Atezolizumab in Combination With Bevacizumab in Patients With Unresectable Locally Advanced or Metastatic Mucosal Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Hoffmann-La Roche

Official Title: Atezolizumab in Combination With Bevacizumab in Patients With 
Unresectable Locally Advanced or Metastatic Mucosal Melanoma 
NCT Number: 
NCT04091217 
Document Date: 
Protocol Version 5: 13-July-2023 

Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol ML41186, Version 5 
PROTOCOL 
TITLE: 
ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB IN PATIENTS WITH UNRESECTABLE 
LOCALLY ADVANCED OR METASTATIC MUCOSAL 
MELANOMA 
PROTOCOL NUMBER: ML41186 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
NA 
TEST PRODUCT: 
Atezolizumab, Bevacizumab 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
See electronic date stamp below
DATES AMENDED: 
Version 1: 5-Mar-2019
Version 2: 30-Apr-2019
Version 3: 28-Feb-2020
Version 4: 08-Aug-2021
FINAL PROTOCOL APPROVAL 
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document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol ML41186, Version 5 
 
PROTOCOL AMENDMENT, VERSION 5 
Comparison with Version 4: 
SUMMARY OF CHANGES 
 
1. Updated the risk associated with atezolizumab (including addition of AEs of special interest for 
atezolizumab: facial paresis and myelitis) and management guidelines (Section 5.1.1 and Section 
5.2.3.1 and Appendix 9) due to the update of safety information for atezolizumab 
2. Additional minor changes were made to ensure clarity and consistency.

Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol ML41186, Version 5 
 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM ................................................................................ 9 
PROTOCOL SYNOPSIS ............................................................................................... 10 
1. 
BACKGROUND ..................................................................................................... 21 
1.1 
Background on MUCOSAL MELANOMA ........................................ 21 
1.2 
Treatment for MUCOSAL MELANOMA .......................................... 22 
1.3 
Background on Atezolizumab ......................................................... 22 
1.4 
Background on Bevacizumab ......................................................... 23 
1.5 
Rationale  for  Testing   Atezolizumab      Bevacizumab 
Combination ................................................................................... 23 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................... 25 
2.1 
Efficacy Objectives ......................................................................... 25 
2.1.1 PRIMARY EFFICACY OBJECTIVE ....................................................................... 25 
2.1.2 SECONDARY EFFICACY OBJECTIVE ................................................................. 25 
2.2 
Safety Objective ............................................................................. 26 
3. 
STUDY DESIGN ................................................................................................... 26 
3.1 
Description of the Study ................................................................. 26 
3.1.1OVERVIEW OF STUDY DESIGN .......................................................................... 26 
3.2 
End of Study and Length of Study .................................................. 27 
3.3 
Rationale for Study Design ............................................................. 27 
3.3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE ....................... 27 
3.3.2 
RATIONALE FOR BEVACIZUMAB DOSE AND SCHEDULE ......................... 28 
3.3.3 
RATIONALE FOR OPEN-LABEL SINGLE-ARM STUDY ................................ 28 
3.3.4 RATIONALE FOR ATEZOLIZUMAB TREATMENT BEYOND 
INITIAL RADIOGRAPHIC PROGRESSION ........................................................... 28 
4. 
MATERIALS AND METHODS ............................................................................... 29 
4.1 
Patients .......................................................................................... 29 
4.1.1 INCLUSION CRITERIA ......................................................................................... 29 

Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol ML41186, Version 5 
 
4.1.2 EXCLUSION CRITERIA ........................................................................................ 31 
4.2 
Study Treatment and Other Treatments Relevant to 
the Study Design ............................................................................ 35 
4.2.1 STUDY     TREATMENT      FORMULATION,      PACKAGING,      AND 
HANDLING ............................................................................................................ 35 
4.2.2 STUDY    TREATMENT     DOSAGE,     ADMINISTRATION,     AND 
COMPLIANCE....................................................................................................... 35 
4.2.3 INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY ........................ 38 
4.3 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions .................................................................... 39 
4.3.1 PERMITTED THERAPY ........................................................................................ 39 
4.3.2 CAUTIONARY       THERAPY       FOR       ATEZOLIZUMAB-TREATED 
PATIENTS ............................................................................................................. 40 
4.3.3 CAUTIONARY THERAPY SPECIFIC TO BEVACIZUMAB .................................... 40 
4.3.4 PROHIBITED THERAPY ....................................................................................... 40 
4.3.5 CONTINUED ACCESS TO ATEZOLIZUMAB AND BEVACIZUMAB ..................... 41 
4.4 
Study Assessments ........................................................................ 41 
4.4.1 INFORMED CONSENT FORMS AND SCREENING LOG ..................................... 41 
4.4.2 MEDICAL HISTORY, CONCOMITANT MEDICATION, AND 
DEMOGRAPHIC DATA ......................................................................................... 42 
4.4.3 PHYSICAL EXAMINATIONS ................................................................................. 42 
4.4.4 VITAL SIGNS ........................................................................................................ 42 
4.4.5 TUMOR AND RESPONSE EVALUATIONS .......................................................... 43 
4.4.6 LABORATORY, BIOMARKER, AND OTHER BIOLOGICAL 
SAMPLES ............................................................................................................. 44 
4.4.7 ELECTROCARDIOGRAMS................................................................................... 45 
4.5 
Treatment, Patient, Study, and Site Discontinuation ....................... 45 
4.5.1 STUDY TREATMENT DISCONTINUATION .......................................................... 45 
4.5.2 PATIENT DISCONTINUATION FROM THE STUDY ............................................. 46 
4.5.3 STUDY DISCONTINUATION ................................................................................ 46 

Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol ML41186, Version 5 
 
4.5.4 SITE DISCONTINUATION .................................................................................... 47 
5. 
ASSESSMENT OF SAFETY ................................................................................. 47 
5.1 
Safety Plan ..................................................................................... 47 
5.1.1 RISKS ASSOCIATED WITH ATEZOLIZUMAB ...................................................... 48 
5.1.2 RISKS ASSOCIATED WITH BEVACIZUMAB ....................................................... 48 
5.2 
Safety Parameters and Definitions ................................................. 48 
5.2.1 ADVERSE EVENTS .............................................................................................. 48 
5.2.2 SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO 
THE SPONSOR) ................................................................................................... 49 
5.2.3 ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) .................................................................... 50 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters .......................................................................... 51 
5.3.1 ADVERSE EVENT REPORTING PERIOD ............................................................ 51 
5.3.2 ELICITING ADVERSE EVENT INFORMATION .................................................... 52 
5.3.3 ASSESSMENT OF SEVERITY OF ADVERSE EVENTS ....................................... 52 
5.3.4 ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS ..................................... 53 
5.3.5 PROCEDURES FOR RECORDING ADVERSE EVENTS ..................................... 53 
5.4 
Immediate Reporting Requirements from Investigator 
to Sponsor ...................................................................................... 59 
5.4.1 EMERGENCY MEDICAL CONTACTS .................................................................. 60 
5.4.2 REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST .............................. 60 
5.4.3 REPORTING REQUIREMENTS FOR PREGNANCIES ........................................ 61 
5.5 
Follow-Up of Patients after Adverse Events .................................... 62 
5.5.1 INVESTIGATOR FOLLOW-UP .............................................................................. 62 
5.5.2 SPONSOR FOLLOW-UP ...................................................................................... 63 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ............................................................................ 63 
5.7 
Expedited Reporting to Health Authorities, 

Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Protocol ML41186, Version 5 
 
Investigators, Institutional Review Boards, and Ethics 
Committees .................................................................................... 63 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .................................. 64 
6.1 
Determination of Sample Size ........................................................ 64 
6.2 
Summaries of Conduct of Study ..................................................... 66 
6.3 
Summaries of Demographic and Baseline 
Characteristics ............................................................................... 66 
6.4 
Efficacy Analyses ........................................................................... 66 
6.4.1 PRIMARY EFFICACY ENDPOINT ........................................................................ 66 
6.4.2 SECONDARY EFFICACY ENDPOINTS ................................................................ 66 
6.5 
Safety Analyses.............................................................................. 67 
6.6 
Interim Analysis .............................................................................. 68 
7. 
DATA COLLECTION AND MANAGEMENT .......................................................... 68 
7.1 
Data Quality Assurance .................................................................. 68 
7.2 
Electronic Case Report Forms ........................................................ 69 
7.3 
Source Data Documentation ........................................................... 69 
7.4 
Use of Computerized Systems ....................................................... 69 
7.5 
Retention of Records ...................................................................... 70 
8. 
ETHICAL CONSIDERATIONS .............................................................................. 70 
8.1 
Compliance with Laws and Regulations ......................................... 70 
8.2 
Informed Consent ........................................................................... 70 
8.3 
Institutional Review Board or Ethics Committee .............................. 71 
8.4 
Confidentiality ................................................................................. 72 
8.5 
Financial Disclosure ....................................................................... 72 
9. 
STUDY        DOCUMENTATION,        MONITORING,         AND 
ADMINISTRATION ................................................................................................ 73 
9.1 
Study Documentation ..................................................................... 73 
9.2 
Protocol Deviations ........................................................................ 73 
9.3 
Site Inspections .............................................................................. 73 
9.4 
Administrative Structure ................................................................. 73 
9.5 
Dissemination    of     Data     and     Protection     of     Trade 
Secrets ........................................................................................... 73 
9.6 
Protocol Amendments .................................................................... 74 

Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol ML41186, Version 5 
 
10. REFERENCES ...................................................................................................... 75 
 
 
 
 
LIST OF TABLES 
 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions ........... 36 
Table 2 
Administration of First and Subsequent Bevacizumab Infusions ........... 38 
Table 3 
Timing for Vital Sign Measurements for First and Subsequent 
Infusions .............................................................................................. 42 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE............................................................................ 52 
Table 5 
Causal Attribution Guidance ................................................................. 53 
Table 6 
Criteria for Overall Response at a Single Timepoint:  Patients with 
Target Lesions (with or without Non-Target Lesions) ............................ 89 
Table 7 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis ......................................................................................... 99 
Table 8 
Management Guidelines for Hepatic Events ....................................... 101 
Table 9 
Management Guidelines for Gastrointestinal Events  (Diarrhea  or 
Colitis) ................................................................................................ 102 
Table 10 
Management Guidelines for Endocrine Events ................................... 104 
Table 11 
Management Guidelines for Ocular Events ........................................ 107 
Table 12 
Management Guidelines for Immune-Mediated Myocarditis ............... 109 
Table 13 Management Guidelines for Infusion-Related Reactions and Cytokine- 
Release Syndrome ............................................................................. 112 
Table 14 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis ........................................................................................ 115 
Table 15 
Management Guidelines for Dermatologic Events .............................. 118 
Table 16 
Management Guidelines for Neurologic Disorders .............................. 120 
Table 17 
Management Guidelines for Immune-Mediated Myelitis ..................... 125 
Table 18 
Management Guidelines for Immune-Mediated 
Meningoencephalitis .......................................................................... 126 
Table 19 
Management Guidelines for Renal Events ......................................... 127 
Table 20 
Management Guidelines for Immune-Mediated Myositis .................... 138 
Table 21 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome ................. 143 
 
 
LIST OF FIGURES 
 
Figure 1 Study Schema ................................................................................................ 26 
Figure 2  Sample Size Allocation ................................................................................... 65 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities .......................................................................... 78 

Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Protocol ML41186, Version 5 
 
Appendix 2 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) ................................................................... 83 
Appendix 3 
New York Heart Association Functional Classification ......................... 92 
Appendix 4 
ECOG Performance Status ................................................................. 93 
Appendix 5 
Corticosteroid Dose Equivalents.......................................................... 94 
Appendix 6 
Preexisting Autoimmune Diseases and Immune Deficiencies .............. 95 
Appendix 7 
Anaphylaxis Precautions ..................................................................... 96 
Appendix 8 
 Overall Guidelines for Management of Patients Who Experience 
Adverse Events .................................................................................... 97 
Appendix 9 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab ........... 98 
Appendix 10 
 Guidelines for Management of Patients Who Experience 
SpecificAdverse Events with Atezolizumab+Bevacizumab ................. 127 

Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol ML41186, Version 5 
 
PROTOCOL ACCEPTANCE FORM 
 
TITLE: 
ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB IN PATIENTS WITH UNRESECTABLE 
LOCALLY ADVANCED OR METASTATIC MUCOSAL 
MELANOMA 
PROTOCOL NUMBER: ML41186 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
NA 
TEST PRODUCT: 
Atezolizumab, Bevacizumab 
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 your local study monitor. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol ML41186, Version 5 
 
PROTOCOL SYNOPSIS 
 
TITLE: 
ATEZOLIZUMAB IN COMBINATION WITH BEVACIZUMAB 
IN PATIENTS WITH UNRESECTABLE LOCALLY 
ADVANCED OR METASTATIC MUCOSAL MELANOMA 
PROTOCOL NUMBER: 
ML41186 
VERSION NUMBER: 
5 
 
EUDRACT NUMBER: 
NA 
 
IND NUMBER: 
NA 
 
TEST PRODUCT: 
Atezolizumab, Bevacizumab 
 
PHASE: 
Phase II 
 
INDICATION: 
Mucosal Melanoma 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab (atezo  bev) in patients with unresectable locally advanced or metastatic 
mucosal melanoma. Specific objectives and corresponding endpoints for the study are outlined 
below. 
Primary Efficacy Objective 
• 
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 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Secondary Efficacy Objective 
• 
Progression-free survival (PFS), defined as the time from the date of first 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 
• 
Overall survival (OS), defined as the time from the date of first treatment to death from any 
cause 
• 
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 
• 
Disease control rate (DCR) (defined as the sum of a complete or partial response or stable 
disease rates) as determined by the investigator according to RECIST v1.1. 
Safety Objective 
The primary safety objective for this study is to evaluate the safety of atezolizumab + 
bevacizumab on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 
(CTCAE v5.0) 
• 
Changes in vital signs, physical examination findings, and clinical laboratory results during 
and following study treatment 

Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol ML41186, Version 5 
 
Study Design 
Description of Study 
This is an open-label, multicenter, single arm, phase II study exploring the efficacy and safety of 
atezo + bev in patients with unresectable locally advanced or metastatic mucosal melanoma. 
The trial will consist of a Screening Period (Day –28 to −1), a Treatment Period, a Treatment 
Discontinuation Visit occurring when atezolizumab and bevacizumab are both discontinued for 
any reason and a Survival Follow-Up Period until death, loss to follow-up, or study termination. 
Patients will be asked to attend clinic visits at regular intervals during the study for safety and 
efficacy assessments. 
The study is divided into 2 stages. Stage I of the study is completed when 22 patients with 
measurable disease have been enrolled and completed ORR evaluation. If the number of 
responders in Stage I is more than 3, another 16 patients may be enrolled to Stage II. 
Considering a drop-out rate of 10%, a total number of 25 subjects (if stops at the first stage) or 
43 subjects (if runs into the second stage) will need to be enrolled in this study. 
Atezolizumab and/or bevacizumab will be administered until unacceptable toxicity or loss of 
clinical benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data (e.g., LDH level), local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease). 
Patients who transiently withhold or permanently discontinue either atezolizumab or 
bevacizumab may continue on single-agent therapy as long as the patients are experiencing 
clinical benefit in the opinion of the investigator. 
Number of Patients 
The study will enroll 38 subjects that fully evaluable for ORR (approximately 43 patients in total 
considering 10% dropout rate), including study Stages I and II. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed Informed Consent Form 
2. 
Age  18 and ≤75 years at time of signing Informed Consent Form 
3. 
Ability to comply with the study protocol, in the investigator's judgment 
4. 
Histologically confirmed unresectable locally advanced(stage III) or metastatic(Stage IV) 
mucosal melanoma 
5. 
May have received prior systemic treatment or treatment naive at enrollment 
6. 
Measurable disease per RECIST v1.1 
7. 
ECOG Performance Status of 0-1 
8. 
Life expectancy  12 weeks 
9. 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment: 
1) 
ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor support, G- 
CSF may be administered until 2 weeks prior to Cycle 1, Day 1 
2) 
Lymphocyte count  0.5  109/L (500/L) 
3) 
Platelet count  100  109/L (100,000/L) without transfusion, transfusion may be 
administered until 2 weeks prior to Cycle 1, Day 1 
4) 
Hemoglobin  90 g/L (9 g/dL) 
i. 
Patients may be transfused to meet this criterion. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol ML41186, Version 5 
 
5) 
AST, ALT, and alkaline phosphatase (ALP)  2.5  upper limit of normal (ULN), with the 
following exceptions: 
i. 
Patients with documented liver metastases:  AST and ALT  5  ULN 
ii. 
Patients with documented liver or bone metastases:  ALP  5  ULN 
6) 
Serum bilirubin  1.5  ULN with the following exception: 
i. 
Patients with known Gilbert disease: serum bilirubin level  3  ULN 
7) 
Serum creatinine  1.5  ULN 
8) 
Serum albumin  25 g/L (2.5 g/dL) 
9) 
For patients not receiving therapeutic anticoagulation: INR or aPTT  1.5  ULN 
10. Negative HIV test at screening 
11. Negative hepatitis B surface antigen (HBsAg) test at screening 
12. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by quantitative hepatitis B virus (HBV) DNA<500 IU/mL at screening 
13. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
1) 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
14. 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: 
1) 
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, or 6 months after the final dose of bevacizumab, whichever is longer. 
Women must refrain from donating eggs during this same period. 
2) 
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. 
3) 
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. 
4) 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol ML41186, Version 5 
 
15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below: 
1) 
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. 
2) 
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. 
3) 
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. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Symptomatic or actively progressing central nervous system (CNS) metastases 
1) 
Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that 
all of the following criteria are met: 
i. 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
ii. 
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
iii. 
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. 
iv. 
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease. Anticonvulsant therapy at a stable dose is permitted. 
v. 
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord). 
vi. 
There is no evidence of interim progression between completion of CNS-directed 
therapy (if administered) and initiation of study treatment. 
2) 
Asymptomatic patients with CNS metastases newly detected at screening are eligible 
for the study after receiving radiotherapy or surgery, with no need to repeat the 
screening brain scan. 
2. 
History of leptomeningeal disease 
3. 
Uncontrolled tumor-related pain 
1) 
Patients requiring pain medication must be on a stable regimen at study entry. 
2) 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol ML41186, Version 5 
 
Patients should be recovered from the effects of radiation. There is no required 
minimum recovery period. 
3) 
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. 
4. 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
1) 
Patients with indwelling catheters are allowed. 
5. 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium  12 
mg/dL or corrected serum calcium  ULN) 
6. 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 
with the following exceptions: 
1) 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
2) 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
3) 
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: 
i. 
Rash must cover  10% of body surface area 
ii. 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
iii. 
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 
7. 
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 
1) 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
8. 
Active tuberculosis 
9. 
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 
1) 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
15/Protocol ML41186, Version 5 
 
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 
2) 
Patients with known LVEF < 40% 
10. 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 
11. History of malignancy other than melanoma 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 
12. 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 
13. Prior allogeneic stem cell or solid organ transplantation 
14. 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 
15. Current treatment with anti-viral therapy for HBV 
16. 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 
17. Current, recent (within 28 days prior to initiation of study treatment) or planned treatment 
with any other investigational agent or participation in another clinical study with anti-cancer 
therapeutic intent 
18. Prior treatment with immune checkpoint agonists, including CD137 agonists and TLR9 
agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and 
antiPD-L1 therapeutic antibodies 
19. Prior treatment with anti-angiogenic therapies 
20. 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 as well as prior cancer vaccines and cellular immunotherapy 
21. Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF- 
agents, as well as T and B cell targeting biologic 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: 
1) 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
16/Protocol ML41186, Version 5 
 
2) 
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. 
22. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
23. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
24. Known allergy or hypersensitivity to any component of the bevacizumab formulation 
25. 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 
1) 
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
26. Inadequately controlled hypertension (defined as systolic blood pressure  150 mmHg 
and/or diastolic blood pressure  100 mmHg) 
1) 
Anti-hypertensive therapy to achieve these parameters is allowable. 
27. Prior history of hypertensive crisis or hypertensive encephalopathy 
28. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1 
29. Patients with a baseline ECG demonstrating a QTc > 460 msec (calculated with use of the 
Fridericia method) 
30. History of Grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood per episode) within 
1 month prior to screening 
31. History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1 
32. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation) 
33. Prophylactic or therapeutic use of low molecular weight heparin (e.g., enoxaparin), direct 
thrombin inhibitors, or warfarin are permitted, provided, where appropriate anticoagulation 
indices are stable. Patients should have been on a stable dose (for therapeutic use) for at 
least 2 weeks (or until reaching steady state level of the drug) prior to the first study 
treatment 
34. Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 325 
mg/day), clopidogrel (> 75 mg/day) or treatment with dipyramidole, ticlopidine, or cilostazol 
1) 
Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purpose is 
permitted as long as the INR and/or aPTT is within therapeutic limits (according to 
institution standards) within 7 days prior to initiation of study treatment and the patient 
has been on a stable dose of anticoagulants for ≥ 2 weeks prior to initiation of study 
treatment. Prophylactic use of anticoagulants is allowed. 
35. Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 calendar days prior to the first dose of bevacizumab 

Atezolizumab—F. Hoffmann-La Roche Ltd 
17/Protocol ML41186, Version 5 
 
36. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 
6 months prior to Cycle 1, Day 1 
37. Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding 
38. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure 
39. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
40. Proteinuria, as demonstrated by urinalysis or  1.0 g of protein in a 24-hour urine collection 
1) 
All patients with  2 protein on urinalysis at baseline must undergo a 24-hour urine 
collection for protein. 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs. The 
end of the study is expected to occur 20 months after the last patient is enrolled. In addition, 
the Sponsor may decide to terminate the study at any time. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2 years and 9 months. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The dose of atezolizumab in this study will be 1200 mg administered by intravenous infusion 
every 3 weeks. 
The dose of bevacizumab in this study will be 7.5 mg/kg administered by intravenous infusion 
every 3 weeks. 
Statistical Methods 
The efficacy analyses will be performed on the Full Analysis Set (FAS) population, defined as all 
enrolled patients who receive any amount of study treatment and evaluable for efficacy 
endpoints. 
The safety analysis will be performed on the safety-evaluable population, defined as all enrolled 
patients who receive at least one dose of any study treatment. 
Other analyses (Demography, Baseline Characteristics, .etc.) will be performed on the basis of 
all enrolled patients (the ITT population), regardless of whether they receive any assigned study 
drug. 
Primary Analysis 
The primary efficacy endpoint is ORR, as assessed by the Investigator using RECIST, v1.1. 
Number and percentage of responders with corresponding Clopper-Pearson 95% confidence 
intervals will be provided. 
Estimates for the time-to-event variables, such as PFS, OS, DOR, will be obtained by using the 
Kaplan-Meier (KM) approach together with associated 95% CI. 
Determination of Sample Size 
The sample size calculation was based on a Simon two-stage design, and the primary end point 
was ORR (H0 = 20%, H1  = 40%). Two-sided alpha is set to be 0.05 and statistical power is set 
to be 80%. 
22 fully evaluable subjects will be included at the first stage, and if the study continues another 
16 fully evaluable subjects will be included in the second stage. Thus, considering a drop-out 
rate of 10%, a total number of 25 subjects (if stops at the first stage) or 43 subjects (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 
22 subjects completes ORR evaluation. According to preplanned stopping rules of Simon 2- 

