SP142 and SP263 IHC assays was similar and 
substantial overlap was observed. The majority (~76%) of the PD-L1 positive patients by SP142 
were also positive by SP263 and vice versa. A similar percentage of patients was positive by one 
assay but not another (13% for SP142 and 14% for SP263) ( Kowanetz M et al. 2018). 
In one retrospective study explore the immunophenotypic signature of patients with de novo 
resistance to EGFR-TKIs, and the results suggested that this population may be benefit from 
programmed death 1 (PD-1) blockade therapy. It suggests the existence of immune mechanisms 
of resistance to targeted therapy（ShanSu et al. 2018）. 
In IMpower 150, EGFR+/ALK+ subgroup, atezolizumab+bevzcizumab+ carboplatin + paclitaxel 
mPFS 9.7m, bevacizumab+CP 6.1m,HR 0.59(95% CI 0.37.0.94).( Martin Reck et al 2019) 
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in some 
patients, and expression of PD-L1 correlates with response to therapy in several tumor types 
(Topalian et al. 2012; Herbst et al. 2014; Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst 
et al. 2016; Rosenberg et al. 2016). 
Data from Study PCD4989g suggest that tumor PD-L1 status as determined by IHC correlates 
with response to atezolizumab in patients with NSCLC.  In a Phase II study (GO28753), patients 
with NSCLC whose tumors expressed PD-L1 (TC1/2/3 or IC1/2/3) had an improvement in OS 
when treated with atezolizumab compared with docetaxel in the second- or third-line setting.  
These data provide a rationale for evaluating the efficacy of atezolizumab in patients with 
advanced NSCLC selected on the basis of tumor PD-L1 expression. 
3.3.4 
Rationale for Open-Label Study  
The primary objective of this study is to assess the efficacy and safety profile of atezolizumab + 
bevacizumab in a non-comparative fashion. The study will have an open-label, single-arm and 
non-randomized design. 


 
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3.3.5 
Rationale for Objective response rate as Primary Endpoint  
In this study, the primary efficacy endpoint will be investigator confirmed objective response rate. 
Phase II studies are limited because they lack a control arm. Objective response rate directly 
measures the efficacy of initial therapy, unaffected by treatment at progression.   
3.3.6 
Rationale for Atezolizumab 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 tumor 
burden.  This initial increase in tumor 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 tumor growth followed by a response was observed in several tumor 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 ICs and no viable cancer cells.  
Because of the potential for a response after pseudoprogression, this study will allow patients to 
continue treatment after apparent radiographic progression per RECIST v1.1, provided the 
benefit-risk ratio is judged to be favorable 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, local 
biopsy results (if available), and clinical status (see Section 3.1.1 for details). 
3.3.7 
Rationale for the Use of Modified Response Criteria 
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 tumor burden.  
Thus, this study will employ tumor response criteria modified for unconventional tumor change 
patterns associated with cancer immunotherapy: modified RECIST v1.1 for immune-based 
therapeutics (iRECIST; Seymour et al. 2017; see Appendix 3).    
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 account for responses that may occur following transient radiographic progression 
caused by immune-cell infiltration in tumors (leading to a transient increase in the size of existing 
lesions, including those that were previously undetectable and consequently appear as new 
lesions).  iRECIST rely on collection of tumor assessment data after initial disease progression 
per RECIST v1.1. 
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 evaluation of iRECIST as improved measures of the 
efficacy of immunotherapies relative to standard RECIST v1.1(see Appendix 2).  


 
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3.3.8 
Rationale for Biomarker Assessments  
Published results suggest that the expression of PD-L1 in tumors correlates with response to 
antiPD-1 and anti-PD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; Borghaei et al. 2015; 
Fehrenbacher et al. 2016; Herbst et al. 2016; Rosenberg et al. 2016).  In the current study, 
archival or baseline tumor specimens will be collected from patients and tested for PD-L1 
expression by a central laboratory during the screening period.  Only patients with tumor PD-L1 
expression categorized as ≥ 1% by SP142 and SP 263 assay , will be enrolled in the study.    
The data form IMpower 150 showed the EGFR mutation patients will get benefit from 
atezolizumab+bevacizumab + CP, The type of EGFR mutation and T790M will confirm duiring 
screening.  
3.3.9 
Rationale for Patient-Reported Outcome Assessments 
PROs provide an understanding of the impact a treatment has on a patient.  The QLQ-C30 is a 
validated instrument that has been widely used in assessing quality of life in patients with cancer.  
The core instrument assesses global health status/quality of life, functions (physical, role, 
emotional, cognitive, and social), and general cancer symptoms.  The EORTC QLQ-LC13 is a 
lung cancer-specific module that can provide information on disease and treatment-related 
symptoms and functional interference that are specific to this patient population. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately  44 patients with PD-L1-expression ≥1%,Stage IIIB-IV Non-Squamous NSCLC 
harbored EGFR mutation after EGFR TKI therapy will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Male or female, Age ≥ 18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Life expectancy ≥ 10 months 
 
Histologically or cytologically confirmed stage IIIB - IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
8th edition) 
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible if 
the major histological component appears to be non-squamous. 
 
No prior treatment for Stage IIIB or IV non-squamous NSCLC, with the following exceptions: 
Patients with a sensitizing mutation in the EGFR gene must have experienced disease 
progression (during or after treatment) or were intolerant to treatment with one or more 
EGFR TKIs, such as erlotinib, gefitinib, icotinib, afatinib, osimertinib, or another EGFR TKI 
appropriate for the treatment of EGFR-mutant NSCLC. 
Patients who have progressed on or were intolerant to first-line osimertinib or other third-
generation EGFR TKIs are eligible. 
Patients who have progressed on or were intolerant to first- or second-generation EGFR 
TKIs, such as erlotinib, gefitinib, afatinib, dacomitinib, and who have no evidence of the 
EGFR T790M mutation after TKI therapy are eligible. 


 
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Patients who have progressed on or were intolerant to first- or second-generation EGFR 
TKIs and who have evidence of the T790M mutation must have also progressed on or were 
intolerant to osimertinib to be eligible. 
 
TKIs approved for treatment of NSCLC discontinued ＞7 days prior to enrollment. 
 
Measurable disease per RECIST v1.1 
 
PD-L1 expression of ≥1% as documented through central testing of a representative tumor 
tissue specimen either from previously obtained archival tumor tissue or tissue obtained 
from a biopsy at screening 
Archival or newly collected tumor tissue sample obtained at baseline for determination of 
PD-L1 expression and EGFR mutation test. 
Optional biopsy at screening is the preferred method to collected the tumor specimens for 
PD-L1 expression at screening and T790M mutation.  
A representative FFPE tumor specimen from in a paraffin block (preferred) or at least 10 
slides containing unstained, freshly cut, serial sections must be submitted, 5 slides for PD-
L1 testing (SP 263 and SP142),5 slides for T790M test. The associated pathology report 
must be submitted prior to study enrollment. If the patient onlyhave archival tumor tissue 
sample, 5 slides must be submietted for PD-L1 expression test (SP 263 and SP142). If less 
than 5 slides are available, the patient may still be eligible for the study, after Medical 
Monitor approval has been obtained, The slides is preferred to do PD-L1 expression test 
with SP263 assay. PD-L1 expression of ≥1%, either SP142 or SP263,is eligible.  
Tumor tissue should be of good quality based on total and viable tumor content.  Samples 
must contain a minimum of 50 viable tumor cells that preserve cellular context and tissue 
architecture regardless of needle gauge or retrieval method.  Samples collected via 
resection, core-needle biopsy at least three cores, embedded in a single paraffin block), or 
excisional, incisional, punch, or forceps biopsy are acceptable.  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell suspension 
and/or smears), brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  Tumor tissue from bone metastases that have been decalcified is not 
acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, 
a pretreatment tumor biopsy is required.  A pretreatment tumor biopsy may also be 
performed if a patient's archival tissue test results do not meet eligibility criteria. (see 
Section 4.5.6 for details) 
 
ECOG Performance Status of 0-1 
 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment: 
- ANC 1.5  109/L (1500/L) without granulocyte colony-stimulating factor support 
- Lymphocyte count 0.5 109/L (500/L) 
- Platelet count 100  109/L (100,000/L) without transfusion  
- Hemoglobin 90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5  upper limit of normal (ULN), with the 
following exceptions: 
Patients with documented liver metastases:  AST and ALT ≤5  ULN 
Patients with documented liver or bone metastases:  ALP ≤5 ULN 
- Bilirubin ≤1.5 ULN with the following exception: 
Patients with known Gilbert disease:   bilirubin level ≤3 ULN 
- Creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula) 
- Albumin  25 g/L (2.5 g/dL) 
- For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤1.5 ULN 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
 
Negative HIV test at screening 


 
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 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening 
The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.  
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of ＜
1% per year during the treatment period and for 5 months after the final dose of 
atezolizumab and/or 6 months after the last dose of bevacizumab, whichever is later. 
Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of ＜ 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile 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 final dose of bevacizumab.  Men must 
refrain from donating sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final 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 preventing drug exposure. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases 
as determined by CT or MRI evaluation during screening and prior radiographic 
assessments 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met: 
- Measurable disease, per RECIST v1.1, must be present outside the CNS. 
- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
- The patient has not undergone stereotactic radiotherapy within 7 days prior to 
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initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment. 
- The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease. Anticonvulsant therapy at a stable dose is permitted. 
- Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord). 
- There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment.  
Asymptomatic patients with CNS metastases newly detected at screening are eligible 
for the study after receiving radiotherapy or surgery, with no need to repeat the 
screening brain 
 
History of leptomeningeal disease 
 
Prior chemotherapy or other systemic therapy for stage IIIB/IV disease 
 
Uncontrolled tumor-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 
enrollment.  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 enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium 12 
mg/dL or corrected calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis 
(see Appendix 6 for a more comprehensive list of autoimmune diseases and immune 
deficiencies), with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
- Rash must cover   10% of body surface area 
- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
- No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 


 
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 
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  
Patients with known coronary artery disease, arrhythmias, congestive heart failure not 
meeting the above criteria must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate. 
Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for 
all patients, especially in those with cardiac risk factors and/or history of coronary 
artery disease or where low LVEF is suspected  
Patients with known LVEF < 40% 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study 
 
History of malignancy other than NSCLC within 5 years prior to 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, or Stage I uterine cancer 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.  
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, or may render the patient at high risk from treatment complications 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 
5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for HBV 
 
Treatment with investigational therapy within 28 days prior to initiation of study treatment 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and 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-
 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 
for orthostatic hypotension or adrenal insufficiency are eligible for the study. 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
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 
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within 5 months after the final dose of atezolizumab, 6 months after the final dose of 
bevacizumab   
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
 
Inadequately controlled hypertension (defined as systolic blood pressure ＞150 mmHg 
and/or diastolic blood pressure ＞100 mmHg) 
Anti-hypertensive therapy to achieve these parameters is allowable. 
 
Prior history of hypertensive crisis or hypertensive encephalopathy 
 
Patients with a baseline ECG demonstrating a QTc > 460 msec 
 
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 Grade ≥ 2 hemoptysis (defined as ≥ one-half teaspoon of bright red blood per 
episode(approximately 2.5ml)) within 1 month prior to enrollment 
 
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation) Current or recent (within 10 days of initiation of study treatment) use of 
aspirin (＞ 325 mg/day), clopidogrel (＞ 75mg/day) or treatment with dipyramidole, 
ticlopidine,  or cilostazol 
 
Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable for ＞ 2 weeks prior to enrollment 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR 
or aPTT is within therapeutic limits (according to the medical standard of the enrolling 
institution) and the patient has been on a stable dose of anticoagulants for at least 2 
weeks prior to enrollment 
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 enrollment. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted. 
 
History of stroke or transient ischemic attack within 6 months prior to enrollment  
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of bevacizumab 
 
History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 
months prior to enrollment 
 
History of intra-abdominal inflammatory process within 6 months prior to initiation of study 
treatment, including but not limited to active peptic ulcer disease, diverticulitis,or colitis 
 
Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding  
 
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure 
 
Serious, non-healing wound, active ulcer, or untreated bone fracture 
 
Proteinuria, as demonstrated by urinalysis or ＞1.0 g of protein in a 24-hour urine collection 
All patients with ≥ 2 ＋ protein on urinalysis at baseline must undergo a 24 hour urine 
collection and must demonstrate ≤ 1 g of protein in 24 hours. 
 
Clear tumor infiltration into the thoracic great vessels is seen on imaging 
 
Clear cavitation of pulmonary lesions is seen on imaging 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label (unblinded) study in which all subjects will be assigned to receive the same 
study treatment, i.e., atezolizumab + bevacizumab. 
 


 
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4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE 
STUDY DESIGN 
The investigational medicinal product (IMP) for this study is atezolizumab and bevacizumab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Atezolizumab 
The atezolizumab Drug Product 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 formulation and handling of atezolizumab, see the pharmacy manual and 
the Atezolizumab Investigator's Brochure. 
4.3.1.2 
Bevacizumab 
Bevacizumab will be supplied by the Sponsor as a clear to slightly opalescent, colorless to pale 
brown, sterile liquid for IV infusion in single-use vials, which are preservative-free. Bevacizumab 
will be supplied in 20-mL glass vials with a 16-mL fill (400 mg, 25 mg/mL).  
For information on the formulation and handling of bevacizumab, see the pharmacy manual, the 
Bevacizumab / Avastin® Investigator’s Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimen (atezolizumab + bevacizumab) is summarized in Section 3.1. 
Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 5 minutes 
between dosing. 
Any dose modification(s) should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF). Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.4.4. 
Guidelines for dosage modification and treatment interruption or discontinuation for patients who 
experience adverse events are provided in Appendix 8, Appendix 9 and Appendix 10. 
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), 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 7. Atezolizumab infusions will be 
administered per the instructions outlined in Table 1. 


 
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Table 1  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 
8 and Appendix 11.  
Cases of accidental overdose or medication error, along with any associated adverse events, 
should be reported as described in Section 5.4.4. 
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. 
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 7 
Bevacizumab infusions will be administered per the instructions outlined in Table 2. 
Guidelines for preparation,administration,disposal, dosage modification and treatment interruption 
or discontinuation because of toxicities are provided in Appendix 10 and Appendix 11 . 


 
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Table 2 Administration of First and Subsequent Bevacizumab Infusions 
First Infusion 
Subsequent Infusions 
No premedication is permitted prior to the 
Bevacizumab infusion  
Vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) should be recorded 
within 60 minutes prior to the infusion. 
Bevacizumab should be infused over 90 (15) 
minutes. 
Vital signs should be 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 at the end of 
infusion and 2 (1) hours after the 
infusion 
 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab, bevacizumab) will be provided by the 
Sponsor where required by local health authority regulations. The study site will acknowledge 
receipt of IMPs supplied by the Sponsor using appropriate documentation form to confirm the 
shipment condition and content. Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site's institutional standard 
operating procedure or be returned to the Sponsor (if supplied by the Sponsor) with the 
appropriate documentation. The site's method of destroying Sponsor-supplied IMPs must be 
agreed to by the Sponsor. The site must obtain written authorization from the Sponsor before any 
Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on the appropriate 
form.   
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to Atezolizumab  
Currently, the Sponsor does not have any plans to provide Roche IMPs (atezolizumab and 
bevacizumab) or any other study treatments or interventions to patients who have completed the 
study. The Sponsor may evaluate whether to continue providing atezolizumab and bevacizumab in 
accordance with the Roche Global Policy on Continued Access to Investigational Medicinal 


 
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Product, available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
4.4 
CONCOMITANT THERAPY 
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 treatment 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 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or 
low-molecular-weight heparin) 
 
Inactivated influenza vaccinations 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief 
of pain) as outlined below: 
After completion of Cycle 1, palliative radiotherapy is permitted, provided it does not 
interfere with the assessment of tumor 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. 
 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below: 
Patients experiencing a mixed response requiring local therapy for control of three or 
fewer lesions may still be eligible to continue study treatment after Medical Monitor 
approval has been obtained. Patients who receive local therapy directed at a target 
lesion will no longer be evaluable for radiographic response but will remain evaluable 
for progression 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
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In general, investigators should manage a patient's care (including preexisting conditions) with 
supportive therapies other than those defined as cautionary or prohibited therapies (see Sections 
4.4.2 and 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 infusion-associated events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 7). 
4.4.2 
Cautionary Therapy  
4.4.2.1 
Corticosteroids and TNF- Inhibitors for Atezolizumab-Treated Patients 
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab.  Therefore, in situations in which systemic corticosteroids 
or TNF- inhibitors would be routinely administered, alternatives, including antihistamines, should 
be considered.  If the alternatives are not feasible, systemic corticosteroids and TNF- inhibitors 
may be administered at the discretion of the investigator. 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the treatment 
of specific adverse events when associated with atezolizumab therapy (refer to Appendix 9 for 
details). 
4.4.2.2 
Cautionary Therapy Specific to Bevacizumab 
Anticoagulants: The use of full-dose oral or parenteral anticoagulants is permitted during the trial 
as long as the INR and/or aPTT is within therapeutic limits (according to the medical standard of 
the treating institution). Prophylactic use of anticoagulation at baseline and during study treatment 
is permitted. Bevacizumab or anticoagulation treatment will be stopped if there is any evidence of 
tumor invasion into major blood vessels on any CT scan. 
Aspirin: Owing to a possible risk of bleeding during treatment with bevacizumab, patients should 
not take more than 325 mg of aspirin daily (or more than 75 mg of clopidogrel daily, or 
equivalent), at least until discontinuation of bevacizumab treatment. 
 
4.4.2.3 
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. 


 
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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 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. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation 
of study treatment, during atezolizumab treatment, and for 5 months after the final dose 
of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) 
are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination with 
atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during 
study treatment because these agents could potentially alter the efficacy and safety of 
atezolizumab. 
 
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.   
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 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 enrollment. 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.  


 
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4.5.2 
Medical History, Concomitant Medication, and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history (including prior 
cancer therapies and procedures), reproductive status, and smoking history, 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. A history of pleural or pericardial effusion or 
ascites requiring intervention should be entered in the medical history. 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. 
Cancer history will include an assessment of tumor histology. 
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. 
Limited, symptom-directed physical examinations should be performed at specified postbaseline 
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 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood 
pressure, and temperature. 
Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 5 minutes 
between dosing. Vital signs should be measured within 60 minutes prior to each atezolizumab 
infusion and, if clinically indicated, during or after the infusion. In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities (see Appendix 1) 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 
weeks following Cycle 1, Day 1, regardless of dose delays.  After 36 weeks, tumor assessment 
will be required every 9 weeks (±7days). Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1 or (for patients who continue treatment after 
radiographic disease progression) loss of clinical benefit as determined by the investigator (see 
Section 3.1 for details).  


