Clinical trial NCT04338269
Conditions: Carcinoma, Renal Cell
Sponsor: Hoffmann-La Roche
Start date: 2020-07-28; Completion date: 2025-03-24
Enrollment: 522 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of atezolizumab given in combination with cabozantinib versus cabozantinib alone in participants with inoperable, locally advanced, or metastatic renal cell carcinoma (RCC) who experienced radiographic tumor progression during or after Immune Checkpoint Inhibitor (ICI) treatment in the metastatic setting.

Detailed description:

Arms: arm 1: Participants will receive atezolizumab every 3 weeks on Day 1 of each 21-day cycle (1 cycle=21 days) plus oral tablets of cabozantinib every day. arm 2: Participants will receive cabozantinib every day.
Interventions: intervention 1: Atezolizumab intervention 2: Cabozantinib
Intervention descriptions: intervention 1: Atezolizumab 1200 mg will be administered at a fixed dose on Day 1 of each 21-day cycle by IV infusion every 3 weeks. intervention 2: Cabozantinib 60 mg (three 20-mg tablets) administered orally once daily.

Protocol documents:
Prot_000.pdf: 


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol WO41994, Version 3
PROTOCOL HISTORY
Protocol
Version
Date Final
2
24 June 2020
1
13 March 2020


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol WO41994, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol WO41994 has been amended to primarily modify inclusion and exclusion 
criteria, and to update severe cutaneous adverse reactions (SCARs) from a potential risk 
to an identified risk associated with atezolizumab. Additional changes to the protocol, 
along with a rationale for each change, are summarized below. The synopsis has been 
updated to reflect changes made to the body of the protocol.

Sections 1.4, 5.1, and Appendix 10 have been revised to include COVID19-specific
risk language to ensure the safety of study participants during the COVID-19
pandemic

Sections 2.1.3 and 6.4.3, Exploratory Efficacy Objectives, now include clarification
of timepoints and instruments for patient-reported outcomes (PROs)

Section 3.1, Description of the Study, has been revised:
–
To clarify sites must continue to provide images until the Independent Review
Facility (IRF) determines disease progression
–
To align the key eligibility criteria changes in the study schema with inclusion
and exclusion criteria

Section 4.1.1, Inclusion Criteria, has been revised:
–
To allow inclusion of patients with the chromophobe subtype of nonclear-cell
renal cell carcinoma (non-ccRCC) if there is sarcomatoid differentiation
because studies have shown improved survival for patients with sarcomatoid
differentiation after treatment with immune checkpoint inhibitors (ICIs)
–
Patients must have been treated with ICIs for at least 2 cycles prior to study
enrollment to reflect a biologically-relevant minimum exposure
–
To allow inclusion of patients who have received ICIs in the adjuvant setting,
provided they progressed during or within 6 months after the last dose of
adjuvant ICI. Phase III renal cell carcinoma (RCC) trials are ongoing in the
adjuvant setting with ICIs. Thus, ICIs are becoming the standard of care in the
adjuvant setting for patients with RCC. Progression during or within 6 months
after the last dose of ICI in the adjuvant setting is a commonly applied inclusion
criterion in oncology clinical trials.
–
Patients must have recovered to baseline or National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5 Grade 1
from toxicities related to any prior treatments, unless adverse events are
clinically nonsignificant and/or stable in the opinion of the investigator to ensure
patient safety. Grade 2 alopecia is allowed for study participation. Exception:
Patients who have received systemic corticosteroids for a prior immune-related
adverse events for 30 days consecutively prior to initiation of study treatment
are excluded to ensure patient safety.


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
Section 4.1.2, Exclusion Criteria, has been revised:
–
The time window has been shortened for “treatment with anti-cancer therapy
prior to initiation of study treatment” from “within 28 days” to “within 14 days.”
The rationale is to “shorten” the 28-day washout period requirement
considering that many RCC-targeted agents have a short half-life.
–
Patients who have received a mammalian target of rapamycin (mTOR) inhibitor
in any setting are excluded from the study to reduce heterogeneity of the study
population. Previously only patients who received an mTOR inhibitor in the
advanced or metastatic settings were excluded.
–
The time window for excluding patients with prior ischemic events or significant
cardiovascular disease risks has been clarified
–
Additional standard language has been added to exclusion criteria.
This language serves to address cabozantinib risks, including hemorrhage,
perforation, and fistulas.

Section 4.3.2.2, Cabozantinib, has been revised so that the requirement for the
1-hour wait time in the clinic after the first dose of cabozantinib has been removed
because it was deemed clinically unnecessary

Section 4.5.10.3, Research Biosample Repository (RBR), and Appendix 2 have
been updated to clarify that RBR sample collection should occur preferably predose
on Day 1 of Cycle 1 but may also be collected anytime thereafter

Section 5.1.1 and Appendix 10 have been updated because SCARs have been
upgraded to an identified risk associated with atezolizumab

Section 5.2.3, Adverse Events of Special Interest, has been updated to reflect the
most up-to-date listing of these events for immediate reporting purposes

Section 5.4.1, Emergency Medical Contacts, has been updated.
The Medical Monitor has been changed.

Section 9.6, Dissemination of Data and Protection of Trade Secrets, has been
updated to correct the name of a Roche policy on data sharing

Appendix 1 and Appendix 2 have been updated:
–
The urine protein-to-creatinine ratio (UPCR) sampling schedule has been
clarified (Appendix 1)
–
A urine biomarker sample is now required for specific visits (Appendix 1 and
Appendix 2)

Appendix 7 has been updated to add language clarifying that hemophagocytic
lymphohistiocytosis and macrophage activation syndrome are considered potential
risks for atezolizumab
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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5/Protocol WO41994, Version 3
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 32
1.1
Background on Renal Cell Carcinoma................................... 32
1.2
First-Line Treatment for Renal Cell Carcinoma ..................... 32
1.3
Second-Line and Third-Line Treatment ................................. 34
1.4
Background on Atezolizumab................................................ 35
1.4.1
Efficacy in Metastatic Renal Cell Carcinoma ......................... 36
1.5
Background on Cabozantinib................................................. 37
1.6
Background on Combination Therapy of 
Atezolizumab and Cabozantinib ............................................ 39
1.7
Rationale for Immune Checkpoint Re-Challenge................... 42
1.8
Study Rationale and BenefitRisk Assessment..................... 42
2.
OBJECTIVES AND ENDPOINTS ............................................................... 43
2.1
Efficacy Objectives ................................................................ 43
2.1.1
Primary Efficacy Objective..................................................... 44
2.1.2
Secondary Efficacy Objective................................................ 44
2.1.3
Exploratory Efficacy Objective............................................... 44
2.2
Safety Objectives................................................................... 45
2.3
Pharmacokinetic Objectives .................................................. 46
2.4
Immunogenicity Objectives.................................................... 46
2.5
Biomarker Objective .............................................................. 46
2.6
Health Status Utility Objective ............................................... 46
3.
STUDY DESIGN......................................................................................... 47
3.1
Description of the Study......................................................... 47
3.1.1
Independent Data Monitoring Committee .............................. 50
3.2
End of Study and Length of Study......................................... 50
3.3
Rationale for Study Design.................................................... 51
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 51
3.3.2
Rationale for Cabozantinib Dose and Schedule .................... 51


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3.3.3
Rationale for Patient Population ............................................ 52
3.3.4
Rationale for Control Group................................................... 53
3.3.5
Rationale for Stratification Factors......................................... 53
3.3.6
Rationale for Open-Label Study ............................................ 54
3.3.7
Rationale for Progression-Free Survival and 
Overall Survival as Multiple Primary Endpoints ..................... 55
3.3.8
Rationale for Atezolizumab or Cabozantinib 
Treatment beyond Initial Radiographic 
Progression per RECIST v1.1 ............................................... 55
3.3.9
Rationale for the Use of iRECIST.......................................... 56
3.3.10
Rationale for Clinical Outcome Assessments........................ 56
3.3.11
Rationale for Biomarker Assessments................................... 57
4.
MATERIALS AND METHODS .................................................................... 58
4.1
Patients.................................................................................. 58
4.1.1
Inclusion Criteria.................................................................... 58
4.1.2
Exclusion Criteria................................................................... 61
4.2
Method of Treatment Assignment and Blinding..................... 67
4.2.1
Treatment Assignment........................................................... 67
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 67
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 67
4.3.1.1
Atezolizumab......................................................................... 67
4.3.1.2
Cabozantinib.......................................................................... 68
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 68
4.3.2.1
Atezolizumab......................................................................... 68
4.3.2.2
Cabozantinib.......................................................................... 69
4.3.3
Investigational Medicinal Product Accountability ................... 70
4.3.4
Continued Access to Atezolizumab and 
Cabozantinib.......................................................................... 71
4.4
Concomitant Therapy ............................................................ 71
4.4.1
Permitted Therapy................................................................. 72
4.4.2
Cautionary Therapy for All Patients....................................... 74
4.4.2.1
Herbal Therapies................................................................... 74


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4.4.3
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 74
4.4.3.1
Corticosteroids, Immunosuppressive Medications, 
and TNF-Inhibitors.............................................................. 74
4.4.4
Cautionary Therapy for Cabozantinib-Treated 
Patients.................................................................................. 74
4.4.4.1
Cytochrome P450.................................................................. 74
4.4.4.2
Protein Binding ...................................................................... 75
4.4.4.3
Concomitant Medications that are Known to 
Prolong the Corrected QT Interval......................................... 75
4.4.4.4
Other Interactions.................................................................. 76
4.4.5
Prohibited Therapy for All Patients ........................................ 76
4.4.6
Prohibited Therapy for Atezolizumab-Treated 
and Cabozantinib-Treated Patients ....................................... 77
4.5
Study Assessments ............................................................... 77
4.5.1
Informed Consent Forms and Screening Log........................ 77
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 78
4.5.3
Physical Examinations........................................................... 78
4.5.4
Vital Signs.............................................................................. 78
4.5.5
Tumor and Response Evaluations......................................... 79
4.5.5.1
Independent Review Facility.................................................. 80
4.5.6
Survival Assessments............................................................ 80
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 81
4.5.8
Electrocardiograms and Echocardiograms............................ 84
4.5.9
Clinical Outcome Assessments ............................................. 85
4.5.9.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 86
4.5.9.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 86
4.5.10
Blood Samples for Whole-Genome Sequencing 
or Whole-Exome Sequencing (Patients at 
Participating Sites)................................................................. 87
4.5.11
Optional Tumor Biopsies ....................................................... 88


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4.5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 89
4.5.12.1
Overview of the Research Biosample Repository.................. 89
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 89
4.5.12.3
Sample Collection.................................................................. 90
4.5.12.4
Confidentiality........................................................................ 90
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 91
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 91
4.5.12.7
Monitoring and Oversight....................................................... 92
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 92
4.6.1
Study Treatment Discontinuation........................................... 92
4.6.2
Patient Discontinuation from the Study.................................. 93
4.6.3
Study Discontinuation............................................................ 93
4.6.4
Site Discontinuation............................................................... 94
5.
ASSESSMENT OF SAFETY....................................................................... 94
5.1
Safety Plan ............................................................................ 94
5.1.1
Risks Associated with Atezolizumab ..................................... 95
5.1.2
Risks Associated with Cabozantinib...................................... 95
5.1.3
Management of Patients who Experience 
Adverse Events and Potential Overlapping 
Toxicities................................................................................ 95
5.1.3.1
Dose Modification.................................................................. 96
5.1.3.2
Treatment Interruption ........................................................... 98
5.2
Safety Parameters and Definitions ........................................ 99
5.2.1
Adverse Events ..................................................................... 99
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 100
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 101
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 101
5.3.1
Adverse Event Reporting Period ......................................... 102


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5.3.2
Eliciting Adverse Event Information..................................... 102
5.3.3
Assessment of Severity of Adverse Events ......................... 102
5.3.4
Assessment of Causality of Adverse Events ....................... 103
5.3.5
Procedures for Recording Adverse Events.......................... 104
5.3.5.1
Infusion-Related Reactions.................................................. 104
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 104
5.3.5.3
Adverse Events that are Secondary to Other 
Events.................................................................................. 105
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 105
5.3.5.5
Abnormal Laboratory Values ............................................... 106
5.3.5.6
Abnormal Vital Sign Values ................................................. 106
5.3.5.7
Abnormal Liver Function Tests............................................ 107
5.3.5.8
Deaths ................................................................................. 107
5.3.5.9
Preexisting Medical Conditions............................................ 108
5.3.5.10
Lack of Efficacy or Worsening of Renal Cell 
Carcinoma ........................................................................... 108
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 108
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 109
5.3.5.13
Patient-Reported Outcome Data ......................................... 111
5.3.5.14
Safety Biomarker Data......................................................... 111
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111
5.4.1
Emergency Medical Contacts.............................................. 112
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 112
5.4.2.1
Events that Occur prior to Study Treatment 
Initiation ............................................................................... 112
5.4.2.2
Events that Occur after Study Treatment Initiation .............. 112
5.4.3
Reporting Requirements for Pregnancies............................ 113
5.4.3.1
Pregnancies in Female Patients.......................................... 113
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 113
5.4.3.3
Abortions ............................................................................. 114
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 114
5.5
Follow-Up of Patients after Adverse Events ........................ 114


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5.5.1
Investigator Follow-Up......................................................... 114
5.5.2
Sponsor Follow-Up .............................................................. 115
5.6
Adverse Events that Occur after the Adverse 
Event Reporting Period........................................................ 115
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 115
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 116
6.1
Determination of Sample Size ............................................. 116
6.2
Summaries of Conduct of Study.......................................... 117
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 118
6.4
Efficacy Analyses ................................................................ 118
6.4.1
Multiple Primary Efficacy Endpoints .................................... 118
6.4.2
Secondary Efficacy Endpoints............................................. 119
6.4.2.1
Objective Response Rate.................................................... 119
6.4.2.2
Duration of Response.......................................................... 119
6.4.3
Exploratory Efficacy Endpoints............................................ 120
6.4.3.1
Analyses at Landmark Timepoints....................................... 120
6.4.3.2
Subgroup Analyses ............................................................. 120
6.4.3.3
Time to Response ............................................................... 120
6.4.3.4
Time to Deterioration of Disease-Related 
Symptoms............................................................................ 120
6.4.3.5
Time to Deterioration of Physical Functioning ..................... 120
6.4.3.6
Time to Deterioration of Global Health 
Status/Quality of Life ........................................................... 121
6.4.3.7
Patient-Reported Outcome Descriptive 
Summaries .......................................................................... 121
6.5
Safety Analyses................................................................... 121
6.5.1
Analyses of Exposure, Adverse Event, 
Laboratory, Vital Signs, and Data........................................ 121
6.5.2
Exploratory Analyses of Patient-Reported 
Treatment Side-Effect Burden ............................................. 122
6.6
Pharmacokinetic Analyses................................................... 122
6.7
Immunogenicity Analyses.................................................... 122


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6.8
Biomarker Analyses............................................................. 123
6.9
Health Status Utility Analyses.............................................. 123
6.10
Interim Analyses .................................................................. 123
6.10.1
Planned Interim Analyses.................................................... 123
7.
DATA COLLECTION AND MANAGEMENT ............................................. 124
7.1
Data Quality Assurance....................................................... 124
7.2
Electronic Case Report Forms............................................. 125
7.3
Source Data Documentation................................................ 125
7.4
Use of Computerized Systems ............................................ 126
7.5
Retention of Records........................................................... 126
8.
ETHICAL CONSIDERATIONS.................................................................. 126
8.1
Compliance with Laws and Regulations .............................. 126
8.2
Informed Consent................................................................ 126
8.3
Institutional Review Board or Ethics Committee.................. 128
8.4
Confidentiality...................................................................... 128
8.5
Financial Disclosure ............................................................ 129
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ................................................................................... 129
9.1
Study Documentation .......................................................... 129
9.2
Protocol Deviations.............................................................. 129
9.3
Management of Study Quality ............................................. 129
9.4
Site Inspections ................................................................... 130
9.5
Administrative Structure....................................................... 130
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 130
9.7
Protocol Amendments ......................................................... 131
10. REFERENCES ......................................................................................... 132


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LIST OF TABLES
Table 1
First-Line Therapy Results for Advanced Renal Cell 
Carcinoma................................................................................... 33
Table 2
Second-Line Therapy Results for Advanced Renal Cell 
Carcinoma................................................................................... 35
Table 3
COSMIC-021 Study ccRCC Expansion Cohort:  
Objective Response Rate (per RECIST v1.1) in 
Cabozantinib 60 mgAtezolizumab-Treated Patients ................. 40
Table 4
COSMIC-021 Study ccRCC Cohort:  Summary of Common 
Adverse Events (30% of Patients) in 
Cabozantinib 60 mgAtezolizumab-Treated Patients ................. 41
Table 5
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 69
Table 6
Timing for Vital Sign Measurements for First and 
Subsequent Infusions ................................................................. 79
Table 7
Guidance for Managing Overlapping Toxicities........................... 96
Table 8
Dose Reduction Levels for Cabozantinib (Oral Dosing).............. 97
Table 9
Dose Modifications for Cabozantinib-Related Adverse 
Events......................................................................................... 98
Table 10
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 103
Table 11
Causal Attribution Guidance ..................................................... 104
Table 12
Operating Characteristics for Proposed Study Design for 
Several Possible True Underlying Hazard Ratios ..................... 123
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 48




Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
GIVEN IN COMBINATION WITH CABOZANTINIB 
VERSUS CABOZANTINIB ALONE IN PATIENTS 
WITH INOPERABLE, LOCALLY ADVANCED, OR
METASTATIC RENAL CELL CARCINOMA WHO 
EXPERIENCED RADIOGRAPHIC TUMOR 
PROGRESSION DURING OR AFTER IMMUNE 
CHECKPOINT INHIBITOR TREATMENT
PROTOCOL NUMBER:
WO41994
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000502-29160
IND NUMBER:
119039
NCT NUMBER:
NCT04338269
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB GIVEN IN COMBINATION WITH CABOZANTINIB 
VERSUS CABOZANTINIB ALONE IN PATIENTS WITH 
INOPERABLE, LOCALLY ADVANCED, OR METASTATIC RENAL 
CELL CARCINOMA WHO EXPERIENCED RADIOGRAPHIC 
TUMOR PROGRESSION DURING OR AFTER IMMUNE 
CHECKPOINT INHIBITOR TREATMENT
PROTOCOL NUMBER:
WO41994
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000502-29160
IND NUMBER:
119039
NCT NUMBER:
NCT04338269
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III
INDICATION:
Renal cell carcinoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab when given in combination with 
cabozantinib compared with cabozantinib alone in patients with advanced clear-cell or 
nonclear-cell renal cell carcinoma (RCC; papillary, chromophobe or unclassified only) who 
experienced radiographic tumor progression during or after immune checkpoint inhibitor (ICI)
treatment in the adjuvant and/or locally advanced/metastatic setting.  Patients with RCC with 
sarcomatoid features are also allowed into this study.  Patients with the chromophobe subtype 
of nonclear-cell RCC must have sarcomatoid differentiation. 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 in combination with cabozantinib or cabozantinib
monotherapy).
Efficacy Objectives
Response will be assessed according to Response Evaluation Criteria in Solid Tumors
(RECIST) Version 1.1.  Objective response at a single timepoint will be determined by 
the investigator and Independent Review Facility (IRF) according to RECIST v1.1.  
Objective response rate (ORR) per modified RECIST for immune-based therapeutics 
(iRECIST) v1.1 may be calculated programmatically by the Sponsor on the basis of investigator 
assessments of individual lesions at each specified timepoint.


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Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with cabozantinib compared with cabozantinib alone in the intent-to-treat (ITT)
population based on the following endpoints:

Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression according to RECIST v1.1, as assessed by an IRF 
(e.g., IRF-PFS) or death from any cause, whichever occurs first

Overall survival (OS), defined as the time from randomization to death from any cause
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with cabozantinib compared with cabozantinib alone on the basis of the following 
endpoints:

PFS assessed by the investigators (investigator-assessed PFS), defined as the time from 
randomization to the first occurrence of disease progression according to RECIST v1.1 or 
death from any cause (whichever occurs first)

Investigator- and IRF-assessed ORR (investigator-assessed ORR and IRF-assessed ORR),
defined as the proportion of patients with a complete response or partial response on 
two consecutive occasions at least 4 weeks apart according to RECIST v1.1

Investigator- and IRF-assessed duration of response (DOR; investigator-assessed-DOR
and IRF-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) 
according to RECIST v1.1
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with cabozantinib compared with cabozantinib alone on the basis of the following 
endpoints:

PFS, OS, and ORR in subgroups, defined by demographic and baseline characteristics 
(e.g., PD-L1 status, prior vascular endothelial growth factor receptor [VEGFR]-tyrosine 
kinase inhibitor [TKI] use, most recent ICI therapy [adjuvant vs. first-line vs. second-line], 
tumor histology, or International Metastatic Renal Cell Carcinoma Database Consortium 
[IMDC] risk group)

Time to response

Time to confirmed deterioration of disease-related symptoms, defined as the time from 
randomization date to the date of a patient’s first 4-point score decrease from baseline on
the Functional Assessment of Cancer TherapyKidney Symptom Index 19 (FKSI-19) 
Disease-Related Symptom-Physical (DRS-P) scale held for at least two consecutive 
timepoints, or followed by death within 3 weeks (if Cycles 112) or 6 weeks (if after 
Cycle 12) from the last patient-reported outcome (PRO) assessment

Change from baseline in patient-reported disease-related symptoms by visit, measured with 
use of the FKSI-19 DRS-P scale

Time to confirmed deterioration of physical functioning, defined as the time from 
randomization date to the date of a patient’s first 10-point score decrease from baseline
on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
LifeCore 30 Questionnaire (QLQ-C30) physical functioning scale held for at least 
two consecutive timepoints, or followed by death within 3 weeks (if Cycles 112) or 
6 weeks (if after Cycle 12) from the last PRO assessment

Time to confirmed deterioration of global health status/quality of life (GHS/QoL), defined 
as the time from randomization date to the date of a patient’s first 10-point score decrease 
from baseline on the EORTC QLQ-C30 GHS/QoL scale held for at least two consecutive 
timepoints, or followed by death within 3 weeks (if Cycles 112) or 6 weeks (if after 
Cycle 12) from the last PRO assessment


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
Change from baseline in patient-reported physical functioning and global health status by 
visit, measured with use of the EORTC QLQ-C30 physical functioning and GHS/QoL scales

Descriptive summary statistics by visit for the remaining FKSI-19 and EORTC QLQ-C30 
scales

Cumulative distribution function curves of score change from baseline to Month 6 for each 
key scale (FKSI-19 DRS-P, EORTC QLQ-C30 physical function, EORTC QLQ-C30 
GHS/QoL)
Safety Objective
The safety objective for this study is to evaluate the safety of atezolizumab in combination with 
cabozantinib compared with cabozantinib alone on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
The exploratory safety objective for this study is to evaluate the overall side-effect burden of 
atezolizumab in combination with cabozantinib compared with cabozantinib alone from the 
patient's perspective, on the basis of the following endpoint:

Patient-reported overall bother with treatment side effects during study treatment, measured 
with use of the FKSI-19 GP5 item
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
atezolizumab and cabozantinib administered in combination on the basis of the following 
endpoints:

Atezolizumab concentrations at specified timepoints

Cabozantinib concentrations at specified timepoints
Immunogenicity Objective
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab
on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of 
ADAs to atezolizumab during the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and demographics, efficacy, safety, or PK endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to atezolizumab in combination with cabozantinib or cabozantinib 
alone (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to atezolizumab in combination with cabozantinib or cabozantinib alone, 
can provide evidence of atezolizumab in combination with cabozantinib or cabozantinib alone
efficacy (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding 
of disease biology and drug safety, on the basis of the following endpoint:

Relationship between biomarkers in blood, tumor tissue, and urine and efficacy, PK, 
immunogenicity, or other biomarker endpoints


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Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with atezolizumab in combination with cabozantinib compared with 
cabozantinib alone to inform economic modeling on the basis of the following endpoint:

Change from baseline in the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
index-based and visual analog scale (VAS) scores by visit
Study Design
Description of Study
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy 
and safety of atezolizumab given in combination with cabozantinib versus cabozantinib alone in 
patients with inoperable, locally advanced, or metastatic RCC who experienced radiographic 
tumor progression during or after ICI treatment in the adjuvant and/or locally 
advanced/metastatic setting.  The study will enroll approximately 500 patients at approximately 
140180 sites globally.
Key inclusion criteria include:

Male and female patients aged 18 years with Karnofsky Performance Status (KPS) score 
70 who have histologically-confirmed locally advanced or metastatic clear-cell or 
nonclear-cell RCC (papillary, chromophobe, or unclassified only)
Sarcomatoid features are allowed.  Patients with the chromophobe subtype of 
nonclear-cell RCC must have sarcomatoid differentiation.
Other subtypes of nonclear-cell RCC (e.g., collecting duct carcinoma, renal medullary 
carcinoma) are not eligible.

Patients who have experienced radiographic tumor progression during or
following ICI treatment for locally advanced or metastatic RCC either in 
first-line or second-line treatment.  Patients who experienced radiographic tumor 
progression during or within 6 months after last dose of adjuvant ICI are also 
eligible.
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening (for a total of two screenings per participant) at the investigator's discretion.
Patients are not required to re-sign the consent form if they are re-screened within 28 days after 
previously signing the consent form.  The investigator will record reasons for screen failure in 
the screening log.
Patients will be randomized in a 1:1 ratio to one of the following two treatments arms:

Experimental arm:  Atezolizumab 1200 mg IV infusions every 3 weeks (Q3W) on Day 1 of 
each 21-day cycle plus cabozantinib 60-mg oral tablets taken once a day 
(QD; 1 cycle 21 days)

Control arm:  Cabozantinib 60-mg oral tablets taken QD (1 cycle 21 days)
Randomization will be stratified by:

IMDC risk groups (favorable, intermediate or poor risk; 0, 12, or 3), which comprises the 
following six risk factors:  time from diagnosis to systemic therapy, KPS, hemoglobin, 
corrected calcium, neutrophil and platelet count

Most recent ICI therapy (adjuvant vs. first-line vs. second-line)

Histology:  dominant clear-cell without sarcomatoid versus dominant nonclear-cell 
(papillary or unclassified only) without sarcomatoid versus any sarcomatoid component 
(clear-cell or nonclear-cell)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle and cabozantinib will be taken orally at a starting dose of 60 mg/day on Days 121 
of each 21-day cycle.  Patients randomized to the atezolizumab and cabozantinib arm who 
transiently withhold or permanently discontinue either atezolizumab or cabozantinib may 
continue on single-agent therapy until disease progression (i.e., patients being withheld from


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cabozantinib transiently for adverse effects may continue atezolizumab monotherapy and vice 
versa). Guidelines for dosage modification, treatment interruption or discontinuation.
Patients will receive atezolizumab and/or cabozantinib until disease progression per 
RECIST v1.1, unacceptable toxicity, or symptomatic deterioration attributed to disease 
progression (e.g., pain secondary to disease or unmanageable ascites) as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local biopsy 
results (if available), and clinical status.
No crossover will be allowed from the control arm to the experimental arm.
Patients will undergo scheduled tumor assessment at baseline, every 9 weeks (7 days) for the 
first 18 months and every 12 weeks (7 days) thereafter.  Tumor assessments will continue 
until disease progression as assessed by the investigator per RECIST v1.1 or, for patients who 
continue study treatment after radiographic disease progression, loss of clinical benefit as 
determined by the investigator.  In the absence of disease progression, tumor assessments 
should continue regardless of whether treatment has been discontinued (e.g., for toxicity) or 
whether patients start new anti-cancer therapy, until consent is withdrawn, death, or the study is 
terminated by the Sponsor, whichever occurs first. Following treatment discontinuation (even in 
the absence of disease progression per RECIST v1.1.), patients will be followed for survival and 
subsequent anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or study 
termination by Sponsor, whichever occurs first. The following information regarding all 
subsequent anti-neoplastic agents upon treatment discontinuation will be collected: line of 
therapy, date of first dose of agent, date of final dose of agent (or if ongoing), patient's best 
response, and date of disease progression.
Sites must continue to provide images until the IRF determines disease progression.  
However, treatment decisions will be made based on investigator assessment of 
disease progression.  Independent Review Facility procedures will be detailed in an 
IRF Charter.
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 pseudo progression) with atezolizumab 
treatment, radiographic progression per RECIST v1.1 may not be indicative of true disease 
progression.  In the absence of unacceptable toxicity, patients who meet criteria for disease 
progression per RECIST v1.1 while receiving atezolizumab and/or cabozantinib will be 
permitted to continue treatment, until loss of clinical benefit, 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 KPS 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 for whom other treatment options/standard therapies exist must provide written 
consent to acknowledge deferring these treatment options in favor of continuing study 
treatment at the time of progression
Tumor tissue will also be collected by biopsy, unless not clinically feasible as assessed and 
documented by the investigator, at the time of first evidence of radiographic disease 
progression per RECIST v1.1 (within 40 days after radiographic progression or prior to the start 
of new anti-cancer treatment, whichever is sooner.  These samples will enable analysis of tumor 
tissue biomarkers related to resistance, disease progression, and clinical benefit of 
atezolizumab and/or cabozantinib.
Number of Patients
Approximately 500 patients will be enrolled in this study at approximately 140180 sites globally.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

Histologically-confirmed locally advanced or metastatic clear-cell or nonclear-cell (papillary, 
chromophobe, unclassified only) RCC
–
Other subtypes of nonclear-cell RCC (e.g., collecting duct carcinoma, renal medullary 
carcinoma) are not eligible.
–
RCC with sarcomatoid features is allowed.  Patients with the chromophobe 
subtype of non-clear-cell RCC must have sarcomatoid differentiation.

Radiographic disease progression to prior ICI therapy for RCC
–
ICI for metastatic disease:  Radiographic disease progression during or 
following ICI treatment for locally advanced or metastatic RCC either in 
first- or second-line treatment
–
ICI for adjuvant therapy:  Patients who experienced radiographic tumor 
progression during or within 6 months after last dose of adjuvant ICI are 
also eligible
–
Examples of ICI regimens include one ICI regimen in first-line treatment 
(e.g., nivolumab plus ipilimumab, pembrolizumab plus axitinib, axitinib plus avelumab), 
or second-line treatment (e.g., TKI as first-line treatment and ICI as second-line 
treatment)
–
ICI is defined by antiPD-L1 or antiPD1 antibody, including atezolizumab, avelumab, 
pembrolizumab, durvalumab, or nivolumab.  Ipilimumab monotherapy is not 
considered an antiPD-L1 or antiPD1 therapy.
–
Patients must have received at least 2 cycles of ICI treatment
–
ICI must have been used in the immediate preceding line of therapy (patients with an 
intervening treatment between ICI and study screening are excluded)
–
Adjuvant treatment with VEGFR-TKIs, except cabozantinib, is allowed

Measurable disease per RECIST v1.1

Evaluable IMDC risk scores

Representative pretreatment tumor specimen(s), for exploratory biomarker research
−
Archival tumor specimen (e.g., at diagnosis, surgery, or prior to initiation of previous 
line of therapy)
−
Pretreatment tumor tissue from fresh biopsy at screening, if clinically feasible.  
Biopsies collected via minor surgery must be performed at least 10 days prior to Day 1 
of Cycle 1 and must be completely healed before first dose.
Availability of tissue sample(s) must be confirmed before randomization.  
Tissue samples must be submitted before or within 4 weeks of randomization.  
Both archival and fresh samples are preferred, if feasible.

KPS score of 70

Recovery to baseline or Grade 1 NCI CTCAE v5.0 from toxicities related to any 
prior treatments, unless adverse events are clinically nonsignificant and/or 
stable in the opinion of the investigator
–
Grade 2 alopecia is allowed for study participation
–
Exception:  Patients who have received systemic corticosteroids for a prior 
immune-related adverse event for 30 days consecutively prior to initiation of 
study treatment are not eligible.  Additional criteria on steroid use for prior 
immune-related adverse events is described in the exclusion criteria.


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
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
−
ANC 1.5109/L (1500 cells/L) without granulocyte colony-stimulating factor support 
within 14 days prior to Day 1 of Cycle 1
−
Lymphocyte count 0.3109/L (300/L)
−
Platelet count 100109/L (100,000/L) without transfusion within 14 days prior to 
Day 1 of Cycle 1
−
WBC counts 2500 cells/L
−
Hemoglobin 90 g/L (9 g/dL) (without transfusion within 14 days prior to Day 1 of 
Cycle 1)
−
AST, ALT, and ALP 2.5upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases:  AST and ALT 5ULN
Patients with documented liver or bone metastases:  ALP 5ULN
−
Bilirubin 1.5ULN with the following exception:
Patients with known Gilbert disease:  bilirubin 3ULN
−
Creatinine clearance 40 mL/min (calculated with use of the Cockcroft-Gault formula, 
or based on 24-hour urine collection)
−
Albumin 25 g/L (2.5 g/dL)
−
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN
−
Proteinuria, as demonstrated by urine protein-to-creatinine ratio 1 mg/mg 
(113.2 mg/mmol)

Negative HIV test at screening

Negative hepatitis B testing at screening:
−
Negative hepatitis B surface antigen (HBsAg) test at screening
−
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. 
The HBV DNA test will be performed only for patients who have a negative HBsAg test 
and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception and agreement to refrain from donating 
eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 4 months after the final dose of 
cabozantinib and for 5 months after the final dose of atezolizumab. Women must 
refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method.


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The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 4 months after 
the final dose of cabozantinib to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.  Females of childbearing potential who are 
partners of male patients should also use contraceptive methods with a failure rate of 
1% per year during their male partner’s therapy and for at least 4 months after 
completing therapy.  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.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Treatment with anti-cancer therapy within 14 days prior to initiation of study treatment

Patients received cabozantinib at any time prior to screening 

Patients who received more than one ICI treatment in the locally advanced or metastatic 
setting (e.g., pembrolizumab and axitinib as first-line treatment and nivolumab as 
second-line treatment)

Patients who received more than two prior lines of therapy in the locally advanced or 
metastatic setting

Patients who have received a mTOR inhibitor in any setting

Symptomatic, untreated, or actively progressing CNS metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met:
−
Measurable disease, per RECIST v1.1, must be present outside the CNS
−
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage
−
The patient has not undergone stereotactic radiotherapy within 7 days prior to 
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.
−
No evidence of significant vasogenic edema
−
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted.
−
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).


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−
There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment.
Asymptomatic patients with CNS metastases newly detected at screening are eligible 
for the study after receiving radiotherapy or surgery, with no need to repeat the 
screening brain scan.

History of leptomeningeal disease

Uncontrolled tumor-related pain
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to enrollment.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Moderate to severe hepatic impairment (Child-Pugh B or C)

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium
12 mg/dL, or corrected calcium ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy or denosumab
Patients who are receiving bisphosphonate therapy or denosumab specifically to 
prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.