Atezolizumab—F. Hoffmann-La Roche Ltd 
19/Protocol ML41186, Version 5 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event Of Special Interest 
ALM 
Acral Lentiginous Melanoma 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATE 
Arterial Thromboembolism 
BRAF 
V-Raf Murine Sarcoma Viral Oncogene Homolog B1 
BUN 
Blood Urea Nitrogen 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CRC 
Carcinoma Of The Colon Or Rectum 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4 
DCR 
Disease Control Rate 
DLT 
Dose Limited Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration Of Response 
EC 
Ethics Committee 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EORTC 
European Organisation For Research And Treatment 
Of Cancer 
EOC 
Epithelial Ovarian Cancer 
EU 
European Union 
FAS 
Full Analysis Set 
FTC 
Fallopian Tube Cancer 

Atezolizumab—F. Hoffmann-La Roche Ltd 
20/Protocol ML41186, Version 5 
 
GBM 
Glioblastoma Multiforme 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IC 
Tumor-Infiltrating Immune Cell 
ICF 
Informed Consent Form 
ICH 
International Council For Harmonisation 
IgG1 
Immunoglobulin G1 
IL-2 
Interleukin 2 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LPLV 
Last Patient, Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary For Regulatory Activities 
MEK 
Mitogen-Activated Protein Kinase (MAPK) Or 
Extracellular Signal―Regulated Kinase (ERK) Kinase 
MRI 
Magnetic Resonance Imaging 
NA 
Not Applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death-Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PPC 
Primary Peritoneal Cancer 
PR 
Partial Response 
Q3W 
Every 3 Weeks 
RBC 
Red Blood Cell 

Atezolizumab—F. Hoffmann-La Roche Ltd 
22/Protocol ML41186, Version 5 
 
may have a poorer stage-matched survival than other melanoma subtypes from the time 
of development of clinical metastatic disease (Shoushtari, et al. 2017). 
1.2 
TREATMENT FOR MUCOSAL MELANOMA 
Since 2011, the treatment of cutaneous melanoma has been revolutionized by targeted 
therapy against BRAF and MEK and immunotherapy against immune-checkpoints. 
 
Although National Comprehensive Cancer Network (NCCN) guidelines suggest that the 
treatment of mucosal melanoma can refer to cutaneous melanoma, responses to 
treatment differ significantly between mucosal and cutaneous melanoma. 
 
In a pooled analysis of 889 patients from 5 studies who received nivolumab 
monotherapy in clinical studies, median progression-free survival was 3.0 months (95% 
Confidence Interval (CI), 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) 
for mucosal and cutaneous melanoma, with objective response rates (ORR)of 23.3% 
(95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively (D’Angelo, 
et al. 2016). 
 
Results from other studies also showed the efficacy of immune-checkpoint inhibitors is 
inferior in mucosal melanoma than in cutaneous melanoma (Del vecchio, et al.2014 
Shoushtari, et al 2016 Butler, et al. 2017). 
 
BRAF mutation rate is relatively low as 10.7% in mucosal melanoma (Bai, et al. 
2017).There have been few reports of BRAF inhibitors specifically in this population. In 
one study, ORR was 20% with PFS and overall survival (OS) of 4.4 (95%CI 0.8-12.7) 
months and 8.2 (95%CI 6.6-19.9) months, respectively (Bai, et al. 2017). 
 
KIT (commonly known as c-KIT) mutations have been associated most commonly with 
mucosal and acral subtypes of melanoma (Curtin, et al. 2006). Phase II studies testing 
imatinib in patients with KIT-mutation or KIT amplified metastatic melanoma (46%-71% 
mucosal) demonstrated 20% to 30% ORR (Guo, et al. 2011 Carvajal, et al. 2011 Hodi, et 
al. 2013 ). 
 
Therefore, alternative treatment options that yield higher responses and enhance PFS 
and OS remain an important focus of research. 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
23/Protocol ML41186, Version 5 
 
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, non-small cell lung 
cancer (NSCLC), triple-negative breast cancer (TNBC), and small cell lung cancer (SCLC) 
 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.4 
BACKGROUND ON BEVACIZUMAB 
Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that 
binds to and inhibits the biologic activity of human vascular endothelial growth factor 
(VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework 
regions and the complementarity-determining regions of a murine antibody that binds to 
VEGF, and has an approximate molecular weight of 149 kD. Bevacizumab is produced 
in a mammalian Chinese hamster ovary cell line. 
 
Bevacizumab was first granted marketing approval in the United States on 
26 February 2004 (international birth date) in combination with IV 5-fluorouracil 
(5-FU)based chemotherapy for the first-line treatment of patients with metastatic 
carcinoma of the colon or rectum (CRC). As of November 2016, bevacizumab has been 
approved for use in over a 100 countries worldwide in a variety of indications, including 
locally recurrent or metastatic breast cancer; advanced, metastatic, or recurrent NSCLC; 
advanced and/or metastatic renal cell cancer (RCC); newly diagnosed glioblastoma 
multiforme (GBM) and GBM after relapse or disease progression; persistent, recurrent, 
or metastatic cervical cancer; front-line treatment of epithelial ovarian cancer (EOC), 
primary peritoneal cancer (PPC), or fallopian tube cancer (FTC); and treatment of 
platinum-sensitive and platinum-resistant recurrent EOC, PPC, or FTC. 
1.5 
RATIONALE FOR TESTING ATEZOLIZUMAB  BEVACIZUMAB 
COMBINATION 
Experience to date with atezolizumab in mucosal melanoma is from Study PCD4989g, in 
which atezolizumab monotherapy only demonstrated limited efficacy in this population. 
Study PCD4989g is an ongoing Phase Ia, open-label, dose-escalation trial to assess the 
safety, pharmacokinetics and efficacy of atezolizumab administered as a single agent to 
patients with solid tumors. As of 1 Jan 2014, a total of 45 patients with melanoma have 
been treated with atezolizumab monotherapy with a minimum follow up of 15 months. 
The confirmed ORR by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 

Atezolizumab—F. Hoffmann-La Roche Ltd 
24/Protocol ML41186, Version 5 
 
was 28% in all efficacy-evaluable patients, 20% in 5 mucosal melanoma patients. 
Median PFS was 4.2 months (range, 0.9-19.6+ months) among all efficacy-evaluable 
melanoma patients(Hodi, et al. 2014). 
 
Beyond its known anti-angiogenic effects (Ferrara, et al. 2004), bevacizumab has been 
shown to give immunomodulatory effects in combination with check-point inhibitors. 
Bevacizumab stimulates dendritic cell maturation which promotes T cell priming and 
activation (Gabrilovich, et al. 1996 Oyama, et al. 1998). The normalization effect of 
bevacizumab on tumor vasculature increases T-cell tumor infiltration (Motz, et al. 2014 
Wallin, et al. 2016). Bevacizumab establishes an immune-permissive tumor 
microenvironment by decreasing myeloid-derived suppressor cells and regulatory T-cell 
populations (Roland, et al. 2009, Facciabene, et al. 2011). 
 
Currently there is no preclinical data or prior clinical experience of the combination of 
atezolizumab  bevacizumab available in mucosal melanoma. However there is 
sufficient rationale for exploring the efficacy and safety of atezolizumab  bevacizumab 
in patients with mucosal melanoma. To address the ongoing high unmet medical need 
for patients with mucosal melanoma, this study aims to evaluate the efficacy and safety 
of atezolizumab  bevacizumab in patients with locally advanced or metastatic mucosal 
melanoma. 
 
In the setting of the COVID-19 pandemic, patients with comorbidities, including those 
with cancer, are considered a more vulnerable population, with the potential for more 
severe clinical outcomes from COVID-19. However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19. 
 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses. In nonclinical models, PD 1/PD L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012). However, there are insufficient and inconsistent clinical 
data to assess if outcome from COVID-19 is altered by cancer immunotherapy. 
 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- 
(Merad and Martin 2020). While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute SARS 
CoV-2 infection while receiving atezolizumab. At this time, there is insufficient evidence 
for causal association between atezolizumab and an increased risk of severe outcomes 
from COVID-19. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
25/Protocol ML41186, Version 5 
 
There may be potential synergy or overlap in clinical and radiologic features for immune 
mediated pulmonary toxicity with atezolizumab and clinical and radiologic features for 
COVID-19-related interstitial pneumonia. Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab (atezo+bev) in patients with unresectable locally advanced or metastatic 
mucosal melanoma. Specific objectives and corresponding endpoints for the study are 
outlined below. 
 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., atezolizumab and bevacizumab). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of atezo  bev on 
the basis of the following endpoint: 
 
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 Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of atezo  bev 
on the basis of the following endpoints: 
 
Progression-free survival (PFS), defined as the time from the date of first 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. 
 
Overall survival (OS), defined as the time from the date of first treatment to death 
from any cause. 
 
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. 
 
Disease control (defined as the sum of the CR, PR and stable disease (SD) rates) 
as determined by the investigator according to RECIST v1.1 

Atezolizumab—F. Hoffmann-La Roche Ltd 
26/Protocol ML41186, Version 5 
 
2.2 
SAFETY OBJECTIVE 
The primary safety objective for this study is to evaluate the safety of atezo  bev on the 
basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (CTCAE v5.0) 
 
Changes in vital signs, physical examination findings, and clinical laboratory results 
during and following study treatment 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is an open-label, multicenter, single arm, phase II study exploring the efficacy and 
safety of atezo + bev in patients with unresectable locally advanced or metastatic 
mucosal melanoma. 
The study will enroll approximately 43 patients (38 patients fully evaluable for ORR) at 
approximately 3 centers, including study Stages I and II. 
The trial will consist of a Screening Period (Day –28 to −1), a Treatment Period, an 
Treatment Discontinuation Visit occurring when atezolizumab and bevacizumab are both 
discontinued for any reason and a Survival Follow-Up Period until death, loss to follow- 
up, or study termination. Day 1 of the study (baseline) will be defined as the first day a 
patient receives atezo + bev. One cycle of therapy will be defined as 21 days of 
treatment. Patients will be asked to attend clinic visits at regular intervals during the 
study for safety and efficacy assessments. 
The study is divided into 2 stages. Stage I of the study is completed when 22 patients 
with measurable disease have been enrolled and completed ORR evaluation. If the 
number of responders in Stage I is more than 3, another 16 fully evaluable patients may 
be enrolled to Stage II. 
Considering a drop-out rate of 10%, a total number of 25 subjects (if stops at the first 
stage) or 43 subjects (if runs into the second stage) will need to be enrolled in this study. 
Figure 1 presents an overview of the study design. A schedule of activities is provided in 
Appendix 1. 
Figure 1 Study Schema 
IV  intravenous; Q3W= every 3 weeks 

Atezolizumab—F. Hoffmann-La Roche Ltd 
27/Protocol ML41186, Version 5 
 
Atezolizumab and/or bevacizumab will be administered until unacceptable toxicity or loss 
of clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data (e.g., LDH level), local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to disease). 
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 will be permitted to continue 
treatment if they meet all of the following criteria: 
 
Evidence of clinical benefit, as determined by the investigator following a review of 
all available data 
 
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients who transiently withhold or permanently discontinue either atezolizumab or 
bevacizumab may continue on single-agent therapy as long as the patients are 
experiencing clinical benefit in the opinion of the investigator (i.e., patients temporarily 
withdrawn from bevacizumab due to adverse effects may continue atezolizumab 
monotherapy and vice versa). 
 