 
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In the absence of disease progression, tumor assessments should continue regardless of 
whether patients start new anti-cancer therapy, until consent is withdrawn, death, or the study is 
terminated by the Sponsor, whichever occurs first. At the investigator's discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected.  
All measurable and evaluable lesions should be assessed and documented at screening. Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 
days prior to initiation of study treatment do not have to be repeated at screening.  
Screening assessments must include computed tomography (CT) scans (with oral or IV contrast 
unless contraindicated) 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 noncontrast CT 
scan of the chest may be performed and MRI scans of the abdomen and pelvis should be 
performed. If a CT scan with contrast is not contraindicated, it is mandatory to obtain a dual-
phase imaging of the liver, and every effort should be made to time the contrast administration so 
that high-quality arterial-phase imaging is obtained throughout the liver on the first run, and high-
quality portal venous-phase imaging is obtained throughout the liver on the second run. 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. Patients with a history of irradiated brain metastases and 
without measurable brain lesion at screening are not required to undergo imaging brain scans at 
subsequent tumor evaluations, unless scans are clinically indicated. 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 tumor assessment is performed in a positron emission tomography (PET)/CT scanner, the CT 
acquisition must be consistent with the standards for a full-contrast diagnostic CT scan. All 
measurable and evaluable lesions should be re-assessed at each subsequent tumor evaluation. 
The same radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (e.g., the same contrast protocol for CT scans). Response will be 
assessed by the investigator using RECIST v1.1 and iRECIST (see Appendix 3，Appendix 4). 
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits. Results must be reviewed by the investigator before dosing at the next 
cycle. At the investigator’s discretion, CT scans should be repeated at any time if progressive 
disease is suspected. 
4.5.6 
 Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
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 
Chemistry panel (serum or plasma):  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, and LDH 
 
Coagulation:  INR, and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or total 
T3 for sites where free T3 is not performed), and free thyroxine (also known as T4) 
 
HIV serology 
 
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an 
HBV DNA test must also be performed to determine if the patient has an HBV infection. 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test must also 
be performed to determine if the patient has an HCV infection. 
 
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 has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted  
 
The following samples will be sent to one or several central laboratories or to the Sponsor or a 
designee for analysis: 
 
Archival or newly collected tumor tissue sample obtained at baseline for determination 
of PD-L1 expression and EGFR mutation test. 
Optional biopsy at screening is the preferred method to collected the tumor specimens 
for PD-L1 expression at screening and T790M mutation.  
A representative FFPE tumor specimen from in a paraffin block (preferred) or at least 
10 slides containing unstained, freshly cut, serial sections must be submitted 5 slides 
for PD-L1 testing (SP 263 and SP142),5 slides for T790M test. The associated 
pathology report must be submitted prior to study enrollment. If the patient only 
have archival tumor tissue sample, 5 slides must be submietted for PD-L1 expression 
test. If less than 5 slides are available , the patient may still be eligible for the study, 
after Medical Monitor approval has been obtained, The slides is preferred to do PD-L1 
expression test with SP263 assay. PD-L1 expression of ≥1%, either SP142 or 
SP263,is eligible. The high expression define as TC3 or IC3 for SP142 or TC ≥50% for 
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Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular context 
and tissue architecture regardless of needle gauge or retrieval method.  Samples 
collected via resection, core-needle biopsy at least three cores, embedded in a single 
paraffin block), or excisional, incisional, punch, or forceps biopsy are acceptable.  Fine-
needle aspiration (defined as samples that do not preserve tissue architecture and yield 
cell suspension and/or smears), brushing, cell pellets from pleural effusion, and lavage 
samples are not acceptable.  Tumor tissue from bone metastases that have been 
decalcified is not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for required 
testing, a pretreatment tumor biopsy is required.  A pretreatment tumor biopsy may also 
be performed if a patient's archival tissue test results do not meet eligibility criteria. 
The Informed Consent Form will contain a separate section that addresses this optional 
screening biopsy. A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies. The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of 
consent, by completing the Optional Biopsy Sample Informed Consent eCRF 
 
Optional biopsy is the preferred method to collected the tumor specimens for T790M 
testing at screening(5 slides, mentioned above), If the tumor tissue is not enough,  
blood 5 ml sample for EGFR and T790M mutation test. 
 
Patiens must submit the EGFR mutated pathology report (original or photocopy), If the 
report is not avealiable, archival tumor tissue is preferred to do EGFR mutation confirm 
testing. The EGFR mutated pathology report is the final reference for EGFR-mutation 
status. 
4.5.7 
Electrocardiograms 
An 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. 
4.5.8 
Patient-Reported Outcomes  
To more fully characterize the clinical profile of atezolizumab, PRO data will be obtained through 
use of the following instruments:  European Organisation for Research and Treatment of Cancer 
(EORTC) quality-of-life questionnaires for cancer (EORTC QLQ-C30) and lung cancer (EORTC 
QLQ-LC13) The questionnaires will be translated as appropriate into the local language.   
To ensure instrument validity and that data standards meet health authority requirements, 
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by the patient before the patient receives any information on disease status and prior to the 
performance of non-PRO assessments and the administration of study treatment.  
Patients will complete paper versions of the EORTC QLQ-C30, EORTC QLQ-LC13 
questionnaires at the clinical site on Cycle 1, Day 1 and every cycle thereafter until the treatment 
discontinuation visit (included); after treatment discontinuation or disease progression, whichever 
comes first, questionnaires will be completed every 3 months (for 1 year), unless the patient 
withdraws consent or the Sponsor terminates the study. Paper PRO questionnaires will be 
provided and collected by site staff. 
Study personnel should review all questionnaires for completeness before a patient leaves the 
investigational site. Patients for whom PRO questionnaires are not available in their native 
language or who are deemed by the investigator incapable of completing their PRO assessment 
may be exempt from all PRO assessments. In the event that PRO questionnaires are not 
administered, site staff will record the reasons for why the measure was not completed in the 
eCRF. 
The Sponsor will not derive adverse events reports from PRO data 
4.5.8.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999) (see Appendix 5).  It consists of 30 questions that assess five aspects of 
patient functioning (physical, emotional, role, cognitive, and social), three symptom scales 
(fatigue, nausea and vomiting, pain), global health/quality of life, and six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the 
previous week.  Scale scores can be obtained for the multi-item scales.  The EORTC QLQ-C30 
module takes approximately 10 minutes to complete.   
4.5.8.2 
EORTC QLQ-LC13 
The EORTC QLQ-LC13 is a modular supplement to the EORTC quality-of-life questionnaire for 
use in lung cancer (see Appendix 4).  This module incorporates one multiple-item scale to assess 
dyspnea and a series of single items assessing pain, coughing, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, and hemoptysis.  The QLQ-LC13 module takes approximately 
5 minutes to complete. 
 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the following: 
 
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 


 
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 
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) 
Patients who discontinue one of the two drugs comprising the study treatment—either 
transiently or permanently—for adverse event or other reason (i.e., discontinue atezolizumab 
but remain on bevacizumab, or discontinue bevacizumab but remain on atezolizumab) may 
continue on the remaining study drug until disease progression if the investigator deems that 
the patient is still deriving clinical benefit. 
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 tumor 
response assessments and PRO assessments as outlined in the schedule of activities (see 
Appendix 1). 
After treatment discontinuation, information on survival follow-up and new anti-cancer therapy will 
be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 
months until death (unless the patient withdraws consent or the Sponsor terminates the study). 
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the investigator has the right to withdraw a patient from the study at any time.  Reasons 
for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study  
 
Investigator or Sponsor determines it is in the best interest of the patient  
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 


 
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Every effort should be made to obtain information on patients who withdraw from the study but 
have not withdrawn consent.  The primary reason for withdrawal 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 enrollment is unsatisfactory 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may include, but 
are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
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 
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discontinuation, are provided in Appendix 8, Appendix 9, and Appendix 10.  Refer to Sections 
5.25.6 for details on safety reporting (e.g., adverse events, pregnancies) for this study. 
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, meningoencephalitis, myocarditis, nephritis, myositis and severe cutaneous 
adverse reactions.  Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  Refer to Appendix 9 
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, hemorrhage, 
arterial thromboembolic events, fistulae, wound-healing complications, hypertension, venous 
thromboembolism, and proteinuria, etc.  
Refer to the Bevacizumab Investigator's Brochure for a detailed description of anticipated safety 
risks for Bevacizumab. 
5.1.3 
Risks Associated with Atezolimab with Bevacizumab 
The risk of overlapping toxicities between atezolizumab and bevacizumab is anticipated to be 
minimal based on the known safety profile of each agent and available data from clinical studies. 
Nevertheless, the attribution and management of certain adverse events that have been 
associated with each agent separately (e.g., hemorrhage,  hypothyroidism, and GI toxicity) may 
be ambiguous 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 8 Appendix 
9 and Appendix 10 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 (in the most recent version of the Atezolizumab and 
Bevacizumab Investigator's Brochures). 
 
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. 


 
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Certain types of events require immediate reporting to the Sponsor, as outlined in Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) (see Sections 5.3.5.9 and 5.3.5.10 for more 
information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study 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. 
 
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). 


 
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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 
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. 
Adverse Events of Special Interest for Atezolizumab 
Adverse events of special interest for atezolizumab are as follows: 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  ULN 
 
Systemic lupus erythematosus 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness. 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 


 
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 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
Adverse Events of Special Interest for Bevacizumab  
 
Grade 3 hypertension  
 
Grade 3 proteinuria  
 
Any grade GI perforation, abscesses, or fistulae  
 
Grade 3 wound-healing complication  
 
Hemorrhage  
- Any grade CNS bleeding  
- Grade 2 hemoptysis 
- Other Grade 3 hemorrhagic event  
 
Any grade arterial thromboembolic event  
 
Grade 3 venous thromboembolic event  
 
Any grade posterior reversible encephalopathy syndrome (PRES; also known as 
reversible posterior leukoencephalopathy syndrome or RPLS)  
 
Grade 3 CHF /left ventricular systolic dysfunction  
 
Grade 2 non-GI fistula or abscess  
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see Section 
5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All adverse events, 
whether reported by the patient or noted by study personnel, will be recorded in the patient's 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study 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 occurs 
first, and serious adverse events and adverse events of special interest will continue to be 


 
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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 3 will be used for assessing severity for adverse events that are 
not specifically listed in the NCI CTCAE. 
Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE v 5.0, 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. 
 


 
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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 4): 
 
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 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., 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. 
Only one adverse event term should be recorded in the event field on the Adverse Event eCRF. 


 
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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, tumor lysis syndrome, early disease 
progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration and are 
judged to be related to study treatment infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "cytokine-release syndrome") on the Adverse Event eCRF.  If 
possible, 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.  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. 
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 9. 
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 hemorrhage 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 timepoints and 
subsequently recurs.  Each recurrence of an adverse event should be recorded as a separate 
event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result must be 
reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or 
a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., "elevated potassium," 
as opposed to "abnormal potassium").  If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the adverse 
event.  For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as 
"hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should only 
be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on recording 
persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should only 
be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on recording 
persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated total 
bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy's Law).  
Therefore, investigators must report as an adverse event the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  ULN 
(of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  ULN 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 


 
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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 NSCLC 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 an outcome and not a distinct event.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF.  Generally, only one such event should be reported.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, "unexplained death" 
should be recorded on the Adverse Event eCRF.  If the cause of death later becomes available 
(e.g., after autopsy), "unexplained death" should be replaced by the established cause of death.  
The term "sudden death" should not be used unless combined with the presumed cause of 
death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as described in 
Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  Such 
conditions should be recorded on the General Medical History and Baseline Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the frequency, 
severity, or character of the condition worsens during the study.  When 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 NSCLC 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as adverse events.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be based on  
RECIST v1.1.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document progression 
through use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event. 


 
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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 preexisting condition, provided that all of the following criteria are 
met: 
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression 
of the disease 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not considered to be a 
serious adverse event, but should be reported as an adverse event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  Sites are not expected to review the PRO data for adverse 
events. However, if any PRO responses suggestive of a possible adverse event are identified 
during site review of the PRO data, the investigator will determine whether the criteria for an 
adverse event have been met and, if so, will report the event on the Adverse Event eCRF 
5.3.5.13 
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.  If the associated adverse event fulfills seriousness criteria, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 


 
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Section 5.4.2).  A report should be downloaded from EDC system and sent the report to Sponsor. 
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 reported to the Sponsor within 30 calendar 
days and recorded on the Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication error" 
boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication error" 
as the event term.  Check the "Medication error" box.  Enter a description of the error in 
the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require the completion 
of two Adverse Event eCRF pages, one to report the accidental overdose and one to report the 
headache.  The "Accidental overdose" and "Medication error" boxes would need to be checked 
on both eCRF pages. 
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) 


 
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 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
The investigator must report new significant follow-up information for these events to the Sponsor 
immediately (i.e., no more than 24 hours after becoming aware of the information).  New 
significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse events to the 
local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts   
Medical Monitor Contact Information for  All sites 
Medical Monitor{Roche Medical Responsible}: 
 (Primary) 
Telephone No.: 
 
 
Mobile Telephone No.
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will access 
the Roche Medical Emergency List, escalate emergency medical calls, provide medical 
translation service (if necessary), connect the investigator with a Roche Medical Responsible 
(listed above and/or on the Roche Medical Emergency List), and track all calls.  The Emergency 
Medical Call Center Help Desk will be available 24 hours per day, 7 days per week.  Toll-free 
numbers for the Help Desk, as well as Medical Monitor and Medical Responsible contact 
information, will be distributed to all 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 


 
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systemic anti-cancer therapy, whichever occurs first.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF on the electronic data capture (EDC) system, generate, and submit the 
report to Sponsor.   
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered in 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 6 momths after the final dose of study 
treatment.  A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study treatment and counsel the patient, discussing 
the risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported on the Adverse Event eCRF. A 
report should be downloaded from EDC system and sent the report to Sponsor. 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 final 
dose of study treatment.  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.  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 


 
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pregnancy becomes available.  An investigator who is contacted by the male patient or his 
pregnant partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
Any 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).  A report should be downloaded from EDC system and sent the report to Sponsor. 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  A therapeutic or elective abortion performed for 
reasons other than an underlying maternal or embryofetal toxicity is not considered an adverse 
event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial Pregnancy 
Reporting Form. 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 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). A report 
should be downloaded from EDC system and sent the report to Sponsor. 
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. 
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 


 
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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/adverse event of special 
interest that is believed to be related to prior exposure to study treatment, the event should be 
reported through use of the Adverse Event eCRF. A report should be downloaded from EDC 
system and sent the report to Sponsor.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by faxing or 
by scanning and emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES  
The Sponsor will promptly evaluate all serious adverse events and adverse events of special 
interest against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health authorities based 
on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
 
Atezolizumab Investigator's Brochure  
 
Bevacizumab Investigator's Brochure 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN. 
This is an open-label, single-arm study. A Simon’s Minimax two-stage design will be used 
(Simon. 1989). 
Parameters estimates and relevant summary statistics will be reported where appropriate. For 
continuous variables, summary statistics will include number of subjects, mean, median, standard 
deviation, minimum and maximum. Categorical endpoints will be summarized using number of 


 
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subjects, frequency, and percentages. Missing data will not be imputed. Data analysis will be 
performed in SAS 9.4. 
Analysis Populations 
This study will include the following analysis populations:  
 
Full Analysis Set (FAS) population: defined as all enrolled patients who receive any 
amount of study treatment and evaluable for efficacy endpoints. The efficacy analyses 
will be performed on the FAS population. 
 
Safety population: defined as all enrolled patients who receive any amount at least one 
dose of any study treatment. The safety analysis will be performed on the safety 
population. 
 
ITT population: defined as all enrolled patients regardless of whether they receive any 
assigned study drug. The ITT population will be used for other analyses (Demography, 
Baseline Characteristics, etc.). 
A per-protocol population will not be defined for this study. However, all major deviations (at study 
entry and on study) will be summarized and reported. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size estimation is based on having sufficient sample in the FAS population to show 
that the ORR is higher than 30%.  Simon’s minimax two-stage design will be used (Simon, 1989).  
The null hypothesis that the true ORR is at least 50% will be tested against a one-sided 
alternative.   
The sample size calculation was based on a Simon two-stage design, and the primary end point 
was ORR (H0 = 30%, H1 = 50%). Two-sided alpha is set to be 0.1 and statistical power is set to 
be 80%. 
19 fully evaluable patients will be included at the first stage.  If there are 6 for fewer responders 
(CR/PR) in these 19 patients, enrollment will be stopped.  Otherwise, additional 20 fully evaluable 
patients will be included in the second stage.  Finally, if we have more than 16 patients in 39 
patients have objective response, the endpoint is reached. Thus, considering a drop-out rate of 
10%, a total number of 22 patients (if stops at the first stage) or 44 patients (if runs into the 
second stage) will need to be finally enrolled in this study. 
Figure 2 presents an overview of the sample size allocation.   


 
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Figure 2 
Sample size allocation 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study drug administration, and discontinuation from the study will be summarized.  
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. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
List the variables that will be summarized to describe the study population and Demographic and 
baseline characteristics (including age, sex, medical history and prior treatment, etc.) will be 
summarized using means, standard deviations, medians, and ranges for continuous variables 
and proportions for categorical variables, as appropriate.  Summaries will be presented 
descriptively using the ITT population.  
6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all enrolled patients who receive 
any amount of study treatment and evaluable for efficacy endpoints.  ORR and DCR will be 
analyzed using all enrolled patients who have measureable disease at baseline.  DOR will be 
assessed in patients who have an objective response. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab on the 
basis of the following endpoint: 
 
ORR defined as the proportion of patients with a CR or PR on two consecutive occasions 
 4 weeks apart, as determined by the investigator according to RECIST v1.1.  Patients not 


 
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meeting these criteria, including patients without any post-baseline tumor assessment, will 
be excluded from the primary analysis. 
Number and percentage of responders with corresponding Clopper-Pearson 90% and 95% 
confidence intervals will be provided. 
The ORR will be the basis for decision whether the study would be continued when Stage 1 is 
completed.  Refer to section 6.1 Determination of sample size for details. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 
Duration of Response 
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time interval from the date of the first 
occurrence of a documented objective response until the first date of disease progression or 
death from any cause (whichever occurs first), as determined by the investigator according to 
RECIST v1.1.   
Patients who have not progressed and who have not died at the time of analysis will be censored 
at the time of last tumor assessment date.  If no tumor assessments were performed after the 
date of the first occurrence of a documented objective response, DOR will be censored at the 
date of the first occurrence of a documented objective response plus 1 day.  The KM approach 
will be used to estimate median DOR.  The Brookmeyer-Crowley methodology (Brookmeyer and 
Crowley 1982) will be used to construct the 95% CI for the median DOR.   
6.4.2.2 
Time to Response  
TTR, defined as the time from the start of the treatment to the first objective tumor response 
observed for patients who achieved CR or PR, as determined by the investigator according to 
RECIST v1.1.  
Patients who are alive and who have not experienced the response at the time of analysis will be 
censored at the date of data cutoff.        
The methodologies detailed for the DOR analysis will be used for the TTR analysis. 
6.4.2.3 
Disease Control Rate 
DCR, defined as the proportion of patients who have a best overall response of CR or 
PR or SD, as determined by the investigator according to RECIST v1.1. 
Number and percentage of patients with DCR with corresponding Clopper-Pearson 95% 
confidence intervals will be provided. 
6.4.2.4 
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), as determined by the investigator 
according to RECIST v1.1.  Patients who have not experienced disease progression or death at 
the time of analysis will be censored at the time of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored at the date of initiation of study treatment plus 1 
day. 