History of malignancy other than renal carcinoma 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

Radiotherapy for RCC within 14 days prior to Day 1 of Cycle 1
Patients who are receiving single-fraction radiotherapy given for the indication of pain 
control are eligible.

Active tuberculosis

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
Minor surgeries (e.g., tumor biopsy, placement of vascular access device) should be 
performed at least 10 days prior to initiation of study treatment. Patients must have 
complete wound healing from major surgery or minor surgery before randomization. 
Patients with clinically relevant ongoing complications from prior surgery are not 
eligible.

Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within 5 months after final dose of atezolizumab and 4 months after final dose of 
cabozantinib
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.

Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, 
or any active infection that, in the opinion of the investigator, could impact patient safety

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


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
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior 
to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 2 weeks prior to initiation of study treatment, or anticipation of 
need for systemic immunosuppressive medication during study treatment, with the following 
exceptions:
Patients who received acute, low-dose systemic immunosuppressant medication 
(e.g., 10 mg/day oral prednisone or equivalent) 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 confirmation has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
COPD exacerbation) are eligible for the study.

Prior allogeneic stem cell or solid organ transplantation

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications

Current treatment with anti-viral therapy for HBV or HCV

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, vasculitis, or 
glomerulonephritis, or multiple sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
−
Rash must cover 10% of body surface area
−
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids
−
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

Pharmacologically uncompensated, symptomatic hypothyroidism

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 scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Malabsorption syndrome

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption


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
Uncontrolled hypertension defined as sustained blood pressure 150 mm Hg systolic or 
90 mm Hg diastolic despite optimal antihypertensive treatment

Tumors invading the gastrointestinal (GI) tract, active peptic ulcer disease, 
acute pancreatitis, acute obstruction of the pancreatic or biliary duct, 
appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction, 
or inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

Stroke (including transient ischemic attack), myocardial infarction, or other symptomatic 
ischemic event, or thromboembolic event (e.g., deep venous thrombosis [DVT], pulmonary 
embolism [PE]) within 6 months before randomization
Upon Sponsor approval, subjects with a diagnosis of incidental PE or DVT within 
6 months are allowed if asymptomatic and stable at screening treated with 
lowmolecular-weight heparins (LMWHs) or the direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban for at least 1 week before first dose.

Significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease, unstable arrhythmia, or unstable angina) within 3 months prior to initiation 
of study treatment

History of clinically significant ventricular dysrhythmias or risk factors for ventricular 
dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic 
dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with 
ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome

History of congenital QT syndrome

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion, including complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction that is considered as 
clinically significant by investigator

QT interval corrected with use of Fridericia's formula (QTcF) 480 ms per ECG within 
14 days before randomization
Note: If a single ECG shows a QTcF with an absolute value480 ms, 2 additional 
ECGs at intervals of approximately 3 minutes must be performed within 30 minutes 
after the initial ECG, and the average of the 3 consecutive results for QTcF must 
be480 ms for the patient to be eligible.

Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring surgical 
repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1

Evidence of bleeding diathesis or significant coagulopathy

Abdominal or tracheoesophageal fistula, bowel obstruction, or GI perforation, or 
intra-abdominal abscess within 6 months before initiation of study treatment
Complete healing of an intra-abdominal abscess must be confirmed before initiation 
of study treatment.

Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitor 
dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel)
The following are allowed anticoagulants:
Prophylactic use of low-dose aspirin for cardio protection (per local applicable 
guidelines) and low-dose LMWHs.
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in patients without known brain metastases 
who are on a stable dose of the anti-coagulant for at least 1 week before 
randomization without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor. 

Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding


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
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

Known cavitating pulmonary lesion(s) or known endobronchial disease 
manifestations

Lesions invading major pulmonary blood vessels

Clinically significant hematuria, hematemesis, hemoptysis of 0.5 teaspoon 
(2.5 mL) of red blood, coagulopathy, or other history of significant bleeding 
(e.g., pulmonary hemorrhage) within 3 months before initiation of study 
treatment

Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

Prior history of hypertensive crisis or hypertensive encephalopathy

Requirement for hemodialysis or peritoneal dialysis

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known allergy or hypersensitivity to any component of the cabozantinib formulation

Patients who are not able to swallow a tablet
End of Study
The end of this study is defined as the date when the required numbers of events for the final 
analysis of OS in the ITT population has occurred.
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 55 months.
Investigational Medicinal Products
The investigational medicinal products for this study are atezolizumab and cabozantinib.
Test Products (Investigational Drugs)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg Q3W.
Cabozantinib will be administered orally QD at a dose of 60 mg (three 20-mg tablets).
Comparator
The comparator of this study is cabozantinib 60 mg (three 20-mg tablets) administered orally 
QD.
Statistical Methods
Efficacy Analyses
The analysis population for the efficacy analyses will consist of all randomized patients, with 
patients grouped according to their assigned treatment.
Multiple Primary Efficacy Endpoints
The multiple primary efficacy endpoints are IRF-assessed PFS per RECIST v1.1 and OS.
Progression-free survival is defined as the time from randomization to disease progression, as 
determined by the IRF per RECIST v1.1, or death from any cause, whichever occurs first.  
Data for patients who have not experienced disease progression or death will be censored at 
the last tumor assessment date.  Data for patients with no post-baseline tumor assessments will 
be censored at the randomization date.
Overall survival is defined as the time from randomization to death due to any cause.  Data for 
patients who are not reported as having died at the date of analysis will be censored at the date 
when they were last known to be alive.  Patients who do not have post-baseline information will 
be censored at the date of randomization.
The following analyses will be performed for both PFS and OS endpoints described above.  
Progression-free survival and OS will be compared between treatment arms with use of the 


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stratified log-rank test at the 2-sided level of significance. The hazard ratio (HR) with a 95% CI 
will be estimated with use of a stratified Cox regression model with the same stratification 
variables used for the stratified log-rank test.  The randomization stratification factors are most 
recent ICI therapy (adjuvant vs. first-line vs. second-line), histology (dominant clear-cell without 
sarcomatoid vs. dominant nonclear-cell [papillary or unclassified only] without sarcomatoid vs. 
any sarcomatoid component [clear-cell or nonclear-cell]), and the IMDC score (0, 12, 3).
If at least 1 stratum has less than 10 events at the time of analysis, the stratification factor that
contains the level with the smallest number of patients will be removed from the stratified 
analyses.  The final set of stratification factors used for the multiple primary endpoints will be 
applied to all other endpoints where stratified analyses are planned.  The stratification factors 
will be obtained from the interactive voice or Web-based response system (IxRS) at the time of 
randomization.  Results from an unstratified analysis will also be provided.  Kaplan-Meier 
methodology will be used to estimate the median PFS and OS for each treatment arm, and 
Kaplan-Meier curves will be produced.  The Brookmeyer Crowley methodology will be used to 
construct the 95% CI for the median PFS and OS for each treatment arm.
Determination of Sample Size
Approximately 500 patients are planned for enrollment globally over 20 months.  The sample 
size calculation is determined based on the below considerations.
Type I Error Control
The type I error () for the entire study is 0.05 (2-sided).  There are multiple primary efficacy 
endpoints for this study:  PFS by IRF assessment per RECIST v1.1 and OS in the 
ITT population. To control the overall type I error rate at 0.05 while accounting for 2 primary 
endpoints, is split between PFS (0.02) and OS (0.03).  The type I error can be recycled 
if PFS results in the ITT population are statistically significant at 0.02, then 0.02 will be 
recycled to OS in the ITT population, and OS in the ITT population will be evaluated at 0.05. 
The study will be considered as a positive study if statistical significance is achieved in favor of 
the experimental arm for either of the multiple primary endpoints, since the type I error () for 
the entire study is controlled at 0.05.
Primary Endpoint:  Progression-Free Survival by Independent Review Facility Assessment per 
RECIST v1.1 in the Intent-to-Treat Population
The analysis of the primary endpoint of PFS by IRF assessment per RECIST v1.1 will take 
place when approximately 325 IRF-assessed PFS events have occurred in the ITT population 
(65% events patient rate) based on the following assumptions:

Two-sided, stratified log-rank test

0.02 (2-sided)

Approximately 90% power

Median PFS for the cabozantinib arm of 8.0 months and estimated median PFS in the 
atezolizumab and cabozantinib arm of 11.9 months (corresponding to HR of 0.67)

5% annual loss to follow-up for PFS

No interim analysis
On the basis of these assumptions, it is projected that an observed HR of 0.77 or lower will 
result in a statistically significant difference between treatment arms (i.e., an HR of 0.77 will be 
the minimum detectable difference [MDD] for the analysis; this corresponds to an improvement 
of 2.4 months in median PFS from 8.0 months in the cabozantinib arm to 10.4 months in the 
atezolizumab and cabozantinib arm).
Primary Endpoint:  Overall Survival in the Intent-to-Treat Population
The final analysis of the primary endpoint of OS will take place when approximately 325 OS 
events have occurred in the ITT population (65% events patient rate) based on the following 
assumptions:

Two-sided, stratified log-rank test

0.03 (2-sided)

Approximately 85% power


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
Median OS in the cabozantinib arm of 22 months and estimated median OS in the 
atezolizumab and cabozantinib arm of 31.4 months (an increase of 9.4 months, 
corresponding to an HR of 0.70)

1% annual loss to follow-up for OS

Two interim OS analyses
At the final OS analysis, on the basis of these assumptions, it is projected that an observed OS 
HR of 0.78 or lower in the ITT population will result in a statistically significant difference 
between treatment arms (i.e., the MDD at the analysis; this corresponds to an improvement of 
6.2 months in median OS, from 22 months in the control arm to 28.2 months in the 
atezolizumab and cabozantinib arm).
Sample Size
With the above assumptions on PFS and OS, the sample size is determined at 500 patients, 
where the PFS and OS final analysis will be conducted when 325 events occur (65% events 
patient rate), respectively. The 500 patients are planned for enrollment globally over 20 months.
Interim Analyses
Primary Endpoint of Progression-Free Survival
There is no planned interim analysis of the primary endpoint of PFS.
Primary Endpoint of Overall Survival
A total of three analyses of OS will be performed, including two interim analyses and one final 
analysis.  The boundary for statistical significance at each OS analysis will be determined based 
on the Lan-DeMets implementation of the O’Brien-Fleming (OBF) function to maintain the 
overall type I error rate at either 0.03 or 0.05 level, depending on whether primary endpoint of 
PFS is significant at 0.02 level.  The OS endpoint will be considered positive in the 
ITT population if statistical significance is achieved in favor of the experimental arm for any of 
the two OS interim analyses or the final analysis.
The first interim analysis of OS will be performed at the time of the PFS primary analysis.  
A total of 175 OS events are expected at the first interim analysis of OS, which corresponds to 
53% of the events information required for the final analysis of OS in the ITT population.  
Statistical significance will be declared if p 0.0019.  If there are significantly fewer (160) OS 
events than the expected 175 OS events, then the first interim analysis will be delayed until
175 OS events occur. An administrative of 0.000001 (negligible impact on overall type I error 
rate) will be spent on the OS hypothesis at the time of the planned PFS.
The second interim analysis of OS will be performed when approximately 260 deaths have 
occurred, which corresponds to approximately 80% of the events information required for the 
final analysis of OS in the ITT population.  Statistical significance will be declared if p 0.0125.
The final analysis of OS will be performed when 325 deaths (65% of 500 patients in the 
ITT population) have occurred.  Statistical significance will be declared if p0.0259 when 
exactly 325 deaths have occurred at the time of the final OS analysis.
The actual OBF boundary will be calculated at time of analysis based on actual number of 
events observed.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
aRCC
advanced renal cell carcinoma
AUC
area under the concentration-time curve
BP
blood pressure
ccRCC
clear-cell renal cell carcinoma
COPD
chronic obstructive pulmonary disease
CR
complete response
CRS
cytokine release syndrome
CSR
Clinical Study Report
CT
computed tomography (scan)
ctDNA
circulating tumor DNA
DLT
dose-limiting toxicity
DOR
duration of response
DRS-P
Disease-Related Symptom-Physical
DVT
deep venous thrombosis
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
Fc
fragment crystallizable
FDA
U.S. Food and Drug Administration
FKSI-19
Functional Assessment of Cancer TherapyKidney Symptom 
Index 19
GI
gastrointestinal
GHS/QoL
global health status/quality of life
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
ICH
International Council for Harmonisation
ICI
immune checkpoint inhibitor
iDMC
independent Data Monitoring Committee


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Abbreviation
Definition
IL
interleukin
IMDC
International Metastatic Renal Cell Carcinoma Database 
Consortium
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
iRECIST
modified RECIST for immune-based therapeutics
IRF
Independent Review Facility
IRR
infusion-related reaction
ITT
intention-to-treat
IxRS
interactive voice or Web-based response system
KPS
Karnofsky Performance Status
LMWH
low-molecular-weight heparin
LVEF
left ventricular ejection fraction
MDD
minimum detectable difference
MDSC
myeloid-derived suppressor cell
mOS
median overall survival
MRI
magnetic resonance imaging
MRP2
multidrug resistance-associated protein 2
MSKCC
Memorial Sloan Kettering Cancer Center
mTOR
mammalian target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next-generation sequencing
nonccRCC
nonclear-cell renal cell carcinoma
NSAID
nonsteroidal anti-inflammatory inhibitor
NSCLC
nonsmall-cell lung cancer
OBF
O’Brien-Fleming
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PE
pulmonary embolism
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PPI
proton pump inhibitor
PPE
palmar-plantar erythrodysesthesia


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Abbreviation
Definition
PR
partial response
PRO
patient-reported outcome
Q3W
every 3 weeks
QD
once a day
QLQ-C30
Quality of LifeCore 30 Questionnaire
QTc
corrected QT interval
QTcF
QT interval corrected with use of Fridericia’s formula
RBR
Research Biosample Repository
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SmPC
Summary of Product Characteristics
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
USPI
U.S. Package Insert
VAS
visual analog scale
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WES
whole-exome sequencing
WGS
whole-genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON RENAL CELL CARCINOMA
Renal cell carcinoma (RCC) was diagnosed in more than 400,000 people and was 
associated with approximately 175,000 deaths worldwide in 2018.  Renal cell carcinoma
is the 9th most common cancer occurring in men, and the 14th most common cancer in 
women (GLOBACON 2018). The incidence of RCC is predominant in men with a peak 
age of 6070 years (Capitanio and Montorsi 2016).  Renal cell carcinoma comprises a 
heterogeneous group of cancers with clear-cell renal cell carcinoma (ccRCC) being the 
most common histologic subtype (75%), followed by nonclear-cell renal cell carcinoma 
(nonccRCC) subtypes of papillary (15%), and chromophobe and oncocytoma (5% each;
Motzer et al. 1996). With the exception oncocytoma, a sarcomatoid component can 
develop in each of these subtypes.
While the majority of patients will present with localized disease, approximately 30% of 
those treated with curative intent will develop distant disease, and approximately
20%25% of patients present with metastatic disease at initial diagnosis 
(Dabestani et al. 2016).  The models to predict survival such as the Memorial Sloan 
Kettering Cancer Center (MSKCC; Motzer et al. 2004) risk stratification model and the
International Metastatic Renal Cell Carcinoma Database Consortium
(IMDC; Heng et al. 2009) risk score have been developed. These models are used as a 
stratification factor for the clinical trials with use of immune checkpoint inhibitors (ICIs).
The IMDC risk category is also validated for the patients receiving second-line targeted 
therapy (Ko et al. 2015).
1.2
FIRST-LINE TREATMENT FOR RENAL CELL CARCINOMA
The tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor (VEGF), 
sunitinib, was the standard of care for treatment-naive patients with RCC for many years 
because of the data showing superior efficacy over conventional cytokines (Table 1).  
However, the first-line treatment landscape has evolved significantly in recent years with 
the upfront use of ICIs and the results suggest that the upfront use of ICIs improves
overall survival (OS) when compared with sunitinib (Table 1).


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Table 1
First-Line Therapy Results for Advanced Renal Cell Carcinoma
Agent and 
Population
Comparison
PFS
(months)
HR
(95% CI)
OS
(months)
HR
(95% CI)
NivoIpi
(intpoor risk) a
Sunitinib
11.6 vs. 8.4
0.82
0.641.05
NR vs. 26.0
0.63
0.440.89
AtezoBev
(PD-L1) b
Sunitinib
11.2 vs. 7.7
0.83
0.700.97
N/A
N/A
AveAxi c
Sunitinib
13.8 vs. 8.4
0.69
0.560.84
NR vs. NR
0.78
0.551.08
PembroAxi d
Sunitinib
15.1 vs. 11.1
0.69
0.570.84
NR vs. NR
0.53
0.380.74
Sunitinib e
IFN-
11.0 vs. 5
0.42
0.320.54
24.5 vs. 20.4
0.82
0.671.00
BevIFN-f
IFN-
10.2 vs. 5.4
0.63
0.520.75
23.0 vs. 21.0
0.96
0.731.04
Pazopanib g
Placebo
9.2 vs. 4.2
0.46
0.340.62
22.9 vs. 20.5
0.91
0.711.16
Temsirolimus h
(poor risk)
IFN-
5.6 vs. 3.2
0.74
0.600.91
10.9 vs. 7.3
0.78
0.630.97
Cabozantinib
(intpoor risk)
Sunitinib
8.2 vs. 5.6 i
0.66
0.460.95
26.6 vs. 21.2 j
0.80
0.531.21
Cabo Nivo k
Sunitinib
16.6 vs. 8.3
0.51
0.410.64
NR vs. NR
0.60
0.400.89 m
Lenv Pembro l
Sunitinib
23.9 vs 9.2
0.39
0.320.49
NR vs NR
0.66
0.490.88
Lenv Eve l
Sunitinib
14.7 vs 9.2
0.65
0.530.80
NR vs NR
1.15
0.881.50
Atezoatezolizumab; Aveavelumab; Axiaxitinib; Bevbevacizumab; Cabo cabozantinib; 
Eve everolimus; HRhazard ratio; intpoorintermediatepoor; Ipiipilimumab; 
Lenv lenvatinib; N/Anot available; Nivonivolumab; NRnot reached; OSoverall survival; 
Pembropembrolizumab; PFSprogression-free survival.
a Source:  Motzer et al. 2018a.
b Source:  Rini et al. 2019a.
c Source:  Motzer et al. 2019b.
d Source:  Rini et al. 2019b.
e Source:  Motzer et al. 2007.
f
Source:  Escudier et al. 2007.
g Source:  Sternberg et al. 2010.
h Source:  Hudes et al. 2007.
i
Source:  Choueiri et al. 2017a.
j
Source:  Choueiri et al. 2018.
k Source:  CabometyxU.S. Package Insert.
l
Source:  Motzer et al. 2021.
m Hazard ratio (98.89% CI).


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1.3
SECOND-LINE AND THIRD-LINE TREATMENT
There are several options available for patients with RCC who received prior systemic 
therapy (Table 2). Everolimus and sorafenib have shown a progression-free survival 
(PFS) benefit for patients previously treated with anti-angiogenic agents over placebo 
(Escudier et al. 2009; Motzer et al. 2010). Later, axitinib demonstrated a longer PFS 
against sorafenib for those previously treated with anti-angiogenic agents or interleukin
(IL)-2 (Rini et al. 2011). Similarly, in a Phase II study, lenvatinib plus everolimus
demonstrated PFS benefit in comparison with everolimus alone in patients with ccRCC 
previously treated with antiVEGF-targeted therapy and progressed in or within 
9 months of stopping the previous treatment. However, the numerical increase seen in 
OS was not statistically significant. Cabozantinib demonstrated a longer PFS and OS 
over everolimus in patients previously treated with VEGF receptor (VEGFR)-TKI 
(Choueiri et al. 2015). Nivolumab demonstrated an OS benefit for those patients 
previously treated with anti-angiogenic therapy in ccRCC regardless of PD-L1 status, 
prior therapy or MSKCC risk group (Motzer et al. 2015a).
With the shift to immunotherapy combinations increasingly being used in first-line 
therapy, there have been no completed Phase III studies in the post-immunotherapy 
setting for RCC. In the pre-immunotherapy era, a report suggested that only 55 patients 
received third-line therapy out of 257 patients who received second-line therapy, and 
treatments vary, including sorafenib, everolimus, axitinib, temsirolimus, and 
bevacizumab (Maroun et al. 2018).  Another report revealed that third-line therapy was 
given to 21% of patients who received first-line therapy. Everolimus was the most 
prevalent therapy, and other treatments included in the third-line therapy were sunitinib, 
sorafenib, pazopanib, temsirolimus, and axitinib. Overall survival for the patients who 
received third-line therapy was 12.4 months and PFS was 3.9 months (Wells et al. 2017).


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Table 2
Second-Line Therapy Results for Advanced Renal Cell 
Carcinoma
Agent and 
Population
Comparison
PFS
(months)
HR
(95% CI)
OS
(months)
HR
(95% CI)
Nivo a
Everolimus
4.6 vs. 4.4
0.88
0.751.03
25.0 vs. 19.6
0.73
0.570.93
Everolimus b
Placebo
4.9 vs. 1.9
0.33
0.250.43
14.8 vs. 14.4
0.87
0.651.17
Sorafenib c
Placebo
5.5 vs. 2.8
0.44
0.350.55
17.8 vs. 15.2
0.88
0.741.04
Axitinib d
Sorafenib
6.7 vs. 4.7
0.67
0.540.81
20.1 vs. 19.2
0.97
0.801.17
LenvaEverolimus e
Everolimus
14.6 vs. 5.5
0.44
0.240.68
25.5 vs. 18.4
0.55
0.301.01
Cabozantinib f
Everolimus
7.4 vs 3.8
0.58
0.450.75
21.4 vs. 16.5
0.66
0.530.83 a
HRhazard ratio; LenvaLenvatinib; NAnot assessed; Nivonivolumab; OSoverall survival; 
PFSprogression-free survival.
a Source:  Motzer et al. 2015a.
b Source:  Motzer et al. 2010.
c Source:  Escudier et al. 2009.
d Source:  Rini et al. 2011.
e Source:  Motzer et al. 2015b.
f
Source:  CabometyxU.S. Package Insert.
1.4
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding
to fragment crystallizable (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 patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single-agent therapy, as well as in combination with 
chemotherapy, targeted therapy, and cancer immunotherapy and is approved for the 
treatment of urothelial carcinoma, nonsmall-cell lung cancer (NSCLC), small-cell lung 
cancer, and triple-negative breast cancer.


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Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
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 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.
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.
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy.
1.4.1
Efficacy in Metastatic Renal Cell Carcinoma
Atezolizumab monotherapy (1200 mg, every 3 weeks [Q3W]) with or without 
bevacizumab (15 mg/kg, Q3W) was compared with sunitinib for treatment-naive 
metastatic RCC in the Phase II Study WO29074 (IMmotion150). In the intent-to-treat 
(ITT) population, PFS hazard ratios (HRs) for atezolizumab in combination with
bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% CI: 
0.691.45) and 1.19 (95% CI: 0.821.71), respectively; PD-L1PFS HRs were 
0.64 (95% CI: 0.381.08) and 1.03 (95% CI: 0.631.67), respectively. The objective 
response rates (ORRs) in the ITT population were 32% (7% complete response [CR], 


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25% partial response [PR]), 25% (11% CR, 14% PR), and 29% (5% CR, 24% PR) with 
atezolizumab in combination with bevacizumab, atezolizumab monotherapy, and 
sunitinib, respectively.  In PD-L1patients, the ORRs were 46% (12% CR, 34% PR), 
28% (15% CR, 13% PR), and 27% (7% CR, 20% PR) with atezolizumab in combination 
with bevacizumab, atezolizumab monotherapy, and sunitinib, respectively 
(McDermott et al. 2018). This trial allowed crossover to atezolizumab and bevacizumab
treatment after treatment failure with sunitinib or atezolizumab monotherapy. The ORRs 
in atezolizumab plus bevacizumab for patients previously treated with sunitinib or 
atezolizumab monotherapy was 28% and 24%, respectively.  The PFS in atezolizumab 
plus bevacizumab for patients previously treated with sunitinib or atezolizumab 
monotherapy was 8.3 months and 12.6 months, respectively (Atkins et al. 2017). 
These results appear to suggest potential use of atezolizumab combination therapy after 
atezolizumab treatment failure, although the results are preliminary.
The Phase III Study WO29637 (IMmotion151) was designed to demonstrate the 
superiority of atezolizumab in combination with bevacizumab compared with sunitinib for 
advanced, treatment-naive patients with ccRCC or RCC with sarcomatoid component
(Rini et al. 2019a). The study met its co-primary endpoint of investigator-assessed PFS 
in PD-L1patients, but OS data was immature at the time of analysis (median PFS for 
atezolizumab plus bevacizumab vs. sunitinib: 11.2 months vs. 7.7 months; HR0.74;
p0.0217; median OS HR0.93). In addition, PFS results with an independent 
radiology committee showed a HR0.93 (95% CI: 0.721.21) in the PD-L1population.
Atezolizumab administered in combination with bevacizumab was also assessed in 
patients with advanced renal cell carcinoma (aRCC) with nonccRCC or RCC with 
sarcomatoid histology in a Phase II study. In this study, 42 patients had nonccRCC 
histology, including papillary, chromophobe, unclassified, and others with or without 
sarcomatoid component. The ORR in papillary was 26% while it was 10% in 
chromophobe (McGregor et al. 2020). In addition, Study WO29637 (IMmotion151)
subgroup analysis for RCC with sarcomatoid component showed longer PFS in patients 
receiving atezolizumab in combination with bevacizumab compared with sunitinib 
(median PFS 8.3 months [95% CI: 5.412.9 months] vs. 5.3 months 
[95% CI: 3.36.7 months]; Rini et al. 2019a).
1.5
BACKGROUND ON CABOZANTINIB
Cabozantinib is an orally bioavailable TKI with potent activity against MET and VEGFR2, 
as well as a number of other receptor tyrosine kinases that have also been implicated in 
tumor pathobiology, including RET, KIT, AXL, and FLT. Cabozantinib suppresses MET 
and VEGFR2 signaling, rapidly inducing apoptosis of endothelial and tumor cells, 
resulting in tumor regression in a variety of xenograft models (Sennino et al. 2009;
Yakes et al. 2011).


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Cabozantinib has shown efficacy in patients with aRCC previously treated with 
VEGF-targeted therapies as well as treatment-naive patients with RCC 
(Choueiri et al. 2017b). The METEOR trial (NCT01865747) was a Phase III study
comparing cabozantinib administered 60 mg once a day (QD) versus everolimus in 
patients with advanced RCC who progressed after a previous VEGFR-TKI treatment.  
The estimated median PFS was 7.4 months (95% CI: 5.69.1 months) with cabozantinib
and 3.8 months (95% CI: 3.75.4 months) with everolimus (OS HR0.58; 95% CI:
0.450.75; p0.001).  Median OS was 21.4 months (95% CI: 18.7 months to not 
estimable) with cabozantinib and 16.5 months (14.718.8 months) with everolimus 
(HR0.66; 95% CI: 0.530.83; p0.00026).  In this trial, approximately 60% of patients 
previously received sunitinib, and approximately 40% of patients received pazopanib.  
Nivolumab was previously used in 5% of patients.  Patients who received 1 prior therapy 
were 71%, while 29% of patients received more than one treatment. In this trial, 
subgroup analyses showed efficacy across different lines of therapy and different types 
of prior therapies, including VEGFR-TKIs and immunotherapy.  Cabozantinib improved 
survival in patients previously treated with sunitinib (PFS: HR0.43; OS: HR0.66) or 
pazopanib (PFS:  HR0.67; OS: HR0.66) irrespective of the number of previous 
treatment lines received. Cabozantinib also improved PFS in patients previously treated 
with ICI compared with everolimus (PFS: HR0.22 [95% CI: 0.070.65], ORR 22% vs.
0%, OS: HR0.56 [95% CI: 0.211.52]).
Also, as indicated in Table 1, in the front-line setting, cabozantinib showed superiority 
against sunitinib in intermediate and poor risk RCC with a median PFS of 8.2 months vs.
5.6 months (HR0.66; 95% CI: 0.460.95; Choueiri et al. 2017b).
In a retrospective single arm study assessing cabozantinib efficacy in nonccRCC, 
cabozantinib was shown to be active with an ORR 27%, PFS of 7 months, and OS of 
12 months in these patients. The safety profile is similar to that of the ccRCC population 
(Chanzá et al. 2019).
Cabozantinib (60 mg, tablets) is approved as a single agent for patients with advanced 
RCC (CabometyxU.S. Package Insert [USPI]), and in combination with nivolumab as 
first-line treatment for patients with advanced RCC (CabometyxUSPI), for adult 
patients with advanced RCC after prior VEGF-targeted therapy or treatment-naïve 
adult patients with intermediate or poor risk RCC (Cabometyx EMA Summary of 
Product Characteristics [SmPC]), and for patients with hepatocellular carcinoma who 
have previously been treated with sorafenib (Cabometyx USPI and EMA SmPC).  
In addition, cabozantinib (140 mg, capsules) is approved for patients with progressive, 
metastatic medullary thyroid cancer (CometriqUSPI and EMA SmPC).  The capsule 
and tablet formulations are not bioequivalent or interchangeable.
The approval of cabozantinib for the treatment of aRCC is based on the results 
described in Table 1 and Table 2 as well as in advanced hepatocellular carcinoma after 
prior sorafenib therapy.


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Refer to the Cabozantinib Investigator's Brochure for details on nonclinical and clinical 
studies.
1.6
BACKGROUND ON COMBINATION THERAPY OF 
ATEZOLIZUMAB AND CABOZANTINIB
Although the main anti-tumor efficacy with cabozantinib is driven by anti-VEGF, 
anti-MET, and other TKIs, cabozantinib also appears to modulate the immune-tumor 
microenvironment and enhances innate immunity (Patnaik et al. 2017).  
Cabozantinib showed a reduction of tumor vascularity and improves T-cell infiltration as 
well as showed a reduction of T regulatory cells (Tregs), myeloid-derived suppressor 
cells (MDSCs), and tumor-associated macrophages when combined with 
immunotherapy (Kwilas et al. 2014). In addition, a report suggests that cabozantinib in 
combination with antiPD-1 treatment suppressed MDSCs, which is known to promote 
tumor infiltration in prostate cancer (Lu et al. 2017). In summary, cabozantinib promotes 
an immune-permissive environment that may enhance response to ICIs.
COSMIC-021 (NCT03170960) is a Phase Ib study of cabozantinib in combination with 
atezolizumab to assess the safety and efficacy of this combination in multiple tumor 
types, including RCC (i.e., treatment-naive patients with RCC). Patients received either 
40 mg or 60 mg of cabozantinib QD orally in combination with 1200 mg of atezolizumab 
IV Q3W. In the dose-escalation stage, 12 patients with RCC (10 clear-cell and 
2 nonclear-cell histology) were enrolled:  6 patients received cabozantinib 40 mg 
(QD orally) and 6 patients received cabozantinib 60 mg (QD orally) in combination with 
1200 mg of atezolizumab IV Q3W for a total of 12 patients.  There were no dose-limiting 
toxicities (DLTs) observed at either dose level. As of 21 August 2018, with a median 
follow-up of 33.4 weeks (range: 2650 weeks), most adverse events were of 
Grade 1 or 2, including immune-related adverse events.  Grade 3 adverse events 
included 5 events of hypertension, 2 events each of diarrhea and hypophosphatemia, 
1 event each of ALT, AST, lymphopenia, hyperglycemia, gamma-glutamyl transferase 
(GGT) increased, pulmonary embolism (PE), oral pain, myositis, and lipase increased. 
There were no Grade 4 or 5 adverse events.  Among 12 patients, investigator-assessed
confirmed ORR was 67% (1 CR, 7 PRs); 4 additional patients had stable disease with a 
disease control rate of 100% (Agarwal et al. 2018).  Based on a favorable safety profile 
and encouraging anti-tumor activity, cabozantinib 40 mg in combination with 
atezolizumab 1200 mg was selected as the recommended dose for expansion cohorts in 
multiple solid tumor cohorts.  Upon evaluation of safety and efficacy data of 
approximately 30 initially-enrolled patients in an expansion cohort, the Study Oversight 
Committee could extend enrollment with an additional 30 patients to explore whether 
cabozantinib 60 mg in combination with atezolizumab will lead to improved clinical 
efficacy and maintain an acceptable safety profile.