Patients will undergo tumor assessments at scheduled intervals during the study (see 
Section 4.4 and Appendix 1 for details). 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) 
occurs. The end of the study is expected to occur 20 months after the last patient is 
enrolled. 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 2 years and 9 months. 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
28/Protocol ML41186, Version 5 
 
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 dose of 7.5 mg/kg Q3W (7.5 mg/kg on Day 1 of 
each 21-day cycle), which is the approved dosage for bevacizumab (Avastin U.S. and 
China Package Insert). 
 
Bevacizumab is approved for use (in combination) at 7.5 mg/kg Q3W and 5mg/kg Q2W 
in metastatic colorectal cancer. Both dosing regimens were selected on the basis of 
nonclinical studies and available clinical pharmacokinetic, efficacy and safety data (refer 
to the Bevacizumab / Avastin® Investigator's Brochure for details). The former dosing 
regimen (7.5 mg/kg Q3W) was chosen in the current study, to more easily accommodate 
the Q3W dosing pattern for atezolizumab, thereby streamlining study design and 
simplifying administration of the combination for the investigators (and potentially future 
clinicians). 
3.3.3 
Rationale for Open-Label Single-Arm Study 
The primary objective of this study is to assess the efficacy profile of atezolizumab 
+bevacizumab in a non-comparative fashion. Thus, as all patients are pre-specified to 
receive active treatment, the study will have an open-label and non-randomized design. 
3.3.4 
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 all 
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 3.1.1). 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). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
29/Protocol ML41186, Version 5 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 38 patients that fully evaluable for ORR and with unresectable locally 
advanced or metastatic mucosal melanoma will be enrolled in this study, including study 
Stages I and II. Considering 10% dropout rate, approximately 43 subjects will be 
included. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Age  18 and ≤75 years at time of signing Informed Consent Form (ICF) 
3. Ability to comply with the study protocol, in the investigator's judgment 
4. Histologically confirmed unresectable locally advanced(stage III) or metastatic 
(Stage IV) mucosal melanoma 
5. May have received prior systemic treatment or treatment naive at enrollment 
6. Measurable disease per RECIST v1.1 
7. ECOG Performance Status of 0-1 
8. Life expectancy  12 weeks 
9. Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
1) ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor 
support, G-CSF may be administered until 2 weeks prior to Cycle 1, Day 1 
2) Lymphocyte count  0.5  109/L (500/L) 
3) Platelet count  100  109/L (100,000/L) without transfusion, transfusion may 
be administered until 2 weeks prior to Cycle 1, Day 1 
4) Hemoglobin  90 g/L (9 g/dL) 
i. 
Patients may be transfused to meet this criterion. 
5) AST, ALT, and alkaline phosphatase (ALP)  2.5  upper limit of normal (ULN), 
with the following exceptions: 
i. 
Patients with documented liver metastases: AST and ALT  5  ULN 
ii. 
Patients with documented liver or bone metastases: ALP  5  ULN 
6) Serum bilirubin  1.5  ULN with the following exception: 
i. 
Patients with known Gilbert disease: serum bilirubin level  3  ULN 
7) Serum creatinine  1.5  ULN 
8) Serum albumin  25 g/L (2.5 g/dL) 
9) For patients not receiving therapeutic anticoagulation: INR or aPTT 
 1.5  ULN 

Atezolizumab—F. Hoffmann-La Roche Ltd 
30/Protocol ML41186, Version 5 
 
10. Negative HIV test at screening 
11. Negative hepatitis B surface antigen (HBsAg) test at screening 
12. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by quantitative hepatitis B virus (HBV) DNA<500 IU/mL at 
screening 
13. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening 
1) The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
14. 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: 
1) 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, or 6 months after the final dose of bevacizumab, 
whichever is longer. Women must refrain from donating eggs during this same 
period. 
2) 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. 
3) 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. 
4) 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. 
15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
1) 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. 
2) 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
31/Protocol ML41186, Version 5 
 
3) The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Symptomatic or actively progressing central nervous system (CNS) metastases 
1) Asymptomatic patients with treated or untreated CNS lesions are eligible, 
provided that all of the following criteria are met: 
i. 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
ii. 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage. 
iii. 
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. 
iv. 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. Anticonvulsant therapy at a stable dose is permitted. 
v. 
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord). 
vi. 
There is no evidence of interim progression between completion of 
CNS-directed therapy (if administered) and initiation of study treatment. 
2) Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to 
repeat the screening brain scan. 
2. History of leptomeningeal disease 
3. Uncontrolled tumor-related pain 
1) Patients requiring pain medication must be on a stable regimen at study entry. 
2) 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. 
3) 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. 
4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
1) Patients with indwelling catheters are allowed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
32/Protocol ML41186, Version 5 
 
5. Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL or corrected serum calcium  ULN) 
6. Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis, with the following exceptions: 
1) Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
2) Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
3) 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: 
i. 
Rash must cover  10% of body surface area 
ii. 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
iii. 
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 
7. 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 
1) History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
8. Active tuberculosis 
9. 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 
1) 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 
2) Patients with known LVEF < 40% 
10. 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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
33/Protocol ML41186, Version 5 
 
11. History of malignancy other than melanoma 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 
12. 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 
13. Prior allogeneic stem cell or solid organ transplantation 
14. 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 
15. Current treatment with anti-viral therapy for HBV 
16. 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 
17. Current, recent (within 28 days prior to initiation of study treatment) or planned 
treatment with any other investigational agent or participation in another clinical 
study with anti-cancer therapeutic intent 
18. Prior treatment with immune checkpoint agonists, including CD137 agonists and 
TLR9 agonists or immune checkpoint blockade therapies, including antiCTLA-4, 
antiPD-1, and antiPD-L1 therapeutic antibodies 
19. Prior treatment with anti-angiogenic therapies 
20. 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 as well as prior cancer 
vaccines and cellular immunotherapy 
21. Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF- agents, as well as T and B cell targeting biologic 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: 
1) 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. 
2) 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
34/Protocol ML41186, Version 5 
 
22. History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
23. Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
24. Known allergy or hypersensitivity to any component of the bevacizumab formulation 
25. 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 
1) Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
26. Inadequately controlled hypertension (defined as systolic blood 
pressure  150 mmHg and/or diastolic blood pressure  100 mmHg) 
1) Anti-hypertensive therapy to achieve these parameters is allowable. 
27. Prior history of hypertensive crisis or hypertensive encephalopathy 
28. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1 
29. Patients with a baseline ECG demonstrating a QTc > 460 msec (calculated with use 
of the Fridericia method) 
30. History of Grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood per 
episode) within 1 month prior to screening 
31. History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1 
32. Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
33. Prophylactic or therapeutic use of low molecular weight heparin (e.g., enoxaparin), 
direct thrombin inhibitors, or warfarin are permitted, provided, where appropriate 
anticoagulation indices are stable. Patients should have been on a stable dose (for 
therapeutic use) for at least 2 weeks (or until reaching steady state level of the drug) 
prior to the first study treatment 
34. Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 
325 mg/day), clopidogrel (> 75 mg/day) or treatment with dipyramidole, ticlopidine, 
or cilostazol 
1) Note: The use of full-dose oral or parenteral anticoagulants for therapeutic 
purpose is permitted as long as the INR and/or aPTT is within therapeutic limits 
(according to institution standards) within 7 days prior to initiation of study 
treatment and the patient has been on a stable dose of anticoagulants for ≥ 2 
weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is 
allowed. 
35. Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 calendar days prior to the first dose of bevacizumab 

Atezolizumab—F. Hoffmann-La Roche Ltd 
35/Protocol ML41186, Version 5 
 
36. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to Cycle 1, Day 1 
37. Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding 
38. Evidence of abdominal free air not explained by paracentesis or recent 
surgical procedure 
39. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
40. Proteinuria, as demonstrated by urinalysis or  1.0 g of protein in a 24-hour 
urine collection 
1) All patients with  2 protein on urinalysis at baseline must undergo a 24-hour 
urine collection for protein. 
4.2 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE 
STUDY DESIGN 
The investigational medicinal products (IMP) for this study are atezolizumab and 
bevacizumab. 
4.2.1 
Study Treatment Formulation, Packaging, and Handling 
The packaging and labeling of the study medication will be in accordance with Roche 
standards and local regulations. 
 
All investigational products must be kept in a secure place under appropriate storage 
conditions. 
 
For further details, see the investigator brochure. 
 
4.2.1.1 
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. 
4.2.1.2 
Bevacizumab 
The Bevacizumab Drug Product 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 further details, see the Bevacizumab Investigator’s Brochure. 
 
4.2.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
36/Protocol ML41186, Version 5 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
 
Any dose modification 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. 
 
Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 5 
minutes between dosing. 
4.2.2.1 
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. 
Table 1 Administration of First and Subsequent Atezolizumab Infusions 

Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Protocol ML41186, Version 5 
 
4.3 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL 
RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the- 
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the treatment discontinuation visit. All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic 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: 
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 second and subsequent atezolizumab and/or bevacizumab infusions only, at the 
discretion of the investigator. 
 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.3.2 to 4.3.4) as clinically indicated, per local 

Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Protocol ML41186, Version 5 
 
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). 
4.3.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.3.2.1 
Corticosteroids and TNF- Inhibitors 
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 7 and Appendix 9 for details). 
4.3.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown. However, herbal therapies not intended for the treatment of cancer (see 
Section 4.3.4) may be used during the study at the discretion of the investigator. 
4.3.3 
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. 
4.3.4 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
41/Protocol ML41186, Version 5 
 
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 4.3.1 for 
details). 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines 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. 
4.3.5 
Continued Access to Atezolizumab and Bevacizumab 
Currently, the Sponsor does not have any plans to provide Roche IMPs (atezolizumab 
and bevacizumab) or any other study treatments 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 Product, available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
 
 
4.4 
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. 
4.4.1 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
42/Protocol ML41186, Version 5 
 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. Patients who fail their first screening for study eligibility 
may qualify for one re-screening opportunity (for a total of two screenings per patient) at 
the investigator’s discretion. All re-screening requests will require approval by the 
Medical Monitor or designee. 
4.4.2 
Medical History, Concomitant Medication, and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, will be recorded 
at baseline. In addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 7 days prior to initiation of study treatment will be recorded. At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
 
Demographic data will include age, sex, and self-reported race/ethnicity. 
 