 
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The methodologies detailed for the DOR analysis will be used for the PFS analysis. 
6.4.2.5 
Overall Survival  
OS, defined as the time from initiation of study treatment to death from any cause.  Patients who 
are alive at the time of the analysis data cutoff will be censored at the last date they were known 
to be alive.  Patients with no post-baseline information will be censored at the date of initiation of 
study treatment plus 1 day.  Methods for OS analyses are similar to those described for the DOR 
endpoint. 
6.4.2.6 
Landmark Analysis on Progression-free Survival and Overall 
Survival 
PFS rate at 6 months and 1 year, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 6 months and 1 year separately, as determined 
by the investigator according to RECIST v1.1.  OS rate at 1 year and 2 years, defined as the 
proportion of patients who have not experienced death from any cause at 1 year and 2 years. 
The PFS rates at 6 months and 1 year after initiation of treatment will be estimated using Kaplan-
Meier methodology, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula.  
Similar analyses will be performed for the OS rates at 1 year and 2 years after initiation of 
treatment. 
6.4.2.7 
ORR, DCR, DOR, and PFS per Modified RECIST 
Analyses using modified RECIST criteria (see Appendix 5) for ORR, DCR, DOR, and PFS as 
determined by the investigator will be conducted. The methods outlined for the primary and 
secondary efficacy endpoint analyses will be used for these analyses. 
6.4.2.8 
Expression of PD-L1 defined by the SP142 and SP263 IHC 
Assay  
Expression of PD-L1 defined by the SP142 and SP263 IHC assay will be investigated. The 
proportions of the patients with PD-L1+ tested by SP142 and SP263 in all patients will be 
presented respectively, with their 95% Clopper-Pearson CI. The consistency between SP142 and 
SP263 IHC assay will be investigated using Chisq-square Test if applicable. 
6.4.2.9 
Patent-Reported Outcomes (PROs) 
TTD using EORTC is defined as the time from baseline to the first time the patient’s score shows 
a ≥10 points increase above baseline in any of the following EORTC-transformed symptom 
subscale scores (whichever occurs first): cough, dyspnea (single item), dyspnea (multi-item 
subscale), chest pain, or arm/shoulder pain, whichever occurs first. The linear transformation 
gives each individual symptom subscale a possible score of 0-100. In order for the symptoms to 
be considered “deteriorated”, acore increase of ≥ 10 points above baseline must be held for at 
least two consecutive assessment or an initial score increase of ≥ 10 points is followed by death 
within 3 weeks from the last assessment. A “≥10 point” change in the symptoms subscale score 
is perceived by patients as clinically significant (Osoba et al. 1998). Patients will be censored at 


 
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the last time when they complete an assessment if they have not deteriorated. If no post-baseline 
assessment is performed, patients will be censored at the randomization date plus 1 day. TTD 
using the EORTC scale will be analyzed using the same methods as for PFS. The analysis 
populations for TTD will be all randomized patients with a non-missing baseline PRO 
assessment. 
PROs of HRQoL, lung cancer related symptoms, and health status will be measured using the 
EORTC QLQ-C30 and EORTC QLQ-LC3. Summary statistics (mean, SD, median, 25th and 75th 
percentiles, minimum and maximum) and mean change from baseline of linear-transformed 
scores will be reported for all of the items and subscales of EORTC QLQ-C30 questionnaire and 
the QLQ-LC13 according to the EORTC scoring manual guidelines. Completion and compliance 
rates will be summarized at each timepoint by treatment arm. The analysis populations for PRO 
changes will be all randomized patients with a non-missing baseline assessment and at least one 
non-missing post-baseline assessment. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all enrolled patients who received at least one dose 
of study treatment.  
Safety will be assessed through summaries of exposure to study treatment, adverse events, 
changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number of cycles 
and dose modifications) will be summarized with descriptive statistics. 
All 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.  All adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, and adverse events leading to study treatment discontinuation that 
occur on or after the first dose of study treatment (i.e., treatment-emergent adverse events) will 
be summarized by mapped term, appropriate thesaurus level, and severity grade.  For events of 
varying severity, the highest grade will be used in the summaries.  Deaths and cause of death will 
be summarized. 
Relevant laboratory, vital sign (respiratory rate, pulse rate, systolic and diastolic blood pressure, 
and temperature), physical examination and ECG data will be displayed by time, with grades 
identified where appropriate.  Changes from baseline in vital signs and ECGs will be summarized. 
6.6 
INTERIM ANALYSES  
One interim analysis is planned. The interim analysis will be performed for futility at the time of 19 
patients completing ORR evaluation. According to preplanned stopping rules of Simon 2-stage 
design, further testing of Atezolizumab and Bevacizumab would be halted if the number of 
patients that respond in the first evaluable 19 patients (stage 1) is less or equal than 6. This study 
has probability of 66.6% terminate at the first stage. 


 
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When the study runs into the second stage, in the end of the study, if more than 16 patients out of 
39 patients have responses, we can recommend this treatment in IIIB-IV Non-squamous NSCLC 
to go to the next step in the clinical trial phase, otherwise, the treatment is rejected. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The CRO will produce a Data Quality Plan that describes the quality checking to be performed on 
the data.  Central laboratory data will be sent directly to the CRO, using the CRO's standard 
procedures to handle and process the electronic transfer of these 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.  
PRO data will be collected on paper questionnaires. The data from the questionnaires will be 
entered into the EDC system by site staff 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from the 
Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be reviewed and 
electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format that must be kept with the study records.  Acknowledgement of receipt of the data is 
required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical and 
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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. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research.  An acceptable computerized data 
collection system allows preservation of the original entry of data.  If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, electronic or paper PRO data, Informed Consent Forms, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at least 
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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 


 
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country in which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline (Clinical Safety 
Data Management:  Definitions and Standards for Expedited Reporting).  Studies conducted in 
the United States or under a U.S. Investigational New Drug (IND) Application will comply with 
U.S. FDA regulations and applicable local, state, and federal laws.  Studies conducted in the 
European Union or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent Forms 
such as a Child's Informed Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of the local 
language.  The Sponsor or its designee must review and approve any proposed deviations from 
the Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by the 
site (collectively, the "Consent Forms") before IRB/EC submission.  The final IRB/ECapproved 
Consent Forms must be provided to the Sponsor for health authority submission purposes 
according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any reason.  
A separate, specific signature will be required to document a patient's agreement to participate in 
optional procedures.  Patients who decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally authorized 
representative before his or her participation in the study.  The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate.  
The final revised IRB/EC-approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/EC 
policy) during their participation in the study.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent process and 
that written informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study. 


 
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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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC.  Investigators are also responsible for promptly informing 
the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements for reporting serious adverse events to the local health authority and 
IRB/EC.  Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor.  Investigators are responsible for ensuring that such reports 
are reviewed and processed in accordance with health authority requirements and the policies 
and procedures established by their IRB/EC, and archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient names are 
not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law. 
Medical information may be given to a patient's personal physician or other appropriate medical 
personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless required by 
law.  The aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication (see Section 9.5). 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 


 
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Study data may be submitted to government or other health research databases or shared with 
researchers, government agencies, companies, or other groups that are not participating in this 
study.  These data may be combined with or linked to other data and used for research purposes, 
to advance science and public health, or for analysis, 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. 
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 
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 F. Hoffmann-La Roche Ltd.  The Sponsor will 
provide clinical operations management, data management, and medical monitoring. 
Approximately 44 patients from China will be enrolled into this study.  


 
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Central facilities will be used for certain study assessments throughout the study (e.g., specified 
laboratory tests, biomarker analyses, and PK analyses), as specified in Section 4.5.6.  Accredited 
local laboratories will be used for routine monitoring; local laboratory ranges will be collected. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, at scientific congresses, in clinical trial 
registries of the U.S. National Institutes of Health and the European Medicines Agency, 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, and 
redacted clinical study reports and other summary reports will be provided upon request (see 
Section 8.4 for more details).  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 Clinical Study Report.  In 
addition, for all clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to publish results from 
analyses of additional endpoints and exploratory data that are clinically meaningful and 
statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation.  This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not yet be 
available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.  Any formal publication of the study in which 
contribution of Sponsor personnel exceeded that of conventional monitoring will be considered as 
a joint publication by the investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of 
data from this study will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise. 


 
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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 
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10. 
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Appendix 1 
 
Schedule of Activities 
I 
 
Screening 
Treatment a 
Treatment 
discontinuation 
Survival follow-up 
Days-28 to -1 
Every 21 days (±3 
Days) 
≤30 days after Final 
Dose or at initiation of 
other anti-cancer 
therapy (whichever 
occurs first) 
Every 3 months after 
disease progression 
or loss of clinical 
benefit 
Informed consent 
Xb 
 
 
 
Tumor tissue specimen for PD-L1 and EGFR 
testing  (5 FFPE slides required; blocks 
preferred) c 
Fresh or archival tissue can be used. 
X 
 
 
 
Demographic data 
X 
 
 
 
Medical history and baseline conditions 
X 
 
 
 
NSCLC Cancer History 
X 
 
 
 
Vital Signsd 
X 
X 
X 
 
Weight 
X 
X 
X 
 
Height 
X 
 
 
 
Complete physical examination 
X 
 
 
 
Limited physical examinatione 
 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
 
12-Lead ECG  
X 
X f 
X f 
 
LVEFg 
X 
 
 
 
Hematologyh 
X 
X 
X 
 


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Chemistryi 
X 
X 
X 
 
Pregnancy testj 
X j 
X k 
X k 
 
Coagulation test (aPTT or INR) 
X 
 
X 
 
TSH, free T3, free T4 
X 
X l 
X l 
 
Viral serology (HIV, HBV, HCV) m 
X 
 
 
 
Urinalysis n 
X 
X 
X 
 
Blood sample for biomarkers o 
X 
 
 
Tumor response assessments 
X p 
X q,r 
 
X s 
Concomitant medications t 
X 
X 
X 
 
Adverse events u 
X 
X 
X 
X 
Study drugs infusion v 
 
X 
 
 
Patient-reported outcomes 
 
X w 
 
X x 
Survival and anti-cancer therapy follow-up 
 
 
X y 
X y 
 
a. Assessments should be performed before study drug infusion unless otherwise noted. 
b. Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
c. Optional biopsy at screening is the preferred method to collected the tumor specimens for PD-L1 expression at screening and T790M mutation 
For PD-L1 testing, if archival tissue is unavailable or is determined to be unsuitable for required testing, a pretreatment tumor biopsy is required.  A 
pretreatment tumor biopsy may also be performed if a patient's archival tissue test results do not meet eligibility criteria.(section 4.5.6)  
d. Includes 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.   


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e. Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
f. ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  Patients should be resting in a supine position 
for at least 10 minutes prior to ECG recording. 
g. Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for all patients, especially in those with cardiac risk factors 
and/or history of coronary artery disease or where low LVEF is suspected. 
h. Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils, and other cells), and platelet count. 
i. Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, 
glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. 
j. All women of childbearing potential will have a serum pregnancy test within 14 days before Cycle 1, Day 1. 
k. Urine pregnancy tests performed at each subsequent visits; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
l. TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter 
m. At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total 
HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection. The patient could be enrolled if 
the HBV DNA is negative (below the lower detection limit of each site). If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
n. Includes pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted. 
o. If T790m mutation unknown and re-biopsy tissue sample unavailable，blood sample will be tested for T790M.  


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p. CT scans (with oral/IV contrast unless contraindicated) or MRI of the chest and abdomen.  A CT or MRI scan of the pelvis is required at 
screening and as clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with contrast) or MRI scan of the 
head must be done at screening to evaluate CNS metastasis in all patients. For patient with unknown bone metastases, if ALP ＞2.5xULN and ≤5x 
ULN and/or have symptom of suspect bone metastases，bone scan should be done at screening.  
q. Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 weeks following Cycle 1, Day 1, regardless of 
dose delays.  After 36 weeks, tumor assessment will be required every 9 weeks (±7days).  Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab treated patients who continue treatment after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.   
r. All measurable and evaluable lesions should be re-assessed at each subsequent tumor evaluation. The same radiographic procedures used to 
assess disease sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). 
s. If a patient discontinues study treatment for any reason other than disease progression, tumor assessments will continue at the same frequency 
as would have been followed if the patient had remained on study treatment untilradiographic disease progression per RECIST v1.1 or loss of 
clinical benefit (for atezolizumab treated patients who continue treatment after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first., even if patient starts another anti-cancer therapy after study 
treatment discontinuation, unless consent is withdrawn. 
t. 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 before screening until the treatment discontinuation visit. 
u. 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. After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special 
interest, regardless of relationship to study treatment, will be reported until 90 days after the last dose of study treatment or initiation of new non-
protocol systemic anti-cancer therapy after the last dose of study treatment, whichever occurs first. After this period, all deaths, regardless of cause, 
should be reported.  In addition, the investigator should report any serious adverse event or adverse events of special interest that is believed to be 
related to prior exposure to study treatment. 


Appendix 1:Schedule of Activities 
  
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v. The initial infusion of atezolizumab will be delivered over 60 (± 15) minutes.  Subsequent infusions will be delivered over 30 (± 10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 (± 15) minutes if the patient experienced an infusion-associated 
adverse event with the previous infusion. 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. The investigator should follow each AE 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 SAEs considered to be related to study drug or study-related procedures until a final outcome can be reported.w. PRO 
assessments will be completed before the patient receives any information on disease status and prior to the performance of non-PRO 
assessments and the administration of study treatment.  Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site.  
x. During survival follow-up, the PRO questionnaires will be completed at 3 and 6 months following disease progression or loss of clinical benefit as 
determined by the investigator(for patients who continue atezolizumab after radiographic disease progression). 
y. After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (unless the patient withdraws 
consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source 
documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public information source (e.g., county 
records) to obtain information about survival status


 
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Appendix 2 
 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)  
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications from the original 
publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below.  All measurable and non-measurable lesions should be assessed at screening 
and at subsequent protocol-specified tumor assessment timepoints.  Additional assessments may 
be performed as clinically indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be  15 mm in the 
short axis when assessed by CT scan (CT scan slice thickness recommended to be  5 mm).  
At baseline and follow-up, only the short axis will be measured and followed.  Additional 
information on lymph node measurement is provided below (see "Identification of Target and 
Non-Target Lesions" and "Calculation of Sum of Diameters"). 
Definition of Non-Measurable Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
                                            
 
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. 


  
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SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and  10 mm in 
diameter as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, 


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


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


  
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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, 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 


  
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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 tumor 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 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-target lesions 
are provided below.  While some non-target lesions may actually be measurable, they need not 
be measured and instead should be assessed only qualitatively at the timepoints specified in the 
schedule of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor 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 tumor burden has increased sufficiently to merit discontinuation of therapy.  A 
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 


  
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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. 
Patients with Non-Measurable Disease Only  
For patients with non-measurable disease only, the same general concepts apply as noted 
above.  However, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in non-
measurable disease cannot be easily quantified (by definition, if all lesions are truly non-
measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion).  
Examples include an increase in a pleural effusion from "trace" to "large" or an increase in 
lymphangitic disease from localized to widespread  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some "new" 
bone lesions may be simply healing or flare of preexisting lesions).  This is particularly important 
when the patient's baseline lesions show 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 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 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 


  
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When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.  
Table 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. 
 
Table 2 
Criteria for Overall Response at a Single Timepoint:  Patients with Non-Target 
Lesions Only  
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a "Non-CR/non-PD" is preferred over "stable disease" for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning "stable disease" 
when no lesions can be measured is not advised. 
 
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 


  
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timepoint response.  This would be most likely to happen in the case of PD.  For example, if a 
patient had a baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, 
regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration."  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy.  The objective response status of such 
patients is to be determined by evaluation of target and non-target lesions as shown in Table 
1and Table 2 
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.   
 


 
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Appendix 3 
 
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST)  
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents, which can produce delayed responses that may be preceded by initial 
apparent radiographic progression, including the appearance of new lesions.  Therefore, 
immunotherapy-specific response criteria adaptations to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1; Eisenhauer et al. 2009) have been developed to allow for 
unconventional response and progression patterns.  These include modified RECIST v1.1 for 
immune-based therapeutics (iRECIST; Seymour et al. 2017), which was developed by the 
RECIST working group in an effort to create a common set of criteria that the cancer 
immunotherapy field could apply to clinical trials. 
Response evaluation through use of iRECIST requires collection of tumor assessment data after 
radiographic progression per RECIST v1.1.  Details regarding lesion evaluation are described 
below.  When not otherwise specified, RECIST v1.1 conventions will apply. 
Criteria for determining overall response at a single timepoint per iRECIST are also summarized 
below.  Of note, overall response per iRECIST will not be captured in the electronic Case Report 
Form (eCRF), but will instead be calculated programmatically by the Sponsor on the basis of 
investigator-assessed individual lesion data recorded in the eCRF.   
iRECIST response status is not a specific component of treatment discontinuation criteria, 
including decisions about whether to continue treatment beyond progression per RECIST v1.1.  
Investigators should instead take into account radiologic data and clinical status in making such 
decisions, as described in Section 3.1. 
EVALUATION OF LESIONS TO SUPPORT iRECIST RESPONSE ASSESSMENT AFTER 
DISEASE PROGRESSION PER RECIST V1.1  
iRECIST is an extension of RECIST v1.1 that allows for response assessment following disease 
progression per RECIST v1.1.  RECIST v1.1 rules for categorizing lesions as measurable or non-
measurable and measuring lesions (see Appendix 2) also apply to iRECIST.  After disease 
progression per RECIST v1.1, the same target and non-target lesions selected at baseline will 
continue to be followed, along with any new lesions that develop, to support iRECIST response 
evaluations, as described below and summarized in Table 1.  Once a lesion has been 
categorized as a target, non-target, or new lesion, it will remain classified as such. 
TARGET LESIONS 
The target lesions selected at baseline should continue to be measured at all tumor assessment 
timepoints after disease progression per RECIST v1.1, according to RECIST v1.1 conventions. 
NON-TARGET LESIONS 
Non-target lesions selected at baseline should continue to be followed at all tumor assessment 
timepoints after disease progression per RECIST v1.1.  At each timepoint, non-target lesions 


  
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should continue to be categorized as "absent" (complete response [CR]), "unequivocal 
progression" relative to baseline (progressive disease [PD]), or "present without unequivocal 
progression" (non-CR/non-PD), as defined by RECIST v1.1.  In addition, any non-target lesions 
that were categorized as PD at the previous timepoint should be evaluated to determine whether 
there has been any further increase in size.   
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of the same 
criteria applied to prospective target lesions at baseline per RECIST v1.1 (e.g., nonlymph node 
lesions must be  10 mm on the longest diameter; new lymph nodes must be  15 mm on the 
short axis [see note below]).  All new lesions (measurable or non-measurable) must be assessed 
and recorded at the time of identification and at all subsequent tumor assessment timepoints. 
Up to a maximum of five measurable new lesions total (with a maximum of two lesions per organ) 
should be selected and measured at each timepoint.  New lesions that are not measurable at first 
appearance but meet measurability criteria at a subsequent timepoint should be measured from 
that point on, if the maximum number of measurable new lesions has not been reached.  
However, for calculation of the sum of diameters for new lesions, iRECIST excludes 
measurements from new lesions that were not measurable at first appearance. 
All non-measurable new lesions (including those that subsequently become measurable) and 
additional measurable new lesions (in excess of five total or two per organ) should be assessed 
to determine whether there is any increase in size relative to the previous assessment timepoint. 
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph node 
lesion is  15 mm, it will be considered a measurable new lesion.  If at first appearance the short 
axis of a lymph node lesion is  10 mm and  15 mm, the lymph node will not be considered 
measurable but will still be considered a new lesion and should be identified as a non-measurable 
new lesion.  If at first appearance the short axis of a lymph node is  10 mm, the lymph node 
should not be considered pathological and should not be considered a new lesion.  A lymph node 
can subsequently become measurable, when the short axis is  15 mm.  Measurable new lymph 
node lesions should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to  15 mm (or even  10 mm). 