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The expansion stage of the COSMIC-021 study has been initiated, enrolling patients 
across 12 different solid tumor types, including RCC of clear-cell and nonclear-cell 
histology across all three IMDC risk categories. The ccRCC expansion cohort initially 
enrolled 30 treatment-naive patients receiving cabozantinib 40 mg in combination with 
1200 mg of atezolizumab. Preliminary data of this cohort indicated that the combination 
therapy was well-tolerated and showed encouraging clinical efficacy.
As of 20 December 2019, 30 patients with ccRCC were enrolled in the cohort receiving 
60-mg cabozantinib in combination with atezolizumab. The median follow-up was 
7.9 months (range: 311 months). Twenty-three (77%) of the 30 patients were actively
on study treatment and 7 patients discontinued all study treatment. The reasons for 
treatment discontinuation were radiographic progression (5 patients), adverse event 
unrelated to disease progression (1 event), and withdrawal (1 patient).  An overview of 
the efficacy data of the 60-mg cabozantinib RCC cohort is shown in Table 3.  The ORR 
per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 was 57% 
(including 1 CR) and the disease control rate was 89%.
Table 3
COSMIC-021 Study ccRCC Expansion Cohort: 
Objective Response Rate (per RECIST v1.1) in
Cabozantinib 60 mgAtezolizumab-Treated Patients
Best Response
Cabozantinib 60 mg
N31 a
N (%)
ORR, including
17 (57)
Unconfirmed PR
1 (3.3)
CR
1 (3.3)
PR
16 (53)
Stable Disease
10 (33)
Progressive Disease
2 (6.7)
Not Evaluable
1 (3.3)
ccRCclear-cell renal cell carcinoma; CRcomplete response; ORRobjective response rate; 
PRpartial response; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  Clinical cutoff date is 20 December 2019.
a Evaluable patients are defined as those with at least 1 post-baseline response assessed by 
the investigator or, if discontinued, prior to assessment.
The most common adverse events of any grade regardless of causality in the 
60-mg cabozantinib ccRCC cohort are provided in Table 4.  Grade 3 adverse events 
regardless of causality were observed in 18 patients (60%), the most common of which 
were ALT increased (13%), hypertension (10%); diarrhea (10%); and hyponatremia 
(10%).  There were 5 Grade 3 immune-related adverse events reported (1 event each of 
AST increased, lipase increased, immune-mediated enterocolitis, transaminases 


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increased, and fatigue).  There were no Grade 4 or Grade 5 adverse events.  
Adverse events that led to a dose reduction or treatment discontinuation were observed 
in 60% and 10% of patients, respectively.
Table 4
COSMIC-021 Study ccRCC Cohort: Summary of Common 
Adverse Events (30% of Patients) in
Cabozantinib 60 mgAtezolizumab-Treated Patients
Adverse Events of any Grade
Cabozantinib 60 mgAtezolizumab
N30
N (%)
Palmar-plantar erythrodysesthesia syndrome
15 (50%)
Aspartate aminotransferase increased
14 (47%)
Diarrhea
14 (47%)
Fatigue
14 (47%)
Alanine aminotransferase increased
13 (43%)
Dysgeusia
13 (43%)
Nausea
13 (43%)
Decreased appetite
12 (40%)
ccRCclear-cell renal cell carcinoma.
Note:  Clinical cutoff date is 20 December 2019.
In addition, the COSMIC-021 study is evaluating an expansion cohort of cabozantinib 
40 mg in combination with atezolizumab in patients with nonccRCC. At the cutoff date 
of 20 December 2019, 30 patients were enrolled. The median follow-up was 6 months 
(range: 113 months). Eighteen patients (60%) were active on study treatment, 
7 patients had discontinued all study treatment due to radiographic progression, 
5 patients due to other reasons (2 adverse events unrelated to progression, 1 adverse 
event related to progression, 2 due to lack of clinical benefit). The majority of enrolled 
patients with nonccRCC, 25 patients (83%), had not yet received prior systemic therapy. 
The ORR by the investigator per RECIST v1.1 was 27%. Eight patients exhibited a PR, 
an additional 2 patients had an unconfirmed PR. Nineteen patients (63%) experienced 
stable disease; the disease control rate was 90%. The most common adverse events of 
any grade regardless of causality included diarrhea (37%), palmar-plantar 
erythrodysesthesia (PPE; 30%), dysgeusia (20%), headache (20%), abdominal pain 
(17%), amylase increased (17%), AST increased (17%), back pain (17%), fatigue (17%), 
and nausea (17%).  One Grade 4 event of myocarditis (related) was reported, and
2 Grade 5 events (both unrelated, 1 death from RCC progression, 1 event of 
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While Study COSMIC-021 is still ongoing, the current results suggest that atezolizumab 
1200 mg in combination with cabozantinib 60 mg is tolerable and potentially active in 
patients with clear-cell and nonclear-cell RCC.
1.7
RATIONALE FOR IMMUNE CHECKPOINT RE-CHALLENGE
There is evidence to support the use of an ICI in combination therapy after progression 
with a prior ICI. Preliminary efficacy of atezolizumab in combination with bevacizumab in 
patients treated beyond progression was seen in Study WO29074 (IMmotion150; 
Atkins et al. 2017).  In Study WO29074, patients who progressed on either sunitinib or 
atezolizumab and had crossed over to the combination of atezolizumab with 
bevacizumab achieved an ORR of 28% and 24% with a median PFS 8.3 months and 
12.6 months, respectively. Similarly, in a cohort of patients with RCC who progressed 
with prior ICI therapy, pembrolizumab in combination with lenvatinib produced an ORR 
of 64% with a median PFS by modified RECIST for immune-based therapeutics 
(iRECIST) v1.1 of 11.3 months (95% CI: 7.3 to not estimable). The most common prior 
ICI therapies were nivolumab monotherapy, nivolumab/ipilimumab, and 
avelumab/axitinib (Lee et al. 2019). These results support the hypothesis that ICIs may 
be effective for patients who experienced progression while on or after receiving ICIs, if 
combined with different agents. Similar phenomena are being observed across tumor 
types. Preliminary results from a combination of sitravatinib (multi-TKI of VEGFR2, KIT, 
MET, AXL, MER, and Tyro) with nivolumab in non-squamous NSCLC after progression 
while on or after receiving an ICI (Leal et al. 2017) produced an ORR of 32% 
(including unconfirmed). In addition, mocetinostat (histone deacetylase inhibitor) in 
combination with durvalumab in patients with NSCLC who have experienced 
documented disease progression following prior treatment with an ICI (N29) produced 
an ORR of 17% (Johnson et al. 2018).
1.8
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
With the rapidly evolving landscape of treatments for metastatic RCC, the use of 
ICI-based treatments is moving to earlier lines of therapy and is becoming the standard 
of care for first- and second-line treatments in most countries.  Thus, there remains a 
need to better understand the sequential use of all available RCC treatments and 
develop effective treatments that fit this evolving landscape (Motzer et al. 2015a; 
Motzer et al. 2018b; Motzer et al. 2019a; Rini et al. 2019a).  A Phase II study of 
lenvatinib in combination with pembrolizumab has already shown promising activity in 
patients with prior ICI treatment, supporting the notion of administering an ICI in 
combination with a VEGFR-TKI in patients previously treated with an ICI.
Both cabozantinib and atezolizumab have shown clinical efficacy in aRCC. 
Cabozantinib single-agent treatment and treatment with atezolizumab in combination 
with bevacizumab have shown clinical efficacy in the post-ICI setting in subgroup 
analyses of prior studies as described in previous sections. These 2 agents are also 
active for patients with clear as well as nonclear-cell RCC (see Sections 1.4 and 1.5).


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The combination of a VEGFR-TKI with immunotherapy may offer an advantage over 
individual treatment. Cabozantinib contributes to modulation of the immune-tumor 
microenvironment and may enhance the efficacy of immunotherapy (Kwilas et al. 2014; 
Lu et al. 2017; Patnaik et al. 2017).
Preliminary results of the administration of the combination of atezolizumab and 
cabozantinib in treatment-naive patients with aRCC in the COSMIC-021 study suggest 
that atezolizumab 1200 mg in combination with cabozantinib 60 mg is tolerable with 
encouraging efficacy, thus warranting further investigation, especially in the patient 
population with prior ICI treatment. However, given the potential for overlapping 
toxicities (e.g., diarrhea), an open-label study would allow for better adverse event 
management. It is anticipated that atezolizumab administered in combination with 
cabozantinib will have a manageable safety profile and has an acceptable benefitrisk 
balance to justify the conduct of the study.
Cabozantinib is an already approved and established therapy for the treatment of RCC 
(METEOR [NCT01865747] and CABOSUN trials [NCT03541902]). The single 
cabozantinib control arm allows for an evaluation of the contribution of atezolizumab in
the combination treatment (experiment arm).
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of atezolizumab when given in 
combination with cabozantinib compared with cabozantinib alone in patients with 
advanced clear-cell or nonclear-cell RCC (papillary, chromophobe or unclassified only) 
who experienced radiographic tumor progression during or after ICI treatment in the
adjuvant and/or locally advanced/metastatic setting. Patients with RCC with 
sarcomatoid features are also allowed into this study. Patients with the chromophobe 
subtype of nonclear-cell RCC must have sarcomatoid differentiation.
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 in combination with cabozantinib or 
cabozantinib monotherapy).
2.1
EFFICACY OBJECTIVES
Response will be assessed according to RECIST v1.1 (see Appendix 3).  
Objective response at a single timepoint will be determined by the investigator and 
Independent Review Facility (IRF) according to RECIST v1.1.  Objective response per 
iRECIST (see Appendix 4) may be calculated programmatically by the Sponsor on the 
basis of the investigator assessments of individual lesions at each specified timepoint.


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2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with cabozantinib compared with cabozantinib alone in the ITT population 
based on the following endpoints:

PFS, defined as the time from randomization to the first occurrence of disease 
progression according to RECIST v1.1, as assessed by an IRF (e.g., IRF-PFS) or 
death from any cause, whichever occurs first

Overall survival, defined as the time from randomization to death from any cause
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
in combination with cabozantinib compared with cabozantinib alone on the basis of the 
following endpoints:

PFS assessed by the investigators (investigator-assessed PFS), defined as the time 
from randomization to the first occurrence of disease progression according to 
RECIST v1.1 or death from any cause (whichever occurs first)

Investigator- and IRF-assessed ORR (investigator-assessed ORR and 
IRF-assessed ORR), defined as the proportion of patients with a CR or PR on 
two consecutive occasions at least 4 weeks apart according to RECIST v1.1

Investigator- and IRF-assessed duration of response (investigatorassessed-DOR
and IRF-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) according to RECIST v1.1
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of 
atezolizumab in combination with cabozantinib compared with cabozantinib alone on the 
basis of the following endpoints:

PFS, OS, and ORR in subgroups, defined by demographic and baseline 
characteristics (e.g., PD-L1 status, prior VEGFR-TKI use, most recent ICI therapy 
[adjuvant vs. first-line vs. second-line], tumor histology, or IMDC risk group)

Time to response

Time to confirmed deterioration of disease-related symptoms, defined as the time 
from randomization date to the date of a patient’s first 4-point score decrease from 
baseline on the Functional Assessment of Cancer TherapyKidney Symptom 
Index 19 (FKSI-19) Disease-Related Symptom-Physical (DRS-P) scale (Appendix 7)
held for at least two consecutive timepoints, or followed by death within 3 weeks 
(if Cycles 112) or 6 weeks (if after Cycle 12) from the last PRO assessment

Change from baseline in patient-reported disease-related symptoms by visit, 
measured with use of the FKSI-19 DRS-P scale


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
Time to confirmed deterioration of physical functioning, defined as the time from 
randomization date to the date of a patient’s first 10-point score decrease from 
baseline on the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of LifeCore 30 Questionnaire (QLQ-C30) physical functioning 
scale held for at least two consecutive timepoints, or followed by death within 
3 weeks (if Cycles 112) or 6 weeks (if after Cycle 12) from the last 
PRO assessment

Time to confirmed deterioration of global health status/quality of life (GHS/QoL), 
defined as the time from randomization date to the date of a patient’s first 10-point 
score decrease from baseline on the EORTC QLQ-C30 GHS/QoL scale held for at 
least two consecutive timepoints, or followed by death within 3 weeks 
(if Cycles 112) or 6 weeks (if after Cycle 12) from the last PRO assessment

Change from baseline in patient-reported physical functioning and global health 
status by visit, measured with use of the EORTC QLQ-C30 physical functioning and 
GHS/QoL scales

Descriptive summary statistics by visit for the remaining FKSI-19 and 
EORTC QLQ-C30 scales

Cumulative distribution function curves of score change from baseline to Month 6 for 
each key scale (FKSI-19 DRS-P, EORTC QLQ-C30 physical function, 
EORTC QLQ-C30 GHS/QoL)
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of atezolizumab in 
combination with cabozantinib compared with cabozantinib alone on the basis of the 
following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE), Version 5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
The exploratory safety objective for this study is to evaluate the overall side-effect 
burden of atezolizumab in combination with cabozantinib compared with cabozantinib 
alone from the patient's perspective, on the basis of the following endpoint:

Patient-reported overall bother with treatment side effects during study treatment, 
measured with use of the FKSI-19 GP5 item


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2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
atezolizumab and cabozantinib administered in combination on the basis of the following 
endpoints:

Atezolizumab concentrations at specified timepoints

Cabozantinib concentrations at specified timepoints
2.4
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and 
incidence of ADAs to atezolizumab during the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and demographics, efficacy, safety, or 
PK endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to atezolizumab in combination with 
cabozantinib or cabozantinib alone (i.e., predictive biomarkers), are early surrogates of 
efficacy, are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with acquired resistance to atezolizumab in combination 
with cabozantinib or cabozantinib alone, can provide evidence of atezolizumab in 
combination with cabozantinib or cabozantinib alone efficacy (i.e., pharmacodynamic 
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoint:

Relationship between biomarkers in blood, tumor tissue, and urine (listed in 
Section 4.5.7) and efficacy, PK, immunogenicity, or other biomarker endpoints
2.6
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with atezolizumab in combination with cabozantinib 
compared with cabozantinib alone to inform economic modeling on the basis of the 
following endpoint:

Change from baseline in the EuroQol 5-Dimension, 5-Level Questionnaire 
(EQ-5D-5L) index-based and visual analog scale (VAS) scores by visit


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy and safety of atezolizumab given in combination with cabozantinib versus 
cabozantinib alone in patients with inoperable, locally advanced, or metastatic RCC who 
experienced radiographic tumor progression during or after ICI treatment in the adjuvant 
and/or locally advanced/metastatic setting.  The study will enroll approximately 
500 patients at approximately 140180 sites globally.
Key inclusion criteria include (for more details please see Section 4.1.1):

Male and female patients aged 18 years with Karnofsky Performance Status (KPS) 
score 70 who have histologically-confirmed locally advanced or metastatic 
clear-cell or nonclear-cell RCC (papillary, chromophobe, or unclassified only)
Sarcomatoid features are allowed. Patients with the chromophobe subtype of 
nonclear-cell RCC must have sarcomatoid differentiation.
Other subtypes of nonclear-cell RCC (e.g., collecting duct carcinoma, renal 
medullary carcinoma ) are not eligible.

Patients who have experienced radiographic tumor progression during or following
ICI treatment for locally advanced or metastatic RCC either in first-line or 
second-line treatment.  Patients who experienced radiographic tumor progression 
during or within 6 months after last dose of adjuvant ICI are also eligible.
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening (for a total of two screenings per participant) at the 
investigator's discretion. Patients are not required to re-sign the consent form if they are 
re-screened within 28 days after previously signing the consent form.  The investigator 
will record reasons for screen failure in the screening log (see Section 4.5.1).
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.


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Figure 1
Study Schema
1L first-line (treatment); 2L second-line (treatment); ICIimmune checkpoint inhibitor; 
IMDCInternational Metastatic Renal Cell Carcinoma Database Consortium; POby mouth; 
Q3W every 3 weeks; RCCrenal cell carcinoma.
Patients will be randomized in a 1:1 ratio to one of the following two treatments arms:

Experimental arm: Atezolizumab 1200 mg IV infusions Q3W on Day 1 of each 
21-day cycle plus cabozantinib 60-mg oral tablets taken QD (1 cycle21 days)

Control arm: Cabozantinib 60-mg oral tablets taken QD (1 cycle21 days)
Randomization will be stratified by:

IMDC risk groups (favorable, intermediate or poor risk; 0, 12, or 3), which 
comprises the following 6 risks factors: time from diagnosis to systemic therapy, 
KPS, hemoglobin, corrected calcium, neutrophil and platelet count (see Appendix 12)

Most recent ICI therapy (adjuvant vs. first-line vs. second-line)

Histology:  dominant clear-cell without sarcomatoid versus dominant nonclear-cell 
(papillary or unclassified only) without sarcomatoid versus any sarcomatoid
component (clear-cell or nonclear-cell)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle and cabozantinib will be taken orally at a starting dose of 60 mg/day
on Days 121 of each 21-day cycle. Patients randomized to the atezolizumab and 
cabozantinib arm who transiently withhold or permanently discontinue either 
atezolizumab or cabozantinib may continue on single-agent therapy until disease 
progression (i.e., patients being withheld from cabozantinib transiently for adverse 
effects may continue atezolizumab monotherapy and vice versa). Guidelines for dosage 
modification, treatment interruption or discontinuation, and the management of specific 
adverse events are provided in Sections 5.1.3.1 and 5.1.3.2.


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Patients will receive atezolizumab and/or cabozantinib until disease progression per 
RECIST v1.1, unacceptable toxicity, or symptomatic deterioration attributed to disease 
progression (e.g., pain secondary to disease or unmanageable ascites) as determined 
by the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status.
No crossover will be allowed from the control arm to the experimental arm.
Patients will undergo scheduled tumor assessment at baseline, every 9 weeks (7 days) 
for the first 18 months and every 12 weeks (7 days) thereafter. Tumor assessments 
will continue until disease progression as assessed by the investigator per RECIST v1.1
(see Appendix 3) or, for patients who continue study treatment after radiographic 
disease progression, loss of clinical benefit as determined by the investigator 
(see Section 3.1 for details).  In the absence of disease progression, tumor assessments 
should continue regardless of whether treatment has been discontinued (e.g., for toxicity) 
or whether patients start new anti-cancer therapy, until consent is withdrawn, death, or 
the study is terminated by the Sponsor, whichever occurs first (see Section 4.5.5 for 
more details). Following treatment discontinuation (even in the absence of disease 
progression per RECIST v1.1.), patients will be followed for survival and subsequent 
anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or study 
termination by Sponsor, whichever occurs first. The following information regarding all 
subsequent anti-neoplastic agents upon treatment discontinuation will be collected:
line of therapy, date of first dose of agent, date of final dose of agent (or if ongoing), 
patient's best response, and date of disease progression.
Schedules of activities are provided in Appendix 1 and Appendix 2.
Sites must continue to provide images until the IRF determines disease 
progression. However, treatment decisions will be made based on investigator 
assessment of disease progression.  Independent Review Facility procedures will 
be detailed in the IRF Charter.
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 pseudo progression) with 
atezolizumab treatment, radiographic progression per RECIST v1.1 may not be 
indicative of true disease progression.  In the absence of unacceptable toxicity, patients
who meet criteria for disease progression per RECIST v1.1 while receiving atezolizumab
and/or cabozantinib will be permitted to continue treatment, until loss of clinical benefit, if 
they meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of 
all available data

Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease


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
Absence of decline in KPS 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 for whom other treatment options/standard therapies exist must provide 
written consent to acknowledge deferring these treatment options in favor of 
continuing study treatment at the time of progression
Tumor tissue will also be collected by biopsy, unless not clinically feasible as assessed 
and documented by the investigator, at the time of first evidence of radiographic disease 
progression per RECIST v1.1 (within 40 days after radiographic progression or prior to 
the start of new anti-cancer treatment, whichever is sooner; see Section 4.5.7 for more 
details).  These samples will enable analysis of tumor tissue biomarkers related to 
resistance, disease progression, and clinical benefit of atezolizumab and/or cabozantinib.
3.1.1
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will evaluate safety data during the 
study.  Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow 
a charter that outlines the iDMC roles and responsibilities.
Safety data will be reviewed on a periodic basis, approximately every 6 months from the 
time of enrollment of the first patient until the time of the analysis of the primary efficacy 
endpoint of PFS according to policies and procedures detailed in an iDMC Charter. 
No interim efficacy analyses are planned for PFS.
All summaries and analyses for the iDMC review will be prepared by an 
independent Data Coordinating Center.  The safety summaries will include demographic 
data, adverse events, serious adverse events, and relevant laboratory data.
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards (IRBs)/Ethics Committees (ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the required numbers of events for the 
final analysis of OS in the ITT population has occurred (see Section 6).
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 55 months.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab, as outlined in the 
prescribing information.  Anti-tumor activity has been observed across doses ranging 
from 120 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached and no DLTs were observed at any dose.  The fixed dose 
of 1200 mg Q3W (equivalent to an average body weightbased dose of 15 mg/kg Q3W) 
was selected on the basis of both nonclinical studies (Deng et al. 2016) and available 
clinical PK, efficacy, and safety data (refer to the Atezolizumab Investigator's Brochure 
for details).
3.3.2
Rationale for Cabozantinib Dose and Schedule
Cabozantinib will be administered orally at a starting dose of 60 mg/day starting on 
Day 1. This is the approved dosage for cabozantinib, as outlined in the Cabometyx
prescribing information.
From the Phase III METEOR trial (NCT01865747) of cabozantinib in patients with RCC, 
exposure-response analyses have shown that the 60-mg starting dose would provide 
greater anti-tumor activity compared with starting doses at 40 mg or 20 mg 
(Lacy et al. 2018). In the Phase Ib COSMIC-021 study (NCT03170960), no DLTs were 
observed in either the 40-mg or 60-dose dose-escalation cohorts.  As described in 
Section 1.6, among the 12 patients enrolled in the dose-escalation stage, the 
investigator-assessed confirmed ORR was 67%. When looking at each dose cohort 
separately, the ORR for patients with RCC treated with 40 mg cabozantinib was 50% 
(1 CR and 2 PRs in 6 patients) and 83% (5 PRs in 6 patients) at 60 mg
(Agarwal et al. 2018). When looking at the total population of patients in the 
dose-escalation stage (6 patients at each dose level of 40 mg and 60 mg) and the 
expansion stage (30 patients at each dose level of 40 mg and 60 mg), the totality of the 
efficacy data in patients with RCC suggests greater efficacy in the 60-mg patient cohort 
compared with the 40-mg cohort, with manageable safety profiles at either dose level.
To optimize the benefit of the combination therapy for patients with aRCC, a starting 
dose of 60 mg cabozantinib (as per the current recommended dose as monotherapy)
was selected in combination with atezolizumab for this trial. Dose reductions are 
allowed to manage side effects according to guidelines outlined in Appendix 11.
Please refer to the Cabozantinib Investigator's Brochure for details.


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3.3.3
Rationale for Patient Population
Immunotherapy with ICIs have become standard of care in aRCC. Currently available 
data in the pre-treated population do not reflect this evolving landscape and; therefore,
there is no established treatment paradigm for patients who have previously been 
treated with an ICI. In addition, it is critical to understand whether immunotherapy can 
be used again after progression, and whether the sequential use of different 
immunotherapies, when combined with other agents, is beneficial. Therefore, the study 
will enroll patients who have progressed on an ICI as their most recent prior therapy in 
the aRCC setting. However, since ICIs are used both in the front-line and second-line
treatment setting, this study will allow up to two prior lines of therapy. Vascular
endothelial growth factor receptor-TKIs are used in the front and subsequent lines of 
therapy either as a single agent or in combination with ICIs. Therefore, this study will 
include patients who have previously received such TKIs, provided that the therapy 
preceding trial enrollment is an ICI. However, this study will exclude patients who have 
previously received a mammalian target of rapamycin (mTOR) inhibitor to reduce 
heterogeneity in the patient population and to enable the assessment of the scientific 
hypothesis driving this study.
As seen in the Phase III studies of the combination of pembrolizumab with axitinib or 
avelumab with axitinib, benefit of the ICI in combination with the VEGFR-TKI was seen 
regardless of PDL-1 expression (Rini et al. 2019b). Therefore, this study will enroll 
patients with RCC regardless of tumor PD-L1 status.  The PD-L1 status is not expected 
to impact treatment efficacy for either cabozantinib monotherapy or atezolizumab in 
combination with cabozantinib treatment. However, archival tumor tissue and fresh 
samples collected at baseline (if feasible) will be evaluated for potential impact on 
outcomes.
This trial will enroll patients with both ccRCC and nonccRCC. Clinical trial data for 
nonccRCC are limited since these patients are often excluded from clinical trials.
There is preliminary data showing the benefit of atezolizumab as well as cabozantinib in 
this subtype of RCC, both in trials of these individual agents and also in combination as 
seen in the nonccRCC cohort of the COSMIC-021 study (see Sections 1.4 and 1.5).
In addition, both nivolumab and pembrolizumab have shown efficacy in nonccRCC with
an ORR of 2025%, demonstrating the efficacy of immunotherapy in nonccRCC 
(Koshkin et al. 2018; McDermott et al. 2019).
However, as seen in all immunotherapy trials mentioned above, including with the 
combination of atezolizumab with bevacizumab, the ORR in the chromophobe subtype 
of nonccRCC have much lower responses (010%) than other subtypes. Due to the 
perceived lack of benefit of immunotherapy in the chromophobe subtype, and the 
benefit of ICI therapy in sarcomatoid subtypes (Rini et al. 2019a and 2019b), only the 
chromophobe subtype with sarcomatoid differentiation will be allowed in the study.


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3.3.4
Rationale for Control Group
There is currently no approved treatment or well-recognized standard of care for patients 
with aRCC who have progressed during or after receiving ICI-based treatment (with or 
without VEGFR-TKI treatment). The use of a VEGFR-TKI after first-line treatment with 
ipilimumab/nivolumab in patients with aRCC was reported in a subset of the 
CheckMate 214 study (NCT02231749) patients (N33). A best response of 36% 
(i.e., unconfirmed) was reported (Auvray et al. 2019), suggesting that VEGFR-TKI is an 
option after receiving first-line ICI-based treatment.
Although the use of ipilimumab/nivolumab and ICIVEGFR-TKIs as first-line treatment 
for patients with aRCC continues to increase, pazopanib and sunitinib (VEGFR-TKIs) 
are still frequently used as initial treatment. Thus, use of pazopanib and sunitinib would 
not be appropriate as a comparator for patients in second- or third-line therapy in the 
proposed Study WO41994. The increasing use of axitinib in combination with ICI-based 
combinations in the initial treatment of aRCC, also reduces the suitability of this 
VEGFR-TKI as a control arm in this second- or third-line patient population 
(Motzer et al. 2019b; Rini et al. 2019a).  In addition, both cabozantinib and nivolumab 
have shown superior efficacy to the standard of care second-line agent everolimus 
(Motzer et al. 2015a; Choueiri et al. 2016) and; therefore, everolimus is also not the ideal 
control arm in this study.
Cabozantinib 60 mg QD oral dose has a broad indication for use in patients with aRCC
in the United States. In the European Union, cabozantinib is approved for use in adult 
patients with aRCC as first-line treatment for intermediate or poor risk disease and
following prior VEGFR-TKI treatment (regardless of risk category). Given the clinical 
efficacy data in this study population described in Sections 1.4.1 and 3.3.3, cabozantinib 
is the ideal choice for a control arm for this study population, especially since the safety 
and efficacy of this agent in combination with atezolizumab has already been tested.
3.3.5
Rationale for Stratification Factors
Clinical factors known to affect outcomes in aRCC were chosen as stratification factors. 
In the IMDC risk model (Heng et al. 2009), six risk factors were identified as being 
associated with poorer survival: time from diagnosis to treatment of less than 1 year, 
KPS 80%, neutrophils greater than upper limit of normal (ULN), platelets ULN, 
corrected calcium ULN, and hemoglobin less than lower limit of normal. Three risk 
categories associated with different outcomes were identified based on these risk factors:
favorable risk (0 risk factors) with a median OS (mOS) not reached, intermediate risk 
(12 risk factors) with a mOS of 27 months, and poor risk (36 risk factors) with an OS 
of 8.8 months.


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As described in Section 1.3, the proportion of patients receiving third-line therapy is 
much less than second-line therapy.  In addition, outcomes in third-line therapy are 
worse. Therefore, stratification by line of therapy is important in this study which plans to 
enroll patients in second- and third-line therapy. Since only patients whose immediate 
preceding therapy was an ICI are eligible, the difference in line of therapy (second-line or 
third-line) will be represented by the most recent ICI (adjuvant or first-line or 
second-line).
Several Phase III trials in the adjuvant setting with ICIs such as CheckMate 914 
(NCT03138512), IMmotion010 (NCT03024996), KEYNOTE 564 (NCT03142334), 
PROSPER RCC (NCT03055013) and RAMPART (NCT03288532) are ongoing.
Thus, ICIs are heading to become standard of care in the adjuvant setting for patients 
with RCC.
In oncology, patients who progress soon after adjuvant therapy are 
considered as those with underdiagnosed metastatic disease and hence are commonly 
included in trials evaluating a refractory population. Progression during or within 
6 months after last dose of adjuvant setting is commonly applied in these trials
(Rittmeyer et al. 2017; Le et al. 2019; NCT04740918). A similar approach will be 
adopted for this study.
As described in Section 3.3.3, this study will enroll both clear-cell and nonclear-cell 
histology. The advances made with VEGFR-directed therapies in ccRCC have only 
produced modest outcomes in nonccRCC (Zhang et al. 2017). Sarcomatoid histology 
is a feature associated with up to 20% of RCCs (Zhang et al. 2017) and has a poor 
prognosis with VEGFR-directed therapies. Given that the outcomes of nonccRCC and 
sarcomatoid RCC are worse than ccRCC, the study will use a stratification factor of 
histology incorporating both cell type (ccRCC or nonccRCC) and any sarcomatoid 
component.  It is worthwhile to note that ICIs appear to have a better outcome in the
sarcomatoid variant than in VEGFR-directed therapies as seen in subgroup analyses of 
the study evaluating atezolizumab and bevacizumab compared with sunitinib 
(Rini et al. 2019a) and the study evaluating pembrolizumab and axitinib compared with
sunitinib (Rini et al. 2019b).
3.3.6
Rationale for Open-Label Study
An open-label study design was chosen for this trial due to the expectation of 
overlapping toxicities that may require significant unblinding to differentiate and manage 
toxicities.
To ensure the validity of data collected in an open-label study, the primary efficacy 
analyses will be based on IRF assessment of progression. To avoid aggregated data 
review of efficacy in each arm during the conduct of the study, the Sponsor will be 
blinded. In addition, the strategy and timing for the final analysis of the primary endpoint,
including censoring rules and methods for handling missing data, have been 
prespecified in the protocol.


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3.3.7
Rationale for Progression-Free Survival and Overall Survival 
as Multiple Primary Endpoints
In this study, the multiple primary efficacy endpoints will be IRF-assessed PFS and OS.  
This study will test the hypothesis that treatment with atezolizumab in combination with 
cabozantinib will prolong PFS and OS compared with treatment with cabozantinib alone.
Overall survival is considered the most reliable endpoint for demonstrating clinical 
benefit for cancer drugs. However, OS may be potentially confounded by subsequent 
therapies. Progression-free survival as an endpoint can reflect tumor growth and can be 
assessed before the determination of a survival benefit (U.S. Food and Drug 
Administration [FDA] Guidance 2018). Additionally, PFS has proven to be a reasonable 
surrogate for clinical benefit in various indications for TKIs: crizotinib and osimertinib 
have been approved by regulatory agencies for previously treated patients with 
advanced NSCLC based on an increase in PFS (XalkoriUSPI and European Medicines 
Agency [EMA] SmPC; TagrissoUSPI and EMA SmPC); cabozantinib has been 
approved by regulatory agencies for previously treated patients with advanced RCC 
based on an increase in PFS (Cabometyx USPI and EMA SmPC). Whether an 
improvement in PFS represents a direct clinical benefit or a surrogate for clinical benefit 
depends on the magnitude of the effect and the benefitrisk profile of the new treatment 
compared with available therapies (EMA Guidance 2017; FDA Guidance 2018).
3.3.8
Rationale for Atezolizumab or Cabozantinib Treatment beyond 
Initial Radiographic Progression per RECIST v1.1
In studies of immunotherapeutic agents, CR, PR, 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 pseudo progression (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 intracellular staining and no viable cancer cells.
In addition, radiographic disease progression may not be correlated with clinical 
conditions. Instead, clinical benefit per the investigator can be used to inform whether 
continued study treatment is an acceptable risk. The continuation of cabozantinib 
treatment after radiographic progression is consistent with the prescribing information 
and was permitted in single-agent trials.
For these reasons, 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 3.3.8). 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).


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3.3.9
Rationale for the Use of iRECIST
Increasing clinical experience indicates that traditional response criteria 
(e.g., RECIST v1.1 and World Health Organization criteria) may not adequately assess 
the efficacy of immunotherapeutic agents because initial radiographic evidence of 
disease progression does not necessarily reflect therapeutic failure.  Patients can 
experience a response in the presence of new lesions or after an increase in tumor 
burden.  Thus, in addition to the traditional RECIST v1.1, this study may employ 
iRECIST (Seymour et al. 2017; see Appendix 4), tumor response criteria that have been 
modified for unconventional tumor change patterns associated with cancer 
immunotherapy.
iRECIST was developed by the RECIST working group in an effort to create a common 
set of criteria that the cancer immunotherapy field could apply to clinical trials 
(Seymour et al. 2017).  iRECIST accounts for responses that may occur following 
transient radiographic progression caused by immune-cell infiltration in tumors 
(leading to a transient increase in the size of existing lesions, including those that were 
previously undetectable and consequently appear as new lesions).  iRECIST relies on 
collection of tumor assessment data after initial disease progression per RECIST v1.1.
Given the proposed immunomodulatory mechanism of action of atezolizumab and the 
possibility of observing delayed responses, analyses based on iRECIST may be 
considered.  These analyses will allow for evaluation of iRECIST as an improved 
measure of the efficacy of immunotherapies relative to the standard RECIST v1.1.
3.3.10
Rationale for Clinical Outcome Assessments
Patient experience data will be collected in this study to inform the benefitrisk profile of 
atezolizumab in combination with cabozantinib.  It is important that the addition of 
atezolizumab to cabozantinib can provide survival benefit and delay disease progression 
without impairing patients’ functioning and quality of life. As such, the patient's 
perspective on symptom and treatment burden, including physical functioning and 
treatment toxicity impacts, is needed to achieve a comprehensive evaluation of clinical 
benefit. 
Patient-reported outcome (PRO) instruments in this study will provide a better 
understanding of the impacts of disease and treatment on patients.  The FKSI-19
(Rao et al. 2009; Rothrock et al. 2013) is a validated disease-specific instrument that 
measures RCC-related symptom burden and health-related quality of life in patients with 
kidney cancer. The FKSI-19 GP5 item is a valid summary measure of overall treatment 
side-effect burden in cancer that complements clinician-reported safety. 
The EORTC QLQ-C30 (Aaronson et al. 1993; Fitzsimmons et al. 1999) is a validated 
instrument that has been widely used in assessing the quality of life in patients with 
cancer. This instrument assesses global health status, functioning (physical, role, 
emotional, cognitive, and social), and symptoms associated with cancer and its 


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treatment (e.g., fatigue). The EQ-5D-5L (EuroQol Group 1990; Brooks 1996; 
Herdman et al. 2011; Janssen et al. 2013) is a generic health status questionnaire that 
will primarily be used to inform health economic modeling.
3.3.11
Rationale for Biomarker Assessments
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 and antiPD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; 
Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; 
Rosenberg et al. 2016).  In the current study, any tumor samples collected may be 
tested for PD-L1 expression by a central laboratory.  In addition to the assessment of 
PD-L1 status, other exploratory biomarkers, such as potential predictive and prognostic 
biomarkers related to the clinical benefit and safety of atezolizumab and cabozantinib, 
tumor immunobiology, mechanisms of resistance, or tumor type, may be analyzed.  
DNA and/or RNA extraction and analysis may be performed to enable next-generation 
sequencing (NGS), including, but not limited to, whole-exome sequencing (WES), to 
evaluate expression of genes to assess their association with efficacy, and to identify 
somatic mutations to increase understanding of disease pathobiology.
Blood and urine-based biomarkers (including, but not limited to, circulating tumor DNA 
[ctDNA]) may be also evaluated and correlated with atezolizumab and cabozantinib
efficacy and evaluated as potential surrogate markers of efficacy.  This evaluation of 
blood and/or urine-based markers may provide evidence for the biologic activity of 
atezolizumab and cabozantinib in patients with RCC, help to identify patients who may
benefit most from atezolizumab and cabozantinib, and help future development of 
tissue-free diagnostic options for patients who have inadequate quality or insufficient 
quantity of tumor tissue for biomarker testing.
Blood and urine samples will be collected in order to better understand the changes in 
biomarker profiles and potential mechanisms of resistance upon progression. 
Blood samples may also be evaluated for additional exploratory biomarkers that may be 
associated with the therapeutic effects of atezolizumab and cabozantinib or the 
pathogenesis of RCC.
Tissue samples will be collected for DNA extraction to enable WES to identify variants 
that are predictive of response to study drugs, are associated with progression to a more 
severe disease state, are associated with acquired resistance to study drug, are 
associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  Whole-exome sequencing
provides a comprehensive characterization of the exome and, along with clinical data 
collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 


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analyzed in the context of this study but may also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 500 patients will be enrolled in this study. Patients with locally advanced 
or metastatic RCC with clear-cell, or nonclear-cell (papillary, chromophobe, or 
unclassified only) histology, and previously treated with an ICI in the adjuvant and/or 
locally advanced/metastatic setting will be enrolled. Patients with RCC with sarcomatoid 
features are also allowed in this study. Patients with the chromophobe subtype of 
nonclear-cell RCC must have sarcomatoid differentiation.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

Histologically-confirmed locally advanced or metastatic clear-cell or nonclear-cell 
(papillary, chromophobe, unclassified only) RCC
–
Other subtypes of nonclear-cell RCC (e.g., collecting duct carcinoma, 
renal medullary carcinoma) are not eligible.
–
RCC with sarcomatoid features is allowed. Patients with the chromophobe 
subtype of non-clear-cell RCC must have sarcomatoid differentiation
(see Appendix 13 for further guidelines regarding the definition of sarcomatoid 
histology).