4.4.3 
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. 
4.4.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature. Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF. At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
 
Vital signs are to be measured before, during, and after infusions as outlined in Table 3, 
and at other specified timepoints as outlined in the schedule of activities (see 
Appendix 1). 
 
Table 3 Timing for Vital Sign Measurements for First and Subsequent Infusions 

Atezolizumab—F. Hoffmann-La Roche Ltd 
43/Protocol ML41186, Version 5 
 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Atezolizumab      Within 60 minutes prior to the 
 Within 60 minutes prior to the 
atezolizumab infusion 
 
atezolizumab infusion 
 Record patient's vital signs during or  Record patient's vital signs during or 
after the infusion if clinically 
after the infusion if clinically indicated 
indicated. 
Bevacizumab      Within 60 minutes prior to the 
 Within 60 minutes prior to the 
bevacizumab infusion 
 
bevacizumab infusion 
 At the end of infusion and 
 At the end of infusion and 2 ( 1) hours 
2 ( 1) hours after the infusion 
 
after the infusion 
 
 
4.4.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the 
first 54 weeks following treatment initiation, and every 12 weeks (1 week) thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 or 
(for patients who continue atezolizumab and/or bevacizumab after radiographic disease 
progression) loss of clinical benefit as determined by the investigator (see Section 3.1.1 
for details). Thus, tumor assessments are to continue according to schedule in patients 
who discontinue treatment for reasons other than disease progression or loss of clinical 
benefit, even if they start new anti-cancer therapy. At the investigator's discretion, 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 CT scans (with oral or IV contrast) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, pelvis, and head. A spiral CT 
scan of the chest may be obtained but is not a requirement. If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed and MRI scans of the abdomen, pelvis, and head should 
be performed. A CT scan with contrast or MRI scan of the head must be done at 
screening to evaluate CNS metastasis in all patients (MRI scan must be performed if CT 
scan is contraindicated). An MRI scan of the head is required to confirm or refute the 
diagnosis of CNS metastases at baseline in the event of an equivocal CT scan. Bone 
scans and CT scans of the neck should also be performed if clinically indicated. At the 
investigator's discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
44/Protocol ML41186, Version 5 
 
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 identified at baseline 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). 
 
Objective response at a single timepoint will be determined by the investigator according 
to RECIST v1.1 (see Appendix 2). Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits. 
4.4.6 
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: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, 
hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
 
Chemistry panel (serum or plasma): sodium, potassium, magnesium, chloride, 
glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and Lactate 
dehydrogenase (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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
45/Protocol ML41186, Version 5 
 
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 
4.4.7 
Electrocardiograms 
An ECG is required at screening and when clinically indicated. Clinically indicated 
situation include when investigators consider it necessary to monitor ECG. 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 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (atezolizumab and 
bevacizumab) if they experience any of the following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another non-protocol anti-cancer therapy 
 
Pregnancy 
 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.1 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment after he or she has 
completed at least 1 post baseline tumor assessment will not be replaced. In other 
situations, patients can be replaced only after approval has been documented by both 
the investigator(or an appropriate delegate) and the Medical Monitor. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
46/Protocol ML41186, Version 5 
 
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 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). 
4.5.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
Every effort should be made to obtain a reason for patient discontinuation from the 
study. The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF. If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
who withdraw from the study prior to receiving study drug will be replaced. Patients who 
have received any dose of study drug and withdraw from the study after he or she has 
completed at least 1 post baseline tumor assessment will not be replaced. In other 
situations, patients can be replaced only after approval has been documented by both 
the investigator(or an appropriate delegate) and the Medical Monitor. 
 
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. 
4.5.3 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
47/Protocol ML41186, Version 5 
 
 
Patient enrollment is unsatisfactory 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
 
4.5.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and bevacizumab in completed and ongoing studies. The anticipated 
important safety risks are outlined below (see Section 5.1.1 and Section 5.1.2). 
 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study. Administration of atezolizumab and bevacizumab will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions. 
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for dosage modification and treatment interruption or 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. 
 
Patients with active infection are excluded from study participation. In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020). If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 

Atezolizumab—F. Hoffmann-La Roche Ltd 
48/Protocol ML41186, Version 5 
 
judgment. If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following: IRRs and immune 
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis,facial paresis, myelitis, meningoencephalitis, 
myocarditis, nephritis, and myositis, and severe cutaneous adverse reactions.In 
addition,immune-mediated reactions may involve any organ system and lead to 
hemophagocytic lymphohistiocytosis. 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 perforation, 
hemorrhage, arterial thromboembolic events, fistulae, wound-healing complications, 
hypertension, venous thromboembolism, and proteinuria. 
 
Refer to Appendix 10 of the protocol and Section 6 of the Bevacizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for bevacizumab. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an 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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
49/Protocol ML41186, Version 5 
 
 
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). 
 
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). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
50/Protocol ML41186, Version 5 
 
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. 
5.2.3.1 
Adverse Events of Special Interest for Atezolizumab 
 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, hypothyroidism 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 and systemic inflammatory response syndrome 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 

Atezolizumab—F. Hoffmann-La Roche Ltd 
51/Protocol ML41186, Version 5 
 
• 
Myelitis 
• 
Facial paresis

Atezolizumab—F. Hoffmann-La Roche Ltd 
52/Protocol ML41186, Version 5 
 
5.2.3.2 
Adverse Events of Special Interest for Bevacizumab 
Adverse events of special interest for bevacizumab are as follows: 
 
 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
54/Protocol ML41186, Version 5 
 
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 5): 
 
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 5 Causal Attribution Guidance 
 
 
 
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. 
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). 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 

Atezolizumab—F. Hoffmann-La Roche Ltd 
55/Protocol ML41186, Version 5 
 
5.3.5.1 
Infusion-Related Reactions 
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") on the Adverse Event eCRF. If possible, 
avoid ambiguous terms such as "systemic reaction." Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF. If a 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. 
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. 
 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
56/Protocol ML41186, Version 5 
 
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. 
 
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." 

Atezolizumab—F. Hoffmann-La Roche Ltd 
57/Protocol ML41186, Version 5 
 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
58/Protocol ML41186, Version 5 
 
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 mucosal melanoma 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"). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
59/Protocol ML41186, Version 5 
 
5.3.5.10 
Lack of Efficacy or Worsening of Mucosal Melanoma 
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. 
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 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
60/Protocol ML41186, Version 5 
 
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 Section 5.4.2). For 
atezolizumab and bevacizumab, adverse events associated with special situations 
should be recorded as described below for each situation: 
 
Accidental overdose: Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose: Enter the adverse event 
term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose: Enter the adverse event term. 
Check the "Accidental overdose" and "Medication error" boxes. 
In addition, all special situations associated with atezolizumab and bevacizumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRFas described below: 
 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of 
the error in the additional case details. 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache. The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
61/Protocol ML41186, Version 5 
 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
62/Protocol ML41186, Version 5 
 
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 3 months 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 and submit the report via the 
electronic data capture (EDC) system. A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system. 
 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the final 
dose of atezolizumab, or within 6 months after the final dose of bevacizumab, whichever 
is longer. A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Pregnancy should not be 
recorded on the Adverse Event eCRF. The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion 
of the pregnancy. Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF. In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
63/Protocol ML41186, Version 5 
 
months after the final dose of bevacizumab. A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators. Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study treatment. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available. An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent. Every effort should be made to follow all 

Atezolizumab—F. Hoffmann-La Roche Ltd 
64/Protocol ML41186, Version 5 
 
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 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 3 months 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/AESI that is 
believed to be related to prior exposure to study treatment, the event should be reported 
through use of the Adverse Event eCRF. However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial 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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
65/Protocol ML41186, Version 5 
 
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. 
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.). 
All major deviations (at study entry and on study) will be summarized and reported. 
General Analysis Methods 
Unless otherwise stated, all statistical analyses specified in the subsequent sections will 
be based on the following general methods. 
All qualitative data will be presented in contingency tables, using absolute and relative 
frequencies, unless otherwise stated. Percentages will be rounded to the first decimal 
place and, therefore, may not always add up to 100%. When applicable, 95% confidence 
intervals (CIs) will be presented with estimates of proportions. 
All quantitative data will be summarized via relevant descriptive statistics, such as 
number of observations with available measurements, mean, standard deviation, 
median, first and third quartiles (Q1and Q3) when applicable, minimum and maximum. 
Time to event data will be summarized via Kaplan-Meier (KM) estimates/curves and 
median with corresponding 95% CI. 
Timing of Analyses 
The primary analysis and reporting of the study will occur 12 months after the last patient 
has been enrolled. The long-term follow-up will be reported in a subsequent report 
following the end of study. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation was based on a Simon two-stage design (Simon 1989). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
66/Protocol ML41186, Version 5 
 
In this Phase II study, an ORR of 20% is a level of activity that is not of interest for 
further clinical development, whereas an ORR of 40% is of clinical interest. 
 
The study hypotheses are: 
 
H0: π ≤ nO 
H1: π  > n1 
 
Where nO= 20% and the assumed ORR under the alternative n1= 40%. 
 
The type I error will be 5% and the study will have 80% power to reject the null 
hypothesis when the true ORR is 40%. 
 
Figure 2 Sample Size Allocation 
 
 
 
NR: Non-Response; ORR: Overall Response Rate 
Assumptions: H0= ORR 20%; H1= ORR 40%; Power=80%; alpha=5% (two-sided) 
 
 
 
The Simon design in this study requires 22 fully evaluable patients for the first stage. If at 
the end of first stage there are less than or equal to 3 patients with ORR, the enrollment 
in to the study will be terminated. Otherwise, if more than 3 patients with ORR are 
observed at the end of the stage I, an additional 16 fully-evaluable patients may be 
enrolled into stage II. 
 
Thus, considering a drop-out rate of 10%, a total number of 25 subjects (if stops at the 
first stage) or 43 subjects (if runs into the second stage) will need to be enrolled in this 
study. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
67/Protocol ML41186, Version 5 
 
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 listed. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
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 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. 
6.4.1 
Primary Efficacy Endpoint 
The primary analysis will be based on Objective response rate (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 treated with study 
drug who have no post-baseline tumor assessment (per protocol mandated timelines), 
and enrolled patients who do not receive any dose of study drug will be replaced. This 
endpoint will be assessed at Stage I and Stage II. The number and proportion of 
responders will be presented with the corresponding Clopper-Pearson 95% CI. 
 
Enrollment into the cohort may continue into Stage II if more than 3 patients (out of 22) 
with ORR are observed at the end of Stage I. In the Stage II, if more than 12 patients out 
of 38 patients have responses and there is no unacceptable toxicity, we can conclude 
that the therapy is statistically significant in improving the ORR in curing mucosal 
melanoma. 
6.4.2 
Secondary Efficacy Endpoints 
 
Progression-free survival (PFS), defined as the time from the date of first 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. A patient 
without a PFS event will be censored at the time of the last evaluable tumor 
assessment. Patients with no tumor assessment after the baseline visit will be 
censored at the time of the first day of study treatment plus 1 day. 
 