  
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Table 1 
Guidelines for Evaluation of Lesions to Support iRECIST Response 
Assessment after Disease Progression per RECIST v1.1 
Lesion Type 
Evaluation of Lesions to Support iRECIST Response Assessment 
after Disease Progression per RECIST v1.1 
Target lesions 
 Measurements should be continued according to RECIST v1.1 
conventions. 
Non-target lesions 
 Non-target lesions should continue to be categorized as absent 
(CR), unequivocal progression (PD), or present without 
unequivocal progression (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were 
categorized as PD at the previous timepoint should be 
evaluated to determine whether there has been any further 
increase in size. 
New lesions 
 New lesions should be evaluated for measurability per 
RECIST v1.1. 
 All new lesions (measurable or non-measurable) must be 
assessed and recorded at the time of identification and at all 
subsequent tumor assessment timepoints. 
 Up to a maximum of five measurable new lesions total (with a 
maximum of two lesions per organ) should be selected and 
measured at each timepoint. 
 All non-measurable new lesions (including those that 
subsequently become measurable) and additional measurable 
new lesions (in excess of five total or two per organ) should be 
assessed to determine whether there is any increase in size 
relative to the previous assessment timepoint. 
CR  complete response; PD  progressive disease; RECIST v1.1  Response Evaluation 
Criteria in Solid Tumors, Version 1. 
 
SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  A 
complete description of the iRECIST criteria can be found in a publication by Seymour et al. 
(2017). 
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.   
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:741220. 
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 
2017;18:e14352. 


 
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Appendix 4 
 
European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire:  EORTC QLQ- LC 13 
 


 
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Appendix 5 
 
European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire:  EORTC QLQ-C30 
 


  
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Appendix 6 
 
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease.  Patients with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study.  
Possible exceptions to this exclusion could be patients with a medical history of such entities as 
atopic disease or childhood arthralgias 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 while receiving another immunostimulatory anti-cancer agent. Contact the 
Medical Monitor regarding any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease  
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular autoimmune 
syndrome 
 Primary biliary cirrhosis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Wegener granulomatosis 


 
  
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Appendix 7 
 
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 as required by patient status and 
directed by the physician in charge. 
6. 
Continue to observe the patient and document observations 
 


 
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Appendix 8 
Risks Associated with Atezolizumab and Guidelines for Management of Adverse Events 
Associated with Atezolizumab and bevacizumab. 
 
Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and 
hypersensitivity reactions 
 Guidelines for management of IRRs for atezolizumab are 
provided in Appendix 9. 
 Guidelines for management of IRRs for bevacizumab are 
provided below. 
 For anaphylaxis precautions, see Appendix 7. 
 For hypersensitivity reactions and allergic reactions, permanently 
discontinue the causative agent. 
IRR to bevacizumab, Grade 1   Systemic intervention is not indicated.  Continue bevacizumab. 
IRR to bevacizumab, Grade 2   Reduce infusion rate to 50% or interrupt infusion at the 
discretion of the investigator per medical judgment.  
 If the infusion is interrupted, it may be resumed at 50% of the 
rate prior to the reaction after the patient's symptoms have 
adequately resolved and increased in 50% increments up to the 
full rate if well tolerated.  Infusions may be restarted at the full rate 
during the next cycle. 
IRR to bevacizumab, Grade 3 
or 4 
 Stop infusion and permanently discontinue bevacizumab.  
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 
IRR  infusion-related reaction. 
 


 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Gastrointestinal toxicity 
GI perforation, any 
grade 
 Withhold atezolizumab. 
 Permanently discontinue bevacizumab.  
 Initiate treatment per institutional guidelines. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
Bowel obstruction, 
Grade 2 
 Atezolizumab may be continued at the discretion of the investigator. 
 Withhold bevacizumab for partial obstruction requiring medical 
intervention. 
 Bevacizumab may be restarted upon complete resolution of event. 
Bowel obstruction, 
Grade 3 or 4 
 Atezolizumab may be continued at the discretion of the investigator.  
 Withhold bevacizumab until complete resolution. 
 If surgery is necessary, patient may restart bevacizumab after full 
recovery from surgery and at the investigator's discretion. 
Posterior reversible encephalopathy syndrome 
Posterior reversible 
encephalopathy syndrome, 
any grade confirmed by 
magnetic resonance 
imaging 
 Withhold atezolizumab.  Permanently discontinue bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
GI  gastrointestinal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit and the Medical Monitor is in agreement. 
 


 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab (cont.) 
 
Hypertension a 
General guidance  
 Treat with antihypertensive medication as needed.  
Hypertension, Grade 1 
 Continue atezolizumab and bevacizumab. 
 Consider inceased BP monitoring. 
Hypertension,  
Grade 2  
 Continue atezolizumab.  
 If asymptomatic, begin or modify baseline anti-hypertensive therapy 
and continue bevacizumab.  
 If symptomatic, start or adjust anti-hypertensive therapy. 
Hypertension, Grade 3 
 Continue atezolizumab.  
 Modify existing anti-hypertensive therapy (more than one drug or 
more intensive therapy than previously indicated). 
 Withold bevacizumab until symptoms resolve AND BP 
 160/90 mmHg 
Hypertension, Grade 4 
 Atezolizumab may be continued at the discretion of the investigator.  
 Permanently discontinue bevacizumab.  
Hemorrhage 
Hemorrhage, Grade 3 or 4 
(excluding cerebral 
hemorrhage) 
 Continue atezolizumab.   
 Permanently discontinue bevacizumab.  
CNS hemorrhage, any 
grade 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Grade 2 hemoptysis 
(2.5 mL 
of bright red blood per 
episode) 
 Continue atezolizumab.   
 Permanently discontinue bevacizumab. 
Bleeding in patients on full-
dose anticoagulant therapy  
 Continue atezolizumab.   
 Permanently discontinue bevacizumab. 
BP  blood pressure. 
a Vascular disorders (including hypertension and hypotension) are possible adverse events of 
atezolizumab, considering the mechanism of action. 
 


 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Thromboembolic events 
Venous thromboembolic event, 
Grade 3 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Withhold bevacizumab treatment.  If the planned duration of 
full-dose anticoagulation is  2 weeks, bevacizumab should be 
withheld until the full-dose anticoagulation period is over.  The 
use of direct oral anticoagulants is not recommended. 
 If the planned duration of full-dose anticoagulation is  2 
weeks, bevacizumab may be resumed during full-dose 
anticoagulation IF all of the criteria below are met: 
– 
The patient must not have pathological conditions that 
carry high risk of bleeding (e.g., tumor involving major 
vessels or other conditions). 
– 
The patient must not have had hemorrhagic 
events   Grade 2 while on study. 
– 
The patient must be on stable dose of heparin, 
low-molecular-weight heparin, or have an in-range INR 
(usually 23) on a stable dose of warfarin prior to restarting 
bevacizumab. 
 If thromboemboli worsen/recur upon resumption of study 
therapy, discontinue bevacizumab.  
Venous thromboembolic event, 
Grade 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab. 
Arterial thromboembolic event, 
any grade 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Permanently discontinue bevacizumab.  
 


 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Proteinuria 
Proteinuria, Grade 1 
(1 by dipstick; urinary 
protein  1.0 g/24 hours) 
 Continue atezolizumab and bevacizumab. 
Proteinuria, Grade 2 (2 and 3  
by dipstick; urinary 
protein 1.03.4 g/24 hours) 
 Continue atezolizumab. 
 For 2 dipstick:  Continue bevacizumab and collect 24-hour 
urine protein prior to subsequent bevacizumab administration. 
 For 3 dipstick:  Obtain 24-hour urine prior to administering 
bevacizumab. 
 Withhold bevacizumab for urinary protein  2 g/24 hours. 
 If bevacizumab is withheld and urine protein improves to 
 2 g/24 hours  42 days after event onset, resume 
bevacizumab.  If not, permanently discontinue bevacizumab.  
Proteinuria, Grade 3 (4  by 
dipstick; urinary protein 
 3.5 g/24 hours) with no 
diagnosis of nephrotic 
syndrome 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Withhold bevacizumab. 
 If urine protein improves to  2 g/24 hours  42 days after event 
onset, resume bevacizumab.  If not, permanently discontinue 
bevacizumab.  
Nephrotic syndrome, Grade 3 
or 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Fistula 
Tracheoesophageal 
fistula, any grade 
 Withhold atezolizumab.   
 Permanently discontinue bevacizumab.  
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
Fistula (non-
tracheoesophageal), 
Grade 4 
 Withhold atezolizumab.   
 Permanently discontinue bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit and the Medical Monitor is in agreement. 
 


 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific Adverse 
Events with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Wound dehiscence 
Wound dehiscence, any grade 
requiring medical or surgical 
therapy 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Congestive heart failure 
Congestive heart failure, Grade 3 
or 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Bevacizumab-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab and bevacizumab. 
Grade 3 
 Continue atezolizumab.  Withhold bevacizumab. 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently discontinue 
bevacizumab. a 
Grade 4 
 Withhold atezolizumab and bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently discontinue 
bevacizumab. a 
Atezolizumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 9. 
 Continue bevacizumab. 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 9. 
 Withhold bevacizumab. 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently discontinue 
bevacizumab. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit and the Medical Monitor is in agreement. 
 


 
  
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Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of Adverse Events 
Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-related adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications.  Discontinuation of atezolizumab may not have an immediate 
therapeutic effect, and in severe cases, immune-related toxicities may require acute management 
with topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents.  
The investigator should consider the benefitrisk balance a given patient may be experiencing 
prior to further administration of atezolizumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered if the patient is 
deriving benefit and has fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor.  
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such 
as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension.  Management guidelines for 
pulmonary events are provided in Tbale 1. 


 
  
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Table 1 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
 Initiate treatment with 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, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with 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 agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor.  
 


 
  
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HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.  
Management guidelines for hepatic events are provided in Tbale 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of the 
next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits or to 
baseline values.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
LFT  liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.  


 
  
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Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
LFT  liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.  
 
GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Tbale 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies.  
For events of significant duration or magnitude or associated with signs of systemic inflammation 
or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia):  
Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five 
specimens for standard paraffin block to check for inflammation and lymphocytic infiltrates to 
confirm colitis diagnosis.  


 
  
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 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 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 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event 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 
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 agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  


 
  
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
(cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact 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 agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine events 
are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present.  
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, 
and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from primary adrenal 
insufficiency. 


 
  
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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-related hyperthyroidism. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.  
 
 


 
  
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with 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 
Hyperglycemia, 
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. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.  


 
  
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact 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; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.  
 


 
  
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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  Management 
guidelines for ocular events are provided in Tbale 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with 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 agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  
 


 
  
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IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a 
patient who reports a recent history of gastrointestinal illness), ischemic events, underlying 
arrhythmias, exacerbation of preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  An endomyocardial biopsy may be 
considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Tbale 6. 
Table 6 Management Guidelines for Immune-Related Myocarditis 


 
  
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Event 
Management 
Immune-related 
myocarditis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Consider treatment with 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 
Immune-related 
myocarditis, Grade 3-4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Initiate treatment with 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. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 
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, anti-
pyretics, 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. 


 
  
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IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7. 


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


 
  
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or venturi 
mask 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; 
monitoring in 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. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 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. 
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. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  For patients who are refractory 
to anti-cytokine therapy, experimental treatments f may be 
considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
 Hospitalize patient until complete resolution of symptoms. 
 


 
  
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level 
positive airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive 
airway pressure; CRS  cytokine-release syndrome; CTCAE  Common Terminology 
Criteria for Adverse Events; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome; NCCN  National Cancer Comprehensive 
Network; NCI  National Cancer Institute. 
Note:  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 (version as specified in the protocol) 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, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as 
oxygen delivered at  6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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.  For subsequent infusions, administer 
oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the 
infusion time may also be considered after consulting the Medical Monitor and 
considering the benefitrisk ratio. 
f Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 


 
  
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PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 8. 
Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider 
treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  


 
  
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Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis (cont.)
  
Event 
Management 
Immune-related pancreatitis, 
Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to GI specialist. 
 Initiate treatment with 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  
Immune-related 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 agreed upon by 
the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  
 
DERMATOLOGIC EVENTS 


 
  
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Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self limited, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab. A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 


 
  
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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. 
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), and, if indicated, biopsy. 
• 
Follow the applicable treatment and management guidelines above. 
• 
Permanently discontinue atezolizumab for confirmed Stevens-Johnson 
syndrome or toxic epidermal necrolysis. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  
 
NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to differentiate 


 
  
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between alternative etiologies.  Management guidelines for neurologic disorders are provided in  
Table 10. 
Table 10 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
Immune-related 
neuropathy, 
Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology. 
 Initiate treatment as per institutional guidelines. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Immune-related 
neuropathy, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c  
 Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of 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 agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.  
 
IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.   


 
  
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All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Tbale 11. 
Table 11 
Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact Medical Monitor. a 
 Refer patient to neurologist. 
 Initiate treatment with 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. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 
RENAL EVENTS 
Immune-related nephritis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, 
should be monitored throughout study treatment.  Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 12. 
Table 12 
Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.  


 
  
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Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor.  
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.  
 
IMMUNE-MEDIATED MYOSITIS 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
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 signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Tbale 13. 
Table 13 
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. 


 
  
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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 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-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.  


 
  
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Table 13 
Management Guidelines for Immune-Mediated Myositis (cont.) 
 
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. 
 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. 
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. 


 
  
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147/Protocol ML41256 Version 3 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-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.  
 
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).   
Patients with suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2014).  A patient should be classified as having HLH if five of the following eight criteria 
are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (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  109/L (181,000/L) 
– 
AST  48 U/L 


 
  
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– 
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 14. 
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent. 
 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. 
 
REFERENCES 
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. 
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. 
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. 
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 Apr;25(4):625-638. 
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. 


  
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Appendix 10  
Overall Guidelines for Management of Patients Who Experience Adverse Events  
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study. Risks associated with 
atezolizumab and guidelines for management of adverse events associated with atezolizumab 
are summarized in Appendix 9. 
The bevacizumab dose will be based on the patient’s weight at randomization and will remain 
the same throughout the study, unless there is a weight change of ≥ 10% from baseline. It is not 
necessary to correct dosing on the basis of ideal weight, unless warranted per institutional 
guidelines/standard. Management of bevacizumab may be performed according to the label. 
Risks associated with bevacizumab and guidelines for management of adverse events 
associated with bevacizumab are summarized in Appendix 8. If adverse events occur that 
necessitate holding bevacizumab, the weight-based dose in mg/kg will remain unchanged after 
treatment resumes. 
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 ≤10 mg/day oral prednisone or equivalent 
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 if the Medical 
Monitor agrees that the patient is likely to derive clinical benefit. Atezolizumab 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. 
Temporary suspension of bevacizumab must occur if a patient experiences a serious adverse 
event or a Grade 3 or 4 adverse event assessed by the investigator as related to bevacizumab. If 
the event resolves to Grade ≤ 1, bevacizumab may be restarted at the same dose level. Patients 
who develop Grade 4 toxicities related to bevacizumab for > 21 days should permanently 
discontinue bevacizumab. 
Atezolizumab or 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 either study drug is withheld or 
discontinued, the other study drug can be continued as long as the patient is experiencing clinical 
benefit, as determined by the investigator per medical judgment. 


  
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Appendix 11 
Instructions for Preparation, Administration, and Disposal of Bevacizumab 
INSTRUCTIONS FOR PREPARATION AND DISPOSAL  
Bevacizumab should be prepared by a healthcare professional using aseptic technique. Withdraw 
the necessary amount of bevacizumab and dilute in a total volume of 100 mL of 0.9% sodium 
chloride injection, United States Pharmacopeia (USP). Bevacizumab infusions should not be 
administered or mixed with dextrose or glucose solutions. In case of administering a total 
dose exceeding 1000 mg, dilute the calculated dose of bevacizumab with a sufficient amount of 
0.9% sodium chloride injection to keep final concentration between 1.4 mg/mL and 16.5 mg/mL. 
Keep 100 mL as the minimal volume to administer and limit the infusion volume as much as 
possible. Discard any unused portion left in a vial, as the product contains no preservatives. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Diluted bevacizumab should be used within 8 hours.  
ADMINISTRATION  
Administration will be as a continuous IV infusion. Anaphylaxis precautions should be observed 
during bevacizumab administration.  
The first dose of bevacizumab should be administered over 90 ± 10 minutes. If the first infusion is 
well tolerated without infusion-associated adverse events (fever or chills), the second infusion 
may be delivered over 60 ± 10 minutes. If the 60-minute infusion is tolerated all subsequent 
infusions may be delivered over 30 ± 10 minutes.  
Although no data are available specifically on bevacizumab, in general, patients experiencing 
mild to moderate hypersensitivity/infusion reactions (Grade 1 or 2 of the NCI CTCAE Infusion-
Related Reactions), in particular after the first exposure, may tolerate re-administration of the 
agent at reduced infusion rates and with treatment using antihistamines and corticosteroids after 
complete resolution of symptoms. Re-challenge is generally discouraged in patients who 
experienced a severe initial reaction (Grade 3 or 4).  
A rate-regulating device should be used for all bevacizumab infusions. When the bevacizumab IV 
bag is empty, 50 mL of 0.9% sodium chloride solution, USP, will be added to the IV bag or an 
additional bag will be hung, and the infusion will be continued for a volume equal to that of the 
tubing to ensure complete delivery of the trial drug. The total infusion time, therefore, should 
always be either 90, 60, or 30 minutes. If more saline is infused, the extent of saline infusion does 
not factor into the trial drug infusion time.  
Should extravasation of bevacizumab infusion occur, the following steps should be taken:  
Discontinue the infusion. Treat the extravasation according to institutional guidelines for 
extravasation of a non-caustic agent. If a significant volume of bevacizumab remains, restart the 
infusion at a more proximal site in the same limb or on the other side. Treat the infiltration 
according to institutional guidelines for infiltration of a non-caustic agent.  
In the event of a suspected anaphylactic reaction during bevacizumab infusion:  
6. Stop the trial drug infusion.  
7. Apply a tourniquet proximal to the injection site to slow systemic absorption of bevacizumab. 
Do not obstruct arterial flow in the limb.  
8. Maintain an adequate airway.  
9. Administer antihistamines, corticosteroids, epinephrine, or other medications as required.  
10. Continue to observe the patient, document observations and administer further treatment as 
required.  
11. Permanently discontinue bevacizumab.  
The above events should be reported as adverse events. 
 