Radiographic disease progression to prior ICI therapy for RCC
–
ICI for metastatic disease: Radiographic disease progression during or 
following ICI treatment for locally advanced or metastatic RCC either in 
first- or second-line treatment
–
ICI for adjuvant therapy: Patients who experienced radiographic tumor 
progression during or within 6 months after last dose of adjuvant ICI are also
eligible
–
Examples of ICI regimens include one ICI regimen in first-line treatment
(e.g., nivolumab plus ipilimumab, pembrolizumab plus axitinib, axitinib plus
avelumab), or second-line treatment (e.g., TKI as first-line treatment and ICI as 
second-line treatment)


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–
ICI is defined by antiPD-L1 or antiPD1 antibody, including atezolizumab, 
avelumab, pembrolizumab, durvalumab, or nivolumab. Ipilimumab 
monotherapy is not considered an antiPD-L1 or antiPD1 therapy.
–
Patients must have received at least 2 cycles of ICI treatment
–
ICI must have been used in the immediate preceding line of therapy
(patients with an intervening treatment between ICI and study screening are 
excluded)
–
Adjuvant treatment with VEGFR-TKIs, except cabozantinib, is allowed

Measurable disease per RECIST v1.1

Evaluable IMDC risk scores

Representative pretreatment tumor specimens, for exploratory biomarker research 
(see Section 4.5.7 for information on suitability of and requirements for tumor 
specimens)
–
Archival tumor specimen (e.g., at diagnosis, surgery, or prior to initiation of 
previous line of therapy)
–
Pretreatment tumor tissue from fresh biopsy at screening, if clinically feasible.
Biopsies collected via minor surgery must be performed at least 10 days prior 
to Day 1 of Cycle 1 and must be completely healed before first dose.
Availability of tissue samples must be confirmed before randomization. 
Tissue samples must be submitted before or within 4 weeks of randomization.
Both archival and fresh samples are preferred, if feasible.

KPS score of 70

Recovery to baseline or Grade 1 NCI CTCAE v5.0 from toxicities related to any 
prior treatments, unless adverse events are clinically nonsignificant and/or stable 
in the opinion of the investigator
– Grade 2 alopecia is allowed for study participation
– Exception: Patients who have received systemic corticosteroids for a prior 
immune-related adverse event for 30 days consecutively prior to 
initiation of study treatment are not eligible. Additional criteria on steroid 
use for prior immune-related adverse events is described in the exclusion 
criteria.

Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment:
–
ANC 1.5109/L (1500 cells/L) without granulocyte colony-stimulating factor 
support within 14 days prior to Day 1 of Cycle 1
–
Lymphocyte count 0.3109/L (300/L)
–
Platelet count 100109/L (100,000/L) without transfusion within 14 days
prior to Day 1 of Cycle 1
–
WBC counts2500 cells/L


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–
Hemoglobin 90 g/L (9 g/dL) (without transfusion within 14 days prior to Day 1 
of Cycle 1)
–
AST, ALT, and ALP 2.5ULN, with the following exceptions:
Patients with documented liver metastases: AST and ALT 5ULN
Patients with documented liver or bone metastases:  ALP 5ULN
–
Bilirubin 1.5ULN with the following exception:
Patients with known Gilbert disease: bilirubin 3ULN
–
Creatinine clearance 40 mL/min (calculated with use of the Cockcroft-Gault 
formula, or based on 24-hour urine collection)
–
Albumin 25 g/L (2.5 g/dL)
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN
–
Proteinuria, as demonstrated by urine protein-to-creatinine ratio (UPCR)
1 mg/mg (113.2 mg/mmol)

Negative HIV test at screening

Negative hepatitis B testing at screening:
–
Negative hepatitis B surface antigen (HBsAg) test at screening
–
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive 
total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at 
screening. The HBV DNA test will be performed only for patients who have a 
negative HBsAg test and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 4 months after the final 
dose of cabozantinib and for 5 months after the final dose of atezolizumab.
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.


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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.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
4 months after the final dose of cabozantinib to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period.  Females of 
childbearing potential who are partners of male patients should also use 
contraceptive methods with a failure rate of 1% per year during their male 
partner’s therapy and for at least 4 months after completing therapy.  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.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Treatment with anti-cancer therapy within 14 days prior to initiation of study 
treatment

Patients who received cabozantinib at any time prior to screening

Patients who received more than one ICI treatment in the locally advanced or 
metastatic setting (e.g., pembrolizumab and axitinib as first-line treatment and 
nivolumab as second-line treatment)

Patients who received more than two prior lines of therapy in the locally advanced 
or metastatic setting


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
Patients who have received a mTOR inhibitor in any setting

Symptomatic, untreated, or actively progressing CNS metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS
–
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage
–
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to 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
–
No evidence of significant vasogenic edema
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anticonvulsant therapy at a stable dose is permitted.
–
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord)
–
There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment
Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to 
repeat the screening brain scan.

History of leptomeningeal disease

Uncontrolled tumor-related pain
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Moderate to severe hepatic impairment (Child-Pugh B or C)


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
Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium12 mg/dL, or corrected calcium ULN) or symptomatic hypercalcemia 
requiring continued use of bisphosphonate therapy or denosumab
Patients who are receiving bisphosphonate therapy or denosumab specifically 
to prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.

History of malignancy other than renal carcinoma 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

Radiotherapy for RCC within 14 days prior to Day 1 of Cycle 1
Patients who are receiving single-fraction radiotherapy given for the indication 
of pain control are eligible.

Active tuberculosis

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
Minor surgeries (e.g., tumor biopsy, placement of vascular access device) 
should be performed at least 10 days prior to initiation of study treatment. 
Patients must have complete wound healing from major surgery or minor 
surgery before randomization. Patients with clinically relevant ongoing 
complications from prior surgery are not eligible.

Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment or within 5 months after final dose of atezolizumab and 4 months after 
final dose of cabozantinib
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.

Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that, in the opinion of the investigator, could 
impact patient safety

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

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment


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
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant 
medication (e.g., 10 mg/day oral prednisone or equivalent) 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 confirmation has been obtained
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or COPD exacerbation) are eligible for the study.

Prior allogeneic stem cell or solid organ transplantation

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications

Current treatment with anti-viral therapy for HBV or HCV

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, vasculitis, or glomerulonephritis, or multiple sclerosis (see Appendix 8 for 
a more comprehensive list of autoimmune diseases and immune deficiencies), with 
the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
–
Rash must cover 10% of body surface area
–
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids


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–
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

Pharmacologically uncompensated, symptomatic hypothyroidism

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Malabsorption syndrome

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption

Uncontrolled hypertension defined as sustained blood pressure (BP)150 mm Hg 
systolic or 90 mm Hg diastolic despite optimal antihypertensive treatment

Tumors invading the GI-tract, active peptic ulcer disease, acute pancreatitis, acute 
obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, 
diverticulitis, gastric outlet obstruction, or inflammatory bowel disease 
(e.g., Crohn's disease, ulcerative colitis)

Stroke (including transient ischemic attack), myocardial infarction, or other 
symptomatic ischemic event, or thromboembolic event (e.g., deep venous 
thrombosis [DVT], PE) within 6 months before randomization
Upon Sponsor approval, subjects with a diagnosis of incidental PE or DVT 
within 6 months are allowed if asymptomatic and stable at screening treated 
with lowmolecular-weight heparins (LMWHs) or the direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban for at least 1 week before first dose.

Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, unstable arrhythmia, or unstable angina) within 3 months 
prior to initiation of study treatment

History of clinically significant ventricular dysrhythmias or risk factors for ventricular 
dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic 
dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or 
with ischemia demonstrated by diagnostic testing), clinically significant electrolyte 
abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family 
history of sudden unexplained death or long QT syndrome

History of congenital QT syndrome

History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block, or evidence of prior myocardial infarction 
that is considered as clinically significant by investigator

QT interval corrected with use of Fridericia's formula (QTcF)480 ms per ECG 
within 14 days before randomization


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Note: If a single ECG shows a QTcF with an absolute value480 ms, 
2 additional ECGs at intervals of approximately 3 minutes must be performed 
within 30 minutes after the initial ECG, and the average of the 3 consecutive 
results for QTcF must be480 ms for the patient to be eligible.

Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring
surgical repair or recent peripheral arterial thrombosis) within 6 months prior to 
Day 1 of Cycle 1

Evidence of bleeding diathesis or significant coagulopathy

Abdominal or tracheoesophageal fistula, bowel obstruction, or gastrointestinal (GI) 
perforation, or intra-abdominal abscess within 6 months before initiation of study 
treatment
Complete healing of an intra-abdominal abscess must be confirmed before 
initiation of study treatment.

Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin 
inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors 
(e.g., clopidogrel)
The following are anticoagulants allowed in this study:
Prophylactic use of low-dose aspirin for cardio protection (per local 
applicable guidelines) and low-dose LMWHs.
Therapeutic doses of LMWH or anticoagulation with direct factor Xa 
inhibitors rivaroxaban, edoxaban, or apixaban in patients without known 
brain metastases who are on a stable dose of the anti-coagulant for at least 
1 week before randomization without clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor.

Clinical signs or symptoms of GI obstruction or requirement for routine parenteral 
hydration, parenteral nutrition, or tube feeding

Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure

Known cavitating pulmonary lesion(s) or known endobronchial disease 
manifestations

Lesions invading major pulmonary blood vessels

Clinically significant hematuria, hematemesis, hemoptysis of 0.5 teaspoon 
(2.5 mL) of red blood, coagulopathy, or other history of significant bleeding 
(e.g., pulmonary hemorrhage) within 3 months before initiation of study treatment

Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

Prior history of hypertensive crisis or hypertensive encephalopathy

Requirement for hemodialysis or peritoneal dialysis

Known hypersensitivity to Chinese hamster ovary cell products or to any component
of the atezolizumab formulation


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
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies 
or fusion proteins

Known allergy or hypersensitivity to any component of the cabozantinib formulation

Patients who are not able to swallow a tablet
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
4.2.1
Treatment Assignment
This is a randomized open-label study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or Web-based 
response system (IxRS).
Patients will be randomly assigned to 1 of 2 treatment arms: atezolizumab and
cabozantinib or cabozantinib alone. Randomization will occur in a 1:1 ratio with use of a 
permuted-block randomization method to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified according to the following criteria:

IMDC score (0 vs. 12 vs. 3)

Most recent ICI therapy (adjuvant vs. first-line vs. second-line)

Histology:  dominant clear-cell without sarcomatoid versus dominant nonclear-cell 
(papillary or unclassified only) without sarcomatoid versus any sarcomatoid
component (with clear-cell or nonclear-cell)
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are atezolizumab and 
cabozantinib. The first dosing day (Day 1 of Cycle 1) should occur within 3 days from 
the date of randomization.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
The dose of atezolizumab to be used in this study is 1200 mg (equivalent to an average 
body weight-based dose of 15 mg/kg) administered by IV infusion Q3W (21 [3] days).
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.


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4.3.1.2
Cabozantinib
The comparator of this study is cabozantinib 60 mg (three 20-mg tablets) administered 
orally QD.  Cabozantinib will be supplied by the Sponsor as 20-mg yellow film-coated 
tablets.  For information on the formulation and handling of cabozantinib, see the 
pharmacy manual and the Cabozantinib Investigator’s Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Sections 4.3.2.1 and 4.3.2.2.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse events, 
should be reported as described in Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Appendix 10 and Appendix 11.
4.3.2.1
Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by 
the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status (see Section 3.1 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 9.  
Atezolizumab infusions will be administered per the instructions outlined in Table 5.


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Table 5
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion

Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
measured within 60 minutes prior to the 
infusion

Atezolizumab should be infused over 
60 (15) minutes

If clinically indicated, vital signs should be 
measured every 15 (5) minutes during the 
infusion and at 30 (10) minutes after the 
infusion

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, anti-pyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator

Vital signs should be measured within 
60 minutes prior to the infusion

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion

If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital signs 
should be measured during the infusion 
and at 30 (10) minutes after the infusion
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
the Appendix 10.
No dose modification for atezolizumab is allowed.
4.3.2.2
Cabozantinib
Cabozantinib will be taken orally 60 mg QD 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 for details).
First Dose of Cabozantinib
The first dose of cabozantinib (on Day 1 of Cycle 1) will be administered in the clinic.  
For patients assigned to the atezolizumab and cabozantinib arm, atezolizumab will be 
administered first.
The patient will fast (with the exception of water) for at least 2 hours before receiving 
cabozantinib. Upon completion of the 2-hour fast, the patient will receive the oral dose 
of cabozantinib with a minimum of 8 oz (240 mL) of water in the clinic and then the 
patient will continue to fast for 1 hour.


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Subsequent Dose of Cabozantinib
Following the first dose of cabozantinib, the patient should take cabozantinib outside the 
clinic at approximately the same time QD, preferentially before going to bed, and should 
adhere to the fasting requirements described in this section.
Patients should fast (with the exception of water) for at least 2 hours after eating the 
evening meal before taking their dose. After the 2-hour fast and before going to bed, 
patients are to take cabozantinib with a full glass of water (minimum of 8 oz or 240 mL) 
with no more food intake for 1-hour postdose. If the patient's schedule requires taking 
cabozantinib during the day, the patient is to be instructed to follow the same fasting 
recommendations.
Cabozantinib tablets should not be crushed or chewed. Grapefruit and Seville oranges 
(and products made from them) should be avoided while being treated with cabozantinib.
Patients are to be instructed to not make up vomited doses and to maintain the planned 
dosing schedule. Patients are not to make up for missed doses if more than 12 hours 
have elapsed after the time the patient would usually take cabozantinib. In the event of 
missed doses, patients are not to take 2 doses to make up for the one the patient
missed.
Any unused study treatment must be returned to the study site for drug accountability 
and disposal.
4.3.3
Investigational Medicinal Product Accountability
The IMPs for this study are atezolizumab and cabozantinib. All IMPs required for 
completion of this study will be provided by the Sponsor. The study site will 
acknowledge receipt of IMPs supplied by the Sponsor, with use of the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.
Investigational medicinal products will either be disposed of at the study site according to 
the study site's institutional standard operating procedure or be returned to the Sponsor 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.


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4.3.4
Continued Access to Atezolizumab and Cabozantinib
The Sponsor will offer continued access to study treatment (atezolizumab and 
cabozantinib) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive atezolizumab and cabozantinib after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive atezolizumab and cabozantinib after completing 
the study if any of the following conditions are met:

The study treatment is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study treatment or data suggest 
that the study treatment is not effective for RCC

The Sponsor has reasonable safety concerns regarding the IMP as treatment 
for RCC

Provision of the study treatment is not permitted under the laws and regulations of 
the patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study treatment until the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.


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4.4.1
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone replacement therapy

Individualized anticoagulation therapy with heparin or direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and
effectively under the following circumstances:
Low-dose LMWHs for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion.
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban at the time of the first dose of study 
treatment are allowed if the patient has no evidence of brain metastasis, has 
been on a stable dose of the anti-coagulant for at least 1 week, and has had no 
clinically significant hemorrhagic complications from the anticoagulation 
regimen or the tumor.
Note: Anticoagulation with the direct thrombin inhibitor dabigatran, or the direct 
factor Xa inhibitor betrixaban is not allowed.
Therapeutic doses of LMWH or anticoagulation with direct factor Xa oral 
inhibitors rivaroxaban, edoxaban, or apixaban after first dose of study treatment
are allowed if clinically indicated (e.g., for the treatment of DVT), and the benefit 
outweighs the risk per the investigator’s discretion.
Note: Anticoagulation with the direct thrombin inhibitor dabigatran or the direct 
factor Xa inhibitor betrixaban is not allowed.
Accepted clinical guidelines regarding appropriate management while receiving
any kind of anticoagulation therapy must be followed. This includes, but is not 
limited to, patient education regarding the potential adverse drug reactions, 
monitoring laboratory parameters, dose adjustments (e.g., due to kidney 
dysfunction). Caution is warranted in settings associated with an increased risk
for bleeding such as GI cancers, urothelial cancers, GI mucosal abnormality 
(e.g., mucositis), renal or hepatic impairment, thrombocytopenia, arterial 
hypertension, or prior history of GI bleed. For direct factor Xa inhibitors, the 
potential for drug-drug interaction with other concomitant medications, as well 
as GI absorption, should be considered. Aspirin and nonsteroidal 
anti-inflammatory drugs (NSAIDs) shouldn’t be used concomitantly with heparin 
or factor Xa inhibitors due to the increased risk for bleeding complications. 
The risks and benefits of the use of anticoagulants should be re-assessed on a 
regular basis. For more information regarding the use of anticoagulants, refer 
to the prescribing information of the anti-coagulant and accepted clinical 
practice guidelines.


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Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed.  This includes, but is 
not limited to, patient education regarding potential adverse drug reactions, 
monitoring laboratory parameters, dose adjustments (e.g., due to kidney 
dysfunction, platelet decrease).

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for COPD or asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Palliative radiotherapy (e.g., treatment of known bone 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 and/or 
cabozantinib may be continued 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 
3 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, anti-pyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
In general, investigators should manage a patient's care (including preexisting conditions) 
with supportive therapies other than those defined as cautionary or prohibited therapies 
(see Sections 4.4.2, 4.4.3, and 4.4.4) as clinically indicated, per local standard practice.  
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 9).


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4.4.2
Cautionary Therapy for All Patients
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 4.4.3) may be used during the study at the discretion of the investigator.
4.4.3
Cautionary Therapy for Atezolizumab-Treated Patients
4.4.3.1
Corticosteroids, Immunosuppressive Medications, and TNF-
Inhibitors
Systemic corticosteroids, immunosuppressive medications, and TNF-inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (see Appendix 10 for details).
4.4.4
Cautionary Therapy for Cabozantinib-Treated Patients
4.4.4.1
Cytochrome P450
Data from a clinical drug interaction study (XL184-008) show that clinically relevant 
steady-state concentrations of cabozantinib appear to have no marked effect on the area 
under the concentrationtime curve (AUC) of coadministered rosiglitazone, a CYP2C8 
substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the 
clinic, and, by inference, is not anticipated to markedly inhibit other CYP450 isozymes 
that have lower [I]/inhibition constant values compared with CYP2C8 (i.e., CYP2C9, 
CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is 
unlikely to induce CYP enzymes, except for possible induction of CYP1A1 at high 
cabozantinib concentrations (30 M).
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a 
CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from 
in vitro studies. Results from a clinical pharmacology study (XL184-006) showed that 
concurrent administration of cabozantinib with the strong CYP3A4 inducer, rifampin, 
resulted in an approximately 77% reduction in cabozantinib exposure (AUC values) after 
a single dose of cabozantinib in healthy volunteers. Chronic coadministration of 
cabozantinib with strong inducers of the CYP3A4 family (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may significantly 
decrease cabozantinib concentrations. The chronic use of strong CYP3A4 inducers 
should be avoided. Other drugs that induce CYP3A4 should be used with caution 


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because these drugs have the potential to decrease exposure (i.e., AUC) to 
cabozantinib. Caution must be used when discontinuing treatment with a strong 
CYP3A4 inducer in a patient who has been concurrently receiving a stable dose of 
cabozantinib, as this could significantly increase the exposure to cabozantinib.  
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme 
induction potential is recommended.
Results from a clinical pharmacology study (XL184-007) showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted 
in a 38% increase in the cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Coadministration of cabozantinib with strong 
inhibitors of the CYP3A4 family (e.g., boceprevir, conivaptan, posaconazole, 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
saquinavir, ritonavir, lopinavir, telaprevir, telithromycin, and voriconazole) may increase 
cabozantinib concentrations. Strong CYP3A4 inhibitors should be avoided and other 
drugs that inhibit CYP3A4 should be used with caution because these drugs have the 
potential to increase exposure (i.e., AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended.
Grapefruit and Seville oranges (and products made from them) should be avoided while 
being treated with cabozantinib.
Please refer to the drug interaction tables at the following website for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm080499.htm.
4.4.4.2
Protein Binding
Cabozantinib is highly bound (99.7%) to human plasma proteins. Therefore, highly 
protein-bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a coadministered highly protein-bound drug (and a corresponding 
increase in pharmacologic effect).
4.4.4.3
Concomitant Medications that are Known to Prolong the 
Corrected QT Interval
Concomitant medications that are known to prolong the corrected QT interval (QTc)
should be avoided in patients who receive cabozantinib until they have permanently 
discontinued cabozantinib treatment (refer to https://www.qtdrugs.org for a list of drugs 
which have the potential to prolong the QTc).


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4.4.4.4
Other Interactions
Food may increase exposure levels of cabozantinib by 57%, fasting recommendations 
should be followed. In vitro data suggest that cabozantinib is unlikely to be a substrate 
for P-glycoprotein (P-gp), but it does appear to have the potential to inhibit the 
P-gp transport activity. Therefore, cabozantinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-gp.  Subjects should be 
cautioned regarding taking P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, 
digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, 
tolvaptan).  In addition, cabozantinib was shown to be a substrate of drug transporter 
multidrug resistance-associated protein 2 (MRP2) in an in vitro assay. Administration of 
MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. 
Therefore, concomitant use of MRP2 inhibitors (e.g., cyclosporine, efavirenz, 
emtricitabine) should be approached with caution. Additional details related to these 
overall conclusions can be found in the Atezolizumab Investigator Brochure.
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant 
use of gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) is 
not contraindicated in patients administered cabozantinib.
Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with 
cabozantinib and may impact absorption (or reabsorption) resulting in potentially 
decreased exposure and should be avoided.
Additional details regarding potential drug interactions with cabozantinib can be found in 
the Cabozantinib Investigator’s Brochure.
4.4.5
Prohibited Therapy for All Patients
Use of the following concomitant therapies is prohibited for all patients:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment, until disease progression is 
documented and the patient has discontinued study treatment (see Section 4.4.1 for 
details, with the exception of palliative radiotherapy)

Any investigational therapy is prohibited within 4 weeks prior to initiation of study 
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4.4.6
Prohibited Therapy for Atezolizumab-Treated and 
Cabozantinib-Treated Patients
Use of the following concomitant therapies is prohibited for patients treated with 
atezolizumab and cabozantinib:

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab

Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab

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

Oral anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitor 
dabigatran, direct factor Xa inhibitor betrixaban, platelet inhibitors (e.g., clopidogrel), 
and chronic use of aspirin above low-dose levels for cardio protection per local 
applicable guidelines), until 4 weeks after cabozantinib has been permanently 
discontinued (for permitted anticoagulants, see Section 4.4.1)
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.
Evaluations (e.g., tumor imaging) performed as part of routine care prior to informed 
consent can be utilized as screening evaluations if permitted by the site’s IRB/EC 
policies. Informed consent may be obtained greater than 28 days before randomization.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  Certain laboratory values must be obtained closer 
to randomization, within 14 days.  The investigator will maintain a screening log to record 


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details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 28 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, IMDC risk assessment, and self-reported 
race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated. The limited physical examination must be 
performed within 96 hours prior to administration of drug. Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic BP, 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 should be measured within 60 minutes prior to each atezolizumab infusion 
and, if clinically indicated, during or after the infusion.  In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1).


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Table 6
Timing for Vital Sign Measurements for First and Subsequent 
Infusions
Drug
Timing for Vital Sign Measurements
First Infusion
Subsequent Infusions
Atezolizumab

Within 60 minutes prior to the 
atezolizumab infusion

Record patient's vital signs during or 
after the infusion if clinically 
indicated

Within 60 minutes prior to the 
atezolizumab infusion

Record patient's vital signs during or 
after the infusion if clinically indicated
4.5.5
Tumor and Response Evaluations
Patients will undergo tumor assessments at baseline, every 9 weeks (7 days) for the 
first 18 months following treatment initiation, and every 12 (7 days) weeks thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 or 
(for patients who continue study treatment after radiographic disease progression) loss 
of clinical benefit as determined by the investigator (see Section 3.1 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 patients, regardless of arm, will also undergo a follow-up post-disease progression
tumor assessment after investigator assessment of radiographic disease progression 
per RECIST v1.1.  When feasible, this subsequent scan will take place on the same 
schedule as prior to progression (at 9 weeks (7 days) if disease progression occurred 
in the first 18 months, and at 12 weeks (7 days) if disease progression occurred after 
the first 18 months following treatment initiation).
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 providing the images allow a full RECIST evaluation.
Screening assessments must include CT scans (with oral or IV contrast) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, and pelvis.  A spiral CT scan of 
the chest may be obtained but is not a requirement.  If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed, and MRI scans of the abdomen and pelvis should be 
performed.  A CT scan with contrast or MRI scan of the head must be done at screening 
to evaluate CNS metastasis in all patients (MRI scan must be performed if CT scan is 
contraindicated).  An MRI scan of the head is required to confirm or refute the diagnosis 
of CNS metastases at baseline in the event of an equivocal CT scan. Bone scans and 
CT scans of the neck should also be performed if clinically indicated.  At the 


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investigator's discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.
If a CT scan for tumor assessment is performed in a positron emission tomography/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 3).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.
Objective response per iRECIST (see Appendix 4) may be calculated programmatically 
by the Sponsor on the basis of investigator assessments of individual lesions at each 
specified timepoint.
To facilitate evaluation of response per iRECIST, a follow-up post-RECIST v1.1 disease 
progression-tumor assessment must be performed in both study arms and tumor 
assessments must be continued until treatment discontinuation for patients who receive 
treatment beyond progression.  This includes continued measurement of target lesions, 
evaluation of non-target lesions (including monitoring for further worsening of any 
non-target lesions that have shown unequivocal progression), and evaluation of any 
newly identified lesions (including measurements, if lesions are measurable; 
see Appendix 4) at all subsequent assessments.
4.5.5.1
Independent Review Facility
An IRF will be used to conduct blinded radiology review of the imaging data and will 
provide an independent assessment of tumor response and progression for all patients. 
Independent Review Facility-assessed endpoints will be used for primary and secondary 
analyses.
All scans must be submitted to an IRF for central review until IRF determination of 
progression.
4.5.6
Survival Assessments
Overall survival follow-up information will be collected via telephone calls, patient 
medical records, and/or clinic visits every 3 months (every 12 weeks [1 month]) or 
more frequently until death, loss to follow-up, or study termination by the Sponsor, 
whichever occurs first.  All patients will be periodically contacted for survival, PROs
(for the first 4 survival follow-up visits only), and new anti-cancer therapy information 


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unless the patient requests to be withdrawn from the survival follow-up (this request 
must be documented in the source documents and signed by the investigator).  If the 
patient specifically withdraws from survival follow-up, the study staff may use a public 
information source (e.g., county records), per local regulations, to obtain information 
about survival status only.
See Appendix 1 for the schedule of follow-up assessments.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells [if applicable])

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, magnesium,
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, 
calcium, total bilirubin, urate, ALP, ALT, AST, and LDH
Note:  Calculated corrected calcium will be collected at screening.

Coagulation:  INR and aPTT

Thyroid function testing:  thyroid-stimulating hormone, T3 (or total T3 for sites where 
free T3 is not performed), and 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. Hepatitis B virus DNA test must be negative.

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 every cycle during study 
treatment (predose), at treatment discontinuation, and as clinically indicated.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.


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A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted

Urine Chemistry (Protein [spot urine; fully quantitative]; Creatinine [spot urine; 
fully quantitative]; UPCR [spot urine])
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Serum sample for analysis of C-reactive protein

Serum samples for atezolizumab PK analysis through use of a validated assay

Plasma samples for cabozantinib PK analysis through use of a validated assay

Serum samples for assessment of ADAs to atezolizumab through use of a validated 
assay

Blood, plasma, serum, and urine samples for exploratory research on biomarkers 
and biomarker assay development
Blood and urine samples may be processed to obtain derivatives, which may 
include plasma, serum, peripheral blood mononuclear cells (PBMCs) and 
others (e.g., RNA, DNA, ctDNA, etc.).

Archival and a newly collected (fresh) tumor tissue sample obtained at baseline
(if clinically feasible) that is suitable for exploratory research on biomarkers 
(e.g., PD-L1 status via central testing), including biomarker assay development.
Pretreatment tumor biopsies collected via minor surgery must be performed at 
least 10 days prior to Day 1 of Cycle 1 and must be completely healed before 
study treatment.
Representative formalin-fixed, paraffin-embedded tumor specimens in a 
paraffin block (preferred) or slides (15 or more) containing unstained, freshly cut, 
serial sections should be submitted.  If 15 slides are not available, 10 slides are 
acceptable with Medical Monitor confirmation.
Tumor tissue samples must be submitted before or within 4 weeks of 
randomization.
Tumor tissue should be of good quality based on total and viable tumor content. 
Samples must contain tumor cells that preserve cellular context and tissue
architecture regardless of needle gauge or retrieval method.  Samples should 
be collected via resection, core-needle biopsy (at least three, embedded in 
a single paraffin block), or excisional, incisional, punch, or forceps biopsy 
are acceptable.  Fine-needle aspiration (defined as samples that do not 


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preserve tissue architecture and yield cell suspension and/or smears), brushing, 
cell pellets from pleural effusion, and lavage samples are not acceptable. 
Tumor tissue from bone metastases that have been decalcified is not 
acceptable.
An optional tumor biopsy while on treatment is discussed further in 
Section 4.5.11.

Tumor tissue sample obtained at the time of progression, if deemed clinically 
feasible, for exploratory research on biomarkers, including biomarker assay 
development
Biopsies at the time of progression should be performed within 40 days after 
progression or prior to the next anti-cancer therapy, whichever is sooner.  
Samples collected via resection, core-needle biopsy, or excisional, incisional, 
punch, or forceps biopsy are preferred.
Cabozantinib must be withheld for biopsies (see Section 4.5.11 for details).

Exploratory biomarker research may include, but will not be limited to, analysis of 
proteins, genes or gene signatures associated with tumor immunobiology, PD-L1, 
markers associated with T-cell activation, or density, localization, and activation 
status of immune cells and their subsets, and may involve extraction of DNA, ctDNA, 
or RNA, analysis of somatic mutations, and use of NGS (including, but not limited to, 
WES)
Screening tumor tissue samples, including those collected from patients who do not 
enroll in the study, may be used for future research and/or development of 
disease-related tests or tools.
For sampling procedures, storage conditions, and shipment instructions, see the
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report (CSR), with the 
following exceptions:

Serum samples collected for atezolizumab PK, cabozantinib PK, or atezolizumab 
immunogenicity analysis may be needed for additional immunogenicity 
characterization and for PK or immunogenicity assay development and validation; 
therefore, these samples will be destroyed no later than 5 years after the final CSR
has been completed

Blood, urine, and tumor samples collected for biomarker research and biomarker 
assay development will be destroyed no later than 5 years after the final CSR has 
been completed. However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).