Overall survival (OS), defined as the time from the date of first treatment to death 
from any cause. Patients for whom no death is captured on the clinical database will 
be censored at the most recent date they were known to be alive. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
68/Protocol ML41186, Version 5 
 
 
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. For patients who do not die or experience disease progression before 
the end of the study or who are lost to follow-up, duration of objective response will 
be censored at the day of the last tumor assessment. 
 
Disease control rate (DCR) (defined as the sum of a complete or partial response or 
stable disease rates.) as determined by the investigator according to RECIST v1.1. 
DCR will be presented along with the 95% Clopper-Pearson CI. 
6.5 
SAFETY ANALYSES 
The safety analysis will be performed on the safety population, defined as all enrolled 
patients who receive at least one dose of any study treatment. 
 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0. 
Other safety variables studied will include: 
 
Drug exposure (treatment duration, number of doses, dose intensity and dose 
modifications/discontinuations, with reasons) 
 
All AEs 
 
SAEs 
 
AEs (Grade 3–5) 
 
AESIs 
 
AEs leading to study drug discontinuation or interruption 
 
Changes in vital signs from baseline 
 
Changes in physical findings from baseline 
 
Changes in selected laboratory parameters from baseline 
 
Deaths and cause of death 
 
Concomitant medications 
The incidence of AEs will be summarized by frequency tables. Corresponding 95% 
Clopper-Pearson CIs will be presented, as applicable. 
 
Treatment exposure, discontinuation rate, and cause of death will be analyzed by 
frequency tables. When appropriate, median time on treatment and 95% CI will be 
estimated by the Kaplan-Meier approach or using univariate statistics, presenting mean, 
median, quartiles, minimum, maximum and standard deviation. 
 
Changes in vital signs and physical findings from baseline will be tabulated and 
presented graphically when applicable. Worst grades for laboratory parameters, newly 

Atezolizumab—F. Hoffmann-La Roche Ltd 
69/Protocol ML41186, Version 5 
 
occurring Grade 3 and 4 laboratory values during treatment, and concomitant 
medications will be summarized by frequency tables. 
6.6 
INTERIM ANALYSIS 
One interim analysis is planned. The interim analysis will be performed for futility at the 
time of 22 subjects completes 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 subjects that respond in the first evaluable 22 patients (stage 1) 
is less or equal than 3. This study has a probability of 33.2% to terminate at the first 
stage. The optimal or minimax are not used because of their high probability of 
termination at the first stage. All decisions above will be made by the Sponsor in 
discussion with the stud team members. 
 
The sample size and stopping rule are calculated with SAS 9.4, and all the tables, 
listings and figures will be generated using SAS 9.4. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will approve eCRF specifications developed by a contract research 
organization (CRO) for this study. A contract research organization (CRO) will be 
responsible for data management of this study, including quality checking of the data. 
Data entered manually will be collected via EDC through use of eCRFs. Sites will be 
responsible for data entry into the EDC system. In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. 
 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO's data management plans and specifications. Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor's 
standard procedures will be used to handle and process the electronic transfer of these 
data. 
 
eCRFs and correction documentation will be maintained in the EDC system's audit trail. 
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO's standard procedures. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
70/Protocol ML41186, Version 5 
 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites 
will receive training and have access to a manual for appropriate eCRF completion. 
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records. Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review. The study site must also 
allow inspection by applicable health authorities. 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
71/Protocol ML41186, Version 5 
 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 25 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, subject to local regulations. 
 
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site. If applicable, it will be provided in a certified translation of 
the local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 

Atezolizumab—F. Hoffmann-La Roche Ltd 
72/Protocol ML41186, Version 5 
 
submission. The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures. Patients who 
decline to participate will not provide a separate signature. 
 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative. All signed and dated Consent Forms must remain in 
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). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
73/Protocol ML41186, Version 5 
 
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. 
 
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 (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 

Atezolizumab—F. Hoffmann-La Roche Ltd 
74/Protocol ML41186, Version 5 
 
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 3 sites in China will participate to enroll approximately 43 patients (38 
subjects that fully evaluable for ORR). 
 
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, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 

Atezolizumab—F. Hoffmann-La Roche Ltd 
75/Protocol ML41186, Version 5 
 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met. 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. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
76/Protocol ML41186, Version 5 
 
10. 
REFERENCES 
Kuk D, Shoushtari AN, Barker CA, et al. Prognosis of Mucosal, Uveal, Acral, Nonacral 
Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis. 
Oncologist. 2016 Jul;21(7):848-54. 
McLaughlin CC, Wu XC, Jemal A, et al. Incidence of noncutaneous melanomas in the 
U.S. Cancer. 2005 Mar 1;103(5):1000-7. 
Zhihong Chi, Siming Li, Xinan Sheng, et al. Clinical presentation, histology, and 
prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive 
cases. BMC Cancer. 2011 Feb 25;11:85. 
Bai X, Kong Y, Chi Z, et al. MAPK Pathway and TERT Promoter Gene Mutation Pattern 
and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 
Cases. Clin Cancer Res. 2017 Oct 15;23(20):6120-6127. 
Chang AE, Karnell LH, Menck HR, et al. The National Cancer Data Base report on 
cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the 
past decade. The American College of Surgeons Commission on Cancer and the 
American Cancer Society. Cancer. 1998 Oct 15;83(8):1664-78. 
Shoushtari AN, Bluth MJ, Goldman DA, et al. Clinical features and response to systemic 
therapy in a historical cohort of advanced or unresectable mucosal melanoma. 
Melanoma Res. 2017 Feb;27(1):57-64. 
D'Angelo SP, Larkin J, Sosman JA, et al. Efficacy and Safety of Nivolumab Alone or in 
Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled 
Analysis. J Clin Oncol. 2017 Jan 10;35(2):226-235. 
Del Vecchio M, Di Guardo L, Ascierto PA, et al. Efficacy and safety of ipilimumab 
3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer. 
2014 Jan;50(1):121-7. 
Shoushtari AN, Munhoz RR, Kuk D, et al. The efficacy of anti-PD-1 agents in acral and 
mucosal melanoma. Cancer. 2016 Nov 15;122(21):3354-3362. 
M. Butler, O. Hamid, A. Ribas, et al. Efficacy of pembrolizumab in patients with 
advanced mucosal melanoma enrolled in the KEYNOTE-001, 002, and 006 
studies. Eur. J. Cancer 72(Suppl. 1), S123 (2017). 
Bai X, Mao LL, Chi ZH, et al. BRAF inhibitors: efficacious and tolerable in BRAF-mutant 
acral and mucosal melanoma. Neoplasma. 2017;64(4):626-632. 
Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of 
melanoma.J Clin Oncol. 2006 Sep 10;24(26):4340-6. 
Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in 
patients with metastatic melanoma harboring c-Kit mutation or amplification.J Clin 
Oncol. 2011 Jul 20;29(21):2904-9. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
77/Protocol ML41186, Version 5 
 
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic 
melanoma.JAMA. 2011 Jun 8;305(22):2327-34. 
Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring 
mutationally activated or amplified KIT arising on mucosal, acral, and chronically 
sun-damaged skin.J Clin Oncol. 2013 Sep 10;31(26):3182-90. 
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, 
open-label, phase 2 randomised controlled trial. Lancet 2016;387:183746. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920. 
F. Stephen Hodi, Donald Lawrence, Omid Hamid, et al. Clinical Activity of the PD-L1 
Inhibitor MPDL3280A in Patients With Metastatic Melanoma: Updated Phase I 
Data. Presented at the Society for Melanoma Research; 13-16 November, 2014; 
Zurich, Switzerland. 
Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an 
anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004 May;3(5):391- 
400. 
Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth 
factor by human tumors inhibits the functional maturation of dendritic cells. Nat 
Med. 1996 Oct;2(10):1096-103. 
Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell 
maturation through the inhibition of nuclear factor-kappa B activation in 
hemopoietic progenitor cells. J Immunol. 1998 Feb 1;160(3):1224-32. 
Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective 
immune barrier promoting tolerance in tumors. Nat Med. 2014 Jun;20(6):607-15. 
Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab 
enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat 
Commun. 2016 Aug 30;7:12624. 
Roland CL, Lynn KD, Toombs JE, et al. Cytokine levels correlate with immune cell 
infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. 
PLoS One. 2009 Nov 3;4(11):e7669. 
Facciabene A, Peng X, Hagemann IS, et al. Tumour hypoxia promotes tolerance and 
angiogenesis via CCL28 and T(reg) cells. Nature. 2011 Jul 13;475(7355):226-30. 
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. MAbs 2016;8:593603. 
doi: 10.1080/19420862.2015.1136043. Epub: 26 February 2016. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
78/Protocol ML41186, Version 5 
 
Hales RK, Banchereau J, Ribas A, et al. Assessing oncologic benefit in clinical trials of 
immunotherapy agents. Ann Oncol 2010;21:194451. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
78/Protocol ML41186, Version 4 
 
 
 
 
 
 
 
 
 
 
Screening 
Period a 
Treatment Period 
Treatment Discontinuation 
b 
Follow-Up 
Days –28 to –1 
Day 1 (±3 days) of 
each 3-week treatment cycle 
 30 Days after Final 
Dose 
(every 3 
months) 
Informed consent c 
x c 
Demographic data 
x 
Medical history and baseline conditions 
x 
Vital signs d 
x 
x 
x 
Weight 
x 
x 
x 
Height 
x 
Complete physical examination e 
x 
x 
Limited physical examination f 
x 
ECOG Performance Status 
x 
x 
x 
ECG g 
x 
x k 
LVEF h 
x 
Hematology i 
x j 
x k 
x 
Chemistry l 
x j 
x k 
x 
Pregnancy test m 
x j 
x k 
Coagulation (INR, aPTT) 
x j 
x 
TSH, free T3 (or total T3), free T4 n 
x 
x k, n 
x 
Viral serology o 
x 
Urinalysis p 
x j 
x q 
Tumor response assessments 
x r 
x s, t 
x s, t 
x s, t 
Concomitant medications u 
x u 
x 
x 
Adverse events v 
x v 
x v 
x 
x v 
Study treatment administration w 
x 

Atezolizumab—F. Hoffmann-La Roche Ltd 
79/Protocol ML41186, Version 4 
 
 
 
 
 
Survival follow-up and anti-cancer treatment 
x x 
eCRF  electronic Case Report Form; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; 
HCV  hepatitis C virus; NA  not applicable; RECIST  Response Evaluation Criteria in Solid Tumors; T3  triiodothyronine; 
T4  thyroxine; TSH  thyroid-stimulating hormone; 
Notes: On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 
may be used; such tests do not need to be repeated for screening. 
b 
Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after 
their final dose of study treatment. The visit at which response assessment shows progressive disease may be used as the 
treatment discontinuation visit. 
c 
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. 
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 
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems. 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. 
f 
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. 
g 
ECG recordings will be obtained during screening and as clinically indicated at other timepoints. Clinically indicated situation 
include when investigators consider it necessary to monitor ECG. Patients should be resting in a supine position for at least 
10 minutes prior to ECG recording. 
h 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
80/Protocol ML41186, Version 4 
 
 
 