SAP_001.pdf: 
Official Title: A Single Arm, Phase II Study of Atezolizumab (MPDL3280A, Anti-PD-
L1 Antibody) in Combination With Bevacizumab in Patients With 
EGFR Mutation Positive Stage IIIB-IV Non-Squamous Non-Small 
Cell Lung Cancer Pretreated With Epidermal Growth Factor 
Receptor Tyrosine-Kinase Inhibitors 
NCT Number: NCT04426825 
Document Dates: SAP Version 1: 19-August-2021 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab (RO5541267), Bevacizumab（RO4876646）—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan ML41256 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A SINGLE ARM, PHASE II STUDY OF ATEZOLIZUMAB 
(MPDL3280A, ANTI-PD-L1 ANTIBODY) IN COMBINATION 
WITH BEVACIZUMAB IN PATIENTS WITH EGFR 
MUTATION POSITIVE STAGE IIIB-IV NON-SQUAMOUS 
NON-SMALL CELL LUNG CANCER PRETREATED WITH 
EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE-
KINASE INHIBITORS 
PROTOCOL NUMBER: 
ML41256 
STUDY DRUG: 
Atezolizumab (RO5541267) 
Bevacizumab（RO4876646） 
VERSION NUMBER: 
Final 1.0 
IND NUMBER: 
Not Applicable 
EUDRACT NUMBER: 
Not Applicable 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
Clinchoice Medical (
) Co, LTD. 
DATE FINAL: 
2021-08-19 
DATE(S) AMENDED: 
 


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STATISTICAL ANALYSIS PLAN AMENDMENT 
 
 


 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT .................................................. 2 
1. 
BACKGROUND ............................................................................................. 7 
2. 
STUDY DESIGN ............................................................................................ 8 
2.1 
Protocol Synopsis ....................................................................... 8 
2.2 
Outcome Measures ..................................................................... 8 
2.2.1 
Primary Efficacy Outcome Measures ........................................... 8 
2.2.2 
Secondary Efficacy Outcome Measures ........................................ 8 
2.2.3 
Exploratory Efficacy Outcome Measures ...................................... 8 
2.2.4 
Safety Outcome Measures ........................................................... 9 
2.2.5 
Health Status Utility Measures .................................................... 9 
2.3 
Determination of Sample Size ..................................................... 9 
3. 
STATISTICAL METHODS ........................................................................... 10 
3.1 
General Rule............................................................................ 10 
3.2 
Definitions And Conventions For Data Handling ......................... 10 
3.2.1 
Baseline Definitions ................................................................. 10 
3.2.2 
Study Day ............................................................................... 10 
3.2.3 
Last Known Alive Date ............................................................ 10 
3.2.4 
Visit Windows ......................................................................... 11 
3.2.5 
Pooling Center ......................................................................... 11 
3.3 
Analysis Populations ................................................................ 11 
3.3.1 
Full Analysis Set ...................................................................... 11 
3.3.2 
Safety Analysis Set .................................................................. 11 
3.3.3 
ITT Population......................................................................... 11 
3.3.4 
Evaluable Population ................................................................ 11 
3.4 
Analysis of Study Conduct ........................................................ 11 
3.5 
Analysis of Subject and Treatment Information ........................... 12 
3.5.1 
Demographics and Baseline Characteristics ................................ 12 
3.5.2 
Medical History ....................................................................... 13 
3.5.3 
Prior and Concomitant Medication ............................................. 13 
3.5.4 
Prior/On-Study/Post-Study Treatment ........................................ 13 


 
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3.5.4.1 Prior NSCLC Treatment ........................................................... 13 
3.5.4.2 On-Study Treatment ................................................................. 13 
3.5.4.3 Post-Study Treatment ............................................................... 13 
3.5.5 
Treatment Compliance .............................................................. 14 
3.6 
Efficacy Analysis ..................................................................... 14 
3.6.1 
Primary Efficacy Endpoint ........................................................ 14 
3.6.2 
Secondary Efficacy Endpoints ................................................... 15 
3.6.2.1 Duration of Response (DOR) .................................................... 15 
3.6.2.2 Time to Response (TTR)........................................................... 17 
3.6.2.3 Disease Control Rate (DCR) ..................................................... 18 
3.6.2.4 Overall Survival (OS) ............................................................... 18 
3.6.2.5 Progression-free Survival (PFS)................................................. 18 
3.6.2.6 PFS rate at 6 and 12 months ...................................................... 20 
3.6.2.7 OS rate at 12 and 24 months ...................................................... 20 
3.6.2.8 Expression of PD-L1 defined by the SP142 and 
SP263 assay. ........................................................................................ 20 
3.6.2.9 Sum of target lesion diameters (SLD) ......................................... 20 
3.6.3 
Exploratory Efficacy Endpoints ................................................. 20 
3.7 
Safety Analyses ....................................................................... 22 
3.7.1 
Exposure of Study Medication ................................................... 23 
3.7.2 
Adverse Events ........................................................................ 23 
3.7.3 
Laboratory Data ....................................................................... 24 
3.7.4 
Vital Signs .............................................................................. 25 
3.7.5 
Physical Examination Finding ................................................... 25 
3.7.6 
ECG Results ............................................................................ 25 
3.7.7 
ECOG performance status ......................................................... 25 
3.8 
Health Status Utility analyses .................................................... 25 
3.9 
Missing Data ........................................................................... 28 
3.9.1 
Date of Initial Diagnosis ........................................................... 28 
3.9.2 
Prior and Concomitant Medications ........................................... 28 
3.9.3 
Adverse Events ........................................................................ 28 
3.9.4 
Last Known Alive Date ............................................................ 29 
3.9.5 
Date of Death .......................................................................... 29 


 
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3.9.6 
Date of Subsequent Anti-tumor Therapy ..................................... 29 
3.10 
Interim Analyses ...................................................................... 30 
4. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES ................................................................................................. 31 
5. 
REFERENCES ............................................................................................. 32 
 
 
LIST OF TABLES 
Table 1 CR and PR confirmation rule for Best Overall Response ....................................14 
Table 2 Censoring Rules for DOR Analysis ......................................................................16 
Table 5 Summary of relevant parameters of QLQ-C30 scoring ........................................26 
Table 6 Summary of relevant parameters of QLQ-LC13 scoring .....................................27 
 
LIST OF FIGURES 
Figure 1 Sample size allocation ...........................................................................................9 
Figure 2 Study Schema ......................................................................................................34 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ......................................................................... 34 
Appendix 2 
 Schedule of Assessments ............................................................... 36 
Appendix 3 
 Preexisting Autoimmune Disease and Immune Deficiencies.............. 39 


 
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Abbreviation 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DI 
Dose Intensity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer 
HRQoL 
Health-Related Quality of Life 
irAE 
Immune-Related Adverse Event 
ITT 
Intention-To-Treat 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PR 
Partial response 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
QLQ-C30 
Quality-of-Life Questionnaire for Cancer 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SOC 
System Organ Class 
TTR 
Time to Response 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


 
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1. 
BACKGROUND 
Genotype-directed therapy has the potential to dramatically improve the balance of benefit and 
toxicity for selected patients with NSCLC (mainly non-squamous histology) characterized by 
alterations of driver oncogenes, including sensitizing EGFR mutations and ALK rearrangements. 
Randomized Phase III trials of the EGFR inhibitors gefitinib, erlotinib, and afatinib showed 
significant improvement of PFS and objective response rate (ORR) compared with platinum 
doublet chemotherapy(Fukuoka et al.2011; Rosell et al.2012；Yang et al.2012). 
Despite the high initial response rate, patients treated with first line EGFR TKIs develop acquired 
resistance after 9–14 months. Salvage treatment with platinum-based doublet chemotherapy gives 
response rate of ~10-20% only (Yang CJ et al 2016, Tseng Y-H et al 2016). Hence novel 
treatment strategies are urgently warranted. 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of 
which function as inhibitory receptors expressed on T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, the treatment of non-small 
cell lung cancer, the treatment of Triple-Negative Breast Cancer and for small cell lung cancer. 
Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor and a key 
regulator of physiological angiogenesis. It is also implicated in pathological angiogenesis such as 
that associated with tumor growth. 
AVASTIN® (bevacizumab) is a recombinant humanized monoclonal antibody to VEGF that 
recognizes all isoforms of VEGF. It may exert a direct anti-angiogenic effect by binding to and 
clearing VEGF from the tumor environment. Bevacizumab has been tested in Phase II and III 
studies in a variety of solid tumors in combination with chemotherapy. Bevacizumab is registered 
in over 40 countries worldwide for the first-line treatment of metastatic colorectal cancer (CRC) 
in combination with chemotherapy, as second-line CRC treatment, and first-line treatment of 
advanced NSCLC, metastatic breast cancer, advanced renal cell carcinoma (RCC), ovarian cancer, 
and glioblastoma (Reck and Crino 2009). 
Some immunosuppressive activities of VEGF can be reversed by inhibition of VEGF signaling. 
Thus, mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell 
function, which could be restored by blockade of VEGFR2 (Huang et al. 2007). In a murine 
melanoma model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by 
improved anti-tumor activity, prolonged survival, and increased trafficking of T cells into tumors 
(Shrimali et al. 2010). 
Synergistic effects have also been observed in a clinical study of melanoma patients combining 
an immunomodulatory antibody (anti−CTLA-4; ipilimumab) and bevacizumab (Hodi et al. 2011). 


 
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Therefore, the combined treatment with atezolizumab and bevacizumab may augment the 
antitumor immune response, resulting in improved and more durable clinical benefit. 
The IMmotion 151 was the front-line, phase III trial of the atezolizumab combination with 
bevacizumab in RCC. The result of IMmotion 151 showed atezolizumab + bevacizumab 
demonstrated a clinically meaningful and statistically significant improvement in PFS (as 
evaluated by the investigators) versus sunitinib in the PD-L1+ population (HR = 0.74 [95% CI: 
0.57, 0.96]). (Brian I Rini et al.2019) 
In the analysis of safety data from Study GO30140 (clinical cutoff date of 7 June 2017) in 20 
patients with HCC (median treatment duration of 2.8 months [range: 1-11 months]), the 
combination of atezolizumab +bevacizumab was generally safe and well tolerated; no new safety 
signals related to the combination therapy were identified beyond the established safety profile 
for each individual agent. There is a global phase III YO40245 is ongoing, which evaluate the 
efficacy and safety of atezolizumab + bevacizumab versus sorafenib in patients with locally 
advanced or metastatic HCC who have received no prior systemic treatment. 
2. 
STUDY DESIGN 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of Assessments 
in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measures 
The primary effectiveness objective of this study is as follows: 
 
Objective response rate (ORR). 
 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary effectiveness objectives of this study are as follows: 
 
Duration of objective response (DOR). 
 
Time to response (TTR). 
 
Disease control rate (DCR). 
 
Overall survival (OS). 
 
Progression-free survival (PFS). 
 
PFS rate at 6 and 12 months. 
 
OS rate at 1 and 2 years. 
 
Expression of PD-L1 defined by the SP142 and SP263 assay 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
 
Exploratory analyses ORR, DOR, PFS, PFS rate at 12m, by investigator according to 
Modified RECIST V1.1(iRECIST). 
 


 
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2.2.4 
Safety Outcome Measures 
The safety objectives for this study are as follows: 
 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0. 
 
Incidence of serious and non-serious immune- mediated adverse events (irAEs) related to 
atezolizumab treatment. 
2.2.5 
Health Status Utility Measures 
 
PROs of lung cancer symptoms, patient functioning, and health-related quality of life 
(HRQoL) as measured by the European Organization for Research and treatment of Cancer 
(EORTC) Quality-of-life Questionnaire Core 30 (QLQ C30) and its Lung Cancer Module 
(QLQ LC13). 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The sample size estimation is based on having sufficient sample in the FAS population to show 
that the ORR is higher than 20%. Simon’s minimax two-stage design will be used. The null 
hypothesis that the true ORR is at least 50% will be tested against a one-sided alternative. 
The sample size calculation was based on a Simon two-stage design, and the primary end point 
was ORR (H0 = 30%, H1 = 50%). Two-sided alpha is set to be 0.1 and statistical power is set to 
be 80%. 
19 fully evaluable patients will be included at the first stage. If there are 6 for fewer responders 
(CR/PR) in these 19 patients, enrollment will be stopped. Otherwise, additional 20 fully evaluable 
patients will be included in the second stage. Finally, if we have more than 16 patients in 39 
patients have objective response, the endpoint is reached. Thus, considering a drop-out rate of 
10%, a total number of 22 patients (if stops at the first stage) or 44 patients (if runs into the 
second stage) will need to be finally enrolled in this study. 
Figure 1 presents an overview of the sample size allocation. 
Figure 1 Sample size allocation 
 
 


 
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3. 
STATISTICAL METHODS 
The following represents an overview of the planned statistical analysis. Additional analyses 
could be performed if deemed appropriate. 
3.1 
GENERAL RULE 
Continuous data will be summarized using n, mean, standard deviation, median, minimum and 
maximum. The minimum and maximum values will be presented to the same number of decimal 
places as recorded in the CRF, mean and median will be presented to one more decimal place 
than the raw data, standard deviation will be presented to two more decimal places than the raw 
data. And each of them will be presented no more than three decimals. 
Categorical variables will be expressed as absolute and relative number and 95% CI. Percentages 
will be rounded to one decimal place, with the denominator being the number of patients in the 
relevant population with non-missing data, unless otherwise stated. For category of Unable to 
evaluate, Not evaluable, Not applicable, Unknown, Not done will be uniformly summarized as 
Missing. 
Time to event variables will be assessed with median survival time, lower quartile, upper quartile 
and its corresponding 95% CI using Kaplan-Meier method, these statistical will be presented to 
two decimal places. Besides, Kaplan-Meier product-limit plot will be produced. No formal 
hypothesis testing is planned. All effectiveness and safety variables documented in this study will 
be analyzed by means of descriptive analyses. 
Statistical programming and analyses will be performed using SAS® Software (SAS Institute Inc., 
Cary, NC) Version 9.4 or higher. 
3.2 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
3.2.1 
Baseline Definitions 
The baseline value is defined as the last non-missing value prior to start of study treatment. Since 
at each treatment cycle, assessments should be performed before study drug infusion unless 
otherwise noted, baseline could include the first dose date. When the date of the assessment is the 
same as the first administration date of study drug, if it is not confirmed that the assessment 
occurred after the first administration of the study drug, the result of the assessment shall be 
considered as the baseline value. However, for adverse events, concomitant medications/ 
therapies etc. is considered to have occurred after baseline, when the onset date is the same as the 
first administration date of study drug. 
3.2.2 
Study Day 
The first dose date is considered as Day 1, patients’ time on study will be determined in study 
days. Study day is defined as follows: 
Study Day = the current date – Day 1 + 1, if the current date ≥ date of Day 1;  
Study Day = the current date – Day 1, if current date < date of Day 1. 
3.2.3 
Last Known Alive Date 
The last known alive date will be derived for patients known to be alive at the analysis cut-off 
date using the latest date among the following data: 
• 
All assessment dates (e.g. vital signs assessment, ECOG performance status assessment, 
and also assessment date of tumor imaging etc.). 
• 
 Medication dates including study medication, concomitant medications, anticancer 
therapies administered after study treatment discontinuation. 


 
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 
Medical history dates including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures, autoimmune diseases). 
• 
Adverse events onset and end dates 
• 
Date at which subjects were confirmed to be still alive during follow-up 
The last known alive date will be used for censoring of patients in the analysis of overall survival. 
3.2.4 
Visit Windows 
The analysis visit will be based on the nominal visits in CRF. The visit window is not applicable. 
3.2.5 
Pooling Center 
This is a multi-center study and centers will be pooled for analysis. 
3.3 
ANALYSIS POPULATIONS 
3.3.1 
Full Analysis Set 
Full analysis set (FAS): defined as all enrolled patients who receive any amount at least one dose 
of any study treatment. All efficacy analysis except for primary analysis of ORR will use FAS, 
and patients without post-baseline radiologic assessment will be regarded as non-responder. 
3.3.2 
Safety Analysis Set 
Safety Analysis Set (SAF): defined as all enrolled patients who receive any amount at least one 
dose of any study treatment. The safety analysis will be performed on the safety population. 
3.3.3 
ITT Population 
ITT population: defined as all enrolled patients regardless of whether they receive any assigned 
study drug. The ITT population will be used for other analyses (Demography, Baseline 
Characteristics, PROs, etc.). 
3.3.4 
Evaluable Population 
Evaluable population: defined as all enrolled patients who receive any amount of study treatment, 
have baseline and at least one post-baseline efficacy measurement. Evaluable population will be 
used for primary analysis of ORR. 
3.4 
ANALYSIS OF STUDY CONDUCT 
Analysis of study conduct will be based on ITT population. 
The patient’s distribution of the analysis population will be provided in study treatment. The 
number of patients enrolled, discontinued from Atezolizumab and Bevacizumab, discontinued 
from study will be summarized. Treatment and study discontinuation will be summarized 
according to the reasons of discontinuation as documented in the Case Report Form (CRF). Based 
on ITT population, the number and percentage of subjects in FAS, SAF and evaluable population, 
and the reasons for subjects who are excluded from specific population will be summarized. 
Disposition information will be displayed by patients in listing.  
In order to evaluate whether the protocol is well executed, all protocol deviations will be 
determined according to data contents, combined protocol requirements before database lock, and 
the major protocol deviations will be summarized as the frequency and percentage of patients in 
each type. 
All protocol deviations will be listed by patients. 


 
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3.5 
ANALYSIS OF SUBJECT AND TREATMENT INFORMATION 
Analyses will be conducted in ITT population, and treatment compliance will be conducted on 
full analysis set. 
3.5.1 
Demographics and Baseline Characteristics 
Subject demographics and baseline disease characteristics will be summarized using descriptive 
statistics. Continuous variables will be summarized using n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized as the frequency and 
percentage of patients in each category. Details as below: 
 
Demographics 
Quantitative index: 
 
Age (Years), where age (Years)= (date of informed consent-date of birth)/365.25, round 
down. 
 
Weight (Kg), 
 
Height (cm), 
 
BMI(Kg/m2), where BMI(Kg/m2) = Weight (Kg)/Height(m)2, keep two decimals. 
Qualitative index: 
 
Sex (Female, Male) 
 
Age group(＜65,≥65) 
 
Ethnicity (Asian, Other) 
 
Smoking history (Never, Current, Previous), if current, number of years of smoking will be 
summarized 
 
LVEF (Normal, Abnormal, not clinically significant, Abnormal, clinically significant) 
 
ECOG (0,1,2,3,4,5) 
 Baseline Disease Characteristics 
Quantitative index: 
 
Months from first diagnosis date to first dose date = (The first dose date- date of initial 
diagnosis+1)/ 30.4375, keep two decimals. 
 