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
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after final closure of the study database, whichever 
occurs first.  For patients who are not enrolled, remaining archival tissue blocks will 
be returned to the site no later than 6 weeks after eligibility determination.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed, or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms and Echocardiograms
An ECG is required at screening, and then prior to Day 1 of treatment cycles as 
indicated in Appendix 1. If no clinical symptoms were identified at screening, ECG does 
not need to be repeated on Day 1 of Cycle 1.
Electrocardiograms for each patient should be obtained from the same machine 
wherever possible.  Lead placement should be as consistent as possible.  
Electrocardiogram recordings must be performed after the patient has been resting in a 
supine position for at least 10 minutes. At screening and during the study, ECGs will be 
performed with standard 12-lead ECG equipment according to standard procedures to 
determine the corrected QTc calculated by the QTcF. If at any time a single ECG shows 
a QTcF with an absolute value 480 ms or an increase in the QTcF of 60 ms above 
baseline, 2 additional ECGs at intervals of approximately 3 minutes must be performed 
within 30 minutes after the initial ECG, and the average of these 3 consecutive results 
for QTcF will be used as the value assessed (see Appendix 8).
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.
Abnormalities in the ECG that lead to a change in patient management (e.g., dose 
reduced or interrupted, treatment discontinued, requirement for additional medication or 
monitoring) or result in clinical signs and symptoms are considered clinically significant 
for the purposes of this study and will be deemed adverse events. If values meet criteria 


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defining them as serious, they must be reported as serious adverse events 
(see Section 5.4.2).
The Fridericia formula is depicted below for calculation of the QTcF value.
QTmeasured QT interval in milliseconds; RRmeasured R to R interval (which can be derived 
from the heart rate as 60/heart rate).
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. In countries where additional cardiac monitoring is considered standard 
(e.g., France), additional cardiac monitoring, including baseline evaluation of LVEF in 
those patients with cardiac risk factors, and/or an abnormal baseline ECG may be 
performed.
4.5.9
Clinical Outcome Assessments
Patient-reported outcome instruments will be completed to more fully characterize the 
clinical profile of atezolizumab and cabozantinib.  In addition, PRO instruments will 
enable the capture of each patient's direct experience with atezolizumab and 
cabozantinib.
Patient-reported outcome data will be collected through use of the following instruments:  
EORTC QLQ-C30, EQ-5D-5L, and FKSI19.
Patient-reported outcome instruments will be completed by patients on Day 1 of each 
cycle for the first 12 cycles and then Day 1 of every other cycle during study treatment, 
at the end-of-treatment visit, and at 4 subsequent survival follow-up visits.
Survival follow-up assessments may be conducted over the telephone.
All patients will complete the EORTC QLQ-C30, FKSI19, and EQ-5D-5L questionnaires 
at 3, 6, 9, and 12 months after radiographic disease progression per RECIST v1.1 or 
(for patients who continue study treatment after radiographic disease progression) loss 
of clinical benefit as determined by the investigator.
Patients who discontinue study treatment for any reason other than progressive disease 
or loss of clinical benefit will complete the questionnaires at the end-of-treatment visit
and then until disease progression when going to the clinic for any study-related 
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4.5.9.1
Data Collection Methods for Clinical Outcome Assessments
Patient-reported outcome instruments will be self-administered at the clinic at specified 
timepoints during the study and survival follow-up (see schedule of activities in
Appendix 1).  At the clinic, instruments will be administered before the patient receives 
any information on disease status, prior to the performance of non-PRO assessments
that may bias patient responses, and prior to the administration of study treatment, 
unless otherwise specified.
Patient-reported outcome instruments, translated into the local language as appropriate, 
will be completed in pre-printed paper booklets provided by the Sponsor.
Patient-reported outcome instruments should be administered as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 23 minutes at each specified visit

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments

Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank.
4.5.9.2
Description of Clinical Outcome Assessment Instruments
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; see Appendix 5).  It consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), 
3 symptom scales (fatigue, nausea and vomiting, and pain), GHS/QoL, and six single 
items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) 
with a recall period of the previous week.  Scale scores can be obtained for the 
multi-item scales.  The functioning and symptoms items are scored on a 4-point scale 
that ranges from "not at all" to "very much," and the GHS and QoL items are scored on a 


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7-point scale that ranges from "very poor" to "excellent."  The EORTC QLQ-C30 module 
takes approximately 10 minutes to complete.
Functional Assessment of Cancer Therapy-Kidney Symptom Index19
The FKSI-19 is a validated self-report measure (Rao et al. 2009; Rothrock et al. 2013; 
see Appendix 7).  It consists of 19 questions that assess symptoms and QoL in kidney 
cancer, including these four domains: physical disease-related symptoms 
(score range: 048), emotional disease-related symptoms (score range: 04), 
treatment side effects (score range: 012), and function/well-being (score range: 012). 
A total scale score comprising all 19 items can also be derived (score range: 076).
Each item is scored on a 5-point scale with response categories ranging from “not at all” 
to “very much.” Higher scale scores indicate lower symptom burden. The patient’s 
perspective on overall side-effect burden is captured by the GP5 item, where patients 
self-report how bothered they were by their treatment side effects (Pearman et al. 2018). 
This standalone item is a valid summary measure of the overall impact of 
treatment-related toxicities in cancer and complements safety reporting by clinicians. 
FKSI-19 items can also be rescored to earlier versions of the FKSI, including the 
FKSI-DRS and the FKSI-15. The FKSI-19 takes approximately 10 minutes to complete.
EQ-5D-5L
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; 
see Appendix 6).  There are two components to the EQ-5D-5L:  a 5-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a VAS that measures health state.  The EQ-5D-5L is 
designed to capture the patient's current health status.  Published weighting systems 
allow for creation of a single composite score of the patient's health status.  
The EQ-5D-5L takes approximately 3 minutes to complete.  It will be used in this study
for informing pharmacoeconomic evaluations.
4.5.10
Blood Samples for Whole-Genome Sequencing or 
Whole-Exome Sequencing (Patients at Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable 
whole-genome sequencing (WGS) or WES to identify variants that are predictive of 
response to study drug, are associated with progression to a more severe disease state, 
are associated with acquired resistance to study drug, are associated with susceptibility 
to developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will be aimed at exploring inherited characteristics.  
DNA extracted from blood may be compared with DNA extracted from tissue to identify 
somatic variants by distinguishing germline variants from somatic variants.  The samples 
may be sent to one or more laboratories for analysis.


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Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.7) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the
laboratory manual.
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
See Section 4.5.7 for details on use of samples after patient withdrawal, confidentiality 
standards for data, and availability of data from biomarker analyses.
4.5.11
Optional Tumor Biopsies
In addition to collection of baseline tissue, consenting patients will undergo optional 
tumor biopsies at any time after treatment initiation and may undergo additional 
on-treatment biopsies at any other time at the investigator's discretion (if deemed 
clinically feasible by the investigator).  Samples collected via resection, core-needle 
biopsy (at least three cores preferred), or excisional, incisional, punch, or forceps biopsy 
are preferred.
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF.
Consenting patients may undergo additional on-treatment biopsies at any time at the 
investigator’s discretion (if deemed clinically feasible by the investigator). 
Biopsies collected at the investigator’s discretion are preferred at the time of clinical 
events (e.g., clinical response).  Optional in-treatment biopsies collected from easily 


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accessible tumor lesions requiring a minimally invasive approach (skin punch biopsy, 
percutaneous lymph node or liver biopsy) will require study treatment interruption 
48 hours prior to collection. Study treatment should not be resumed until a minimum of 
7 days after the in-treatment biopsy, the decision to resume study treatment should be 
based on clinical judgment of complete wound healing. Biopsies from lesions which 
require major surgery or are deemed not easily accessible and put a patient at an 
unacceptable risk from the procedure are not permitted. Tumor tissue from bone lesions 
is not acceptable unless taken from a soft-tissue component of the bone lesion.
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  See Section 4.5.7 for details on duration of sample storage, use of 
samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses.
4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  
The collection, storage, and analysis of RBR samples will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  Research Biosample Repository samples will be 
analyzed to achieve one or more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.7) will 
not be applicable at that site.


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4.5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to atezolizumab, 
cabozantinib, diseases, or drug safety:

Blood and urine samples collected predose on Day 1 of Cycle 1 and anytime 
thereafter

Leftover blood, serum, plasma, PBMC, urine, and tumor tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover 
tissue samples from medically indicated procedures 
(e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the 
investigator's discretion during the course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods. Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  
Whole-genome sequencing and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Research Biosample Repository samples are to be stored until they are no longer 
needed or until they are exhausted.  However, the RBR storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
4.5.12.4
Confidentiality
Research Biosample Repository samples and associated data will be labeled with a 
unique patient identification number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.


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Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
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.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate RBR 
Subject Withdrawal Form and must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
e-mail address:
global_rcr-withdrawal@roche.com


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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.12.7
Monitoring and Oversight
Research Biosample Repository samples will be tracked in a manner consistent with 
Good Clinical Practice by a quality-controlled, auditable, and appropriately validated 
laboratory information management system, to ensure compliance with data 
confidentiality as well as adherence to authorized use of samples as specified in this 
protocol and in the Informed Consent Form.  Sponsor monitors and auditors will have 
direct access to appropriate parts of records relating to patient participation in the RBR 
for the purposes of verifying the data provided to the Sponsor.  The site will permit 
monitoring, audits, IRB/EC review, and health authority inspections by providing direct 
access to source data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients in the experimental arm (atezolizumab in combination with cabozantinib) are 
allowed to discontinue one component of the study treatment but continue to receive the 
other component as described in Section 5.1.3 for management of adverse events.
Patients must permanently discontinue study treatment if they experience any of the 
following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event

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

Disease progression per RECIST v1.1. 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 (e.g., symptomatic 
deterioration such as pain secondary to disease; see Section 3.1 for details)
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
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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 may choose to withdraw from treatment, the study, or both. Patients who 
withdraw from treatment are encouraged to continue survival follow-up to gather data 
which is valuable to the study.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  
Patients who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and cabozantinib 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 as indicated below.  Administration of atezolizumab and the 
first dose of cabozantinib 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. Subsequent doses of cabozantinib will be 
self-administered at home (Section 4.3.2.2). Guidelines for managing patients who 
experience anticipated adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided in Appendix 10 for atezolizumab 
and Appendix 11 for cabozantinib.  See Sections 5.25.7 for details on safety reporting 
(e.g., adverse events, pregnancies) for this study.
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe 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 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines.


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5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis, myocarditis, nephritis, myositis, and severe cutaneous adverse 
reactions.  Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  
See Appendix 10 of the protocol and Section 6.4.1 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for
atezolizumab.
5.1.2
Risks Associated with Cabozantinib
Cabozantinib has been associated with risks such as the following: GI disorders, non-GI 
fistula formation, hemorrhage, thromboembolic events, hypertension, stomatitis and 
mucositis, skin disorders, osteonecrosis, proteinuria, nervous system disorders, 
hepatocellular toxicity, infections and infestations, blood system disorders, fatigue, 
weight loss, QTc prolongation, electrolyte disorders, endocrine disorders, and respiratory 
disorders. See Appendix 11 of the protocol and the Cabozantinib
Investigator's Brochure for a detailed description of anticipated safety risks for 
cabozantinib.
5.1.3
Management of Patients who Experience Adverse Events and 
Potential Overlapping Toxicities
Atezolizumab and cabozantinib have molecule-specific safety profiles based on their 
mechanism of action and adverse events that may also overlap.  These include, but are 
not limited to, hepatotoxic, endocrine, GI, dermatologic, neurologic, renal, and 
pulmonary events, as well as signs and symptoms such as fatigue and, decreased 
appetite that may be related to multiple system organ class events. The attribution of 
each drug in certain adverse events may be uncertain when the products are 
administered as combination treatment and warrant diagnostic work up. For the 
management of such potentially overlapping adverse events in patients treated with 
atezolizumab in combination with cabozantinib, adverse events should be managed 
according to the recommendations in Appendix 10 (atezolizumab), and 
Appendix 11 (cabozantinib) and applied to the component of the study treatment judged 
to be the primary cause. If individual component causality for adverse events cannot be 
determined, conservative management should be followed to include dose 
modification/interruption of both agents.


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Table 7
Guidance for Managing Overlapping Toxicities
Toxicity
Atezolizumab
Cabozantinib
Pulmonary events
Appendix 10, Table 1
Appendix 11, Respiratory 
Disorders
Hepatic events
Appendix 10, Table 2
Appendix 11, Table 5
Gastrointestinal events
Appendix 10, Table 3
Appendix 11, Table 1
Endocrine events
Appendix 10, Table 4
Appendix 11, Endocrine 
Disorders
Dermatologic events
Appendix 10, Table 9
Appendix 11, Table 3
Neurologic events
Appendix 10, Table 10
Appendix 11, Nervous System 
Disorders
Renal events
Appendix 10, Table 12
Appendix 11, Table 4
5.1.3.1
Dose Modification
Atezolizumab
There will be no dose reductions for atezolizumab in this study. For dose interruptions of 
atezolizumab see Section 5.1.3.2 and Appendix 10.
Cabozantinib
Dose modifications for cabozantinib are as follows:

Two dose reduction levels of cabozantinib (40 mg QD and 20 mg QD) are permitted 
(see Table 8)

Dose modification criteria for treatment-related adverse events of cabozantinib are 
shown in Table 9

Dose reinstitution and re-escalation after dose interruptions and/or reductions:
If the patient recovers from his or her toxicities to Grade1 per 
NCI CTCAE v5.0 or to the baseline value (or lower) and the adverse event was 
unrelated to cabozantinib, then cabozantinib may be restarted with no change 
in dose.
If the patient recovers from his or her toxicities to Grade1 or to the baseline 
value (or lower) and the adverse event was deemed possibly related to 
cabozantinib, then cabozantinib may be restarted at a reduced dose 
(see Table 9). Patients who initiated treatment with cabozantinib at 60 mg and 
experience a possibly related adverse event of Grade 1 or 2 severity may be 
restarted with no dose change after recovery of the toxicities to Grade1 or to 
the baseline value (or lower) if appropriate supportive care can prevent or 
minimize the risk of the adverse event.


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Patients receiving a dose of 20 mg QD who have cabozantinib interrupted may 
be restarted at the same dose if deemed safe at the discretion of the 
investigator. Patients unable to tolerate a dose of 20 mg QD must discontinue 
cabozantinib.
Re-escalation to the previous dose may be allowed at the discretion of the 
investigator but no sooner than 2 weeks beyond resolution of adverse events 
that led to the dose reduction, which have resolved or recovered to Grade 1 
(or baseline value) and deemed tolerable and easily managed by optimized 
supportive treatment. Dose re-escalation is not allowed following a 
cabozantinib-related dose reduction for Grade 4 hematologic toxicities or 
Grade 4 adverse events affecting major organs (e.g., CNS, cardiac, hepatic, 
renal, pulmonary, GI).
Table 8
Dose Reduction Levels for Cabozantinib (Oral Dosing)
Assigned Starting Dose
First Dose Level 
Reduction
Second Dose Level Reduction
60 mg QD
40 mg QD
20 mg QD a
QDonce a day.
a Cabozantinib will be discontinued if a dose of 20-mg QD of cabozantinib is not tolerated.


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Table 9
Dose Modifications for Cabozantinib-Related Adverse Events
Grade per NCI CTCAE v5
Recommended Guidelines for Management a
Grade 1 AEs
Add supportive care as indicated. Continue cabozantinib 
at the current dose level if AE is manageable and 
tolerable.
Grade 2 AEs which are tolerable 
and are easily managed
Grade 2 AEs which are intolerable
and cannot be adequately 
managed
Continue cabozantinib at the current dose level with 
supportive care.
Cabozantinib should be dose reduced or interrupted b
Note: It is recommended that dose interruptions be as 
brief as possible.
Grade 3 AEs
(except clinically non-relevant 
laboratory abnormalities)
Cabozantinib should be interrupted unless the toxicity can 
be easily managed with a dose reduction of cabozantinib 
and optimal medical care b
Note: It is recommended that dose interruptions be as 
brief as possible.
Grade 4 AEs
(except clinically non-relevant 
laboratory abnormalities)
Cabozantinib must be interrupted immediately.
In general, cabozantinib should be discontinued unless 
the following criteria are met:

Patient is deriving clear clinical benefit as determined 
by the investigator and agreed by the Sponsor

Toxicity can be managed with a dose reduction of 
cabozantinib following recovery to Grade 1 
(or baseline) and optimal medical care
Sponsor must be contacted to discuss treatment 
continuation upon resolution of AEs.
AEadverse event; NCI CTCAENational Cancer Institute Common Terminology Criteria for 
Adverse Events; QDonce a day.
a Cabozantinib will be discontinued if a dose of 20-mg QD of cabozantinib is not tolerated.
b Cabozantinib must be interrupted until the adverse event resolves to Grade1.
Note: In exceptional cases, treatment with cabozantinib may be continued at a reduced dose 
(without interruption) if, according to the investigator’s judgment, the toxicity can be easily 
managed with a dose reduction of cabozantinib and optimal medical care.
For guidelines on dose modifications to manage specific adverse events associated
cabozantinib treatment, see Appendix 11.
5.1.3.2
Treatment Interruption
Dose interruptions of study treatment may occur at any time and independently at the 
discretion of the investigator for management of adverse events. If either or both study 
treatments in the experimental arm (atezolizumab in combination with cabozantinib) are 
interrupted more than 12 weeks, the Sponsor should be contacted to discuss potential 
treatment continuation.


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Patients in the experimental arm will be allowed to discontinue one component of the 
study treatment but continue to receive the other; the investigator is encouraged to 
discuss such circumstances with the Sponsor.
Atezolizumab treatment may be temporarily suspended in patients who experience 
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.
For guidelines on treatment interruption to manage specific adverse events associated
with atezolizumab and cabozantinib, see Appendix 10 for atezolizumab and Appendix 11
for cabozantinib.
Dose interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed with Medical Monitor approval.  The investigator and the Medical Monitor will 
determine the acceptable length of treatment interruption.
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

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)


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
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 v5.0; 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).


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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.

Systemic lupus erythematosus

Events suggestive of hypersensitivity, IRRs, CRS, hemophagocytic 
lymphohistiocytosis, and macrophage activation syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

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)
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 
assess seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the final dose of study treatment
or until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity.  Table 10 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE v5.0.


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Table 10 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an
adverse event is considered to be related to study treatment, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 11):

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


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Table 11 Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than study treatment
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only 1 adverse event term should be recorded in the event field on the 
Adverse Event eCRF.
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 


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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 
1 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 GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF

If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the 
Adverse Event eCRF.  If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from "non-serious" to "serious," providing the date 
that the event became serious, and completing all data fields related to serious adverse 
events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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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., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 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


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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 BP), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of RCC 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). An independent monitoring committee will monitor the frequency of 
deaths from all causes.
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 1 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 


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replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Renal Cell Carcinoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  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.


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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 Overdose, Medication Error, Drug Abuse, or Drug
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse}
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
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 or cabozantinib, adverse events associated with special situations 
should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the 
"Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  
If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  
Check the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with atezolizumab or cabozantinib,
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and 
"drug abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and 
"intentional overdose" as the event term.  Check the "Intentional overdose" and 
"Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and 
"drug misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and 
"intentional overdose" as the event term.  Check the "Intentional overdose" and 
"Drug misuse" boxes.


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
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor. Sites are not 
expected to review the PRO data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event


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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:
, M.D. (Primary)
Telephone No.:
E-mail:
Medical Monitor:
, M.D. (Secondary)
Telephone No.:
E-mail:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as 
Medical Monitor and Medical Responsible contact information, will be distributed to all 
investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
e-mail address provided to investigators.
5.4.2.2
Events that Occur after Study Treatment Initiation
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  
Investigators should record all 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.


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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 e-mail 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 and within 5 months after the final
dose atezolizumab and 4 months after the final dose of cabozantinib, whichever is later.  
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 e-mail 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 
4 months after the final dose of cabozantinib. 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 e-mail 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 


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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
embryo fetal 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 
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
(see Section 5.4.3)


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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, e-mail, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study 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 e-mail
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 through use of the reference safety 
information in the documents listed below:
Drug
Document
Atezolizumab
Atezolizumab Investigator's Brochure
Cabozantinib
Cabozantinib Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
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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 a Phase III, randomized, open-label study designed to evaluate the efficacy and 
safety of atezolizumab plus cabozantinib as compared with cabozantinib monotherapy.
Analysis populations are defined as follows:

The ITT populations defined as all randomized patients whether or not the assigned 
treatment was received

The measurable disease population is defined as patients in the ITT population with 
measurable disease at baseline

The DOR population is defined as patients with objective response

The PRO-evaluable population is defined as patients with a non-missing baseline 
PRO assessment

The safety-evaluable population is defined as patients who received any amount of 
any component of the study treatments
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 500 patients are planned for enrollment globally over 20 months. 
The sample size calculation is determined based on the below considerations.
Type I Error Control
The type I error () for the entire study is 0.05 (2-sided).  There are multiple primary 
efficacy endpoints for this study:  PFS by IRF assessment per RECIST v1.1 and OS in 
the ITT population. To control the overall type I error rate (Bretz et al. 2009) at 0.05 
while accounting for 2 primary endpoints, is split between PFS (0.02) and OS 
(0.03).  The type I error can be recycled (Burman et al. 2009) if PFS results in the 
ITT population are statistically significant at 0.02, then 0.02 will be recycled to OS 
in the ITT population, and OS in the ITT population will be evaluated at 0.05. 
The study will be considered as a positive study if statistical significance is achieved in 
favor of the experimental arm for either of the multiple primary endpoints, since the type I 
error () for the entire study is controlled at 0.05.
Primary Endpoint:  Progression-Free Survival by Independent Review 
Facility Assessment per RECIST v1.1 in the Intent-to-Treat Population
The analysis of the primary endpoint of PFS by IRF assessment per RECIST v1.1 will 
take place when approximately 325 IRF-assessed PFS events have occurred in the 
ITT population (65% events patient rate) based on the following assumptions:

Two-sided, stratified log-rank test

0.02 (2-sided)

Approximately 90% power


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
Median PFS for the cabozantinib arm of 8.0 months and estimated median PFS in 
the atezolizumab and cabozantinib arm of 11.9 months (corresponding to HR of 
0.67)

5% annual loss to follow-up for PFS

No interim analysis
On the basis of these assumptions, it is projected that an observed HR of 0.77 or lower 
will result in a statistically significant difference between treatment arms (i.e., an HR of 
0.77 will be the minimum detectable difference [MDD] for the analysis; this corresponds 
to an improvement of 2.4 months in median PFS from 8.0 months in the cabozantinib
arm to 10.4 months in the atezolizumab and cabozantinib arm).
Primary Endpoint:  Overall Survival in the Intent-to-Treat Population
The final analysis of the primary endpoint of OS will take place when approximately 
325 OS events have occurred in the ITT population (65% events patient rate) based on 
the following assumptions:

Two-sided, stratified log-rank test

0.03 (2-sided)

Approximately 85% power

Median OS in the cabozantinib arm of 22 months and estimated median OS in the 
atezolizumab and cabozantinib arm of 31.4 months (an increase of 9.4 months, 
corresponding to an HR of 0.70)

1% annual loss to follow-up for OS

Two interim OS analyses
At the final OS analysis, on the basis of these assumptions, it is projected that an 
observed OS HR of 0.78 or lower in the ITT population will result in a statistically 
significant difference between treatment arms (i.e., the MDD at the analysis; this 
corresponds to an improvement of 6.2 months in median OS, from 22 months in the 
control arm to 28.2 months in the atezolizumab and cabozantinib arm).
Sample Size
With the above assumptions on PFS and OS, the sample size is determined at 
500 patients, where the PFS and OS final analysis will be conducted when 325 events
occur (65% events patient rate), respectively. The 500 patients are planned for 
enrollment globally over 20 months.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol deviations, including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized by treatment 
arm. Study treatment administration and reasons for discontinuation from the study 
treatment will be summarized by treatment arm.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic variables such as age, sex, race/ethnicity, stratification factors 
(IMDC score, line of therapy, histology), and baseline characteristics will be summarized 
by treatment arm for the ITT population.  Continuous variables will be summarized with 
use of means, standard deviations, medians, and ranges.  Categorical variables will be 
summarized by proportions.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment.
6.4
EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment.
6.4.1
Multiple Primary Efficacy Endpoints
The multiple primary efficacy endpoints are IRF-assessed PFS per RECIST v1.1 and OS.
Progression-free survival is defined as the time from randomization to disease 
progression, as determined by the IRF per RECIST v1.1, or death from any cause, 
whichever occurs first.  Data for patients who have not experienced disease progression 
or death will be censored at the last tumor assessment date.  Data for patients with no 
post-baseline tumor assessments will be censored at the randomization date.
Overall survival is defined as the time from randomization to death due to any cause.  
Data for patients who are not reported as having died at the date of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.
The following analyses will be performed for both PFS and OS endpoints described 
above.  Progression-free survival and OS will be compared between treatment arms with 
use of the stratified log-rank test at the 2-sided level of significance. The HR with a 
95% CI will be estimated with use of a stratified Cox regression model with the same 
stratification variables used for the stratified log-rank test. The randomization 
stratification factors are most recent ICI therapy (adjuvant vs. first-line vs. second-line), 
histology (dominant clear-cell without sarcomatoid vs. dominant nonclear-cell [papillary 
or unclassified only] without sarcomatoid vs. any sarcomatoid component [clear-cell or 
nonclear-cell]), and the IMDC score (0, 12, 3). If at least 1 stratum has less than 
10 events at the time of analysis, the stratification factor that contains the level with the 
smallest number of patients will be removed from the stratified analyses. The final set of 
stratification factors used for the multiple primary endpoints will be applied to all other 
endpoints where stratified analyses are planned. The stratification factors will be 
obtained from the IxRS at the time of randomization.  Results from an unstratified 
analysis will also be provided.  Kaplan-Meier methodology will be used to estimate the 


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median PFS and OS for each treatment arm, and Kaplan-Meier curves will be produced.  
The Brookmeyer Crowley methodology will be used to construct the 95% CI for the 
median PFS and OS for each treatment arm (Brookmeyer and Crowley 1982).
6.4.2
Secondary Efficacy Endpoints
The following secondary efficacy endpoints per RECIST v1.1 will be analyzed:

Investigator-assessed-PFS

Investigator- and IRF-assessed ORR

Investigator- and IRF-assessed duration of objective response
Statistical methods for treatment arm comparison of investigator-assessed PFS as the 
secondary endpoint will be the same as the methods for treatment comparisons for the 
primary efficacy endpoint of IRF-PFS.
6.4.2.1
Objective Response Rate
An objective response is defined as either a CR or PR (confirmation is required, i.e., with 
CR or PR at two consecutive tumor assessments at least 28 days apart) based on 
RECIST v1.1.  Patients not meeting this criterion, including patients without any 
post-baseline tumor assessments, will be considered non-responders.  
Objective response rate is defined as the proportion of patients who had an objective 
response among patients with measurable disease at baseline.  Unconfirmed response 
rate will also be evaluated.
Objective response rate will be compared between treatment arms with use of the 
stratified Cochran-Mantel-Haenszel test.  The stratification factors will be the same as 
those described in the analysis of the multiple primary efficacy endpoints of PFS and OS.  
An estimate of ORR will be calculated for each treatment arm, and its 95% CI will be 
calculated with use of the Clopper-Pearson method.  The difference in ORR between 
treatment arms will be calculated, and its 95% CI will be calculated with use of the 
normal approximation to the binomial distribution.
6.4.2.2
Duration of Response
Duration of response is defined for patients who had a confirmed objective response as 
the time from the first occurrence of response (CR or PR) to disease progression or 
death, whichever occurs first.  Data for patients who have not experienced disease 
progression or death will be censored at the last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of CR or PR, data for 
DOR will be censored at the date of the first occurrence of CR or PR.
Duration of response is based on a non-randomized subset of patients (those who 
achieved an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between two arms will be made for 
descriptive purposes only.  Methods for comparison of DOR between treatment arms will 


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be the same as the methods for treatment comparison for the multiple primary efficacy 
endpoints of PFS and OS.
6.4.3
Exploratory Efficacy Endpoints
6.4.3.1
Analyses at Landmark Timepoints
The PFS and OS rates at various timepoints (i.e., every 6 months after randomization) 
will be estimated by the Kaplan-Meier methodology for each treatment arm and the 
95% CI will be calculated with use of Greenwood’s formula.
6.4.3.2
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics (e.g., PD-L1 status, prior VEGFR-TKI use, most recent 
ICI therapy (adjuvant vs. first-line treatment vs. second-line treatment), tumor histology,
or IMDC risk group), PFS, ORR, and OS in these subgroups investigator-assessed DOR
and IRF-assessed DOR will be examined.  Summaries of PFS and OS, including 
unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of the median, will be produced separately for each level of the 
categorical variables.  Objective response rate will be summarized for each level of the 
categorical variables.
6.4.3.3
Time to Response
Time to response is defined as the time from randomization to first response of PR or 
CR among responders.
6.4.3.4
Time to Deterioration of Disease-Related Symptoms
Time to confirmed deterioration of disease-related symptoms is defined as the time from 
randomization date to the date of a patient’s first 4-point or more score decrease from 
baseline on the FKSI-19 DRS-P scale held for at least two consecutive timepoints or
followed by death within 3 weeks (if Cycles 112) or 6 weeks (if after Cycle 12) from the 
last PRO assessment. Kaplan-Meier methods will be applied to this endpoint.
6.4.3.5
Time to Deterioration of Physical Functioning
Time to confirmed deterioration of physical functioning is defined as the time from 
randomization date to the date of a patient’s first 10-point or more score decrease from 
baseline on the EORTC QLQ-C30 physical functioning scale held for at least 
2 consecutive timepoints or followed by death within 3 weeks (if Cycles 112) or 
6 weeks (if after Cycle 12) from the last PRO assessment. Kaplan-Meier methods will be 
applied to this endpoint.


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6.4.3.6
Time to Deterioration of Global Health Status/Quality of Life
Time to confirmed deterioration of (GHS/QoL) is defined as the time from randomization 
date to the date of a patient’s first 10-point or more score decrease from baseline on the 
EORTC QLQ-C30 GHS/QoL scale held for at least 2 consecutive timepoints or followed 
by death within 3 weeks (if Cycles 112) or 6 weeks (if after Cycle 12) from the last 
PRO assessment. Kaplan-Meier methods will be applied to this endpoint.
6.4.3.7
Patient-Reported Outcome Descriptive Summaries
Compliance rates in the ITT population will be calculated as the number of patients who 
completed the assessment divided by the number of patients expected to complete the 
assessment at each timepoint for each treatment arm. Reasons for missing 
assessments, if available, will be summarized with use of frequencies and percentages.
Descriptive analyses will include summary statistics (mean, standard deviation, median, 
interquartile range [IQR], minimum, maximum) of PRO scores and score changes from 
baseline at each assessment timepoint by treatment arm. Additional timepoints of 
interest include PRO score at radiographic disease progression (i.e., a patient’s last
PRO assessment score within 30 days prior to or on the day of diagnosis of disease 
progression) and treatment discontinuation due to adverse events (i.e., a patient’s last 
PRO assessment within the 30 days prior to treatment discontinuation due to adverse 
events). Graphs of mean scores and/or score changes from baseline along with 2-sided 
95% CIs may be presented. Descriptive summaries will be reported for the key scales 
(FKSI-19 DRS-P, EORTC QLQ-C30 physical functioning, and EORTC QLQ-C30 
GHS/QoL) as well as the remaining FKSI-19 and EORTC QLQ-C30 scales.
Cumulative distribution function plots of score change from baseline to Month 6 by 
treatment arm will be presented for each key scale (FKSI-19 DRS-P, EORTC QLQ-C30 
physical function, EORTC QLQ-C30 GHS/QoL).
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least 1 dose of study treatment, with patients grouped according to treatment received.
6.5.1
Analyses of Exposure, Adverse Event, Laboratory, Vital Signs, 
and Data
Safety analyses will be performed on the safety-evaluable population.  Specifically, a 
patient will be included in the atezolizumab and cabozantinib experimental arm in the 
safety analyses if the patient receives any amount of atezolizumab or cabozantinib, 
regardless of the initial treatment assignment at randomization.
Safety endpoints will include the incidence and severity of adverse events, with severity 
determined according to the NCI CTCAE v5.0, including serious adverse events and 
adverse events of special interest, and clinical laboratory results following the 
administration of study drugs.  Drug exposure will be summarized, including duration,


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dosage, and dose intensity.  Verbatim description of adverse events will be mapped to 
the MedDRA thesaurus terms and graded according to the NCI CTCAE v5.0.  
All adverse events will be summarized by treatment arm and NCI CTCAE grade.  
In addition, serious adverse events and adverse events leading to study treatment 
discontinuation or interruption will be summarized accordingly.  Multiple occurrences of 
the same event will be counted once at the maximum severity.  Laboratory data with 
values outside of the normal ranges will be identified.  Additionally, selected laboratory 
data, including ADA results, will be summarized by treatment arm.  Deaths and causes 
of deaths will be summarized.
6.5.2
Exploratory Analyses of Patient-Reported Treatment 
Side-Effect Burden
Descriptive analysis of the patient-reported overall side-effect bother item (FKSI-19 GP5) 
will be performed by treatment arm at each visit in the safety-evaluable population. 
Distribution of responses will be summarized as frequencies and percentages. 
Change from baseline may be summarized as no change; improved by 1, 2, 3, or 
4 levels; and worsened by 1, 2, 3, or 4 levels. Stacked bar charts may also be used to 
illustrate the distribution of responses or the change from baseline at each timepoint by 
treatment arm.
6.6
PHARMACOKINETIC ANALYSES
Sparse concentrations of atezolizumab and cabozantinib will be reported as individual 
values and as group descriptive statistics as data allow (mean, standard deviation, 
coefficient of variation, median, range, geometric mean, and geometric mean coefficient 
of variation).  The concentration-time course will also be plotted for each drug.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of patients who received any 
amount of atezolizumab with at least one ADA assessment for atezolizumab.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining post-baseline incidence, 
patients are considered to be ADA-positive if they are ADA-negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
of 1 or more post-baseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA-negative if they are ADA-negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA-positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).


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The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data
may be analyzed in the context of this study and in aggregate with data from other 
studies.
6.9
HEALTH STATUS UTILITY ANALYSES
Change from baseline in EQ-5D-5L health utility index-based and VAS scores will be 
calculated at specified timepoints.
6.10
INTERIM ANALYSES
6.10.1
Planned Interim Analyses
Primary Endpoint of Progression-Free Survival
There is no planned interim analysis of the primary endpoint of PFS.
Primary Endpoint of Overall Survival
A total of three analyses of OS will be performed, including two interim analyses and 
one final analysis.  The boundary for statistical significance at each OS analysis will be 
determined based on the Lan-DeMets implementation of the O’Brien-Fleming (OBF) 
function (Lan and DeMets 1983) to maintain the overall type I error rate 
(Hung et al. 2007; Glimm et al. 2009) at either 0.03 or 0.05 level, depending on whether 
primary endpoint of PFS is significant at 0.02 level.  The OBF boundary for statistical 
significance is provided in Table 12.  The OS endpoint will be considered positive in the 
ITT population if statistical significance is achieved in favor of the experimental arm for 
any of the two OS interim analyses or the final analysis.
Table 12 Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Hazard Ratios
OS Interim Analysis 1
OS Interim Analysis 2
Final OS
Percent Information
53%
175 events
80%
260 events
100%
325 events
Timing (from FPI)
27 months
(PFS primary)
39 months
52 months
OBF Boundary when 
0.03 (0.05)
0.0019 (0.0045)
0.0125 (0.0231)
0.0259 (0.0424)
MDD when 0.03 (0.05)
HR0.62
(HR0.65)
HR0.73
(HR0.75)
HR0.78
(HR0.80)
FPIfirst patient in; HRhazard ratio; MDDminimum detectable difference; 
OBFO’Brien-Fleming; OS overall survival; PFSprogression-free survival.


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The first interim analysis of OS will be performed at the time of the PFS primary analysis.  
A total of 175 OS events are expected at the first interim analysis of OS, which 
corresponds to 53% of the events information required for the final analysis of OS in the 
ITT population.  Statistical significance will be declared if p0.0019. If there are 
significantly fewer (160) OS events than the expected 175 OS events, then the first 
interim analysis will be delayed until 175 OS events occur. An administrative of 
0.000001 (negligible impact on overall type I error rate) will be spent on the OS 
hypothesis at the time of the planned PFS.
The second interim analysis of OS will be performed when approximately 260 deaths 
have occurred, which corresponds to approximately 80% of the events information 
required for the final analysis of OS in the ITT population.  Statistical significance will be 
declared if p0.0125.
The final analysis of OS will be performed when 325 deaths (65% of 500 patients in the 
ITT population) have occurred.  Statistical significance will be declared if p0.0259 when 
exactly 325 deaths have occurred at the time of the final OS analysis.
The actual OBF boundary will be calculated at time of analysis based on actual number 
of events observed.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor 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 Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
Electronic Case Report Forms and correction documentation will be maintained in the 
EDC system's audit trail.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor's standard procedures.
Patient-reported outcome data will be collected on paper questionnaires. The data from 
the questionnaires will be entered into the EDC system by site staff.


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7.2
ELECTRONIC CASE REPORT FORMS
Electronic Case Report Forms 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.  Electronic Case Report Forms 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.  Electronic Case Report 
Forms 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, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
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 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 


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the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, and
other processes outlined above apply except that IRB review and approval may not be 
required per study site policies.