 
 
i 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
j 
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment. 
k 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
l 
Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH. 
m All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study 
treatment. 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. 
n 
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 (i.e., Cycles 5, 9, 13, etc.). 
o 
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. 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. Patients with a positive quantitative HBV DNA at screening (must be <500 IU/mL per the eligibility 
criteria) will undergo additional HBV DNA tests at Cycle 4 Day 1, 
Cycle 8 Day 1 and at treatment discontinuation visit (±7 days). 
Study treatment and procedures may proceed while HBV DNA is being processed, but results should be reviewed by the 
investigator as soon as they are available. If HBV DNA increases to ≥500 IU/mL, consultation with the Medical Monitor is 
required prior to continuation of study treatment and consultation with a hepatologist or gastroenterologist with specialty in 
hepatitis B is recommended. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
81/Protocol ML41186, Version 4 
 
 
 
 
 
p 
Includes pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted. 
q 
Urinalysis should be performed as clinically indicated during study treatment. Clinically indicated situation include when 
investigators consider it necessary to monitor urinalysis. 
r 
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 CT scans (with oral or IV contrast) or MRI scans of the chest, 
abdomen, pelvis, and head. A spiral CT scan of the chest may be obtained but is not a requirement. If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI 
scans of the abdomen, pelvis, and head should be performed. A CT scan with contrast or MRI scan of the head must be done at 
screening to evaluate CNS metastasis in all patients (MRI scan must be performed if CT scan is contraindicated). An MRI scan of 
the head is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT scan. Bone 
scans and CT scans of the neck should also be performed if clinically indicated. At the investigator's discretion, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used. 
s 
Patients will undergo tumor assessments at baseline, every 6 weeks(1 week) for the first 54 weeks following treatment initiation, 
and every 12 weeks(1 week) thereafter, regardless of dose delays, until radiographic disease progression per RECIST v1.1 or 
(for patients who continue treatment after radiographic disease progression) loss of clinical benefit as determined by the 
investigator (see Section 3.1.1 for details). Thus, tumor assessments are to continue according to schedule in patients who 
discontinue treatment for reasons other than disease progression or loss of clinical benefit, even if they start new anti-cancer 
therapy. 
t 
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). 
u 
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 until the treatment 
discontinuation visit. 
v 
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 will continue to be reported until 3 months after the final dose of 
study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first. After this period, all deaths, 
regardless of cause, should be reported. In addition, the investigator should report any SAEs or AESIs believed to be related to 
prior study drug treatment. 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
82/Protocol ML41186, Version 4 
 
 
 
 
 
w 
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. 
x 
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 only. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
83/Protocol ML41186, Version 4 
 
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"). 
 
 
 
 
 
 
 
 
 
 
 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
84/Protocol ML41186, Version 4 
 
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. 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
85/Protocol ML41186, Version 4 
 
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, 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 . 

Atezolizumab—F. Hoffmann-La Roche Ltd 
86/Protocol ML41186, Version 4 
 
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. 
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"). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
87/Protocol ML41186, Version 4 
 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study. Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
88/Protocol ML41186, Version 4 
 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis. 
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations. In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of non- 
target lesions. 
 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective 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

Atezolizumab—F. Hoffmann-La Roche Ltd 
89/Protocol ML41186, Version 4 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of 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 6 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 6 Criteria for Overall Response at a Single Timepoint: Patients with Target Lesions 
(with or without Non-Target Lesions) 

Atezolizumab—F. Hoffmann-La Roche Ltd 
90/Protocol ML41186, Version 4 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response. This 
would be most likely to happen in the case of PD. For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration." Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an 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 6. 
 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
91/Protocol ML41186, Version 4 
 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
92/Protocol ML41186, Version 4 
 
Appendix 3 
New York Heart Association Functional Classification 
 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary 
physical activity (e.g., shortness of breath when walking, climbing 
stairs, etc.) 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity 
III 
Marked limitation in activity due to symptoms, even during less-than- 
ordinary activity (e.g., walking short distances [20–100 m]). 
Comfortable only at rest 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients 

Atezolizumab—F. Hoffmann-La Roche Ltd 
93/Protocol ML41186, Version 4 
 
Appendix 4 
ECOG Performance Status 
 
Zubrod-ECOG-WHO 
Grade 
Performance status 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, eg, light 
housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Death 

Atezolizumab—F. Hoffmann-La Roche Ltd 
94/Protocol ML41186, Version 4 
 
Appendix 5 
Corticosteroid Dose Equivalents 
 
Equivalent Dose 
Steroid 
1.2 mg 
Betamethasone (long-acting) 
1.5 mg 
Dexamethasone (long-acting) 
8 mg 
Methylprednisolone (intermediate-acting) 
8 mg 
Triamcinolone (intermediate-acting) 
10 mg 
Prednisone (intermediate-acting) 
10 mg 
Prednisolone (intermediate-acting) 
40 mg 
Hydrocortisone (short-acting) 
50 mg 
Cortisone (short-acting) 
http://emedicine.medscape.com/article/2172042-overview. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
95/Protocol ML41186, Version 4 
 
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 or pericardial disorder 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 
 Autoimmue myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease 
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious 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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
96/Protocol ML41186, Version 4 
 
 
 
 
EQUIPMENT NEEDED 
 
Tourniquet
 
Oxygen
Appendix 7 
Anaphylaxis Precautions 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice
 
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. 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment. Do not obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
5. 
Continue to observe the patient and document observations. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
97/Protocol ML41186, Version 4 
 
Appendix 8 
Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
DOSE MODIFICATIONS 
 
There will be no dose modifications for atezolizumab in this study. 
 
The bevacizumab dose will be based on the patient’s weight at C1D1 and will remain the 
same throughout the study, unless there is a weight change of ≥ 10% from C1D1. 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. 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 the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed. If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab. 
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment. Atezolizumab can be resumed after being 
withheld for  12 weeks 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—F. Hoffmann-La Roche Ltd 
98/Protocol ML41186, Version 4 
 
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-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications. Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
 
The 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-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. 
Guidelines for managing patients who experience selected adverse events are provided 
in the following sections. Management guidelines are presented by adverse event 
severity based on the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) and in some instances may vary by CTCAE version (4.0 vs. 
5.0). 
 
For patients developing a new autoimmune disease not listed in this Appendix or for 
patients having been enrolled in the study with an autoimmune disease who develop a 
flare, the following dosing guidance should be applied: 
• 
Grade 1 event: atezolizumab dosage should be maintained 
• 
Grade 2 or 3 event: atezolizumab should be suspended until the subject 
responds to treatment of the autoimmune disease and the disease becomes 
stable (see rules above regarding maximum suspended time). The subject 
should be referred to an appropriate specialist 
• 
Grade 4 event: atezolizumab should be permanently discontinued and the 

Atezolizumab—F. Hoffmann-La Roche Ltd 
99/Protocol ML41186, Version 4 
 
subject should be referred to an appropriate specialist 
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 table 7. 
Table 7 Management Guidelines for Pulmonary Events, Including Pneumonitis 

Atezolizumab—F. Hoffmann-La Roche Ltd 
100/Protocol ML41186, Version 4 
 
Event 
Management 
Pulmonary 
event, Grade 1 
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist.\ 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c,d 
 For recurrent events or events with no improvement after 48–72 
hours of corticosteroids,, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 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. CTCAE= Common Terminology Criteria for Adverse 
Events; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be based on the investigator's benefit-risk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re challenge patients with atezolizumab should 
be based on the investigator’s benefit-risk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation.

Atezolizumab—F. Hoffmann-La Roche Ltd 
101/Protocol ML41186, Version 4 
 
HEPATIC EVENTS 
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 table 8. 
 
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 8 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 12 mg/kg/day oral prednisone or 
equivalent. 
 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. 
CTCAE= Common Terminology Criteria for Adverse Events; LFT  liver function tests; 
NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where 
indicated. 
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  10 mg/day 
oral prednisone or equivalent. The acceptable length of the extended period of 
time must be based on the investigator's benefit risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on the investigator’s 
benefit risk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
102/Protocol ML41186, Version 4 
 
Table 8 
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 12 mg/kg/day oral prednisone or 
equivalent. 
 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. 
CTCAE= Common Terminology Criteria for Adverse Events; LFT  liver function tests; 
NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where 
indicated. 
 
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  10 mg/day 
oral prednisone or equivalent. The acceptable length of the extended period of 
time must be based on the investigator’s benefit risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on the investigator’s 
benefit risk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed . 
 
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in table 9. 
 
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. 
Table 9 Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 

Atezolizumab—F. Hoffmann-La Roche Ltd 
103/Protocol ML41186, Version 4 
 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. If the event does not 
improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement. If the event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
CTCAE= Common Terminology Criteria for Adverse Events; GI  gastrointestinal; NCI=National 
Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re challenge 
patients with atezolizumab should be based on the investigator’s benefit-risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
104/Protocol ML41186, Version 4 
 
Table 9 
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 gastrointestinal specialist for evaluation and 
confirmation biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
CTCAE= Common Terminology Criteria for Adverse Events; GI  gastrointestinal; NCI=National 
Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in table 10. 
 
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. 
Table 10 Management Guidelines for Endocrine Events 

Atezolizumab—F. Hoffmann-La Roche Ltd 
105/Protocol ML41186, Version 4 
 
Event 
Management 
Grade 1  
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
Grade 2 
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. 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid 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-mediated 
hyperthyroidism. c 
CTCAE= Common Terminology Criteria for Adverse Events; MRI magnetic resonance 
imaging; TSH  thyroid-stimulating hormone; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
106/Protocol ML41186, Version 4 
 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
107/Protocol ML41186, Version 4 
 
Table 10 
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 1-2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1-2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 If event 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 
CTCAE v4.0 guidelines 
 Continue atezolizumab. 
 Initiate treatment with insulin if needed. 
 Monitor for glucose control. 
CTCAE v5.0 guidelines 
 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. 
CTCAE= Common Terminology Criteria for Adverse Events; MRI magnetic resonance 
imaging; TSH  thyroid-stimulating hormone; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
108/Protocol ML41186, Version 4 
 
Table 10 
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 1-2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1-2 mg/kg/day oral prednisone 
or equivalent upon improvement.a 
 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 1-2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1-2 mg/kg/day oral prednisone 
or equivalent upon improvement.a 
 Initiate hormone replacement if clinically indicated. 
CTCAE= Common Terminology Criteria for Adverse Events; MRI magnetic resonance 
imaging; TSH  thyroid-stimulating hormone; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
 
 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in table 11. 
Table 11 Management Guidelines for Ocular Events 

Atezolizumab—F. Hoffmann-La Roche Ltd 
109/Protocol ML41186, Version 4 
 
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 1-2 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
CTCAE= Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must be 
based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
110/Protocol ML41186, Version 4 
 
IMMUNE-MEDIATED CARDIAC EVENTS 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest 
pain, palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac 
conditions, or progression of malignancy. Myocarditis may also be a clinical 
manifestation of myositis or associated with pericarditis (see section on pericardial 
disorders below) and should be managed accordingly. 
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in table 12. 
 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
 
Immune-mediated pericarditis should be suspected in any patient presenting 
with chest pain and may be associated with immune-mediated myocarditis (see 
section on myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be 
suspected in any patient presenting with chest pain associated with dyspnea or 
hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as 
infection (commonly viral), cancer related (metastatic disease or chest 
radiotherapy), cardiac injury related (post myocardial infarction or iatrogenic), 
and autoimmune disorders, and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated 
by performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be 
consulted.  Pericardiocentesis should be considered for diagnostic or 
therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 12.  Withhold treatment with atezolizumab 
for Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine 
the etiology and manage accordingly. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
111/Protocol ML41186, Version 4 
 
 
Table 12 Management Guidelines for Immune-Mediated Cardiac Events  

Atezolizumab—F. Hoffmann-La Roche Ltd 
112/Protocol ML41186, Version 4 
 
Event 
Management 
Immune-mediated 
myocarditis, Grades 
2-4 
 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and 
consider antiarrhythmic drugs, temporary pacemaker, 
ECMO, VAD or pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
CTCAE= Common Terminology Criteria for Adverse Events; ECMO extracorporeal membrane 
oxygenation; NCI=National Cancer Institute; VAD ventricular assist device. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are 
applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated. 
 