Months from last recurrence date to first dose date = (The first dose date- date of last 
recurrence +1)/ 30.4375, keep two decimals. 
Qualitative index: 
 
Brain MRI/CT Status 
 
Brain metastasis (Yes, No) 
 
Bone Scan  
 
Bone metastasis (Yes, No) 
 
Histology at time of initial diagnosis (Squamous, Non-squamous), If Non-Squamous, select 
one option (Adenocarcinoma, Large cell, Large cell with neuroendocrine differentiation, 
Poorly differentiated, Mixed (not including small cell), NSCLC/NOS, Other) 
 
Initial diagnosis staging (Occult, Stage 0, Stage I (including Stage IA, Stage IB), Stage II 
(including Stage IIA, Stage IIB), Stage IIIA, Stage IIIB, Stage IIIC, Stage IV) 
 
Primary tumor location (Left lung, Right lung, Double-lung, Other) 
 
Status of disease (Locally recurrent disease, Locally advanced unresectable disease, 
Metastatic disease) 
 
Anatomical locations of metastatic disease at time of study enrollment (Bone, Brain) 
 
EGFR mutation (L858R or Ex.19 deletion, Other EGFR mutation, No mutation) 


 
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 
PD-L1 expression (Yes,No) 
 
Stage of NSCLC at Study entry (Stage IIIB, Stage IIIC, Stage IV) 
Demographics and baseline disease characteristics will also be listed by patients. 
3.5.2 
Medical History  
Medical history, including clinically significant diseases, surgeries, cancer history (including 
autoimmune diseases) and reproductive status will be recorded at baseline.  
The following information will be presented in frequency tables by system organ class (SOC) and 
preferred terms (PT) based on Medical dictionary for regulatory affairs (MedDRA) version xx or 
the latest version before database lock. 
• 
General medical history and baseline conditions (non- NSCLC related); 
• 
Surgery and procedure history (non-NSCLC related)  
• 
History of autoimmune diseases 
A patient data listing of medical history will also be presented. 
3.5.3 
Prior and Concomitant Medication 
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 treatment to the treatment 
discontinuation visit. All such medications should be reported to the investigator and recorded on 
the Concomitant Medications eCRF. 
For summarization purposes, medications other than study medications will be coded to a generic 
term based on the World Health Organization (WHO) dictionary version xx or the latest version 
before database lock. Prior medications will be defined as all medications that stopped prior to the 
first dose of study drug. 
Concomitant medications will be defined as follows: 
all medications that started on or after the first dose of study medication, or 
all medications that started before the first dose date and stopped after the first dose date. 
Prior and concomitant medication will be listed by patients. 
3.5.4 
Prior/On-Study/Post-Study Treatment 
3.5.4.1 
Prior NSCLC Treatment 
Prior NSCLC treatment including NSCLC Therapy, Radiotherapy and Surgeries/Procedures. 
For summarization purposes, prior NSCLC therapy will be coded to a generic term based on the 
World Health Organization (WHO) dictionary version xx or the latest version before database 
lock.  
3.5.4.2 
On-Study Treatment 
On-Study treatment including surgery and procedure as well as radiotherapy. 
On-Study Surgery and Procedure will be presented in frequency tables by System Organ Class 
(SOC) and preferred terms (PT) based on Medical Dictionary for Regulatory Affairs (MedDRA) 
version xx or the latest version before database lock. 
A patient data listing of on-study treatment will also be presented. 
3.5.4.3 
Post-Study Treatment 
Post-study treatment including NSCLC therapy and radiotherapy. 


 
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For summarization purposes, Post-study treatment NSCLC Therapy will be coded to a generic 
term based on the World Health Organization (WHO) dictionary version xx or the latest version 
before database lock.  
Post-Study treatment will be listed by patients. 
3.5.5 
Treatment Compliance 
The compliance will be summarized with descriptive statistics and the categorical variable of 
compliance (>100%, 75%~100%, 50%~75%, <50%) will also be summarized. 
For Atezolizumab, treatment compliance=Total Atezolizumab dose (mg)/(1200*Number of 
cycles) *100%; 
For Bevacizumab, treatment compliance=Total Bevacizumab actual dose (mg)/Total 
Bevacizumab planned dose (mg) *100%. 
3.6 
EFFICACY ANALYSIS 
The efficacy analyses and sensitivity analysis of ORR will be performed on the FAS, Primary 
analysis of ORR will be analyzed using evaluable population, DOR will be assessed in patients 
who have an objective response. All effectiveness variables documented in this study will be 
analyzed by means of descriptive analyses. All interval estimation will be reported using 2-sided 
95% confidence intervals, unless otherwise specified. Tumor assessment will be listed at each 
visit point by patients. 
3.6.1 
Primary Efficacy Endpoint 
The best overall response (BOR) is the best response recorded from the start of the study 
treatment until disease progression or subsequent anti-tumor therapies started. For subjects 
without disease progression or subsequent anti-tumor therapies, BOR will be determined based on 
all available tumor assessments. Complete response (CR) or partial response (PR) should be 
confirmed on two consecutive occasions ≥4 weeks apart during the study treatment. When SD is 
believed to be best response, it must also meet the interval between the first dose of study drug 
and the determination of SD was at least 39 days. If the interval is not met when SD is otherwise 
the best time point response, the patient’s best response depends on the subsequent assessments. 
The same patient lost to follow-up after the first SD assessment would be considered not 
evaluable. PD will not to be confirmed, and NE will be determined as BOR if there are no 
evidence of CR/PR or SD or PD. 
The detailed BOR after confirmation is clarified in below Error! Reference source not found.. 
Table 1 CR and PR confirmation rule for Best Overall Response 
Overall response  
First time point  
Overall response  
Subsequent time pointa 
Best overall response  
CR  
CR  
CR  
CR  
PR  
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, PD 
CR  
SD  
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, PD  
CR  
PD  
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, PD  
CR  
NE 
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  


 
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CR 
 
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE 
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, PD  
PR  
NE 
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
PR  
 
SD if SD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
NE  
NE  
NE  
a Subsequent confirmed tumor response should be at least 4 weeks after previous tumor response. In the case where a 
patient has two non-consecutive visit responses of PR, then, as long as the time between the 2 visits of PR is greater 
than 4 weeks and there is no PD between the PR visits, the patient will be defined as a responder. Similarly, if a patient 
has visit responses of CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then a 
best response of CR will be assigned. 
Objective response rate (ORR), defined as the proportion of patients with a complete response 
(CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the 
investigator according to RECIST v1.1. 
Patients without any post-baseline tumor assessments will be considered non-responders.  
Number and percentage of responders with corresponding Clopper-Pearson 90% and 95% 
confidence intervals will be provided. 
The ORR will be the basis for decision whether the study would be continued when Stage 1 is 
completed. 
The frequency and percent for the responders and non-responders will be summarized as well. 
Sample SAS code as following: 
proc freq data = dd; 
 
table response / alpha=0.05; 
 
exact binomial; 
run; 
3.6.2 
Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
bevacizumab in the evaluable population on the basis of the following endpoints and the analysis 
will be performed in FAS population. 
3.6.2.1 
Duration of Response (DOR) 
For patients who have experienced an objective response (CR or PR) during the study, duration of 
objective response (DOR) is defined as the time from the first occurrence of a documented 
objective response to disease progression or death from any cause whichever occurs first, as 
determined by the investigator according to RECIST v1.1. 
Patients who are alive and who have not experienced disease progression at the time of analysis 
will be censored at the time of the last tumor assessment date. If no tumor assessments were 
performed after the date of the first occurrence of a complete or partial response, DOR will be 
censored at the date of the first occurrence of a complete or partial response plus 1 day. 


 
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The analysis population will be FAS that have experienced an objective response (CR or PR). 
The DOR will be derived based on imaging dates, not visit or RECIST response assessment dates. 
RECIST imaging contributing towards a particular visit may be performed on different dates. The 
following rules will be applied to determine the progression or censoring date: 
• For progressions patients, progression date will be determined based on the earliest of the 
dates contribution to a particular overall visit tumor assessment. 
• For censoring patients, censored date will be determined at the latest of the dates 
contributing to a particular overall visit assessment. 
If progression or death happened, DoR (months) = (date of progression or death –date of first 
documented response (CR or PR) +1) /30.4375, 
If censored, DoR (months) = (censoring date –date of first documented response (CR or PR) +1) 
/30.4375. 
Censoring rules are displayed in Error! Reference source not found.. 
Table 2 Censoring Rules for DOR Analysis 
Sequence  Category 
Situation  
Date 
of 
Progression 
or 
Censoring 
Outcome 
1 
No tumor assessments after 
the date of the first 
occurrence of CR or PR 
No tumor assessments after the date 
of the first occurrence of CR or 
PR(without death or death reported 
without 2 visit/tumor assessment from 
the date of first occurrence of CR or 
PR) 
Date of the first 
occurrence of a CR 
or PR+1 
Censored 
2 
Progression 
Progression documented between 
scheduled visits(all conditions are 
met: a. progression reported within 2 
visit/tumor assessment from previous 
adequate tumor assessment, or from 
the date of first occurrence of a CR or 
PR if no adequate tumor assessment 
before progression; b no new 
anticancer treatment or new 
anticancer treatment is after than PD 
date) 
Date of first 
radiologic PD 
assessment 
Progressed 
3 
No progression 
No progression(have tumor 
assessments after the date of first 
occurrence of CR or PR, without PD, 
death, new anticancer treatment) 
Date of last 
adequate radiologic 
assessment 
Censored 
4 
Received another kind of 
anti-cancer therapy before 
progression/death 
New anticancer treatment started(any 
of the following conditions are met :a. 
no progression/death missed 2 
visit/tumor assessment or 
progression/death missed 2 scan 
intervals and new anticancer treatment 
started earlier than date of last 
adequate radiologic assessment before 
missed tumor assessments; b. no 
Date of last 
adequate radiologic 
assessment prior to 
or on date of new 
anticancer 
treatment(If no 
adequate radiologic 
assessment prior to 
or on date of new 
anticancer 
treatment, censor to 
the date of the first 
Censored 


 
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progression/death or 
progression/death within 2 visit/tumor 
assessment and new anticancer 
treatment started earlier than PD date, 
if progressed) 
occurrence of a CR 
or PR +1) 
5 
Death 
No tumor assessments after the date 
of the first occurrence of CR or PR 
and death within 2 visit/tumor 
assessment  [1] (no tumor assessments 
after the date of the first occurrence of 
CR or PR and death reported within 2 
visit/tumor assessment from the date 
of first occurrence of CR or PR, 
without new anticancer treatment) 
Date of death 
Progressed 
6 
Death 
Death between adequate assessment 
visits(death reported within 2 
visit/tumor assessment from previous 
adequate tumor assessment, and 
without new anticancer treatment and 
no PD) 
Date of death 
Progressed 
7 
Death or progression after 
more than two missed 
visit/tumor assessment 
Death or progression after more than 
two missed visit/tumor assessment [2] 
(without new anticancer treatment or 
new anticancer treatment date is after 
than the date of last adequate 
radiologic assessment before missed 
tumor assessments) 
Date of last 
adequate radiologic 
assessment before 
missed tumor 
assessments(If no 
adequate radiologic 
assessment before 
death or 
progression, censor 
to the date of the 
first occurrence of 
a CR or PR +1) 
Censored 
Note: Adequate assessment including the tumor evaluations are the followings: CR, PR, SD, PD. 
[1] Refers to date of death from the first dose date of study drug is less than or equal to 12 weeks+7 days. 
[2] If death or progression is before or on 36th week, it refers to the date of death or progression is larger or equal to 12 
weeks +7 days from the last adequate tumor assessment , if there are no adequate radiologic assessment before death or 
progression, will compare with the first dose date of study drug. If death or progression is after 36th week, it refers to 
the date of death or progression larger or equal to 18 weeks +7 days from the last adequate tumor assessment. 
 
The median for DOR will be calculated using the Kaplan- Meier product-limit method, and 
presented with two-sided 95% CI, and the Kaplan-Meier plot will be produced by time. 
3.6.2.2 
Time to Response (TTR) 
Time to response (TTR), defined as the time from the start of the treatment to the first objective 
tumor response observed for patients who achieved CR or PR (which must be confirmed 
subsequently), as determined by the investigator according to RECIST v1.1. 
TTR will be analyzed for patients who achieved CR or PR, for non-responders will be excluded 
from the TTR analysis population. 
TTR (months) = (date of first documented response (CR or PR) – the first administration date of 
study medication +1) /30.4375. 


 
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TTR will be summarized using n, mean, standard deviation, median, minimum and maximum. 
3.6.2.3 
Disease Control Rate (DCR) 
DCR, defined as the proportion of patients who have a best overall response of CR or PR or SD, 
as determined by the investigator according to RECIST v1.1. 
Number and percentage of patients with DCR with corresponding Clopper-Pearson 95% 
confidence intervals will be provided. 
3.6.2.4 
Overall Survival (OS) 
Overall survival (OS) after enrollment, defined as the time from enrollment to death from any 
cause. 
Patients who do not have post-baseline information will be censored at the date of initiation of 
study treatment + 1 day. Patients who are alive at the time of analysis will be censored at the last 
known survival date + 1 day, and will be  categorized as off-study:(lost to follow-up, withdrew 
consent, other) and still on-study at the time of analysis. 
The median for overall survival, and the survival rates will be calculated using the Kaplan- Meier 
product-limit method, and presented with two-sided 95% CI, and the Kaplan-Meier plot will be 
produced by time.  
3.6.2.5 
Progression-free Survival (PFS) 
Progression-free survival (PFS), defined as the time from enrollment 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. 
PFS will be summarized descriptively using the Kaplan-Meier (KM) product-limit method. 
Median values of PFS, if available, along with two-sided 95% CIs (based on the log-log 
transformation), will also be calculated. The source of progression (death vs. progression) will be 
summarized. KM curve of PFS will be generated.  
Patients who are alive and have not experienced disease progression at the time of analysis will 
be censored at the time of the last tumor assessment.  
The PFS will be derived based on imaging dates, not visit or RECIST response assessment dates. 
RECIST imaging contributing towards a particular visit may be performed on different dates. The 
following rules will be applied to determine the progression or censoring date: 
• For progressions patients, progression date will be determined based on the earliest of the 
dates contribution to a particular overall visit tumor assessment. 
• For censoring patients, censored date will be determined at the latest of the dates 
contributing to a particular overall visit assessment. 
If progression or death happened, PFS (months) = (date of progression or death –date of first dose 
of trial treatment +1) /30.4375, 
If censored, PFS (months) = (censoring date –date of first dose of trial treatment+1) /30.4375. 
The PFS censoring rules are displayed in Error! Reference source not found.. 
Table 3Censoring Rules for PFS Analysis 
Sequence  Category 
Situation  
Date of Progression or 
Censoring 
Outcome 
1 
No 
baseline 
or 
post-
baseline 
tumor 
assessments 
No baseline or post-baseline tumor 
assessments (without death or death 
reported 
without 
2 
visit/tumor 
assessment from the first dose date 
of study drug) 
Date of first dose date 
of study drug+1 
Censored 


 
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2 
Progression 
Progression documented between 
scheduled visits  (all conditions are 
met: a. progression reported within 
2 visit/tumor assessment from 
previous adequate tumor 
assessment, or from first dose date 
of study drug if no adequate tumor 
assessment before progression; b no 
new anticancer treatment or new 
anticancer treatment started is after 
than PD date) 
Date of first radiologic 
PD assessment 
Progressed 
3 
No progression 
No progression(have baseline and  
post-baseline tumor assessments, 
without PD, death, new anticancer 
treatment) 
Date of last adequate 
radiologic assessment 
Censored 
4 
Received another kind of 
anti-cancer therapy before 
progression/death 
New anticancer treatment 
started(any of the following 
conditions are met : a. no 
progression/death missed 2 
visit/tumor assessment or 
progression/death missed 2 scan 
intervals and new anticancer 
treatment started earlier than date of 
last adequate radiologic assessment 
before missed tumor assessments; b. 
no progression/death or 
progression/death within 2 scan 
intervals and new anticancer 
treatment started earlier than PD 
date, if progressed) 
Date of last adequate 
radiologic assessment 
prior to or on date of 
new anticancer 
treatment (If no 
adequate radiologic 
assessment prior to or 
on date of new 
anticancer treatment, 
censor to the first dose 
date of study drug+1) 
Censored 
5 
Death 
No post-baseline and death within 2 
visit/tumor assessment [1] (no post-
baseline tumor assessments and 
death reported within 2 visit/tumor 
assessment from first dose date of 
study drug, without new anticancer 
treatment) 
Date of death 
Progressed 
6 
Death 
Death between adequate assessment 
visits(death reported within 2 
visit/tumor assessment from 
previous adequate tumor 
assessment, and without new 
anticancer treatment and no PD) 
Date of death 
Progressed 
7 
Death or progression after 
more than two missed 
visit/tumor assessment 
Death or progression after more 
than two missed visit/tumor 
assessment [2] (without new 
anticancer treatment or new 
anticancer treatment date is  after 
than the date of last adequate 
Date of last adequate 
radiologic assessment 
before missed tumor 
assessments (If no 
adequate radiologic 
assessment before 
Censored 


 
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radiologic assessment before missed 
tumor assessments) 
death or progression, 
censor to the first dose 
date of study drug+1) 
Note: Adequate assessment including the tumor evaluations are the followings: CR, PR, SD, PD. 
[1] Refers to date of death from the first dose date of study drug is less than or equal to 12 weeks+7 days. 
[2] If death or progression is before or on 36th week, it refers to the date of death or progression is larger or equal to 12 
weeks +7 days from the last adequate tumor assessment, if there are no adequate radiologic assessment before death or 
progression, will compare with the first dose date of study drug. If death or progression is after 36th week, it refers to 
the date of death or progression larger or equal to 18 weeks +7 days from the last adequate tumor assessment.   
 