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


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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 CSRs and other 
summary reports will be provided upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 


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from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
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.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 140180 sites globally will participate to randomize approximately 
500 patients.  Screening and enrollment will occur through an IxRS.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An iDMC will monitor and evaluate patient safety until the primary PFS analysis
throughout the study.  Tumor response and progression will be evaluated by an IRF.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted CSRs and other summary reports will be made available upon request.  
For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information 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 CSR.  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, 


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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.
9.7
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).


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10.
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Appendix 1 Schedule of Activities
Assessment Window (Days) a
Screening b
Treatment Cycles
(21-day cycles)
Treatment 
Discontinuation
Follow-Up 
(1 month)
Days –28 to –1
Days –14 to –1
Day 1
(3 days)
30 Days after Final 
Dose
Informed consent
x c
Tumor tissue specimens d
x
Demographic data
x
Medical history, including cancer and RCC 
history, and baseline conditions
x
Patient-reported outcome e
x
x
x f, g
Vital signs h
x
x
x
C-reactive protein
x
Weight
x
x
x
Height
x
Complete physical examination i
x
x
Limited physical examination j
x k
Karnofsky Performance Status
x
x k
x
ECG (12-lead)/ Echocardiogram l
x l
x
x
Hematology m
x
x k
x
Chemistry n
x
x k
x
Pregnancy test o
x
x k
x
Coagulation (INR, aPTT)
x
x
TSH, free T3 (or total T3), free T4 p
x
x
x
Viral serology q
x


Appendix 1: Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol WO41994, Version 3
Assessment Window (Days) a
Screening b
Treatment Cycles
(21-day cycles)
Treatment 
Discontinuation
Follow-Up 
(1 month)
Days –28 to –1
Days –14 to –1
Day 1
(3 days)
30 Days after Final 
Dose
Urinalysis r, s
x
x k
UPCR
x
x k, t
PK samples
See Appendix 2
ADA samples
See Appendix 2
Blood sample for biomarkers
(central laboratory)
See Appendix 2
Urine sample for biomarkers
(central laboratory)
See Appendix 2
Blood sample for RBR (optional) u
x
Tumor biopsy, if clinically feasible
At time of radiographic progression v
Tumor tissue biopsy at other timepoints 
(optional) w
Any time during study treatment, observation FU or survival FU
(at investigator's discretion)
Tumor response assessments
x x
x y, z
Concomitant medications aa
x
x
x
Adverse events bb
x
x
x
x
Atezolizumab administration
x cc
Cabozantinib dispensing/reconciliation
x dd
Survival follow-up and anti-cancer treatment
x ee


Appendix 1: Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol WO41994, Version 3
ADAanti-drug antibody; CRPC-reactive protein; CTcomputed tomography; EORTCEuropean Organisation for Research and Treatment of 
Cancer; EQ-5D-5LEuroQol 5-Dimension, 5-Level Questionnaire; FKSI-19Functional Assessment of Cancer Therapy-Kidney Symptom Index 19; 
FUfollow-up; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; LVEFleft 
ventricular ejection fraction; MRImagnetic resonance imaging; NAnot applicable; PKpharmacokinetic; PRO patient-reported outcome; 
QLQ-C30Quality of Life QuestionnaireCore 30 Questionnaire; RBRResearch Biosample Repository; RCCrenal cell carcinoma; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; TSHthyroid-stimulating hormone; UPCRUrine Protein/Creatinine ratio.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a The first dosing day (Day 1 of Cycle 1) should occur within 3 days from the date of randomization.
b Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
outside the 28-day screening period.  Results of standard of care tests or examinations performed prior to obtaining informed consent and within 
28 days prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests.  
If re-screening is required, then HBV, HCV, HIV, and CRP from the initial screening may be acceptable for screening assessment if performed 
60 days from Day 1 of Cycle 1.
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 Representative archival tumor tissue sample and, if clinically feasible, a fresh tumor sample obtained at baseline for exploratory research on 
biomarkers (e.g., PD-L1 status via central testing), including biomarker assay development.  See Section 4.5.7 for tissue sample requirements.
e Patient-reported outcome assessments (EORTC QLQ-C30, FKSI-19, and EQ-5D-5L questionnaires) will be completed before the patient 
receives any information on disease status and prior to the performance of non-PRO assessments that could bias patient’s rating and the 
administration of study treatment.  Study personnel should confirm all questionnaires for completeness before the patient leaves the 
investigational site.  Patient-reported outcome instruments will be completed by patients on Day 1 of each cycle for the first 12 cycles and then 
on Day 1 of every other cycle during study treatment, and at the end-of-treatment visit.  For PROs after treatment discontinuation, please see 
footnotes f and g.
f
Patients who discontinue study treatment for any reason other than progressive disease or loss of clinical benefit will complete the 
questionnaires (EORTC QLQ-C30, FKSI19, and EQ-5D-5L) at the end-of-treatment visit and then until disease progression when going to the 
clinic for any study-related assessments.
g All patients will complete the EORTC QLQ-C30, FKSI19 and EQ-5D-5L questionnaires at 4 subsequent survival follow- up visits (i.e., at 3, 6, 9, 
and 12 months after radiographic disease progression per RECIST v1.1) or, for patients who continue atezolizumab after radiographic disease
progression, loss of clinical benefit as determined by the investigator.  Survival follow-up assessments may be conducted over the telephone.


Appendix 1: Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol WO41994, Version 3
h Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  For the first infusion, vital signs should be 
measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 (5) minutes during the infusion and at 30 (10) minutes 
after the infusion.  For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if 
symptoms occurred during the previous infusion, during the infusion and at 30 (10) minutes after the infusion.
i
The complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.
j
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.
k If screening laboratory assessments were performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated.  At all cycles 
subsequent to Day 1 of Cycle 1, Karnofsky Performance Status and limited physical examination must be performed within 96 hours prior to 
study treatment administration.
l
12-lead ECG recordings will be obtained during screening (within 14 days prior to initiation of study treatment), on Day 1 of Cycle 1 (predose), on 
Day 1 of Cycle 2, on Day 1 of Cycle 3, and every 4 cycles thereafter (i.e., Day 1 of Cycle 7, Day 1 of Cycle 11, and so on) and at the 
end-of-treatment visit.  Patients should be resting in a supine position for at least 10 minutes prior to ECG recording.  Electrocardiograms will be 
reviewed by the investigator to determine patient eligibility at screening.  Baseline evaluation of LVEF (echocardiogram) should be considered for 
all patients, especially in those with cardiac risk factors and/or history of coronary artery disease, and/or other arterial thromboembolic disease.  
If no clinical symptoms were present at screening, ECG does not need to be repeated on Day 1 of Cycle 1.
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, urate, ALP, ALT, 
AST, and LDH.
o 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 every cycle (predose) during study treatment, at treatment discontinuation, and as clinically indicated.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
p Thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening, on Day 1 
of Cycle 1 and every 4 cycles thereafter (i.e., Cycles 5, 9, 13, and so on).
q 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.
r
Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.
s Urinalysis should be performed at screening and every 3 weeks or as clinically indicated during study treatment.


Appendix 1: Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol WO41994, Version 3
t
UPCR should be performed at screening, Cycle 1 (not repeated if screening UPCR is performed within 72 hours of Day 1 of Cycle 1, please 
see footnote k), Cycle 3, and every other cycle (i.e., every 6 weeks) thereafter during study treatment or more frequently as clinically indicated.
u Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  The RBR blood sample can be accepted on Day 1 of Cycle 1 and anytime thereafter and 
should only be collected at one timepoint during the study.
v Patients will undergo a tumor biopsy sample collection, if deemed clinically feasible by the investigator, at the time of first evidence of 
radiographic disease progression per RECIST v1.1.  Biopsies should be performed within 40 days after progression or prior to the next 
anti-cancer therapy, whichever is sooner. See Section 4.5.7 for tissue sample requirements and Section 4.5.11 for biopsy in relation to 
cabozantinib dosing.
w Optional tumor tissue biopsies are to be performed only for patients at participating sites who have provided written informed consent to 
participate.  Biopsies collected at the investigator’s discretion are preferred at the time of clinical events (e.g., clinical response).  Patients must 
sign a separate Optional Biopsy Informed Consent Form to undergo optional biopsies.  See Section 4.5.7 for details.  See Appendix 2 for 
schedule.  See Section 4.5.11 for instructions on cabozantinib dosing for patients undergoing biopsy.
x 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.  All known 
sites of disease, including measurable and/or non-measurable disease, must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of the chest, abdomen and pelvis.  
A spiral CT scan of the chest may be obtained but is not a requirement.  If a CT scan with contrast is contraindicated (e.g., in patients with 
impaired renal clearance), a non-contrast CT scan of the chest may be performed, and MRI scans of the abdomen and pelvis should be 
performed.  A CT scan with contrast or MRI scan of the head must be done at screening to evaluate CNS metastasis in all patients (MRI scan 
must be performed if CT scan is contraindicated).  An MRI scan of the head is required to confirm or refute the diagnosis of CNS metastases at 
baseline in the event of an equivocal CT scan.  At subsequent (post-screening) tumor assessments, patients with a history of irradiation brain 
metastasis at screening are not required to undergo brain scan unless clinically indicated.  The same radiographic modality (e.g., CT scan with 
contrast) and procedures (e.g., the same contrast protocol for CT scans) used to assess disease sites at screening should be used for 
subsequent tumor assessments. Bone scans and CT scans of the neck should also be performed at baseline, if clinically indicated.
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At the investigator's discretion, other methods of
assessment of measurable disease as per RECIST v1.1 may be used.


Appendix 1: Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol WO41994, Version 3
y Patients will undergo tumor assessments at baseline, every 9 weeks (7 days) for the first 18 months following treatment initiation, and every 
12 weeks (7 days) thereafter, regardless of dose delays, until radiographic disease progression per RECIST v1.1 or (for patients who continue 
study treatment after radiographic disease progression) loss of clinical benefit as determined by the investigator (see Section 3.1 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.  Patients who discontinue treatment for reasons other than 
radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments at the
frequency described above until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first. All patients, regardless of arm, will also undergo a follow-up post-disease progression tumor assessment after 
investigator assessment of radiographic disease progression per RECIST v1.1.  When feasible, this subsequent scan will take place on the 
same schedule as prior to progression at 9 weeks (7 days) if disease progression occurred in the first 18 months, and at 12 weeks (7 days) if 
disease progression occurred after the first 18 months following treatment initiation.
z 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).
aa 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.
bb 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 the end of the special reporting period defined as 90 days 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 Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior exposure to study treatment (see Section 5.6).
cc 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.
dd Cabozantinib tablets will be given on Day 1 of Cycle 1 after atezolizumab infusion.  On Day 1 of Cycle 1, the patient will fast (with the exception 
of water) for at least 2 hours before receiving cabozantinib.  Upon completion of the 2-hours fast, the patient will receive the oral dose of 
cabozantinib with a minimum of 8 oz (240 mL) of water in the clinic and then the patient will continue to fast for 1 hour.  Patients will take tablets 
once daily at home thereafter until study treatment is discontinued.  Tablets should be taken at approximately the same time QD, preferentially 
before going to bed, and should adhere to the fasting requirements described in Section 4.3.2.2.


Appendix 1: Schedule of Activities (cont.)
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ee 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 (1 month) until death, loss to 
follow-up, or study termination by the Sponsor, whichever occurs first.  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 where allowed per local regulations.


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Appendix 2 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples
Visit
Timepoint
Sample Type in Each Arm
AtezolizumabCabozantinib
Cabozantinib
Screening
NA

Archival biopsy

Fresh biopsy

Archival biopsy

Fresh biopsy
Day 1 of 
Cycle 1
Prior to the first infusion 
Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (PBMC, plasma, 
serum, urine)

RBR (blood) a 

Biomarker (PBMC, 
plasma, serum, 
urine)

RBR (blood) a
30 (10) minutes after 
end of atezolizumab 
infusion

Atezolizumab PK (serum)

Day 1 of 
Cycle 2
Predose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Cabozantinib PK (plasma)

Biomarker (PBMC, plasma, 
serum, urine)

Biomarker (PBMC, 
plasma, serum, 
urine)

Cabozantinib PK 
(plasma)
Day 1 of 
Cycles 3 and 4
Predose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Cabozantinib PK (plasma)

Biomarker (PBMC, 
plasma, serum, urine)

Biomarker (PBMC, 
plasma, serum, 
urine)

Cabozantinib PK 
(plasma)
Day 1 of Cycles 
8, 12 and 16
Predose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

At timing of 
fresh biopsy 
(during 
treatment or at 
progression)
At visit

Biomarker (PBMC, plasma,
serum, urine) b

Biomarker (PBMC, 
plasma, serum, 
urine) b


Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
(cont.)
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Visit
Timepoint
Sample Type in Each Arm
AtezolizumabCabozantinib
Cabozantinib
Treatment 
discontinuation 
visit (30 days 
after final dose)
NA

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Cabozantinib PK (plasma)

Biomarker (PBMC, plasma,
serum, urine)

Biomarker (PBMC, 
plasma, serum, 
urine)

Cabozantinib PK 
(plasma)
ADAanti-drug antibody; PBMCperipheral blood mononuclear cell; NAnot applicable; 
PKpharmacokinetic; RBR Research Biosample Repository
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.
a Not applicable for a site that has not been granted approval for RBR sampling.  
Performed only for patients at participating sites who have provided written informed consent 
to participate.  The RBR blood sample can be accepted at Cycle 1, Day 1 and anytime 
thereafter, and should only be collected at one timepoint during the study.
b Blood and urine collections should be performed within 40 days after progression or prior to 
the next anti-cancer therapy, whichever is sooner.  If the progression visit is at the same time 
as the treatment discontinuation visit, only one set of biomarker samples needs to be 
collected.


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Appendix 3 Response Evaluation Criteria in Solid Tumors, 
(RECIST) Version 1.1
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST)
Version 1.1 (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.


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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


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed with use of 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
Computed tomography 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.  Magnetic resonance imaging is 
also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (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 


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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lesions on a different modality, since the same lesion may appear to have a different 
size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
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 2 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 


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF; e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
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 (CR) 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).


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph 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:

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

Disease progression:  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 disease progression


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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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-disease progression:  Persistence of one or more non-target lesions 
and/or (if applicable) maintenance of tumor marker level above the normal limits

Disease progression:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  
The designation of overall progression solely on the basis of change in non-target 
lesions in the face of SD or PR in target lesions will; therefore, be extremely rare.
Patients with Non-Measurable Disease Only
For patients with non-measurable disease only, the same general concepts apply as 
noted above. However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-measurable disease cannot be easily quantified (by definition, 
if all lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare disease progression for measurable 
disease, that is, an increase in tumor burden representing an additional 73% increase in 
volume (which is equivalent to a 20% increase in diameter in a measurable lesion).  
Examples include an increase in a pleural effusion from "trace" to "large" or an increase 
in lymphangitic disease from localized to widespread.  If unequivocal progression is seen, 
the patient should be considered to have had overall disease progression at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the 


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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very nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
When patients have non-measurable (therefore, non-target) disease only, Table 2 is to 
be used.


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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Table 1
Criteria for Overall Response at a Single Timepoint:  
Patients with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-DP
No
PR
CR
Not all evaluated
No
PR
PR
Non-DP or not all 
evaluated
No
PR
SD
Non-DP or not all 
evaluated
No
SD
Not all evaluated
Non-DP
No
NE
PD
Any
Yes or no
DP
Any
DP
Yes or no
DP
Any
Any
Yes
DP
CRcomplete response; DPdisease progression; NEnot evaluable; PRpartial response; 
SDstable disease.
Table 2
Criteria for Overall Response at a Single Timepoint:  
Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-DP
No
Non-CR/non-DP a
Not all evaluated
No
NE
Unequivocal DP
Yes or no
DP
Any
Yes
DP
CRcomplete response; DPdisease progression; NEnot evaluable.
a "Non-CR/non-DP" is preferred over "stable disease" for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning "stable disease" when no lesions can be measured is not advised.
MISSING ASSESSMENTS AND NOT EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of disease progression.  For example, if a patient had a baseline 


Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (cont.)
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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 disease 
progression 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 1 and Table 2.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.


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Appendix 4 Modified RECIST for Immune-Based Therapeutics 
(iRECIST) v1.1
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immunotherapy-specific response criteria adaptations to 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
(Eisenhauer et al. 2009) have been developed to allow for unconventional response and 
progression patterns.  These include modified RECIST for immune-based therapeutics 
(iRECIST; Seymour et al. 2017) v1.1, which was developed by the RECIST working 
group in an effort to create a common set of criteria that the cancer immunotherapy field
could apply to clinical trials.
Response evaluation through use of iRECIST requires collection of tumor assessment 
data after radiographic progression per RECIST v1.1.  Details regarding lesion 
evaluation are described below.  When not otherwise specified, RECIST v1.1 convention
will apply.
Criteria for determining overall response at a single timepoint per iRECIST are also 
summarized below.  Of note, overall response per iRECIST will not be captured in the 
eCRF but will instead be calculated programmatically by the Sponsor on the basis of 
investigator-assessed individual lesion data recorded in the eCRF.
Immune-modified RECIST response status is not a specific component of treatment 
discontinuation criteria, including decisions about whether to continue treatment beyond 
progression per RECIST v1.1.  Investigators should instead take into account radiologic 
data and clinical status in making such decisions, as described in Section 3.1.
EVALUATION OF LESIONS TO SUPPORT iRECIST RESPONSE 
ASSESSMENT AFTER DISEASE PROGRESSION PER RECIST v1.1
Immune-modified RECIST is an extension of RECIST v1.1 that allows for response 
assessment following disease progression per RECIST v1.1.  Response Evaluation 
Criteria in Solid Tumors v1.1 rules for categorizing lesions as measurable or 
non-measurable and measuring lesions (see Appendix 3) also apply to iRECIST.  
After disease progression per RECIST v1.1, the same target and non-target lesions 
selected at baseline will continue to be followed, along with any new lesions that develop, 
to support iRECIST response evaluations, as described below and summarized in 
Table 1.  Once a lesion has been categorized as a target, non-target, or new lesion, it 
will remain classified as such.


Appendix 4: Modified RECIST.1 for Immune-Based Therapeutics Version 1.1 (cont.)
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TARGET LESIONS
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions.
NON-TARGET LESIONS
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1.  At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (disease progression), or "present 
without unequivocal progression" (non-CR/non-disease progression), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were categorized as disease 
progression at the previous timepoint should be evaluated to determine whether there 
has been any further increase in size.
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST v1.1 
(e.g., nonlymph node lesions must be 10 mm on the longest diameter; new lymph 
nodes must be 15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints.
Up to a maximum of five measurable new lesions total (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint.  New lesions that are 
not measurable at first appearance but meet measurability criteria at a subsequent 
timepoint should be measured from that point on, if the maximum number of measurable 
new lesions has not been reached.  However, for calculation of the sum of diameters for 
new lesions, iRECIST excludes measurements from new lesions that were not 
measurable at first appearance.
All non-measurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions (in excess of five total or two per organ) should 
be assessed to determine whether there is any increase in size relative to the previous 
assessment timepoint.
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is 10 mm and 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 


Appendix 4: Modified RECIST.1 for Immune-Based Therapeutics Version 1.1 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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axis of a lymph node is 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is 15 mm.  Measurable new lymph node lesions 
should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to 15 mm (or even 10 mm).
Table 1
Guidelines for Evaluation of Lesions to Support iRECIST 
Response Assessment after Disease Progression per 
RECIST v1.1
Lesion Type
Evaluation of Lesions to Support iRECIST Response 
Assessment after Disease Progression per RECIST v1.1
Target lesions

Measurements should be continued according to RECIST v1.1 
conventions
Non-target lesions

Non-target lesions should continue to be categorized as absent 
(CR), unequivocal progression (disease progression), or 
present without unequivocal progression (non-CR/non-disease 
progression), as defined by RECIST v1.1.  In addition, any 
non-target lesions that were categorized as disease 
progression at the previous timepoint should be evaluated to 
determine whether there has been any further increase in size.
New lesions

New lesions should be evaluated for measurability per 
RECIST v1.1

All new lesions (measurable or non-measurable) must be 
assessed and recorded at the time of identification and at all 
subsequent tumor assessment timepoints

Up to a maximum of five measurable new lesions total (with a 
maximum of one lesion per organ) should be selected and 
measured at each timepoint

All non-measurable new lesions (including those that 
subsequently become measurable) and additional measurable 
new lesions (in excess of five total or two per organ) should be 
assessed to determine whether there is any increase in size 
relative to the previous assessment timepoint
CRcomplete response; iRECIST modified RECIST for immune-based therapeutics; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A SINGLE 
TIMEPOINT
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  
A complete description of the iRECIST criteria can be found in a publication by 
Seymour et al. (2017).


Appendix 4: Modified RECIST.1 for Immune-Based Therapeutics Version 1.1 (cont.)
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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.
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for
use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e14352.


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Appendix 5 European Organisation for Research and Treatment 
of Cancer Quality of Life–Core 30 Questionnaire
(EORTC QLQ-C30)
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 5: European Organisation for Research and Treatment of Cancer Quality
of Life–Core 30 Questionnaire (EORTC QLQ-C30) (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol WO41994, Version 3


Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol WO41994, Version 3
Appendix 6 EuroQol 5-Dimension, 5-Level Questionnaire
(EQ-5D-5L)
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.
English version for the USA


Appendix 6: EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol WO41994, Version 3
Under each heading, please check the ONE box that best describes 
your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g., work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed



Appendix 6: EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol WO41994, Version 3

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box below.
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95


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Appendix 7 Functional Assessment of Cancer Therapy-Kidney
Symptom Index 19
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.


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Appendix 8 Preexisting Autoimmune Diseases and Immune 
Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  
Contact the Medical Monitor regarding any uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory
demyelinating
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Good pasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 9 Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.


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Appendix 10 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.
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab in this study.
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.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
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171/Protocol WO41994, Version 3
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 1.
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1

Continue atezolizumab and monitor closely

Re-evaluate on serial imaging

Consider patient referral to pulmonary specialist
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c

For recurrent events, treat as a Grade 3 or 4 event
Pulmonary 
event,
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Bronchoscopy or BAL is recommended

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
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172/Protocol WO41994, Version 3
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.)
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-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.
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested 
by measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol WO41994, Version 3
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab

Monitor LFTs until values resolve to within normal limits or to baseline 
values
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset a

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury. 

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol WO41994, Version 3
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with 35 specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.
Table 3
Management Guidelines for Gastrointestinal Events
(Diarrhea or Colitis)
Event
Management
Diarrhea or colitis, 
Grade 1

Continue atezolizumab

Initiate symptomatic treatment

Endoscopy is recommended if symptoms persist for 7 days

Monitor closely
Diarrhea or colitis, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a

Initiate symptomatic treatment

Patient referral to GI specialist is recommended

For recurrent events or events that persist 5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c
Diarrhea or colitis, 
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to GI specialist for evaluation and confirmatory biopsy

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
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Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) (cont.)
Event
Management
Diarrhea or colitis, 
Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-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.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
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Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab

Initiate treatment with thyroid replacement hormone

Monitor TSH weekly
Symptomatic 
hypothyroidism

Withhold atezolizumab

Initiate treatment with thyroid replacement hormone

Monitor TSH weekly

Consider patient referral to endocrinologist

Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab

Monitor TSH every 4 weeks
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism
Symptomatic 
hyperthyroidism

Withhold atezolizumab

Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed

Consider patient referral to endocrinologist

Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving

Permanently discontinue atezolizumab and contact 
Medical Monitor for life-threatening immune-mediated
hyperthyroidism c
Symptomatic adrenal 
insufficiency, Grade 24

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to endocrinologist

Perform appropriate imaging

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact 
Medical Monitor c
Hyperglycemia,
Grade 1 or 2

Continue atezolizumab

Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as 
per institutional guidelines.

Monitor for glucose control


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol WO41994, Version 3
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
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
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to endocrinologist

Perform brain MRI (pituitary protocol)

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement

Initiate hormone replacement if clinically indicated

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c

For recurrent hypophysitis, treat as a Grade 4 event
Hypophysitis 
(pan-hypopituitarism), 
Grade 4

Permanently discontinue atezolizumab and contact 
Medical Monitor c

Refer patient to endocrinologist

Perform brain MRI (pituitary protocol)

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement

Initiate hormone replacement if clinically indicated
MRImagnetic resonance imaging.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol WO41994, Version 3
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1

Continue atezolizumab

Patient referral to ophthalmologist is strongly recommended

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy

If symptoms persist, treat as a Grade 2 event
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a

Patient referral to ophthalmologist is strongly recommended

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to ophthalmologist

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol WO41994, Version 3
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated 
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate

Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol WO41994, Version 3
Table 6
Management Guidelines for Immune-Mediated Myocarditis (cont.)
Event
Management
Immune-mediated 
myocarditis, Grade 34

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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.
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
Infusion-related reactions 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.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol WO41994, Version 3
Cytokine release syndrome 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).  Cytokine release syndrome
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 medical management of IRRs and CRS are provided in Table 7.
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 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome
Event
Management
Grade 1 a
Fever b with or without 
constitutional 
symptoms

Immediately interrupt infusion

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at rate to half the rate being given at the time of event onset

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate

If symptoms recur, discontinue infusion of this dose

Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration

In case of rapid decline or prolonged CRS (2 days) or in patients 
with significant symptoms and/or comorbidities, consider managing 
as per Grade 2

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol WO41994, Version 3
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)
Event
Management
Grade 2 a
Fever b with 
hypotension not 
requiring vasopressors
and/or
Hypoxia requiring low-
flow oxygen d by nasal 
cannula or blow-by

Immediately interrupt infusion

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset

If symptoms recur, discontinue infusion of this dose

Administer symptomatic treatment c

For hypotension, administer IV fluid bolus as needed

Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated and
manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours)

Consider anti-cytokine therapy e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact Medical Monitor.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol WO41994, Version 3
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)
Event
Management
Grade 3 a
Fever b with 
hypotension requiring 
a vasopressor (with
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d by 
nasal cannula, face 
mask, non-rebreather 
mask, or Venturi mask

Permanently discontinue atezolizumab and contact Medical Monitor f

Administer symptomatic treatment c

For hypotension, administer IV fluid bolus and vasopressor as 
needed

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated and manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours)

Consider anti-cytokine therapy e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension requiring 
multiple vasopressors
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., CPAP, 
Bi-PAP, intubation and 
mechanical ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor f

Administer symptomatic treatment c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours)

Consider anti-cytokine therapy. e For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered 
at the discretion of the investigator and in consultation with the 
Medical Monitor.

Hospitalize patient until complete resolution of symptoms


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol WO41994, Version 3
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine release syndrome; 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 CTCAENational 
Cancer Institute Common Terminology Criteria for Adverse Events.
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.  
Nation Cancer Institute Common Terminology Criteria for Adverse Events v5.0 should be used 
when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the 
Adverse Event eCRF.  Organ toxicities associated with CRS should not influence overall 
CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade
is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment 
may be administered as per institutional practice.
d Low-flow is defined as oxygen delivered at 6 L/min, and high-flow is defined as oxygen 
delivered at 6 L/min.
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  For subsequent infusions, administer oral premedication with antihistamines, 
anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication with 
corticosteroids and extending the infusion time may also be considered after consulting the 
Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol WO41994, Version 3
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:

Continue atezolizumab

Monitor amylase and lipase weekly

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone
Asymptomatic with amylase and/or lipase 2.05.0ULN:

Treat as a Grade 3 event
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to GI specialist

Monitor amylase and lipase every other day

If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor c


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol WO41994, Version 3
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to GI specialist

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact 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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month
GIgastrointestinal; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol WO41994, Version 3
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, with or without pruritus.  
A dermatologist should evaluate persistent and/or severe rash or pruritus.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.  
A biopsy should be considered unless contraindicated.  Management guidelines for 
dermatologic events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1

Continue atezolizumab

Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines)
Dermatologic 
event, Grade 2

Continue atezolizumab

Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy

Initiate treatment with topical corticosteroids

Consider treatment with higher-potency topical corticosteroids if event 
does not improve
Dermatologic 
event, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to dermatologist for evaluation and, if indicated, biopsy

Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monito. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor c
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis
(any grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy

Follow the applicable treatment and management guidelines above

If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol WO41994, Version 3
Table 9
Management Guidelines for Dermatologic Events (cont.)
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, 
Grade 1

Continue atezolizumab

Investigate etiology
Immune-mediated 
neuropathy, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a

Investigate etiology

Initiate treatment as per institutional guidelines

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c
Immune-mediated 
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor c 

Initiate treatment as per institutional guidelines
Myasthenia gravis 
and Guillain-Barré 
syndrome
(any grade)

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to neurologist

Initiate treatment as per institutional guidelines

Consider initiation of corticosteroids equivalent to 12 mg/kg/day oral or 
IV prednisone


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol WO41994, Version 3
Table 10 Management Guidelines for Neurologic Disorders (cont.)
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  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 11.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol WO41994, Version 3
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated 
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor a

Refer patient to neurologist

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol WO41994, Version 3
Table 12 Management Guidelines for Renal Events
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until values resolve 
to within normal limits or to baseline values
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to renal specialist

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor

Refer patient to renal specialist and consider renal biopsy

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-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.
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol WO41994, Version 3
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab

Refer patient to rheumatologist or neurologist

Initiate treatment as per institutional guidelines
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor

Refer patient to rheumatologist or neurologist

Initiate treatment as per institutional guidelines

Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement

If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol WO41994, Version 3
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor

Refer patient to rheumatologist or neurologist

Initiate treatment as per institutional guidelines

Respiratory support may be required in more severe cases

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, resume atezolizumab b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to rheumatologist or neurologist

Initiate treatment as per institutional guidelines

Respiratory support may be required in more severe cases

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol WO41994, Version 3
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 IL-2 receptor (soluble CD25) elevated 2 standard deviations above 
age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
195/Protocol WO41994, Version 3
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical Monitor

Consider patient referral to hematologist

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines

Consider initiation of IV corticosteroids an immunosuppressive agent, 
and/or anti-cytokine therapy

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019)

If event 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
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.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
196/Protocol WO41994, Version 3
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role 
for monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 11 Risks Associated with Cabozantinib and Guidelines 
for Management of Adverse Events Associated with 
Cabozantinib
This appendix provides guidelines for management of patients who experience 
cabozantinib-associated adverse events (e.g., GI disorders, hemorrhage, 
thromboembolic events, hypertension, osteonecrosis, proteinuria, hepatocellular toxicity, 
blood system disorders, QTc prolongation, electrolyte disorders, endocrine disorders, 
and respiratory disorders).
DOSE MODIFICATIONS
For information on dose modification, see Section 5.1.3.1.
TREATMENT INTERRUPTION
For information on treatment interruption, see Section 5.1.3.2.
MANAGEMENT GUIDELINES
The most frequent adverse events experienced by 20% of patients treated with 
cabozantinib in descending order of frequency were diarrhea, fatigue, nausea, 
decreased appetite, vomiting, weight decreased, palmar-plantar erythrodysesthesia 
(PPE), constipation, hypertension, dysgeusia, dysphonia, and asthenia. For a full 
description of the safety profile of cabozantinib, refer to the Cabozantinib 
Investigator Brochure.
Other medically important but less frequent adverse events include arterial thrombotic 
adverse events (e.g., transient ischemic attack [TIA], and myocardial infarction [MI]) and 
venous thrombotic adverse events (e.g., deep venous thrombosis [DVT] and pulmonary 
embolism [PE]), severe hemorrhagic events, proteinuria, wound healing complications, 
GI perforation, abscesses, including intra-abdominal and pelvic abscess, GI and non-GI 
fistula formation, osteonecrosis, and reversible posterior leukoencephalopathy syndrome 
(RPLS; preferred term: posterior reversible encephalopathy syndrome [PRES]).
Adverse events associated with laboratory test abnormalities that were experienced by 
5% of cabozantinib-treated patients in descending order of frequency were anemia, 
AST increased, ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, 
thrombocytopenia, hypocalcemia, hypophosphatemia, lactate dehydrogenase (LDH) 
increased, lipase increased, neutropenia, hyponatremia, ALP increased, leukopenia, 
and hyperglycemia.
Adverse events may occur within the first few weeks in the course of treatment with 
cabozantinib, as cabozantinib is expected to reach steady-state exposure at 
approximately 2 weeks following first dose. Events that generally have an early onset 
include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPE, abdominal 


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol WO41994, Version 3
pain, mucosal inflammation, constipation, diarrhea, and vomiting. Adverse events 
should be managed with supportive care at the earliest signs of toxicity.
Dose reductions and treatment interruptions should be considered. Dose reductions are 
recommended for events that, if persistent, could become serious or intolerable 
(see Section 5.1.3).
Cabozantinib should be discontinued for the following adverse events:
visceral perforation or fistula formation, severe hemorrhage, serious arterial 
thromboembolic events, nephrotic syndrome, hypertensive emergency, persistent 
uncontrolled hypertension despite optimal medical management, and RPLS.
GASTROINTESTINAL DISORDERS
Gastrointestinal (GI) perforation, GI fistula, and intra-abdominal and pelvic abscess: 
After starting treatment with cabozantinib, patients should be monitored for early signs of 
GI perforation such as abdominal pain, nausea, emesis, constipation, and fever 
especially if known risk factors for developing GI perforation or fistula 
(Turnage and Badgwell 2016) are present. Discontinue cabozantinib and initiate 
appropriate management in patients who have been diagnosed with GI perforation or 
fistula.
Diarrhea: Patients should be instructed to notify their physician immediately at the first 
signs of poorly formed or loose stool or an increased frequency of bowel movements. 
Guidelines for the evaluation and management of diarrhea are shown in Table 1. 
Administration of anti-diarrheal/anti-motility agents is recommended at the first sign of 
diarrhea as initial management. Some patients may require concomitant treatment with 
more than one anti-diarrheal agent. When therapy with anti-diarrheal agents does not 
control the diarrhea to tolerable levels, cabozantinib should be temporarily interrupted or 
dose reduced. When the diarrhea is controlled, re-treatment with cabozantinib may be 
acceptable per investigator decision. In addition, general supportive measures should 
be implemented such as continuous oral isotonic hydration, correction of fluid and 
electrolyte abnormalities, small frequent meals, and stopping lactose-containing 
products, high-fat meals, and alcohol.
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions 
which increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene 
should be emphasized. Regular examinations of the perianal region should be 
performed whenever diarrhea has occurred during treatment with cabozantinib. 
Infections of the perianal region should be treated per local guidelines.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
199/Protocol WO41994, Version 3
Table 1
Management of Diarrhea Associated with Cabozantinib
Status
Management
Tolerable Grade 12 
(duration48 hours)

Continue with study treatment and consider dose reduction

Initiate treatment with an anti-diarrheal agent (e.g., loperamide 
4 mg followed by 2 mg after each episode of diarrhea [maximum: 
16 mg loperamide per day])

Dietary modifications (e.g., small lactose-free meals, bananas 
and rice)

Intake of isotonic fluids (11.5 L/day)

Reassess after 24 hours:
−
Diarrhea resolving to baseline bowel habits: gradually add 
solid foods and discontinue or decrease anti-diarrheal 
treatment after 12 h diarrhea-free interval
−
Diarrhea not resolving: Continue/resume anti-diarrheal 
treatment
Intolerable Grade 2,
Grade 248 hours,
or Grade 3

Interrupt study treatment

Ask patient to attend clinic

Rule out infection (e.g., stool sample for culture)
−
Administer antibiotics as needed (e.g., if fever or Grade 34 
neutropenia persists 24 hours)

Administer fluids (11.5 L/day orally or IV, as appropriate) for 
hydration or to correct electrolyte abnormalities

For Grade 34 or complicated lower-grade diarrhea consider 
hospitalization and IV hydration

Reassess after 24 hours
−
Diarrhea resolving to baseline bowel habits or Grade1: 
consider restarting study treatment at reduced dose
−
Diarrhea not resolving:  Start and or continue anti-diarrheal 
treatment (e.g., loperamide 4 mg followed by 2 mg after each 
episode of diarrhea [maximum: 16 mg loperamide per day]). 
Consider starting second-line anti-diarrheal or referral to 
gastroenterologist.
Nausea and vomiting: Anti-emetic agents are recommended as clinically appropriate for 
treatment or prophylaxis of nausea and vomiting, along with supportive care. 
Dehydration and electrolyte abnormalities may be associated with vomiting and 
monitoring for, and correction of fluid and electrolyte disturbances should be 
implemented. Anti-emetic medications should be assessed for potential drug 
interactions (see Section 4.4 for further details).