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) atezolizumab may receive premedication with antihistamines, 
antipyretics and/or analgesics (e.g., acetaminophen) for subsequent infusions. 
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab. These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(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 13. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
113/Protocol ML41186, Version 4 
 
 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020). If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment. If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
114/Protocol ML41186, Version 4 
 
Table 13 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, antipyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2 a 
fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
hypoxia requiring 
low-flow oxygen d by 
nasal cannula or 
blow-by 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. 
 Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact the Medical 
Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, antipyretic medications, and/or analgesics and 
monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact the Medical Monitor. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
115/Protocol ML41186, Version 4 
 
Grade 3 a 
fever b with 
hypotension 
requiring a 
vasopressor 
(with or without 
vasopressin) 
and/or 
hypoxia requiring 
high-flow oxygen 
d by nasal 
cannula, face 
mask, 
nonrebreather 
mask, or 
Venturi-mask 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ toxicities 
as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. 
 Hospitalize 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
116/Protocol ML41186, Version 4 
 
Event 
Management 
Grade 4 a 
fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
hypoxia 
requiring 
oxygen by 
positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
 Hospitalize patient until complete resolution of symptoms. 
 

Atezolizumab—F. Hoffmann-La Roche Ltd 
117/Protocol ML41186, Version 4 
 
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, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.  For subsequent 
infusions, administer oral premedication with antihistamines, antipyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids and 
extending the infusion time may also be considered after assessing the benefitrisk ratio. 
f Refer to Riegler et al. (2019). 

Atezolizumab—F. Hoffmann-La Roche Ltd 
118/Protocol ML41186, Version 4 
 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis. 
Appropriate workup should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests. Management guidelines for pancreatic events, 
including pancreatitis, are provided in table 14. 
 
Table 14 
Management Guidelines for Pancreatic Events, Including Pancreatitis 

Atezolizumab—F. Hoffmann-La Roche Ltd 
119/Protocol ML41186, Version 4 
 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
CTCAE v4.0 guidelines 
 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. 
CTCAE v5.0 guidelines 
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 10 mg/day oral prednisone or equivalent. 
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 1-2 mg/kg/day 
oral prednisone or equivalent. 
 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 
CTCAE=Common Terminology Criteria for Adverse Events; GI  gastrointestinal; NCI= National 
Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated. 
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  10 mg/day oral prednisone or 
equivalent. The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
120/Protocol ML41186, Version 4 
 
Table 14 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
(cont.) 
 
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to GI specialist. 
 Initiate treatment with 1-2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1-2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to GI specialist. 
 Initiate treatment with 1-2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1-2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
CTCAE=Common Terminology Criteria for Adverse Events; GI  gastrointestinal; NCI= National 
Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated. 
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  10 mg/day oral prednisone or 
equivalent. The acceptable length of the extended period of time must be based the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
121/Protocol ML41186, Version 4 
 
DERMATOLOGIC EVENTS 
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 15. 
Table 15 
Management Guidelines for Dermatologic Events 

Atezolizumab—F. Hoffmann-La Roche Ltd 
122/Protocol ML41186, Version 4 
 
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 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.
 If event resolves to Grade 1 or better, resume atezolizumab. b
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
Stevens Johnson 
syndrome or toxic 
epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens Johnson syndrome or toxic epidermal 
necrolysis: 
 
Withhold atezolizumab for suspected Stevens Johnson 
syndrome or toxic epidermal necrolysis. 
 
Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant) for 
evaluation and, if indicated, biopsy. 
 
Follow the applicable treatment and management guidelines 
above. 
 
If Stevens Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue atezolizumab. 
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day 
oral prednisone or equivalent. The acceptable length of the extended period of 
time must be based on the investigator’s benefit-risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 

Atezolizumab—F. Hoffmann-La Roche Ltd 
123/Protocol ML41186, Version 4 
 
is available to advise as needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
124/Protocol ML41186, Version 4 
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies. Management guidelines for neurologic disorders are provided in 
table 16, with specific guidelines for myelitis provided in table 17. 
 
Table 16 
Management Guidelines for Neurologic Disorders 
 
Event 
Management 
Immune- 
mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune- 
mediated 
neuropathy, 
including facial 
paresis, Grade 
2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology and refer patient to neurologist.. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– If event resolves to Grade 1 or better, resume atezolizumab. b 
– If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
 For facial paresis: 
– If event resolves fully, resume atezolizumab b 
– If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Immune- 
mediated 
neuropathy, 
including 
facial 
paresis, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent. 
CTCAE=Common Terminology Criteria for Adverse Events; NCI= National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral 
prednisone or equivalent. The acceptable length of the extended period of time must 
be based on the investigator’s benefit-risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
125/Protocol ML41186, Version 4 
 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
 
Table 17 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day 
oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
126/Protocol ML41186, Version 4 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
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 table 17. 
 
Table 18 
Management Guidelines for Immune-Mediated Meningoencephalitis 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact Medical Monitor. 
 Refer patient to neurologist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
CTCAE=Common Terminology Criteria for Adverse Events; NCI= National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are 
applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
 
 
RENAL EVENTS 
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 

Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol ML41186, Version 4 
 
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 19. 
 
Table 19 
Management Guidelines for Renal Events 
 
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 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. 
CTCAE=Common Terminology Criteria for Adverse Events; NCI= National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day 
oral prednisone or equivalent. The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with atezolizumab should 
be based on the investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol ML41186, Version 4 
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/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 table 20. 
 
Table 20 
Management Guidelines for Immune-Mediated Myositis 
 
Event 
Management 
Immune- 
mediated 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
Immune- 
mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with 1-2 mg/kg/day IV methylprednisolone 
or equivalent 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 
CTCAE=Common Terminology Criteria for Adverse Events; NCI= National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day 
oral prednisone or equivalent. The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.b If 
corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with atezolizumab should 
be based on the investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.

Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol ML41186, Version 4 
 
Table 20 
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 12 mg/kg/day IV methylprednisolone or 
equivalent, 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 
CTCAE v4.0 guidelines 
 For recurrent events permanently discontinue atezolizumab 
and contact Medical Monitor. c 
CTCAE v5.0 guidelines 
 For recurrent events, treat as a Grade 4 event. Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
Immune- 
mediated 
myositis, Grade 4 
(CTCAE v5.0 
guidelines only) 
CTCAE v5.0 guidelines 
 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 12 mg/kg/day IV methylprednisolone or 
equivalent, 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol ML41186, Version 4 
 
CTCAE=Common Terminology Criteria for Adverse Events; NCI= National Cancer Institute. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
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  10 mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be based on the investigator’s 
benefitrisk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with atezolizumab should 
be based on the investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION 
SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). Clinical and laboratory features of severe CRS overlap with HLH, and HLH 
should be considered when CRS presentation is atypical or prolonged.  Patients with 
suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2014). A patient should be classified as having HLH if five of the following 
eight criteria are met: 
 
Fever  38.5°C
 
Splenomegaly
 
Peripheral blood cytopenia consisting of at least two of the following:
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/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)

Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol ML41186, Version 4 
 
 
At least two of the following:
– 
Platelet count  181  109/L (181,000/L) 
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
table 21. 
Table 21 
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, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the Medical 
Monitor and initiate treatment as appropriate according to published 
guidelines (La Rosée 2015; Schram and Berliner 2015; La Rosée et al. 
2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol ML41186, Version 4 
 
Appendix 10 
Guidelines for Management of Patients Who Experience 
SpecificAdverse Events with Atezolizumab+Bevacizumab 
 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and 
 Guidelines for management of IRRs for atezolizumab are 
hypersensitivity reactions 
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  Stop infusion and permanently discontinue bevacizumab. 
or 4 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 
IRR  infusion-related reaction. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol ML41186, Version 4 
 
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 
 
Withhold atezolizumab. Permanently discontinue 
encephalopathy 
bevacizumab. 
syndrome, any grade 
 
If event improves, consider resuming atezolizumab. If not, 
confirmed by magnetic 
permanently discontinue atezolizumab. a 
resonance imaging 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol ML41186, Version 4 
 
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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol ML41186, Version 4 
 
Guidelines for Management of Patients Who Experience Specific Adverse Events 
with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Thromboembolic events 
Venous thromboembolic event, 
 Atezolizumab may be continued at the discretion of the 
Grade 3 
 
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, 
 Atezolizumab may be continued at the discretion of the 
Grade 4 
 
investigator. 
 Permanently discontinue bevacizumab. 
Arterial thromboembolic event, 
 Atezolizumab may be continued at the discretion of the 
any grade 
 
investigator. 
 Permanently discontinue bevacizumab. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol ML41186, Version 4 
 
Guidelines for Management of Patients Who Experience Specific Adverse Events 
with AtezolizumabBevacizumab (cont.) 
 
Event 
Action to Be Taken 
Proteinuria 
Proteinuria, Grade 1 
 Continue atezolizumab and bevacizumab. 
(1 by dipstick; urinary 
protein  1.0 g/24 hours) 
Proteinuria, Grade 2 
 Continue atezolizumab. 
(2 and 3  by dipstick; urinary 
 For 2 dipstick: Continue bevacizumab and collect 24-hour 
protein 1.03.4 g/24 hours) 
 
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 
 Atezolizumab may be continued at the discretion of the 
(4  by dipstick; urinary protein 
 
investigator. 
 3.5 g/24 hours) with no 
 Withhold bevacizumab. 
diagnosis of nephrotic 
 If urine protein improves to  2 g/24 hours  42 days after event 
syndrome 
 
onset, resume bevacizumab. If not, permanently discontinue 
bevacizumab. 
Nephrotic syndrome, 
 Atezolizumab may be continued at the discretion of the 
Grade 3 or 4 
 
investigator. 
 Permanently discontinue bevacizumab. 
Fistula 
Tracheoesophageal 
 Withhold atezolizumab. 
fistula, any grade 
 Permanently discontinue bevacizumab. 
 If event improves, consider resuming atezolizumab. If not, 
permanently discontinue atezolizumab. a 
Fistula (non- 
 Withhold atezolizumab. 
tracheoesophageal), 
 Permanently discontinue bevacizumab. 
Grade 4 
 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. 

Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol ML41186, Version 4 
 
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 
 Atezolizumab may be continued at the discretion of the 
requiring medical or surgical 
 
investigator. 
therapy 
 Permanently discontinue bevacizumab. 
Congestive heart failure 
Congestive heart failure, 
 Atezolizumab may be continued at the discretion of the 
Grade 3 or 4 
 
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. 

Signature Page for Affiliate Protocol Amendment ML41186 atezolizumab, China
System identifier: RIM-CLIN-034261
Approval Task
13-Jul-2023 00:37:03 GMT+0000