3.6.2.6 
PFS rate at 6 and 12 months 
PFS rate at 6 and 12 months, defined as the proportion of patients who have not experienced 
disease progression or death from any cause at 6 and 12 months, as determined by the 
investigator according to RECIST v1.1.  
The PFS rates at 6 months and 1 year after initiation of treatment will be estimated using Kaplan- 
Meier methodology, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula. 
3.6.2.7 
OS rate at 12 and 24 months 
OS rate at 12 and 24 months, defined as the proportion of patients who have not experienced 
death from any cause at 12 and 24 months. The analysis method is similar with PFS rate at 6 and 
12 months.  
3.6.2.8 
Expression of PD-L1 defined by the SP142 and SP263 assay. 
Expression of PD-L1 defined by the SP142 and SP263 IHC assay will be investigated. The 
proportions of the patients with PD-L1+ tested by SP142 and SP263 in all patients will be 
presented respectively, with their 95% Clopper-Pearson CI. The consistency between SP142 and 
SP263 IHC assay will be investigated using chisq-square test. 
3.6.2.9 
Sum of target lesion diameters (SLD) 
The SLD is the sum of all target lesion diameters (including longest for non-nodal lesions, short 
axis for nodal lesions). 
The best percentage change of the SLD from baseline is defined as the minimum value of the 
percentage change from the baseline to the SLD in all visits after the study treatment. The 
specific calculation formulas are as follow: 
The best change of the SLD from baseline = the minimum value of SLD at post-baseline – 
baseline SLD; 
The best percentage change of the SLD from baseline = (the minimum value of SLD at post-
baseline – baseline SLD)/ baseline SLD*100%. 
The best percentage change of the SLD from baseline will be summarized using n, mean, 
standard deviation, median, minimum, and maximum. 
Waterfall plot of the best percentage change of the SLD from baseline will be generated. 
Tumor assessment will be listed for each subject. 
3.6.3 
Exploratory Efficacy Endpoints 
Exploratory analyses ORR, DOR, PFS, PFS rate at 12m, by investigator according to Modified 
RECIST V1.1(iRECIST). And the following points for iRECIST require to be noted: 
(1) Immune-Modified RECIST Response 


 
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Since immune-modified RECIST response assessment collected in CRF does not correspond with 
iRECIST, especially for progressive disease. For CR/PR/SD will be derived as iCR/iPR/iSD 
respectively by adding ‘i’. For PD, will be derived as iUPD or iCPD according to the following 
rules from iRECIST V1.1: 
iRECIST defines iUPD on the basis of RECIST 1.1 principles; however, iUPD requires 
confirmation, which is done on the basis of observing either a further increase in size (or in the 
number of new lesions) in the lesion category in which progression was first identified in (ie, 
target or non-target disease), or progression (defined by RECIST 1.1) in lesion categories that had 
not previously met RECIST 1.1 progression criteria. However, if progression is not confirmed, 
but instead tumour shrinkage occurs (compared with baseline), which meets the criteria of iCR, 
iPR, or iSD, then the bar is reset so that iUPD needs to occur again (compared with nadir values) 
and then be confirmed (by further growth) at the next assessment for iCPD to be assigned. If no 
change in tumour size or extent from iUPD occurs, then the timepoint response would again be 
iUPD. 
Each timepoint response is based on the assessment of target lesions, non-target lesions, and new 
lesions. 
Progression is confirmed in the target lesion category if the next imaging assessment after iUPD 
(4–8 weeks later) confirms a further increase in sum of measures of target disease from iUPD, 
with an increase of at least 5 mm. However, the criteria for iCPD (after iUPD) are not considered 
to have been met if complete response, partial response, or stable disease criteria (compared with 
baseline and as defined by RECIST 1.1) are met at the next assessment after iUPD. 
Progressive disease in the non-target lesion category is confirmed if subsequent imaging, done 4–
8 weeks after iUPD, shows a further increase from iUPD. 
If a new lesion is identified (thus meeting the criteria for iUPD) and the patient is clinically stable, 
treatment should be continued. New lesions should be assessed and categorised as measurable or 
non-measurable using RECIST 1.1 principles. Five lesions (no more than two per organ) should 
be measured and recorded as a new lesion target, but should not be included in the sum of 
measures of the original target lesions identified at baseline. Other measurable and non-
measurable lesions are recorded as new lesion non-target. New lesions do not need to meet the 
criteria for new lesion target to result in iUPD (or iCPD); new lesion non-target can also drive 
iUPD or iCPD. Progressive disease is confirmed (iCPD) in the new lesion category if the next 
imaging assessment, done at 4–8 weeks after iUPD, confirms additional new lesions or a further 
increase in new lesion size from iUPD (sum of measures increase in new lesion target ≥5 mm, 
any increase for new lesion non-target). Notably, if iUPD criteria were met on the basis of 
progression in the target or non-target disease, or the appearance of new lesions, then RECIST 
1.1-assigned progression in another lesion category in the confirmatory scan also confirms iCPD. 
(2) Best Overall Response (iBOR) 
For iRECIST, the best overall response (iBOR) is the best timepoint response recorded from the 
start of the study treatment until confirmed disease progression(iCPD) or subsequent anti-tumor 
therapies started, taking into account any requirement for confirmation. 
Confirmation of response which required in RECIST 1.1 is also recommended for iRECIST. The 
duration of iCR and iPR is from the timepoint when the criteria for iCR or iPR are first met, 
whereas the duration of iSD is still calculated from baseline. Specific rules are as follows: 
Table 4 iCR and iPR confirmation rule for Best Overall Response(iBOR) 
Overall response  
First time point  
Overall response  
Subsequent time pointa 
Best overall response  
iCR  
iCR  
iCR  
iCR  
iPR  
iSD if iSD duration of no less than 39 days from 


 
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first administration date of study drug was met, 
otherwise, iUPD 
iCR  
iSD  
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, iUPD  
iCR  
iUPD  
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, iUPD  
iCR  
NE  
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
iCR  
 
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
iPR  
iCR  
iPR  
iPR  
iPR  
iPR  
iPR  
iSD  
iSD  
iPR  
iUPD  
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise, iUPD  
iPR  
NE  
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
iPR  
 
iSD if iSD duration of no less than 39 days from 
first administration date of study drug was met, 
otherwise NE  
NE  
NE  
NE  
a Subsequent confirmed tumor response should be at least 4 weeks after previous tumor response. In the case where a 
patient has two non-consecutive visit responses of iPR, then, as long as the time between the 2 visits of iPR is greater 
than 4 weeks and there is no iUPD between the iPR visits, the patient will be defined as a responder. Similarly, if a 
patient has visit responses of iCR, NE, iCR, then, as long as the time between the 2 visits of iCR is greater than 4 weeks, 
then a best response of iCR will be assigned. 
iBOR will be assigned as iCPD if iUPD is confirmed at the next imaging assessment after 4–8 
weeks later and there are no evidence of iCR/iPR or iSD. For the situation of assessments that are 
not done or are not evaluable should be disregarded, for example, an iUPD followed by an 
assessment that was not done or not evaluable, and then another unconfirmed progressive disease, 
would be indicative of iCPD. 
 iUPD will be determined as iBOR if there are evaluable response assessment and no evidence of 
iCR/iPR or iSD or iCPD. 
NE will be determined as iBOR if there are no evidence of iCR/iPR or iSD or iUPD/ iCPD . 
(3) Event Date 
The event date to be used for calculation of progression date should be the first date at which 
progression criteria are met (ie, the date of iUPD) provided that iCPD is confirmed at the next 
assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that iUPD date 
should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the iUPD date 
should still be used in the following scenarios: if the patient stops study treatment, or no further 
response assessments are done; the next timepoint responses are all iUPD, and iCPD never occurs; 
or the patient dies from disease progression. 
3.7 
SAFETY ANALYSES 
Safety analysis will be based on safety analysis set. Descriptive statistics will be used to 
summarize all safety data.  


 
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3.7.1 
Exposure of Study Medication 
For administration of Atezolizumab and Bevacizumab, details information will be provided as 
below:  
 
Number of cycles (actual number of the administrations) 
 
Duration of exposure (week) = (min (date of last dose +21 days, date of death, date of 
subject discontinued the Atezolizumab/ Bevacizumab, subsequent anti-tumor treatment-1day) 
– date of first dose)/7; 
 
Cumulative dose (mg) 
 
Mean Dose Per Cycle(mg/cycle) = cumulative dose (mg)/number of cycles 
 
 For atezolizumab, dose intensity (DI) (mg/week) = cumulative dose (mg)/ duration of 
exposure (week); 
For bevacizumab, DI (mg/kg/week) = sum of the actual dose per cycle (mg/kg)/ duration of 
exposure (week), where, sum of the actual dose per cycle (mg/kg) = sum(dose actual 
administered(mg) per cycle /weight(kg) per cycle) 
 
For atezolizumab, relative dose intensity (RDI)(%) = 100*(DI (mg/week)/ planned dose 
intensity(mg/week)), planned dose intensity(mg/week) = (1200* number of cycles)/ duration 
of exposure (week);  
For bevacizumab, RDI (%) = 100*(DI (mg/kg/week)/ planned dose intensity(mg/kg/week)), 
planned dose intensity(mg/kg/week) = sum of the planned dose per cycle(mg/kg)/ duration 
of exposure (week), where sum of the planned dose per cycle(mg/kg)= sum(dose planned 
administered(mg) per cycle /weight(kg) per cycle) 
 
Premedication given? (Yes, No) 
 
Injection/infusion modified (Yes, No) 
 
Reason for injection/infusion modification (including Adverse Event, Medication error, 
Other) 
 
Treatment modification (Infusion Stopped and Restarted at the same rate, Infusion Stopped 
and Restarted at a lower rate, Prematurely stopped and not restarted) 
The exposure of study medication will be descriptively summarized. The number and percentage 
of patients with dose modification and the reasons will be summarized.  
Administration of Atezolizumab and Bevacizumab will be displayed by patients. 
3.7.2 
Adverse Events 
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. Adverse events will be coded to primary System Organ Class (SOC) and preferred term (PT) 
using MedDRA, Version xx or the latest version before database lock.  
The adverse event severity grading scale for the NCI CTCAE (V5.0) will be used for assessing 
adverse event severity. 
A treatment-emergent adverse event(TEAE) is defined as any adverse event reported, or 
worsening of an existing condition, on or after the first dose of study drug. AE analysis will be 
based on TEAEs, all AEs will be listed regardless of whether they are a TEAEs. 
An overview table, all AEs occurring after the initiation of treatment will be summarized. 
Summaries of AEs by grade, seriousness, and relationship to Atezolizumab or Bevacizumab will 
be presented, as well as summaries of adverse events of special interest (AESI) for this study, 
AESI related to Atezolizumab, AESI related to Bevacizumab, irAE, serious irAE related to 
Atezolizumab, Non- serious irAE related to Atezolizumab, infusion-related reaction (IRR), AEs 
leading to death, drug interrupted, drug withdrawn, study discontinuation from study.  


 
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The number (percent) of patients with AEs will also be summarized by SOC, PT and maximum 
grade according to CTCAE, Version 5.0. If a MedDRA term is reported more than once for a 
subject, that subject will be counted only once in the incidence count for that MedDRA term with 
closest relationship to study treatment. 
The number (percent) of patients with AEs will also be summarized by highest grade (≥ Grade 3) 
according to CTCAE, Version 5.0. 
AEs includes: 
 
TEAE 
 
Most Common(Incidence rate≥10%) TEAE 
 
TEAEs related to Atezolizumab 
 
TEAEs related to Bevacizumab 
 
TEAEs lead to drug interrupted (Atezolizumab) 
 
TEAEs lead to drug interrupted (Bevacizumab) 
 
TEAEs lead to drug withdrawn (Atezolizumab) 
 
TEAEs lead to drug withdrawn (Bevacizumab) 
 
TEAEs related to Atezolizumab lead to study discontinuation  
 
TEAEs related to Bevacizumab lead to study discontinuation  
 
Serious adverse events (SAE) 
 
≥ Grade 3 adverse events 
 
AESI 
 
AESI related to Atezolizumab 
 
AESI related to Bevacizumab 
 
TEAEs lead to death 
3.7.3 
Laboratory Data 
Laboratory results will be converted into System International (SI) units. For quantitative 
parameters (hematology, chemistry, coagulation, thyroid), descriptive statistics will be performed 
on the results and their changes from baseline of the scheduled visits. If the laboratory test result 
is ">" or "<", the lower limit or upper limit of the test result will be used as the analysis value. For 
example, if the result is'>100', the analysis value will be assigned as 100. 
For qualitative parameters (urinalysis) will be summarized base on reference range (normal, high, 
low) by visit. 
In order to further evaluate the laboratory test results of potential clinical significance, some 
specific parameters of hematology, chemistry and coagulation will be graded with CTCAE 
(version 5.0) if applicable. And shift table from baseline to maximum toxicity grade during 
treatment period will be summarized (based on all visits, including unscheduled visits). 
All grades will be based on lab values (direct or some derived values, or corrected values), 
regardless of the measures or symptoms consequences taken against them. 
A severity grade of 0 will be assigned when the value is within normal limits. 
In addition, some modifications to the grading system will be applied: 


 
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• 
Grade 5 refers to fatal outcomes, which cannot be determined solely by lab values, therefore 
will not appear in the grading system. 
• 
Grade 0 would include all other lab values without corresponding grades except missing 
values. 
• 
Missing results shall be graded as missing. 
For some specific parameters with CTCAE grading in both high and low direction (e.g., 
hemoglobin, lymphocyte count), CTCAE in high and low directions will be presented separately, 
i.e. hyper for higher values of concern and hypo for lower values of concern. 
All laboratory test, including thyroid function testing, pregnancy test and urinalysis will be 
performed in study and except pregnancy test, the abnormal results will be listed. 
3.7.4 
Vital Signs 
Descriptive statistics for vital signs parameters (respiratory rate, pulse rate, systolic and diastolic 
blood pressure, temperature and weight) and change from baseline will be presented by visit. 
These vital signs will be listed for each subject by visit. 
3.7.5 
Physical Examination Finding 
Physical examination findings are to be assessed as normal and abnormal (including Clinically 
Significant and Not Clinically Significant). Numbers and proportions of patients will be presented 
by visit and the worst findings of post-treatment (based on all visits, including unscheduled visits). 
And abnormal is worse than normal, abnormal, CS is worse than abnormal, NCS. A listing of 
physical examination findings will be provided by patients. 
3.7.6 
ECG Results 
At each visit, the ECG result is to be assessed as being normal, abnormal, not clinically 
significant, abnormal and clinically significant. Numbers and proportions of patients will be 
presented by visit and the worst findings of post-treatment (based on all visits, including 
unscheduled visits). And abnormal is worse than normal, abnormal, CS is worse than abnormal, 
NCS. A listing of ECG findings and parameter values will be provided by patients. 
3.7.7 
ECOG performance status 
ECOG performance status will be listed by subject. 
3.8 
HEALTH STATUS UTILITY ANALYSES 
To more fully characterize the clinical profile of atezolizumab, PRO data will be obtained 
through use of the following instruments: European Organization for Research and Treatment of 
Cancer (EORTC) quality-of-life questionnaires for cancer (EORTC QLQ-C30) and lung cancer 
(EORTC QLQ-LC13).  
The EORTC QLQ-C30 is an internationally validated cancer-specific HRQOL questionnaire. The 
30-item EORTC QLQ-C30 version 3 is composed by five multi-item function scales (physical, 
role, cognitive, emotional, and social), three multi-item symptom scales (fatigue, nausea and 
vomiting, and pain), six single-item symptom scales (dyspnea, insomnia, appetite loss, 
constipation, diarrhoea, and financial impact), and a two-item global quality of life scale (QL). 
For questions 1 to 28, the scores from 1 to 4 correspond to 'Not at All', 'A Little', 'Quite a Bit' and 
'Very Much' respectively. For questions 29 and 30, the scores range from 1 to 7, ranging from 
'Very poor' to 'Excellent'. The scoring rules state that higher scores for functional areas and 
general health areas indicate better functional status and quality of life, and higher scores for 


 
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symptom areas indicate more symptoms or problems (poor quality of life). Therefore, the scores 
in various fields are standardized as follows: 
The raw score for each field is calculated by dividing the total scores of items in each field by the 
number of entries. Second, the raw scores in each area will be standardized. The standard 
formulas are as follows: 
 
 
Function scales: Standard score= (1 − 
Raw score−1
Range
) × 100; 
 
Symptom scales and global quality of life scale: Standard score= (
Raw score−1
Range
) × 100. 
Where, the range represents the range of the entry scores, for example, if the item score range of 
an item is 1~4, then the range is 3. Similarly, if the item score range of an item is 1~7, then the 
range is 6. Error! Reference source not found. summarizes the scoring rules for each field. 
Table 3 Summary of relevant parameters of QLQ-C30 scoring 
Scales 
Nature of Scales 
Number of Item 
Range of 
Item 
Calculation of Raw Scores 
Global quality of life 
Global quality of life 
scale 
2 
6 
(Q29+Q30)/2 
Physical Functioning 
Functional 
5 
3 
(Q1+Q2+Q3+Q4+Q5)/5 
Role functioning 
Functional 
2 
3 
(Q6+Q7)/2 
Emotional 
functioning 
Functional 
4 
3 
(Q21+Q22+Q23+Q24)/4 
Cognitive functioning 
Functional 
2 
3 
(Q20+Q25)/2 
Social functioning 
Functional 
2 
3 
(Q26+Q27)/2 
Fatigue 
Symptom 
3 
3 
(Q10+Q12+Q18)/3 
Nausea and vomiting 
Symptom 
2 
3 
(Q14+Q15)/2 
Pain 
Symptom 
2 
3 
(Q9+Q19)/2 
Dyspnoea 
Symptom 
1 
3 
Q8 
Insomnia 
Symptom 
1 
3 
Q11 
Appetite loss 
Symptom 
1 
3 
Q13 
Constipation 
Symptom 
1 
3 
Q16 
Diarrhoea 
Symptom 
1 
3 
Q17 
Financial difficulties 
Symptom 
1 
3 
Q28 
Note：Qxx represents the score of question XX. 
 
EORTC QLQ-LC13 is a specific module for lung cancer. It consists of 13 items covering lung 
cancer symptoms (dyspnea, coughing, hemoptysis, pain in chest, pain in arm or shoulder and pain 
in other parts) and the side effects of chemo- and radiotherapy (alopecia, peripheral neuropathy, 


 
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sore mouth, and dysphagia), which are divided into 10 fields, all of which are symptom types. 
Error! Reference source not found. summarizes the scoring rules for each field. 
Table 4 Summary of relevant parameters of QLQ-LC13 scoring 
Scales 
Nature of Scales 
Number of Item 
Range of 
Item 
Calculation of Raw Scores 
Dyspnea 
Symptom 
3 
3 
(Q33+Q34+Q35)/3 
Coughing 
Symptom 
1 
3 
Q31 
Hemoptysis 
Symptom 
1 
3 
Q32 
Sore mouth 
Symptom 
1 
3 
Q36 
Dysphagia 
Symptom 
1 
3 
Q37 
Peripheral neuropathy 
Symptom 
1 
3 
Q38 
Alopecia 
Symptom 
1 
3 
Q39 
Pain in chest 
Symptom 
1 
3 
Q40 
Pain in arm or 
shoulder 
Symptom 
1 
3 
Q41 
Pain in other parts 
Symptom 
1 
3 
Q42 
Note：Qxx represents the score of question XX. 
 
Summary statistics will be reported for all of the items and subscales of EORTC QLQ-C30 
questionnaire and the QLQ-LC13 according to the EORTC scoring manual guidelines. The mean 
change of the linear transformed scores from baseline will also be assessed as well as the 
proportion of patients with improved, stable, or worsened outcomes. A patient will be classified 
as improved if a decrement of 10 points or worse is observed in the average change from baseline 
scores across all available timepoints; and a patient will be classified as worsened if a 10-point or 
greater increase is observed in the average change from baseline scores across all available 
timepoints. Otherwise, classified as stable. 
Completion and compliance rates will be summarized at each time point will be calculated as the 
number of patients who completed the assessment divided by the number of patients expected to 
complete the assessment at each time. Reasons for missing assessments, will be summarized 
using frequencies and percentages. 
A listing of questionnaires values will be provided by patients. 
Time to Deterioration (TTD) 
The analysis populations for TTD will be all enrolled patients with a non-missing baseline PRO 
assessment. 
TTD using EORTC is defined as the time from baseline (the start of the study treatment) to the 
first time the patient’s score shows a ≥10 points increase above baseline in any of the following 
EORTC-transformed symptom subscale scores (whichever occurs first):  
 
Cough (single item, question 31 on the EORTC QLQ-LC13),  
 
Dyspnea (single item, each question of 33,34,35 on the QLQ-LC13),  
 
Dyspnea (multi-items, questions 33-35 on the QLQ-LC13),  
 
Chest pain (single item, question 40 on the QLQ-LC13) 
 
Arm/shoulder pain (single item, question 41 on the QLQ-LC13) 
In order for the symptoms to be considered “deteriorated”, score increase of ≥ 10 points above 
baseline must be held for at least two consecutive assessment or an initial score increase of ≥ 10 


 
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points is followed by death within 3 weeks from the last assessment. A “≥10 point” change in the 
symptoms subscale score is perceived by patients as clinically significant. 
Patients will be censored at the last time when they complete an assessment if they have not 
deteriorated. If no post-baseline assessment is performed, patients will be censored at the first 
dose date plus 1 day.  
TTD using the EORTC scale will be analyzed using the same methods as for PFS. 
 