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol WO41994, Version 3
NON-GASTROINTESTINAL FISTULA
Complications from radiation therapy especially of the thoracic cavity, including 
mediastinum, have been identified as a possible predisposing risk factor for non-GI 
fistula formation in patients undergoing treatment with VEGF pathway inhibitors.
Discontinue cabozantinib and initiate appropriate management in patients who have 
been diagnosed with a non-GI fistula.
HEMORRHAGE
Hemorrhagic events, including serious and sometimes fatal events, have been reported 
with cabozantinib. Patients should be monitored for bleeding events with serial complete 
blood counts and physical examination while in the study. The risk of hemorrhage in 
cabozantinib-treated patients with brain metastases has not been thoroughly analyzed. 
Patients enrolled with treated and stable brain metastases should be monitored with a 
high index of suspicion if symptoms that could be due to a CNS hemorrhage occur.
Cabozantinib should be discontinued in patients with serious and life-threatening 
bleeding events or recent hemoptysis (2.5 mL of red blood).
THROMBOEMBOLIC EVENTS 
Thromboembolic events are frequent in cancer patients due to procoagulant changes 
induced by the malignancy or anti-cancer therapy. Deep vein thrombosis and PE have 
been observed in clinical studies with cabozantinib, including fatal events. Patients who 
develop a PE and/or DVT should have study treatment interrupted until therapeutic 
anticoagulation is established. Treatment with cabozantinib may be resumed in patients 
with PE or DVT if it is determined that the event is uncomplicated and that the patient is 
deriving clinical benefit from cabozantinib treatment and that anticoagulation does not 
place them at a significant risk that outweighs the benefit of resuming treatment per the 
discretion of the investigator and according to individual protocols. Low-molecular 
weight heparin (LMWH) or anticoagulation with direct factor Xa oral inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed for the treatment of thromboembolic 
events if clinically indicated and the benefit outweighs the risk per the investigator’s 
discretion.
Note: Anticoagulation with the direct thrombin inhibitor dabigatran, or the direct factor 
Xa inhibitor betrixaban is not allowed. See Sections 4.4.1 and 4.4.6 for detailed 
information regarding the use of anticoagulants.
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with 
cabozantinib. Further treatment with cabozantinib should be discontinued in patients 


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol WO41994, Version 3
who develop an acute MI, cerebral infarction, or any other clinically significant arterial 
thromboembolic complication.
HYPERTENSION
Table 2 provides treatment guidelines for hypertension deemed related to cabozantinib. 
Blood pressure (BP) should be monitored in a constant position visit to visit, either sitting 
or supine in a relaxed setting. Decisions to reduce or interrupt the dose of study 
treatment must be based on BP readings taken by a medical professional and must be 
confirmed with a second measurement at least 5 minutes following the first 
measurement.
Cabozantinib should be discontinued in patients with hypertensive emergency.
Table 2
Management of Hypertension Associated with Cabozantinib
Criteria for Dose Modifications
Treatment/Cabozantinib Dose Modification
150 mm Hg (systolic) a
and 160 mm Hg
OR
100 mm Hg (diastolic)
and 110 mm Hg

Optimize antihypertensive medications by adding 
new or additional antihypertensive medications 
and/or increase dose of existing medications

Reduce cabozantinib treatment by one dose level 
if optimal antihypertensive therapy (usually to 
include 3 agents) does not result in 
BP150 mm Hg systolic and 100 mm Hg 
diastolic

If patient is symptomatic interrupt cabozantinib 
treatment
160 mm Hg (systolic)
OR
110 mm Hg (diastolic)

Reduce cabozantinib by one dose level or 
interrupt cabozantinib treatment per investigator 
discretion

Add new or additional antihypertensive 
medications and/or increase dose of existing 
medications and monitor patient closely for 
hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not 
result in BP 150 mm Hg systolic and 
100 mm Hg diastolic, cabozantinib treatment 
should be dose reduced further or interrupted.

Cabozantinib treatment should be dose 
interrupted if upper limits of systolic BP 
(160 mmHg) are sustained and not adequately 
manageable or if systolic BP is 180 mmHg or 
sustained diastolic BP110 mm Hg, or if patient 
is symptomatic

Restart cabozantinib treatment at the most 
tolerable dose and re-escalate only if BP falls to 


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol WO41994, Version 3
Criteria for Dose Modifications
Treatment/Cabozantinib Dose Modification
and is sustained at 150 mm Hg systolic and 
100 mm Hg diastolic


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol WO41994, Version 3
Table 2
Management of Hypertension Associated with Cabozantinib
(cont.)
Criteria for Dose Modifications
Treatment/Cabozantinib Dose Modification
Hypertensive emergency b

Discontinue cabozantinib treatment
BP blood pressure.
a The Investigator may decide to initiate or adjust antihypertensive treatment at a lower 
threshold than systolic BP150 mmHg or diastolic BP 100 mmHg based on their clinical 
judgment and assessment of the individual patient.
b Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of 
progressive or impending end-organ damage (e.g., myocardial infarction/ischemia, intracranial 
hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, kidney damage).
STOMATITIS AND MUCOSITIS
Preventive measures may include a comprehensive oral examination to identify and 
treat any potential risk for complications before study treatment is initiated. Appropriate 
correction of local factors should be instituted as indicated, such as modification of 
ill-fitting dentures and appropriate care of gingivitis. During treatment with cabozantinib, 
good oral hygiene and standard local treatments such as non-traumatic and 
non-irritating cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained. Lips should be kept moisturized with lip balm. The use of 
lipstick, lip-gloss, and Vaseline should be avoided.
Local treatment should be instituted at the earliest onset of symptoms. 
Obtain bacterial/viral culture if oral infection is suspected and treat infection as clinically 
indicated.
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Wound healing and surgery: Cabozantinib has the potential to cause wound healing 
complications and wound dehiscence, which may even occur long after a wound has 
been considered healed. Therefore, surgical and traumatic wounds must not only be 
completely healed prior to starting cabozantinib treatment but must also be monitored for 
wound dehiscence, wound infection and other signs of impaired wound healing while the 
patient is being treated with cabozantinib. If dehiscence occurs, cabozantinib treatment 
should not be restarted until complete healing has taken place.
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled 
surgery. The decision to resume treatment with cabozantinib after surgery should be 
based on clinical judgment of adequate wound healing.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol WO41994, Version 3
Palmar-plantar erythrodysesthesia (PPE; also known as hand-foot syndrome):  Skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have 
been reported with cabozantinib. All patients in the study should be advised on 
prophylactic measures, including the use of emollients, removal of calluses, avoidance 
of exposure of hands and feet to hot water leading to vasodilatation, protection of 
pressure-sensitive areas of hands and feet, and use of cotton gloves and socks to 
prevent injury and keep the palms and soles dry.
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical 
red and swollen areas on the palms and soles. The lateral sides of the fingers or 
periungual zones may also be affected. Adequate interventions are required to prevent 
worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of 
affected areas. Analgesics may be required for pain control.
Aggressive management of symptoms is recommended, including early dermatology 
referral. Treatment recommendations in response to PPE are summarized in Table 3.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol WO41994, Version 3
Table 3
Management of Hand-Foot Syndrome Associated with 
Cabozantinib
NCI CTCAE v5 Grade
Action To Be Taken
Grade 1
Cabozantinib treatment may be continued at the current dose if PPE 
is clinically insignificant and tolerable.  Otherwise, cabozantinib 
should be reduced to the next lower dose level. a  Start urea 20% 
cream twice daily AND clobetasol 0.05% cream once daily.  
Reassess at least weekly; if PPE worsens at any time or does not 
improve after 2 weeks, proceed to the intervention guidelines for 
Grade 2.
Grade 2
Cabozantinib treatment may be continued if PPE is tolerated.  
Cabozantinib should be dose reduced or interrupted if PPE is 
intolerable.  Continue urea 20% cream twice daily AND high potency 
steroid cream (e.g., clobetasol 0.05%) once daily and add analgesics 
(e.g., NSAIDs/gamma-aminobutyric acid agonists) for pain control if 
needed.  Reassess at least weekly; if PPE worsens or affects 
self-care, proceed to the intervention guidelines for Grade 3.
Grade 3
Interrupt cabozantinib treatment until severity decreases to Grade 1 
or 0.  Continue treatment of skin reaction with high potency steroid 
cream (e.g., clobetasol 0.05%) twice daily AND analgesics.  
Resume cabozantinib at a reduced dose if PPE recovers to Grade1.  
Discontinue the patient from study treatment if PPE does not improve 
within 6 weeks.
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAIDnonsteroidal anti-inflammatory drug; PPEpalmar-plantar erythrodysesthesia.
a Permitted dose levels are defined by individual protocols.


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OSTEONECROSIS
Osteonecrosis has been reported in patients treated with cabozantinib. Additional risk 
factors include use of bisphosphonates and denosumab, chemotherapy and 
anti-angiogenic drugs, use of corticosteroids, local radiotherapy, and dental or orofacial 
surgery procedures.
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone 
erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. 
Persistent pain or slow healing of the mouth or jaw after dental surgery may also be 
manifestations of osteonecrosis.
Advise patients regarding oral hygiene practice and to quickly report symptoms to the 
investigator. Caution should be used in patients receiving bisphosphonates.
Invasive dental procedures should be avoided. In cases where dental procedures are 
unavoidable, treatment with cabozantinib should be interrupted for at least 4 weeks prior 
to the procedure and resumed after complete wound healing has occurred.
Bone healing may often require a protracted time.
PROTEINURIA
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by 
measuring urine protein-to-creatinine ratio (UPCR). Table 4 provides treatment 
guidelines for proteinuria deemed related to cabozantinib.
Cabozantinib should be discontinued in patients who develop nephrotic syndrome 
(proteinuria 3.5 grams per day in combination with low blood protein levels, high 
cholesterol levels, high triglyceride levels, and edema).


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
207/Protocol WO41994, Version 3
Table 4
Management of Proteinuria Associated with Cabozantinib
Severity of Proteinuria 
(UPCR)
Management of Proteinuria
1 mg/mg
(113.1 mg/mmol)

No change in cabozantinib treatment or monitoring
1 and 3.5 mg/mg
(113.1 and 395.9 mg/mmol)

Consider confirming with a 24-hour protein assessment 
within 7 days

No change in cabozantinib treatment required if 
UPCR2 mg/mg or urine protein2 g/24 hours on 24-hour
urine collection

Reduce dose or interrupt cabozantinib treatment if 
UPCR2 mg/mg on repeat UPCR testing or urine 
protein2 g/24 hours on 24-hour urine collection.  
Continue cabozantinib on a reduced dose if UPCR 
decreases to 2 mg/mg.  Consider interrupting 
cabozantinib treatment if UPCR remains 2 mg/mg despite 
a dose reduction until UPCR decreases to 2 mg/mg.  
Restart cabozantinib treatment at a reduced dose after a 
dose interruption unless otherwise approved by the 
Sponsor.

If UPCR 2 mg/mg, repeat UPCR monitoring within 7 days 
and once per week.  If UPCR 2 mg/mg on two
consecutive readings, UPCR monitoring can revert to 
protocol-specific times.
(Second reading is confirmatory and can be done within 
1 week of first reading).
3.5 mg/mg
(395.9 mg/mmol)

Interrupt cabozantinib treatment pending repeat UPCR 
monitoring within 7 days and/or 24-hour urine protein

If 3.5 mg/mg on repeat UPCR monitoring, continue to 
interrupt cabozantinib treatment and check UPCR every 
7 days.  If UPCR decreases to 2 mg/mg, restart 
cabozantinib treatment at a reduced dose and monitoring 
of UPCR until it remains 2 mg/mg on two consecutive 
measurements. If UPCR monitoring is determined to be 
stable (20% change) for 1 month, then continue with 
UPCR monitoring per protocol or as clinically indicated.
Nephrotic syndrome

Discontinue cabozantinib treatment
UPCRurine protein-to-creatinine ratio.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol WO41994, Version 3
NERVOUS SYSTEM DISORDERS
Cabozantinib appears to represent minimal risk of adverse neurological effects based on 
nonclinical Good Laboratory Practice (GLP)-compliant toxicology studies. 
Dysphonia, dysgeusia, headache, dizziness, confusional state, convulsion, depression, 
memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and 
encephalopathy have been observed in clinical studies with cabozantinib. 
The development of any new or progressive, unexplained neurological symptoms should 
be assessed for underlying causes.
RPLS has been reported. RPLS should be considered in any patient presenting with 
seizures, headache, visual disturbances, confusion or altered mental function. 
Cabozantinib treatment should be discontinued in patients with RPLS.
HEPATOCELLULAR TOXICITY
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib. It is recommended that patients with elevation of ALT, AST, 
and/or bilirubin have more frequent laboratory monitoring of these parameters.
If possible, hepatotoxic concomitant medications should be discontinued in patients who 
develop increased values of ALT, AST, or bilirubin and other causes 
(e.g., cancer-related, or infection) should be evaluated.
Management guidelines for hepatotoxicity related to cabozantinib treatment are provided 
in Table 5.


Atezolizumab—F. Hoffmann-La Roche Ltd
209/Protocol WO41994, Version 3
Table 5
Management of Hepatotoxicity Associated with Cabozantinib
Severity of Transaminase (ALT or AST) 
Elevations by NCI CTCAE
Treatment/Cabozantinib Dose Modification
Grade 1

Dose adjustment is usually not required

Consider discontinuing concomitant 
hepatotoxic medications and adding 
supportive care as indicated
Grade 2

Interrupt cabozantinib

Restart cabozantinib, at the same dose or a 
reduced dose at investigator discretion, after 
laboratory abnormalities have resolved to no 
higher than NCI CTCAE Grade1 or baseline 
grade
Grade3

Interrupt cabozantinib and consider more 
frequent monitoring of ALT and/or AST

Restart cabozantinib at a reduced dose after 
laboratory abnormalities have resolved to 
NCI CTCAE Grade1 or baseline grade

Discontinue if laboratory abnormalities cannot 
be reversed despite interruption of 
cabozantinib
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
The following conditions require discontinuation of cabozantinib unless these laboratory 
abnormalities have recovered to Grade 1 or baseline grade after an interruption and the 
Sponsor has approved reinstitution of cabozantinib:

Drug-related ALT or AST 8upper limit of normal (ULN)

Drug-related ALT or AST 3ULN in combination with total bilirubin 2ULN 
without reasonable other explanation, consistent with drug-induced liver injury
INFECTIONS AND INFESTATIONS
Infections are commonly observed in patients with cancer. Predisposing risk factors 
include decreased immune status (e.g., after myelosuppressive anti-cancer therapies, 
splenectomy), destructive growth of the underlying malignancy, including bone marrow 
infiltration with suppression of normal hematopoiesis, as well as the presence of IV
devices.
Infections and abscesses should be treated with appropriate local care and systemic 
therapy. Cabozantinib should be interrupted until adequate healing has taken place.
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated 
complications have been observed after administration of cabozantinib and may be 


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
210/Protocol WO41994, Version 3
managed with dose interruptions and/or dose reductions. Patients with hematologic 
toxicities may require additional or more frequent laboratory tests according to 
institutional guidelines.
Dose reductions or dose interruptions for hematological toxicities are not mandated but 
can be applied as clinically indicated. However, for patients with thrombocytopenia dose 
modifications should be followed in accordance with Table 9 in Section 5.1.3.1.  
Supportive care for thrombocytopenia or anemia, such as transfusions, may be 
managed according to institutional guidelines. The use of colony-stimulating growth 
factors should be considered. Febrile neutropenia or evidence of infection associated 
with neutropenia must be assessed immediately and treated appropriately and in a 
timely manner according to institutional guidelines.
FATIGUE
Common causes of fatigue, such as anemia, deconditioning, emotional distress 
(depression and/or anxiety), poor nutrition, dehydration, sleep disturbance, and 
hypothyroidism should be ruled out and treated according to standard of care. 
Pharmacological management should be considered after disease-specific morbidities 
have been excluded when not prohibited.
WEIGHT LOSS
Anorexia and weight loss should be managed according to local standard of care,
including nutritional support. Pharmacologic therapy should be considered for appetite 
enhancement when not prohibited by a particular protocol.
CORRECTED QT PROLONGATION
The effect of orally administered cabozantinib 140 mg once a day (QD) on corrected 
QT interval (QTc) was evaluated in a placebo-controlled study in patients with medullary 
thyroid cancer. A mean increase in QT interval corrected with use of Fridericia’s formula 
(QTcF) of 1015 ms was observed after 4 weeks after initiating cabozantinib treatment. 
A concentration-QTc relationship could not be definitively established. Changes in 
cardiac wave form morphology or new rhythms were not observed. No
cabozantinib-treated patients in this study had a QTcF 480 ms. Review of the larger 
safety database (approximately 5000 patients exposed to cabozantinib in clinical trials 
and in post-marketing experience) confirmed the absence of safety concerns associated 
with QT prolongation. There were no events of torsades de pointes reported.
Concomitant treatment with strong CYP450 3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
211/Protocol WO41994, Version 3
If at any time in the study there is an increase in QTcF to an absolute value 480 ms or 
an increase of 60 ms above baseline per the site’s ECG read, 2 additional ECGs must 
be performed with intervals not less than 3 minutes apart within 30 minutes after the 
initial ECG.
If the average QTcF from the 3 ECGs is 480 ms or the average increase is 60 ms 
above baseline, the following actions must be taken:

Interrupt cabozantinib treatment

Immediately notify the Sponsor

Hospitalize symptomatic patients (e.g., with palpitations, dizziness, syncope, 
orthostatic hypotension), or those with a significant ventricular arrhythmia on ECG for 
a thorough cardiology evaluation and management

Consider cardiology consultation for asymptomatic patients for evaluation and 
management

Check electrolytes, especially magnesium, potassium and calcium; correct 
abnormalities as clinically indicated

Check concomitant medications for any medication that may have contributed to 
QT prolongation, and if possible, discontinue these medications 
(https://www.qtdrugs.org)

Repeat ECG triplicates hourly until the average QTcF is 480 ms and the average 
increase is 60 ms above baseline, or a consulting cardiologist or appropriate expert 
determines that the frequency of ECGs may revert to the schedule in the protocol
Patients with QTc prolongation and symptoms must be monitored closely until the 
QTc elevation and symptoms have resolved. Cabozantinib treatment may be restarted 
but only at a reduced dose level if all of the following conditions are met:

Symptoms are determined to be unrelated to the QT interval prolongation

The QTcF value 480 ms or increase of 60 ms above baseline is not confirmed by 
local cardiologist

Cabozantinib treatment has been interrupted through a minimum of 1 week following 
the return of the QTcF to 480 ms or increase of 60 ms above baseline

QT prolongation can be unequivocally associated with an event other than
cabozantinib administration and is treatable/has been resolved

Sponsor has reviewed all available information and has agreed to the continuation of 
study treatment
Following re-initiation of study treatment, ECGs must be repeated weekly for 2 weeks, 
then every 2 weeks for 1 month, then according to the protocol-defined timepoints.


Appendix 11: Risks Associated with Cabozantinib and Guidelines for Management 
of Adverse Events Associated with Cabozantinib (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
212/Protocol WO41994, Version 3
Cabozantinib treatment must be permanently discontinued if either of the following 
applies:

Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation

Recurrence of QTcF prolongation after re-initiation of study treatment is at a reduced 
dose
ELECTROLYTE DISORDERS
Serum electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, 
and hypophosphatemia has been reported during treatment with cabozantinib. 
There are many causes for an electrolyte imbalance, including loss of body fluids 
(e.g., from prolonged vomiting or diarrhea), inadequate diet, kidney disease, and use of 
certain concomitant medications (e.g., diuretics). Electrolyte imbalance may create a 
variety of symptoms (e.g., weakness, fatigue, confusion, muscle spasm, constipation, 
and irregular heartbeat). Serum electrolyte levels should be monitored closely while 
receiving cabozantinib. Clinically relevant electrolyte disorders should be managed 
according to the dose modification guidelines (see Section 5.1.3.1, Table 9) and may 
include oral or IV replacement.
ENDOCRINE DISORDERS
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed 
with cabozantinib treatment. Currently available data are insufficient to determine the 
mechanism of thyroid function test alterations and its clinical relevance. Management of 
thyroid dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical 
practice guidelines.
RESPIRATORY DISORDERS
Dyspnea has been reported in clinical studies with cabozantinib.  Symptoms should be 
managed according to locally accepted clinical practice, including an assessment for 
underlying causes.  Pulmonary embolism should be considered as possible causes for 
new onset dyspnea given the risk of thrombosis associated with inhibition of VEGF 
signaling.  Furthermore, fistula formation and pneumonia have been reported in subjects 
treated with cabozantinib and should be considered as clinically indicated in subjects 
presenting with pulmonary symptoms.


Atezolizumab—F. Hoffmann-La Roche Ltd
213/Protocol WO41994, Version 3
Appendix 12 International Metastatic Renal Cell Carcinoma
Database Consortium Risk Factors
Prognostic factors:

Less than 1 year from time of diagnosis to systemic therapy

Karnofsky Performance Status 80%

Hemoglobinlower limit of normal (ULN; normal: 120 g/L or 12 g/dL)

Corrected calciumupper limit of normal (normal: 8.510.2 mg/dL)

NeutrophilsULN (normal: 2.07.0109/L)

PlateletsULN (normal: 150,000400,000)
Risk groups:

Favorable Risk: If patient has 0 factors

Intermediate Risk: If patient has 12 factor(s)

Poor Risk: If patient has 36 factors
Suggested corrected calcium formula:
Corrected calcium[0.8(normal albumin patient's albumin)] serum calcium


Atezolizumab—F. Hoffmann-La Roche Ltd
214/Protocol WO41994, Version 3
Appendix 13 Definition of Sarcomatoid Renal Cell Carcinoma: 
Stanford Surgical Pathology Criteria
SARCOMATOID RENAL CELL CARCINOMA
Definition
Renal cell carcinoma (RCC) of any type exhibiting at least focal sarcomatoid/spindle cell 
differentiation.
Diagnostic Criteria

Represents a form of high-grade transformation, not a distinct subtype of RCC

May occur in any of the standard subtypes of RCC

Reported to occur in 58% of RCCs
Less common in our experience.

Should not be reported as the subtype of RCC
Requires Evidence of Epithelial Differentiation

Concurrent areas of RCC of any type, OR

Immunohistochemical positivity for keratin or EMA
(Keratin and EMA expression may be appropriate for some sarcomas, 
including leiomyosarcomas).
Requires a Spindle Cell Component Measuring at Least 
1 Low-Power (40) Field

May be discrete or intermixed with epithelial elements

May be very focal
Most Common Patterns are Fibrosarcoma and Malignant Fibrous 
Histiocytoma

Rare cases reported with patterns of rhabdomyosarcoma, chondrosarcoma,
osteosarcoma, and hemangiopericytoma

Pattern does not appear to affect prognosis
Grade of Sarcoma is Not Clinically Significant

May range from low to high
Based on cellularity, atypia, mitotic figures.


Appendix 13: Definition of Sarcomatoid Renal Cell Carcinoma:  Stanford Surgical Pathology 
Criteria
Atezolizumab—F. Hoffmann-La Roche Ltd
215/Protocol WO41994, Version 3
REFERENCES
Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an
examination of underlying histologic subtype and an analysis of associations with 
patient outcome. Am J Surg Pathol 2004;28:43541.
Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urology
Pathology (ISUP) grading system for renal cell carcinoma and other prognostic
parameters. Am J Surg Pathol 2013;37:1490504.
Stanford Medicine. Surgical Pathology Criteria [resource on the Internet]. 2011 
[cited: 24 February 2020]. Available from: 
https://surgpathcriteria.stanford.edu/kidney/sarcomatoid-renal-cell-carcinoma/.

SAP_001.pdf: 
 
Official Title: 
 
A Phase III, Multicenter, Randomized, Open-Label Study 
to Evaluate the Efficacy and Safety of Atezolizumab 
Given in Combination With Cabozantinib Versus Cabozantinib 
Alone in Patients With Inoperable, Locally Advanced, or 
Metastatic Renal Cell Carcinoma who Experienced 
Radiographic Tumor Progression During or After Immune  
Checkpoint Inhibitor Treatment 
NCT Number: NCT04338269 
Document Date: SAP Amendment Version 2: 02-Sep-2022 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
 
This is F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WO41994 
 
 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
GIVEN IN COMBINATION WITH CABOZANTINIB 
VERSUS CABOZANTINIB ALONE IN PATIENTS 
WITH INOPERABLE, LOCALLY ADVANCED, OR 
METASTATIC RENAL CELL CARCINOMA WHO 
EXPERIENCED RADIOGRAPHIC TUMOR 
PROGRESSION DURING OR AFTER IMMUNE 
CHECKPOINT INHIBITOR TREATMENT 
STUDY NUMBER: 
WO41994 
VERSION NUMBER: 
2 
ROCHE COMPOUND(S): 
Atezolizumab (RO5541267) 
EUDRACT NUMBER: 
2020-000502-29160 
IND NUMBER: 
119,039 
NCT NUMBER: 
NCT04338269 
PLAN PREPARED BY: 
, M.S. 


Atezolumab — F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan WO41994                                                                                        
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document Version 2, 26 October 2020. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
2 
see electronic date stamp 
on title page 
Version 4, 14 February 2022 
1 
28 March 2022 
Version 4, 14 February 2022 
2 


Atezolumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WO41994 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
Key changes to the SAP, along with the rationale(s) for each change, are summarized 
below. 
Section 
Description of Change 
Rationale for Change 
5.3.3.1 
Updated criteria for conducting the 
sensitivity analyses for PFS: 
removed the pre-specified criteria 
of >5% of patients in either 
treatment arm who missed two or 
more tumor assessments scheduled 
immediately prior to the date of 
disease progression or death in any 
treatment arm 
Based on FDA feedback of 
SAP version 1, received on 
11 August 2022 
Additional minor changes have been made throughout to improve clarity and 
consistency.
3 


Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WO41994 
4 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1.
INTRODUCTION ............................................................................. 9
1.1 
Objectives and Endpoints .......................................................... 9 
1.2 
Study Design ........................................................................... 11 
1.2.1 
Treatment Assignment and Blinding ........................................ 13 
1.2.2 
Independent Review Facility .................................................... 13 
1.2.3 
Data Monitoring ....................................................................... 14 
2.
STATISTICAL HYPOTHESES ...................................................... 14 
3.
SAMPLE SIZE DETERMINATION ................................................ 14 
3.1 
Type I Error Control ................................................................. 15 
3.2 
Primary Endpoint:  IRF-PFS per RECIST v1.1 in the ITT 
Population ................................................................................ 16 
3.3 
Primary Endpoint: OS in the ITT Population ............................ 16 
3.4 
Sample Size ............................................................................. 17 
4.
ANALYSIS SETS .......................................................................... 17 
5.
STATISTICAL ANALYSES ........................................................... 17 
5.1 
General Considerations ........................................................... 17 
5.2 
Patient Disposition ................................................................... 18 
5.3 
Primary Endpoint Analyses ...................................................... 18 
5.3.1 
Definition of Primary Endpoints ................................................ 18 
5.3.2 
Main Analytical Approach for Primary Endpoints ..................... 18 
5.3.3 
Sensitivity Analyses for Primary Endpoints .............................. 19 
5.3.3.1 
Analysis of IRF-PFS Accounting for Missing Tumor 
Assessments ........................................................................... 19 
5.3.3.2 
Analysis of OS Accounting for Loss to Follow-up .................... 19 
5.3.3.3 
Analysis of IRF-PFS and OS Accounting for Non-Protocol 
Anti-Cancer Therapy ................................................................ 20 
5.3.3.4 
Analysis of IRF-PFS and OS Accounting for Discrepancy 
of Stratification Factors Between IxRS and eCRF ................... 20 
5.3.4 
Supplementary Analyses for Primary Endpoints ...................... 20 
5.3.4.1 
Subgroup Analyses for Primary Endpoints .............................. 20 


Atezolizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WO41994 
5 
5.4 
Secondary Endpoint Analyses ................................................. 20 
5.4.1 
IRF-assessed Objective Response Rate ................................. 20 
5.4.2 
IRF-assessed Duration of Response ....................................... 21 
5.4.3 
Investigator-assessed PFS, ORR, and DOR ........................... 21 
5.5 
Exploratory Endpoint Analyses ................................................ 21 
5.5.1 
PFS and OS Rates at Selected Time Points............................ 21 
5.5.2 
Time to Response .................................................................... 22 
5.5.3 
Patient Reported Outcome ...................................................... 22 
5.5.3.1 
Time to Confirmed Deterioration in Disease-Related 
Symptoms ................................................................................ 22 
5.5.3.2 
Time to Confirmed Deterioration in Physical Functioning ........ 22 
5.5.3.3 
Time to Confirmed Deterioration in Global Health 
Status/Quality of Life ................................................................ 22 
5.5.3.4 
Patient-Reported Outcome Descriptive Summaries ................ 23 
5.5.3.5 
Patient-Reported Outcome Side-Effect Burden ....................... 23 
5.5.3.6 
Health Status Utility Analyses .................................................. 23 
5.6 
Safety Analyses ....................................................................... 24 
5.6.1 
Extent of Exposure .................................................................. 24 
5.6.2 
Adverse Events ........................................................................ 24 
5.6.3 
Laboratory Data ....................................................................... 25 
5.6.4 
Vital Signs ................................................................................ 25 
5.6.5 
ECGs ....................................................................................... 25 
5.7 
Other Analyses ........................................................................ 25 
5.7.1 
Summaries of Conduct of Study .............................................. 25 
5.7.2 
Summaries of Treatment Group Comparability ........................ 25 
5.7.3 
Pharmacokinetic Analyses ....................................................... 25 
5.7.4 
Immunogenicity Analyses ........................................................ 26 
5.7.5 
Biomarker Analyses ................................................................. 26 
5.7.6 
Analyses of Subgroups of Interest ........................................... 27 
5.8 
Interim Analyses ...................................................................... 27 
5.8.1 
Planned Interim Analyses ........................................................ 27 
6.
SUPPORTING DOCUMENTATION .............................................. 28 
7.
REFERENCES.............................................................................. 28


 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ..................................... 9 
Table 2 
Analysis Sets .............................................................................. 17 
Table 3 
Analysis Timing and Stopping Boundaries for Overall 
Survival Interim and Final Analyses ............................................ 27 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 12 
Figure 2 
Progression Free Survival and Overall Survival Analysis 
α-Allocation and α-Recycling ...................................................... 15 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
anti-drug antibody 
AE 
adverse event 
CI 
confidence interval 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
DRS-P  Disease-Related Symptom-Physical 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form  
EORTC 
European Organization for Research and Treatment of Cancer 
FKSI-19 
Functional Assessment of Cancer Therapy−Kidney Symptom 
Index 19 
GHS 
global health status 
HR 
hazard ratio 
ICI 
immune checkpoint inhibitor 
iDMC 
independent Data Monitoring Committee 
IMDC 
International Metastatic Renal Cell Carcinoma Database Consortium 
IRF 
Independent Review Facility 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice/web-based response system 
KPS 
Karnofsky Performance Status 
MDD 
minimally detectable difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute  
NPT 
non‑protocol anti‑cancer therapy 
OBF 
O’Brien-Fleming 
ORR 
objective response rate 
OS 
overall survival 
PD-L1 
programmed death-ligand 1 
PF 
physical functioning 
PFS 
progression-free survival 
PK 
pharmacokinetic 


 
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Abbreviation or Term 
Description 
PR 
partial response 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
QLQ-C30 
Quality-of-Life Questionnaire Core 30 
QD 
once a day 
QoL 
Quality of Life 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
VEGFR-TKI 
vascular endothelial growth factor receptor-tyrosine kinase inhibitor  
 
 


 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study WO41994, a Phase III, multicenter, randomized, open-label 
study of atezolizumab given in combination with cabozantinib versus cabozantinib alone 
in patients with inoperable, locally advanced, or metastatic renal cell carcinoma (RCC) 
who experienced radiographic tumor progression during or after immune checkpoint 
inhibitor (ICI) treatment in the adjuvant and/or locally advanced/metastatic setting.  
Detailed background information on the study can be found in the study protocol. 
1.1 
OBJECTIVES AND ENDPOINTS  
Study WO41994 evaluates the efficacy and safety of atezolizumab in combination with 
cabozanitinib (herein referred to as Atezo+Cabo) compared with cabozanitinib alone 
(herein referred to as Cabo) in RCC patients with an immediate preceding treatment of 
ICI in the adjuvant and/or locally advanced/metastatic setting.  Specific objectives and 
corresponding endpoints for the study are outlined in Table 1.   
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoints 
• 
To evaluate the efficacy of 
atezolizumab in combination 
with cabozantinib compared 
with cabozantinib alone  
• 
Progression-free survival (PFS) assessed 
by an Independent Review Facility (IRF), 
defined as the time from randomization to 
the first occurrence of disease progression, 
as assessed by an IRF according to 
Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) or death 
from any cause, whichever occurs first  
• 
Overall survival (OS), defined as the time 
from randomization to death from any cause  
Secondary Efficacy Objective 
Corresponding Endpoints 
• 
To evaluate the efficacy of 
atezolizumab in combination 
with cabozantinib compared 
with cabozantinib alone 
• 
PFS assessed by the investigators, defined 
as the time from randomization to the first 
occurrence of disease progression, as 
assessed by the investigators according to 
RECIST v1.1 or death from any cause, 
whichever occurs first  
• 
Investigator- and IRF-assessed objective 
response rate (ORR), defined as the 
proportion of patients with a complete 
response or partial response on two 
consecutive occasions at least 4 weeks 
apart according to RECIST v1.1  


 
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• 
Investigator- and IRF-assessed duration of 
response, defined as the time from the first 
occurrence of a documented, confirmed 
objective response to disease progression 
according to RECIST v1.1, or death from 
any cause, whichever occurs first   
Safety Objective 
Corresponding Endpoints 
• 
To evaluate the safety of 
atezolizumab in combination 
with cabozantinib compared 
with cabozantinib 
• 
Incidence and severity of adverse events, 
with severity determined according to 
National Cancer Institute Common 
Terminology Criteria for Adverse Events, 
Version 5.0 
• 
Change from baseline in targeted vital signs 
• 
Change from baseline in targeted clinical 
laboratory test results 
Pharmacokinetic Objective 
Corresponding Endpoints 
• 
To characterize the 
pharmacokinetic (PK) profile of 
atezolizumab and cabozantinib  
• 
Serum concentrations of atezolizumab at 
specified timepoints 
• 
Plasma concentrations of cabozantinib at 
specified timepoints 
Immunogenicity  Objective 
Corresponding Endpoints 
• 
To evaluate the immune 
response to atezolizumab 
• 
Prevalence of anti-drug antibodies (ADAs) 
to atezolizumab at baseline and incidence of 
ADAs to atezolizumab during the study 
• 
Relationship between ADA status and 
demographics, efficacy, safety, or 
PK endpoints 
Exploratory Objectives 
Corresponding Endpoints 
To evaluate the efficacy of 
atezolizumab in combination 
with cabozantinib compared 
with cabozantinib alone 
• 
PFS, OS, and ORR in subgroups, defined 
by demographic and baseline characteristics  
• 
Time to response 
To evaluate the 
patient-reported outcomes of 
atezolizumab in combination 
with cabozantinib compared 
with cabozantinib alone 
• 
Time to confirmed deterioration in symptoms 
based on the Functional Assessment of 
Cancer Therapy−Kidney Symptom Index 19 
(FKSI-19) Disease-Related 
Symptom-Physical (DRS-P) scale  
• 
Time to confirmed deterioration in physical 
functioning (PF) and global health 
status/quality of life (GHS/QoL), based on 
the corresponding scales from the European 
Organisation for Research and Treatment of 


 
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Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) 
• 
Change from baseline in symptoms, 
function, and QoL, based on FKSI-19 
DRS-P scale, EORTC QLQ-C30 PF scale, 
and EORTC QLQ-C30 GHS/QoL scale by 
visit 
• 
Overall bother with treatment side effects 
during study treatment, based on FKSI-19 
GP5 item 
• 
Change from baseline in the EQ-5D-5L 
index-based and visual analog scale scores 
by visit 
• 
To identify and/or evaluate 
biomarkers  
• 
Relationship between biomarkers in tumor 
tissue and blood and efficacy, safety, PK, or 
other biomarker endpoints 
ADA = anti-drug antibody; DRS-P = Disease-Related Symptom-Physical; EORTC = European 
Organisation for the Research and Treatment of Cancer; FKSI-19 = Functional Assessment of 
Cancer Therapy−Kidney Symptom Index 19; GHS = Global Health Status; IRF= Independent 
Review Facility; NCI = National Cancer Institute; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetic; QLQ-C30 = Quality-of-Life 
Questionnaire Core 30; QoL = Quality of Life; RECIST = Response Evaluation Criteria in Solid 
Tumors. 
  