3.9 
MISSING DATA 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing unless specified. 
3.9.1 
Date of Initial Diagnosis 
Partial date of initial diagnosis will be imputed as below: 
• 
If year is missing (or completely missing), do not impute; 
• 
15th of the month will be imputed as the initial diagnosis date if only the day is missing; 
• 
July 1st of the year will be imputed as the initial diagnosis date if both the day and the 
month are missing; 
The imputed date will be compared to start date of study drug. If it is later than the study drug 
start date, the start date of study drug will be used to impute the incomplete date. 
3.9.2 
Prior and Concomitant Medications 
Start date of prior and concomitant medications 
• 
If only the day of the month is missing, use the first day of the month to replace the 
missing part.  
• 
If both the day and month are missing, January 1st will be used to replace the missing 
part.  
• 
If Day, Month and Year are all missing, use a date one day before the first 
administration date of study drug. 
End date of prior and concomitant medications 
• 
If only Day is missing, use the last day of the month. 
• 
If Day and Month are both missing, use the last day of the year. 
• 
If Day, Month and Year are all missing, assign ‘continuing’ status to stop date 
If the imputed concomitant end date is after the death date or the last known alive date, then the 
date of the death or last known alive will be imputed as the concomitant end date. 
3.9.3 
Adverse Events 
Onset date of AE  
If the AE onset date is completely missing, the AE start date will be imputed as the first 
administration date of study drug; 
If the AE onset date is partial missing, then  
• 
If both the year and month are available and the year and month are the corresponding 
year and month of the first administration date of study drug, then the AE onset date will be 
imputed as the first administration date of study drug; 


 
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• 
If both the year and month are available and the year or the month are not equal to the 
corresponding year and month of the first administration date of study drug, then the AE onset 
date will be imputed as the 1st date of the month; 
• 
If only the year is available and the available year is the corresponding year of the first 
administration date of study drug, then the AE onset date will be imputed as the first 
administration date of study drug; 
• 
If only the year is available, and the available year is not equal to the corresponding 
year of the first administration date of study drug, then the AE onset date will be imputed as the 
January 1st of the year.  
End date of AE 
• 
If both the year and month are available, AE end date will be imputed as the last day of 
the month; 
• 
If only the year is available, AE end date will be imputed as the December 31 of the 
year. 
• 
If the imputed AE end date is after the death date or the last known alive date, then the 
date of the death or last known alive will be imputed as the AE end date.  
For adverse events continuing at the cut-off date, the end date will not be imputed and will be 
reported as “ongoing”.  
3.9.4 
Last Known Alive Date 
Partial missing last known alive date will be imputed as below: 
• 
If both the day and the month are missing, January 1st of the year will be imputed.  
• 
If only the day of the month is missing, use the 1st of the month to impute the last 
known alive date. 
3.9.5 
Date of Death 
Missing or partial missing date of death will be imputed as below: 
• 
If the year is missing (or completely missing), death dates will be imputed as the last 
known alive date + 1 day.  
• 
If both the day and the month are missing, January 1st of the year will be imputed as the 
death dates.  
• 
If only the day of the month is missing, use the 1st of the month to impute the date of 
death. 
The imputed death date will be compared with the last known alive date (date of censoring for 
survival). The maximum of the (imputed death date, last known alive date + 1) will be considered 
as the date of death. 
3.9.6 
Date of Subsequent Anti-tumor Therapy 
Subsequent anti-tumor therapies include Post-Study Treatment NSCLC Therapy. 
• 
If only the day of the month is missing, the subsequent therapy will be assumed to start 
on the first day of given month if this day is latter than the last administration date of study drug. 
Otherwise, the subsequent therapy will be assumed to start on the next day following the last 
administration date of study drug. 
• 
If both the day and month are missing the subsequent therapy will be assumed to start 
on the first day of given year if this day is latter than the last administration date of study drug. 


 
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Otherwise, the subsequent therapy will be assumed to start on the next day following the last 
administration date of study drug. 
• 
 If the start date is totally missing, the subsequent therapy will be assumed on the next 
day following the last dosing date. 
3.10 
INTERIM ANALYSES 
One interim analysis is planned. The interim analysis will be performed for futility at the time of 
19 patients completing ORR evaluation. According to preplanned stopping rules of Simon 2-stage 
design, further testing of Atezolizumab and Bevacizumab would be halted if the number of 
patients that respond in the first evaluable 19 patients (stage 1) is less or equal than 6. This study 
has probability of 66.6% terminate at the first stage. 
The 19 subjects in phase I will be determined according to the order of enrollment (according to 
the date of informed consent) from evaluable population. 
When the study runs into the second stage, in the end of the study, if more than 16 patients out of 
39 patients have responses, we can recommend this treatment in IIIB-IV Non-squamous NSCLC 
to go to the next step in the clinical trial phase, otherwise, the treatment is rejected.  


 
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4. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
The Statistical Analysis Plan is developed based on this version 3.0 of the protocol. Three major 
changes are made to SAP from the protocol Amendment 3.0. Any further analysis changes made 
after this SAP is finalized will be documented with a SAP amendment or described in the clinical 
study report (CSR). 
Three major changes are as follows: 
1. In the protocol, the efficacy analysis will be based on FAS, which defined as all enrolled 
patients who receive any amount of study treatment and evaluable for efficacy endpoints. The 
analysis is not conservative for efficacy, hence in the SAP, FAS is defined as all enrolled patients 
who receive any amount at least one dose of any study treatment. All efficacy analysis except for 
primary analysis of ORR will use FAS, and patients without post-baseline radiologic assessment 
will be regarded as non-responder. 
2.For ORR analysis, the primary analysis will be based on evaluable population, which defined as 
all enrolled patients who receive any amount of study treatment, have baseline and at least one 
post-baseline efficacy measurement. 
3.In protocol, TTR analysis based on FAS, In the SAP, TTR will be analyzed for patients who 
achieved CR or PR, for non-responders will be excluded from the TTR analysis population. 
 


 
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5. 
REFERENCES 
Brian I Rini, Thomas Powles, Michael B Atkins et al.Atezolizumab plus bevacizumab versus 
sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a 
multicentre, open-label, phase 3,randomised controlled trial Lancet 2019; 393: 2404–15 
Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results 
from a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel 
in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin 
Oncol 2011;29:2866-74. 
Hodi FS, Friedlander PA, Atkins MB, et al. A phase I trial of ipilimumab plus bevacizumab in 
patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2011;29:8511. 
Huang Y, Chen X, Dikov MM, et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant 
hematopoiesis associated with elevated levels of VEGF. Blood 2007;110:624−31. 
Martin Reck, Tony S K Mok, Makoto Nishio et al Atezolizumab plus bevacizumab and 
chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients 
with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial 
Lancet Respir Med 2019; 7: 387–401 
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cell lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 
2012;13:239-46. 
Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte 
infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. 
Cancer Res 2010;70:6171−80. 
Tseng Y-H, Hung H-Y, Sung Y-C, Tseng Y-C, Lee Y-C, Whang-Peng J, et al. Efficacy of 
chemotherapy in epidermal growth factor receptor (EGFR) mutated metastatic pulmonary 
adenocarcinoma patients who had acquired resistance to first-line EGFR tyrosine kinase inhibitor 
(TKI). Journal of Chemotherapy. 2016 2016/01/02;28(1):50-8. 
Yang CJ, Tsai MJ, Hung JY, Liu TC, Chou SH, Lee JY, et al. Pemetrexed had significantly better 
clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations 
receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib 
treatment. OncoTargets and therapy. 2016;9:1579-87. 
E3, Structure and content of clinical study reports, International conference on harmonisation of 
technical requirements for registration of pharmaceuticals for human use, ICH harmonised 
tripartite guideline 


 
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E9, Statistical principles for clinical trials, International conference on harmonisation of technical 
requirements for registration of pharmaceuticals for human use, ICH harmonised tripartite 
guideline 
 
 
 


 
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Appendix 1 
 
Protocol Synopsis 
This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy 
and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with 
Stage IIIB-IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy. 
Patients should have received at least one EGFR TKI and have disease progressed before 
enrollment. 
This study will consist of a screening period (Day -28 to Day -1), a treatment period, a treatment 
discontinuation visit period (≤30 days after last dose) and a follow-up period. It is anticipated that 
this study will enroll about 44 patients at multiple sites in China. 
At screening, tumor specimens (either fresh or archival) from each potentially eligible patient will 
be tested for PD-L1 expression by a central laboratory using an IHC assay. The specimens will be 
tested PD-L1 expression by Ventana SP142 and SP 263.The patients will be tested T790M by 
blood or re-biospy tissue sample. Tumor EGFR mutation status will also be confirmed by central 
laboratory using either tissue or blood samples. 
Figure 2 presents an overview of the study design. A schedule of activities is provided in 
Appendix 2. 
Figure 2 Study Schema 
 
 
IV = intravenous; NSCLC = non-small cell lung cancer; 
All eligible enrollees will receive atezolizumab by intravenous (IV) infusion at a fixed dose of 
1200 mg on Day 1 of each 21-day cycle. Bevacizumab will be administered by IV infusion at 15 
mg/kg on Day 1 of each 21-day cycle. Patients will continue treatment until progressive disease, 
unacceptable toxicity, or death. Patients may continue treatment beyond radiographic progression 
by RECIST v1.1, provided they are experiencing clinical benefit as assessed by investigator (i.e., 
in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of radiographic data, 
biopsy results (if available), and clinical status (see below). Patients who temporarily or 
permanently discontinue either atezolizumab or bevacizumab may continue on single-agent 
therapy until disease progression (i.e., patients temporarily withdrawn from bevacizumab due to 
adverse effects may continue atezolizumab monotherapy and vice versa). Because of the 
possibility of an initial increase in tumor burden caused by immune-cell infiltration in the setting 
of a T-cell response (termed pseudoprogression) with atezolizumab treatment, radiographic 


 
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progression per RECIST v1.1 may not be indicative of true disease progression. In the absence of 
unacceptable toxicity, patients who meet criteria for disease progression per RECIST v1.1 while 
receiving atezolizumab will be permitted to continue atezolizumab if they meet all of the 
following criteria: 
 
 Evidence of clinical benefit, as determined by the investigator following a review of all 
available data 
 
 Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease 
 
 Absence of decline in ECOG Performance Status that can be attributed to disease 
progression 
 
 Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions. 
Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 
weeks following Cycle 1, Day 1, regardless of dose delays. After 36 weeks, tumor assessment 
will be required every 9 weeks (±7days). Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab 
treated patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs 
first. Patients who discontinue treatment for reasons other than radiographic disease progression 
(e.g., toxicity) will continue scheduled tumor assessments until radiographic disease progression 
per RECIST v1.1 or loss of clinical benefit (for atezolizumab treated patients who continue 
treatment after radiographic disease progression according to RECIST v1.1), withdrawal of 
consent, study termination by Sponsor, or death, whichever occurs first, even if patient starts 
another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn. 
 


 
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Appendix 2 
 
Schedule of Assessments 
 
Screening 
Treatment a 
Treatment 
discontinuation 
Survival follow-
up 
Days-28 to 
-1 
Every 21 days 
(±3 Days) 
≤30 days after 
Final Dose or at 
initiation of other 
anti-cancer therapy 
(whichever occurs 
first) 
Every 3 months 
after disease 
progression or 
loss of clinical 
benefit 
Informed consent 
Xb 
 
 
 
Tumor tissue specimen for PD-L1 and 
EGFR testing (5 FFPE slides required; 
blocks preferred)c 
Fresh or archival tissue can be used. 
X 
 
 
 
Demographic data 
X 
 
 
 
Medical history and baseline conditions 
X 
 
 
 
NSCLC Cancer History 
X 
 
 
 
Vital Signs d 
X 
X 
X 
 
Weight 
X 
X 
X 
 
Height 
X 
 
 
 
Complete physical examination 
X 
 
 
 
Limited physical examination e 
 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
 
12-Lead ECG 
X 
X f 
X f 
 
LVEFg 
X 
 
 
 
Hematology h 
X 
X 
X 
 
Chemistry i 
X 
X 
X 
 
Pregnancy testj 
X j 
X k 
X k 
 
Coagulation test (aPTT or INR) 
X 
 
X 
 
TSH, free T3, free T4 
X 
X l 
X l 
 
Viral serology (HIV,HBV,HCV）m 
X 
 
 
 
Urinalysis n 
X 
X 
X 
 
Blood sample for biomarkers o 
X 
 
 
Tumor response assessments 
X p 
X q,r 
 
X s 
Concomitant medications t 
X 
X 
X 
 
Adverse events u 
X 
X 
X 
X 
Study drugs infusion v 
 
X 
 
 
Patient-reported outcomes 
 
X w 
 
X x 
Survival and anti-cancer therapy follow-up 
 
 
X y 
X y 
a. Assessments should be performed before study drug infusion unless otherwise noted. 
b. Informed consent must be documented before any study-specific screening procedure is performed, and may be 
obtained more than 28 days before initiation of study treatment. 


 
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c. Optional biopsy at screening is the preferred method to collected the tumor specimens for PD-L1 expression at 
screening and T790M mutation For PD-L1 testing, if archival tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required. A pretreatment tumor biopsy may also be performed if a 
patient's archival tissue test results do not meet eligibility criteria. (section 4.5.6) 
d. Includes 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.  
e. Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other 
timepoints. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  
f. ECG recordings will be obtained during screening and as clinically indicated at other timepoints. Patients should be 
resting in a supine position for at least 10 minutes prior to ECG recording.  
g. Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for all patients, especially in 
those with cardiac risk factors and/or history of coronary artery disease or where low LVEF is suspected.  
h. Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential 
(neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count.  
i. Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total 
CO2, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  
j. All women of childbearing potential will have a serum pregnancy test within 14 days before Cycle 1, Day 1.  
k. Urine pregnancy tests performed at each subsequent visits; if a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test.  
l. TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 
and every four cycles thereafter  
m. At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody. If a patient has a negative 
HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to determine if the 
patient has an HBV infection. The patient could be enrolled if the HBV DNA is negative (below the lower detection 
limit of each site). If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed 
to determine if the patient has an HCV infection.  
n. Includes pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted.  
o. If T790m mutation unknown and re-biopsy tissue sample unavailable，blood sample will be tested for T790M.  
p. CT scans (with oral/IV contrast unless contraindicated) or MRI of the chest and abdomen. A CT or MRI scan of the 
pelvis is required at screening and as clinically indicated or as per local standard of care at subsequent response 
evaluations. A CT (with contrast) or MRI scan of the head must be done at screening to evaluate CNS metastasis in all 
patients. For patient with unknown bone metastases, if ALP ＞2.5xULN and ≤5x ULN and/or have symptom of suspect 
bone metastases，bone scan should be done at screening.  
q. Patients will undergo tumor assessments at baseline and every 6 weeks (±7days) for the first 36 weeks following 
Cycle 1, Day 1, regardless of dose delays. After 36 weeks, tumor assessment will be required every 9 weeks (±7days). 
Patients will undergo tumor assessments until radiographic disease progression per RECIST v1.1 or loss of clinical 
benefit (for atezolizumab treated patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
r. All measurable and evaluable lesions should be re-assessed at each subsequent tumor evaluation. The same 
radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., 
the same contrast protocol for CT scans).  
s. If a patient discontinues study treatment for any reason other than disease progression, tumor assessments will 
continue at the same frequency as would have been followed if the patient had remained on study treatment 
untilradiographic disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab treated patients who 
continue treatment after radiographic disease progression according to RECIST v1.1), withdrawal of consent, study 
termination by Sponsor, or death, whichever occurs first., even if patient starts another anti-cancer therapy after study 
treatment discontinuation, unless consent is withdrawn. 
t. 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 before screening until the 
treatment discontinuation visit.  
u. 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. After initiation of study treatment, all adverse events 
will be reported until 30 days after the final dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first, and serious adverse events and adverse events of special interest, regardless of 
relationship to study treatment, will be reported until 90 days after the last dose of study treatment or initiation of new 
non-protocol systemic anti-cancer therapy after the last dose of study treatment, whichever occurs first. After this 
period, all deaths, regardless of cause, should be reported. In addition, the investigator should report any serious 
adverse event or adverse events of special interest that is believed to be related to prior exposure to study treatment.  
v. The initial infusion of atezolizumab will be delivered over 60 (± 15) minutes. Subsequent infusions will be delivered 
over 30 (± 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 (± 15) 
minutes if the patient experienced an infusion-associated adverse event with the previous infusion. The initial dose of 


 
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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. The investigator should follow each AE 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 SAEs considered to be related to 
study drug or study-related procedures until a final outcome can be reported.w. PRO assessments will be completed 
before the patient receives any information on disease status and prior to the performance of non-PRO assessments and 
the administration of study treatment. Study personnel should review all questionnaires for completeness before the 
patient leaves the investigational site.  
x. During survival follow-up, the PRO questionnaires will be completed at 3 and 6 months following disease 
progression or loss of clinical benefit as determined by the investigator(for patients who continue atezolizumab after 
radiographic disease progression).  
y. After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted 
therapy and immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months (unless the patient withdraws consent or the Sponsor terminates the study). If a patient 
requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the 
investigator. If the patient withdraws from the study, the study staff may use a public information source (e.g., county 
records) to obtain information about survival status. 
 
 
 


 
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Appendix 3 
 
Preexisting Autoimmune Disease 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). Contact the Medical 
Monitor regarding any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
• 
Acute disseminated 
encephalomyelitis 
• 
Addison disease 
• 
Ankylosing spondylitis 
• 
Antiphospholipid antibody syndrome 
• 
Aplastic anemia 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune hepatitis 
• 
Autoimmune hypoparathyroidism 
• 
Autoimmune hypophysitis 
• 
Autoimmune myocarditis 
• 
Autoimmune oophoritis 
• 
Autoimmune orchitis 
• 
Autoimmune thrombocytopenic 
purpura 
• 
Behçet disease 
• 
Bullous pemphigoid 
• 
Chronic fatigue syndrome 
• 
Chronic inflammatory demyelinating 
polyneuropathy 
• 
Churg-Strauss syndrome 
• 
Crohn disease 
• 
Dermatomyositis  
• 
Diabetes mellitus type 
1  
• 
Dysautonomia  
• 
Epidermolysis bullosa 
acquisita  
• 
Gestational 
pemphigoid  
• 
Giant cell arteritis  
• 
Goodpasture 
syndrome  
• 
Graves disease  
• 
Guillain-Barré 
syndrome Hashimoto 
disease  
• 
IgA nephropathy  
• 
Inflammatory bowel 
disease  
• 
Interstitial cystitis  
• 
Kawasaki disease  
• 
Lambert-Eaton 
myasthenia syndrome  
• 
Lupus erythematosus  
• 
Lyme disease, chronic  
• 
Meniere syndrome  
• 
Mooren ulcer  
• 
Morphea  
• 
Multiple sclerosis  
• 
Myasthenia gravis  
 
Neuromyotonia  
• 
Opsoclonus myoclonus 
syndrome  
• 
Optic neuritis  
• 
Ord thyroiditis  
• 
Pemphigus  
• 
Pernicious anemia  
• 
Polyarteritis nodosa  
• 
Polyarthritis  
• 
Polyglandular autoimmune 
syndrome  
• 
Primary biliary cirrhosis  
• 
Psoriasis  
• 
Reiter syndrome  
• 
Rheumatoid arthritis  
• 
Sarcoidosis  
• 
Scleroderma  
• 
Sjögren syndrome  
• 
Stiff-Person syndrome  
• 
Takayasu arteritis  
• 
Ulcerative colitis  
• 
Vitiligo  
• 
Vogt-Koyanagi-Harada 
disease  
• 
Wegener granulomatosis