1.2 
STUDY DESIGN 
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy and safety of atezolizumab given in combination with cabozantinib versus 
cabozantinib alone in patients with inoperable, locally advanced, or metastatic RCC who 
experienced radiographic tumor progression during or after ICI treatment in the adjuvant 
and/or locally advanced/metastatic setting.  The study will enroll approximately 500 
patients at approximately 140-180 sites globally.  
Eligible patients will be randomized in a 1:1 ratio to one of the following two treatments 
arms: 
• 
Experimental arm (Atezo+Cabo):  Atezolizumab 1200 mg intravenous (IV) infusions 
every 3 weeks (Q3W) on Day 1 of each 21-day cycle plus cabozantinib 60-mg oral 
tablets taken once a day (QD; 1 cycle = 21 days) 
• 
Control arm (Cabo):  Cabozantinib 60-mg oral tablets taken QD (1 cycle = 21 days) 
 
The study schema is shown in Figure 1.  


 
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Figure 1 Study Schema  
 
1L = first-line (treatment); 2L = second-line (treatment); ICI = immune checkpoint inhibitor; 
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; PO = by mouth; 
Q3W = every 3 weeks; RCC = renal cell carcinoma. 
  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle and cabozantinib will be taken orally at a starting dose of 60 mg/day 
on Days 1−21 of each 21-day cycle.  Patients randomized to the Atezo+Cabo arm who 
transiently withhold or permanently discontinue either atezolizumab or cabozantinib may 
continue on single-agent therapy until disease progression (i.e., patients being withheld 
from cabozantinib transiently for adverse effects may continue atezolizumab 
monotherapy and vice versa).   
Patients will receive atezolizumab and/or cabozantinib until disease progression per 
RECIST v1.1, unacceptable toxicity, or symptomatic deterioration attributed to disease 
progression (e.g., pain secondary to disease or unmanageable ascites) as determined 
by the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status. 
No crossover will be allowed from the control arm to the experimental arm. 
Patients will undergo scheduled tumor assessments at baseline, every 9 weeks 
(± 7 days) for the first 18 months, and every 12 weeks (± 7 days) thereafter.  Tumor 
assessments will continue until disease progression as assessed by the investigator per 
RECIST v1.1 or, for patients who continue study treatment after radiographic disease 
progression, loss of clinical benefit as determined by the investigator.  In the absence of 
disease progression, tumor assessments should continue regardless of whether 
treatment has been discontinued (e.g., for toxicity) or whether patients start new 
anti-cancer therapy, until consent is withdrawn, death, or the study is terminated by the 
Sponsor, whichever occurs first. 


 
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All patients, regardless of arm, are required to perform a follow-up post-disease 
progression tumor assessment after investigator assessment of radiographic disease 
progression per RECIST v1.1.  This subsequent scan will take place on the same 
schedule as prior to progression at 9 weeks (± 7 days) if disease progression occurred in 
the first 18 months, and at 12 weeks (± 7 days) if disease progression occurred after the 
first 18 months following treatment initiation. 
Following treatment discontinuation, patients will be followed for survival and subsequent 
anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or study 
termination by Sponsor, whichever occurs first.   
1.2.1 
Treatment Assignment and Blinding 
This is a randomized open-label study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or web-based 
response system (IxRS). 
Patients will be randomly assigned to 1 of 2 treatment arms:  Atezo+Cabo arm or Cabo 
arm.  Randomization will occur in a 1:1 ratio with use of a permuted-block randomization 
method to ensure a balanced assignment to each treatment arm.  Randomization will be 
stratified according to the following criteria: 
• 
International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk 
groups (favorable, intermediate, or poor risk; 0, 1−2, or ≥ 3), which comprises the 
following 6 risks factors:  time from diagnosis to systemic therapy, Karnofsky 
Peformance Status (KPS), hemoglobin, corrected calcium, neutrophil, and platelet 
count 
• 
Most recent ICI therapy (adjuvant vs. locally advanced/metastatic first-line vs. locally 
advanced/metastatic second-line) 
• 
Histology:  dominant clear-cell without sarcomatoid versus dominant non−clear-cell 
(papillary or unclassified only) without sarcomatoid versus any sarcomatoid 
component (with clear-cell or non−clear-cell) 
  
1.2.2 
Independent Review Facility 
An idependent review facility (IRF) will be used to conduct blinded radiology review of 
the imaging data and will provide an independent assessment of tumor response and 
progression for all patients.  Independent Review Facility-assessed endpoints will be 
used for primary and secondary analyses. 
All scans performed as part of defined tumor assessments must be submitted to an IRF 
for central review. 


 
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1.2.3 
Data Monitoring 
An independent Data Monitoring Committee (iDMC) will evaluate safety data during the 
study.  Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow 
a charter that outlines the iDMC roles and responsibilities. 
Safety data will be reviewed on a periodic basis, approximately every 6 months from the 
time of enrollment of the first patient until the time of the analysis of the primary efficacy 
endpoint of PFS according to policies and procedures detailed in an iDMC Charter.  
No interim efficacy analyses are planned for PFS. 
All summaries and analyses for the iDMC review will be prepared by an 
independent Data Coordinating Center.  The safety summaries will include demographic 
data, adverse events (AEs), serious adverse events (SAEs), and relevant laboratory 
data. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor. 
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees. 
2. 
STATISTICAL HYPOTHESES 
The purpose of this study is hypothesis testing and estimation regarding the effect of 
atezolizumab in combination with cabozantinib on the duration of progression-free 
survival (PFS) and/or overall survival (OS) compared with cabozantinib alone.  
The null hypothesis of no difference in PFS or OS between the two treatment arms in the 
intent-to-treat (ITT) population will be tested using the stratified log-rank test.  The null 
and alternative hypotheses in terms of the survival functions SA (t) and SB (t) in 
Atezo+Cabo and Cabo arms, respectively, are phrased as below: 
H0: SA(t) = SB(t) versus H1: SA(t) ≠ SB(t) 
The Hazard Ratio (HR), λA/λB, where λA and λB represent the hazard rates for having a 
PFS or OS event in the Atezo+Cabo and Cabo arms, respectively, and the respective 
95% CI will be estimated using the proportional Cox regression model.  
3. 
SAMPLE SIZE DETERMINATION 
Approximately 500 patients are planned for enrollment globally over 20 months.  
The sample size calculation is determined based on the below considerations. 


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3.1 
TYPE I ERROR CONTROL 
The type I error (α) for the entire study is 0.05 (2-sided; Figure 2).  There are multiple 
primary efficacy endpoints for this study:  PFS by IRF assessment (IRF-PFS) per 
RECIST v1.1 and OS in the ITT population.  To control the overall type I error rate 
(Bretz et al. 2009) at α = 0.05 while accounting for 2 primary endpoints, α is split between 
PFS (α = 0.02) and OS (α = 0.03).  The type I error can be recycled (Burman et al. 2009) 
if PFS results in the ITT population are statistically significant at α = 0.02, then α = 0.02 
will be recycled to OS in the ITT population, and OS in the ITT population will be 
evaluated at α = 0.05.  The study will be considered as a positive study if statistical 
significance is achieved in favor of the experimental arm for either of the multiple primary 
endpoints, since the α for the entire study is controlled at 0.05. 
Figure 2 Progression Free Survival and Overall Survival Analysis 
α-Allocation and α-Recycling 
OS = overall survival; PFS = progression-free survival 


 
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3.2 
PRIMARY ENDPOINT:  IRF-PFS PER RECIST V1.1 IN THE ITT 
POPULATION 
The analysis of the primary endpoint of IRF-PFS per RECIST v1.1 will take place when 
approximately 325 IRF-PFS events have occurred in the ITT population (65% events to 
patients ratio) based on the following assumptions: 
• 
Two-sided, stratified log-rank test 
• 
Patients randomized to Atezo+Cabo and Cabo arms in a 1:1 ratio 
• 
PFS follows an exponential distribution 
• 
α = 0.02 (2-sided) 
• 
Approximately 90% power 
• 
Median PFS for the Cabo arm of 8.0 months and estimated median PFS in the 
Atezo+Cabo arm of 11.9 months (corresponding to HR of 0.67) 
• 
5% annual loss to follow-up for PFS 
• 
No interim analysis 
 
On the basis of these assumptions, it is projected that an observed HR of 0.77 or lower 
will result in a statistically significant difference between treatment arms (i.e., an HR of 
0.77 will be the minimum detectable difference [MDD] for the analysis; this corresponds 
to an improvement of 2.4 months in median PFS from 8.0 months in the Cabo arm to 
10.4 months in the Atezo+Cabo arm). 
3.3 
PRIMARY ENDPOINT: OS IN THE ITT POPULATION 
The final analysis of the primary endpoint of OS will take place when approximately 
325 OS events have occurred in the ITT population (65% events to patients ratio) based 
on the following assumptions: 
• 
Two-sided, stratified log-rank test 
• 
Patients randomized to Atezo+Cabo and Cabo arms in a 1:1 ratio 
• 
OS follows an exponential distribution 
• 
α = 0.03 (2-sided) 
• 
Approximately 85% power 
• 
Median OS in the Cabo arm of 22 months and estimated median OS in the 
Atezo+Cabo arm of 31.4 months (an increase of 9.4 months, corresponding to an 
HR of 0.70) 
• 
1% annual loss to follow-up for OS 
• 
Two interim OS analyses (see Section 5.8 for details) 
 
At the final OS analysis, on the basis of these assumptions, it is projected that an 
observed OS HR of 0.78 or lower in the ITT population will result in a statistically 
significant difference between treatment arms (i.e., the MDD at the analysis; this 


 
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corresponds to an improvement of 6.2 months in median OS, from 22 months in the 
Cabo arm to 28.2 months in the Atezo+Cabo arm). 
3.4 
SAMPLE SIZE 
With the above assumptions on IRF-PFS and OS, the sample size is determined at 
approximately 500 patients, where the IRF-PFS and OS final analyses will be conducted 
with sufficient statistical power for testing the target HRs or lower when approximately 
325 events occur (65% events to patients ratio), respectively.   
4. 
ANALYSIS SETS  
The analysis sets used for analyses are defined in Table 2 below. 
Table 2 
Analysis Sets 
Analysis set 
Definition 
ITT 
All randomized patients, whether or not the patient received the 
assigned treatment 
ORR-evaluable 
All randomized patients with measurable disease at baseline 
Safety-evaluable 
All randomized patients who received at least one dose of study 
treatment   
PK-evaluable  
All patients who received at least one dose of study treatment and 
who have at least one post-baseline PK sample available 
Atezolizumab 
ADA-evaluable 
All patients who received at least one dose of atezolizumab 
treatment and with an ADA assay result from at least one sample 
result 
ADA = anti-drug antibody; ITT = intent-to-treat; ORR = objective response rate 
PK=pharmacokinetic 
 
5. 
STATISTICAL ANALYSES 
The analyses described in this SAP will supersede those specified in the protocol for the 
purposes of a regulatory filing. 
5.1 
GENERAL CONSIDERATIONS 
All efficacy analyses will be performed in the ITT poulation, unless otherwise specified.  
Patients will be analyzed according to the treatment assigned at randomization by IxRS, 
regardless of whether they receive any assigned study treatment.   
Safety analyses will be conducted on the safety-evaluable patients, and will be 
performed based on the actual treatment patients received, regardless of the initial 
treatment assignment at randomization.  Specifically, a patient will be included in the 
Atezo+Cabo arm in the safety analyses if the patient receives any amount of 
atezolizumab, regardless of the initial treatment assignment at randomization.  Similarly, 
a patient will be included in the Cabo arm in the safety analyses if the patient receives 


 
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any amount of cabozanitib without any atezolizumab, regardless of the initial treatment 
assignment at randomization.  
Unless otherwise stated, baseline values are the last available data obtained prior to the 
patient receiving the first dose of study treatment on Cycle 1, Day 1 (or at screening, for 
patients who were not treated). 
5.2 
PATIENT DISPOSITION 
Study enrollment and reasons for discontinuation from the study will be summarized by 
assigned treatment arm for the ITT population.  Study treatment disposition and reasons 
for discontinuation from study treatment will be summarized for the safety-evaluable 
patients by actual treatment arm. 
5.3 
PRIMARY ENDPOINT ANALYSES 
5.3.1 
Definition of Primary Endpoints 
The multiple primary efficacy endpoints are IRF-PFS per RECIST v1.1 and OS. 
IRF-PFS is defined as the time from randomization to disease progression, as 
determined by the IRF per RECIST v1.1, or death from any cause, whichever occurs 
first.  Data for patients who have not experienced disease progression or death will be 
censored at the last tumor assessment date.  Data for patients with no post-baseline 
tumor assessments will be censored at the randomization date. 
Overall survival is defined as the time from randomization to death due to any cause.  
Data for patients who are not reported as having died at the date of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization. 
The hypothesis testing for PFS in the ITT population will be conducted at a two-sided 
α of 0.02.  If PFS is not statistically significant in the ITT population, the hypothesis 
testing for OS in the ITT population will be conducted at a two-sided α of 0.03.  If PFS is 
statistically significant in the ITT population, OS will be tested at a two-sided α level of 
0.05. 
5.3.2 
Main Analytical Approach for Primary Endpoints 
The stratified log‑rank test at the 2-sided 5% level of significance will be used to 
compare PFS and OS between the treatment arms, according to the protocol‑defined 
stratification factors as entered in IxRS for the ITT patients.  The stratified Cox 
proportional hazards model will be used to estimate the HRs between the two treatment 
arms and its 95% confidence interval (CI).    
For the stratification factors, most recent ICI therapy (adjuvant vs. locally 
advanced/metastatic first-line vs. locally advanced/metastatic second-line), histology 
(dominant clear-cell without sarcomatoid vs. dominant non−clear-cell [papillary or 


 
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unclassified only] without sarcomatoid vs. any sarcomatoid component [clear-cell or 
non−clear-cell]), and the IMDC score (0, 1−2, ≥ 3), if at least one stratum has less than 
10 events at the time of analysis, the stratification factor that contains the level with the 
smallest number of patients will be removed from the stratified analyses.  The final set of 
stratification factors used for the multiple primary endpoints will be applied to all other 
endpoints where stratified analyses are planned.  The stratification factors will be 
obtained from the IxRS at the time of randomization.  
Results from an unstratified analysis for log-rank test and Cox proportional hazards 
model, respectively, will also be provided.   
Kaplan-Meier methodology will be used to estimate the median PFS and OS for each 
treatment arm, and Kaplan-Meier curves will be produced.  The Brookmeyer Crowley 
methodology will be used to construct the 95% CI for the median PFS and OS for each 
treatment arm (Brookmeyer and Crowley 1982). 
5.3.3 
Sensitivity Analyses for Primary Endpoints 
5.3.3.1 
Analysis of IRF-PFS Accounting for Missing Tumor 
Assessments 
The impact of missing scheduled tumor assessments on IRF-PFS will be assessed with 
the following two sensitivity analyses: 
• 
Patients who missed two or more consecutive scheduled tumor assessments 
immediately prior to the date of disease progression by IRF-assessment per 
RECIST v1.1 or death will be censored at the last tumor assessment prior to the 
missed visits. 
• 
Patients who missed two or more consecutive scheduled tumor assessment 
immediately prior to the date of disease progression by IRF-assessment per 
RECIST v1.1 or death will be counted as having progressed on the date of the first 
of these missing tumor assessments 
  
5.3.3.2 
Analysis of OS Accounting for Loss to Follow-up 
Patients who are lost to follow-up will be censored at the last date they were known to be 
alive for the primary analysis of OS.  If >5% of patients are lost to follow-up for OS in 
either treatment arm, a sensitivity analysis will be performed for the comparison between 
two treatment arms in which patients who are lost to follow-up will be considered as 
having died at the last date they were known to be alive. 


 
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5.3.3.3 
Analysis of IRF-PFS and OS Accounting for Non-Protocol 
Anti-Cancer Therapy 
The impact of non-protocol anti-cancer treatment (NPT) prior to an IRF-PFS or OS event 
will be assessed depending on the number of patients who receive NPT.  
If >5% of patients received any NPT prior to an IRF-PFS or an OS event in either 
treatment arm, sensitivity analyses for IRF-PFS and OS will be performed for the 
comparisons between treatment arms in which patients who received NPT before the 
event will be censored at the last tumor assessment date before the initiation of NPT.   
Additionally, if >5% of patients received any NPT prior to an IRF-PFS, a sensitivity 
analysis for IRF-PFS will be performed in which patients who received NPT prior to the 
IRF-PFS event will be considered as having progressed at the date of initiation of NPT.    
5.3.3.4 
Analysis of IRF-PFS and OS Accounting for Discrepancy of 
Stratification Factors Between IxRS and eCRF 
The sensitivity analyses for IRF-PFS and OS based on the strata recorded in the 
electronic Case Report Forms (eCRF) will be performed for the comparsion between the 
treatment arms if >10% of patients have been assigned to a stratum by IxRS that is 
different from the one recorded in the eCRF.   
Additional sensitivity analyses may be conducted. 
5.3.4 
Supplementary Analyses for Primary Endpoints 
5.3.4.1 
Subgroup Analyses for Primary Endpoints 
The generalizability of IRF-PFS and OS results when comparing the Atezo+Cabo arm to 
the Cabo arm will be investigated by estimating the treatment effect across subgroups in 
the ITT population.  The subgroups are defined by the following: 
• 
Demographics (e.g., age, sex, and race/ethnicity)  
• 
Baseline prognostic characteristics (e.g., programmed death-ligand 1 [PD-L1] 
status, prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor 
[VEGFR-TKI] use, most recent ICI therapy [adjuvant vs. locally advanced/metastatic 
first-line treatment vs. locally advanced/metastatic second-line treatment], tumor 
histology, or IMDC risk group).   
Summaries of IRF-PFS and OS, including unstratified HRs estimated from Cox 
proportional hazards models and Kaplan-Meier estimates of median IRF-PFS and OS, 
will be provided separately for each level of the subgroups for the comparisons between 
the treatment arms. 
5.4 
SECONDARY ENDPOINT ANALYSES 
5.4.1 
IRF-assessed Objective Response Rate 
An IRF-assessed objective response is defined as either a complete response (CR) or 
partial response (PR; confirmation is required, i.e., with CR or PR at two consecutive 


 
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tumor assessments at least 28 days apart) based on RECIST v1.1, as assessed by an 
IRF.  Patients not meeting this criterion, including patients without any post-baseline 
tumor assessments, will be considered non-responders.  Objective response rate (ORR) 
is defined as the proportion of patients who had an objective response in the 
ORR-evaluable population, defined as patients with measurable disease at baseline.  
Unconfirmed response rate will also be evaluated. 
Objective response rate will be compared between treatment arms with use of the 
stratified Cochran-Mantel-Haenszel test.  The stratification factors will be the same as 
those described in the analysis of the multiple primary efficacy endpoints of IRF-PFS 
and OS.  An estimate of ORR will be calculated for each treatment arm, and its 95% CI 
will be calculated with use of the Clopper-Pearson method.  The difference in ORR 
between treatment arms will be calculated, and its 95% CI will be calculated with use of 
the normal approximation to the binomial distribution. 
5.4.2 
IRF-assessed Duration of Response 
IRF-assessed duration of response (DOR) is defined for patients who had a confirmed 
objective response as the time from the first occurrence of response (CR or PR) to 
disease progression, as assessed by an IRF or death, whichever occurs first.  Data for 
patients who have not experienced disease progression or death will be censored at the 
last tumor assessment date.  If no tumor assessments were performed after the date of 
the first occurrence of CR or PR, data for DOR will be censored at the date of the first 
occurrence of CR or PR. 
Duration of response is based on a non-randomized subset of patients (those who 
achieved an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between two arms will be made for 
descriptive purposes only.  Methods for comparison of DOR between treatment arms will 
be the same as the methods for treatment comparison for the multiple primary efficacy 
endpoints of IRF-PFS and OS. 
5.4.3 
Investigator-assessed PFS, ORR, and DOR  
Investigator-assessed PFS, ORR, and DOR follow the same definitions and analysis 
methods for IRF-assessed ones with the exception that tumor assessments are 
performed by the investigators. 
 
5.5 
EXPLORATORY ENDPOINT ANALYSES 
5.5.1 
PFS and OS Rates at Selected Time Points 
The PFS rates at selected time points (e.g., 6 and 12 months) are defined as the 
proportion of patients who have not experienced disease progression according to 
RECIST v1.1 or death from any cause at selected time points after randomization. 


 
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The OS rates at selected time points (e.g., 12 and 24 months) are defined as the 
proportion of patients who have not died from any cause at selected time points after 
randomization.  
The IRF- or investigator-assessed PFS and OS rates at selected time points will be 
estimated by the Kaplan-Meier methodology for each treatment arm and the 95% CI will 
be calculated with use of Greenwood’s formula. 
5.5.2 
Time to Response 
Time to response is defined as the time from randomization to first response of PR or 
CR among responders, as assessed by the investigators and an IRF according to 
RECIST v1.1.  Descriptive statistics will be used to summarize the mean, median, 
minimum, and maximum time to response.  
5.5.3 
Patient Reported Outcome  
5.5.3.1 
Time to Confirmed Deterioration in Disease-Related Symptoms 
Time to confirmed deterioration of disease-related symptoms is defined as the time from 
randomization date to the date of a patient’s first 4-point or more score decrease from 
baseline on the Functional Assessment of Cancer Therapy−Kidney Symptom Index 19 
(FKSI-19) Disease-Related Symptom-Physical (DRS-P) scale held for at least two 
consecutive timepoints or followed by death within 3 weeks (if Cycles 1−12) or 6 weeks 
(if after Cycle 12) from the last patient reported outcome (PRO) assessment.  
Kaplan-Meier methods will be applied to this endpoint.  Patients who have not 
experienced confirmed deterioration will be censored at the last time of completed 
assessment.  Patients with no post-baseline assessments will be censored at the 
randomization date. 
5.5.3.2 
Time to Confirmed Deterioration in Physical Functioning 
Time to confirmed deterioration in physical functioning (PF) is defined as the time from 
randomization date to the date of a patient’s first 10-point or more score decrease from 
baseline on the European Organisation for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire-Core 30 (QLQ-C30) PF scale held for at least 
2 consecutive timepoints or followed by death within 3 weeks (if Cycles 1−12) or 
6 weeks (if after Cycle 12) from the last PRO assessment.  Kaplan-Meier methods will 
be applied to this endpoint. 
5.5.3.3 
Time to Confirmed Deterioration in Global Health 
Status/Quality of Life 
Time to confirmed deterioration in global health status/quality of life (GHS/QoL) is 
defined as the time from randomization date to the date of a patient’s first 10-point or 
more score decrease from baseline on the EORTC QLQ-C30 GHS/QoL scale held for at 
least two consecutive timepoints or followed by death within 3 weeks (if Cycles 1−12) or 


 
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6 weeks (if after Cycle 12) from the last PRO assessment.  Kaplan-Meier methods will 
be applied to this endpoint. 
5.5.3.4 
Patient-Reported Outcome Descriptive Summaries 
Compliance rates in the ITT population will be calculated as the number of patients who 
completed the assessment divided by the number of patients expected to complete the 
assessment at each timepoint for each treatment arm.  Reasons for missing 
assessments, if available, will be summarized with use of frequencies and percentages. 
Descriptive analyses will include summary statistics (mean, standard deviation, median, 
interquartile range, minimum, maximum) of PRO scores and score changes from 
baseline at each assessment timepoint by treatment arm.  Additional timepoints of 
interest include PRO score at radiographic disease progression (i.e., a patient’s last 
PRO assessment score within 30 days prior to or on the day of diagnosis of disease 
progression) and treatment discontinuation due to adverse events (i.e., a patient’s last 
PRO assessment within the 30 days prior to treatment discontinuation due to adverse 
events).  Graphs of mean scores and/or score changes from baseline along with 95% 
CIs may be presented.  Descriptive summaries will be reported for the key scales 
(FKSI-19 DRS-P, EORTC QLQ-C30 PF, and EORTC QLQ-C30 GHS/QoL) as well as 
the remaining FKSI-19 and EORTC QLQ-C30 scales.  Linearly transformed scores for 
the EORTC QLQ-C30 scales (per the EORTC scoring manual) will be calculated. 
Cumulative distribution function plots of score change from baseline to Month 6 by 
treatment arm will be presented for each key scale (FKSI-19 DRS-P, EORTC QLQ-C30 
physical function, EORTC QLQ-C30 GHS/QoL). 
These descriptive summaries may not be included in the Clinical Study Report for this 
study. 
5.5.3.5 
Patient-Reported Outcome Side-Effect Burden 
Descriptive analysis of the patient-reported overall side-effect bother item (FKSI-19 GP5) 
will be performed by treatment arm at each visit in the safety-evaluable population.  
Distribution of responses will be summarized as frequencies and percentages.  
Change from baseline may be summarized as no change; improved by 1, 2, 3, or 
4 levels; and worsened by 1, 2, 3, or 4 levels.  Stacked bar charts may also be used to 
illustrate the distribution of responses or the change from baseline at each timepoint by 
treatment arm. 
These analyses may not be included in the Clinical Study Report for this study. 
5.5.3.6 
Health Status Utility Analyses 
To evaluate health status utility scores of patients treated with atezolizumab in 
combination with cabozantinib compared with cabozantinib alone, change from baseline 
in EQ-5D-5L health utility index-based, and visual analog scale scores will be calculated 


 
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at specified timepoints.  EQ-5D-5L is collected for use in economic models for 
reimbursement. 
These analyses will not be included in the Clinical Study Report for this study. 
5.6 
SAFETY ANALYSES 
Unless specified otherwise, safety analyses described below will be conducted for the 
safety evaluable patients, with patients grouped according to actual treatment received 
as defined in Section 5.1 for safety analyses. 
5.6.1 
Extent of Exposure 
Study drug exposure, including treatment duration, dosage, and dose intensity, will be 
summarized by treatment arm and for each study drug with descriptive statistics. 
5.6.2 
Adverse Events 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms.  Severity for all AEs will be graded by the 
investigator according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 5.0 (v5.0).  
For the safety analyses, “treatment-emergent” is defined as AEs occurring on or after the 
first dose of study drug treatment or pre-existing condition that worsened on or after the 
first dose of the study treatment up to the data cutoff date. 
Incidence and severity of all treatment-emergent AEs will be summarized by treatment 
arm and NCI CTCAE grade.  In addition, common AEs, treatment-related AEs, SAEs, 
AEs leading to study treatment discontinuation or interruption, Grade 3-4 AEs, and fatal 
AEs (Grade 5) will be summarized accordingly.  For the purpose of analyses, adverse 
events of special interest, identified by a set of comprehensive definitions using 
standardized MedDRA queries, High-Level Terms, and Sponsor-defined adverse event 
grouped terms from the AE clinical database by medical concept, will be summarized by 
treatment arm and CTCAE grade.  Medical concepts include atezolizumab-associated 
identified risks, potential risks, and class effects reported with other ICIs. 
Multiple occurrence of the same event will be counted once at the maximum severity.  
Listings of adverse events will include all treatment emergent AEs collected up to the 
data cutoff date.  
Deaths during the study treatment period and those reported during the follow-up period 
after treatment completion or discontinuation and causes of death will be summarized by 
treatment arm. 


 
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5.6.3 
Laboratory Data 
Laboratory data will be summarized by treatment arm.  Selected laboratory data will be 
graded according to NCI CTCAE v5.0 and will be summarized descriptively.  Shift tables 
from baseline to worst post-baseline values will also be presented.   
5.6.4 
Vital Signs 
Vital signs, including diastolic and systolic blood pressure, pulse rate, respiratory rate, 
and temperature, outside of normal limits will be summarized by treatment arm.  
5.6.5 
ECGs 
Electrocardiograms (ECGs) of clinical significant abnormality will be summarized by 
treatment arm.  
5.7 
OTHER ANALYSES 
5.7.1 
Summaries of Conduct of Study 
Study enrollment and major protocol deviations, including major deviations of 
inclusion/exclusion criteria, will be summarized by treatment arm for the ITT population.   
5.7.2 
Summaries of Treatment Group Comparability 
Demographic variables, such as age, sex, race/ethnicity, stratification factors 
(IMDC score, line of therapy, histology), and baseline characteristics will be summarized 
by treatment arm as well as for all patients in the ITT population.  Continuous variables 
will be summarized with use of means, standard deviations, medians, and ranges.  
Categorical variables will be summarized by proportions. 
Medical history will be summarized for the safety evaluable patients. The summary will 
be separately reported for resolved events or conditions versus ongoing events or 
conditions as collected at baseline.  Concomitant medications, used by the patient within 
7 days prior to initiation of study treatment, will also be summarized for the safety 
evaluable patients by treatment arm for medications taken prior to the first dose of study 
treatment regardless of whether medications were ongoing or not after starting treatment 
versus the initial medications taken after the first dose of study treatment.  
5.7.3 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be conducted for the PK-evaluable population that consist 
of all patients who received at least one dose of study treatment and who have at least 
one post-baseline PK sample available. 
Atezolizumab serum concentration data (minimum serum concentration [Cmin] and 
maximum serum concentration [Cmax]) will be tabulated and summarized. Descriptive 
statistics will include means, medians, ranges, coefficients of variation, and standard 
deviations, as appropriate. 


 
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Cabozantinib plasma concentration data will be summarized using descriptive statistics 
as described above. 
The concentration-time course will also be plotted for each drug.  Additional PK analyses 
may be conducted, as appropriate, based on the availability of the data. 
5.7.4 
Immunogenicity Analyses 
The immunogenicity analyses will be conducted for the atezolizumab ADA-evaluable 
population that consist of all patients who received any amount of atezolizumab with at 
least one ADA assessment for atezolizumab. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized.  When determining post-baseline incidence, patients are considered 
to be ADA-positive if they are ADA-negative or have missing data at baseline but 
develop an ADA response following study drug exposure (treatment-induced ADA 
response), or if they are ADA-positive at baseline and the titer of one or more 
post-baseline samples is at least 0.60 titer unit greater than the titer of the baseline 
sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA-negative if they are ADA-negative or have missing data at baseline and all 
post-baseline samples are negative, or if they are ADA-positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics. 
5.7.5 
Biomarker Analyses 
Exploratory biomarker analyses may be performed in an effort to understand the 
association of biomarkers in tumor tissue, blood, and urine with study treatment, and to 
identify and/or evaluate biomarkers that are predictive of response to atezolizumab in 
combination with cabozantinib or cabozantinib alone (i.e., predictive biomarkers), are 
early surrogates of efficacy, are associated with progression to a more severe disease 
state (i.e., prognostic biomarkers), are associated with acquired resistance to 
atezolizumab in combination with cabozantinib or cabozantinib alone, can provide 
evidence of atezolizumab in combination with cabozantinib or cabozantinib alone 
efficacy (i.e., pharmacodynamic biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety.   
These exploratory analyses may not be included in the Clinical Study Report for this 
study. 


 
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5.7.6 
Analyses of Subgroups of Interest 
The consistency of confirmed IRF-assessed ORR results when comparing the 
Atezo+Cabo arm to the Cabo arm will be investigated across subgroups, as defined in 
Section 5.3.4.1.  The odds ratio of Atezo+Cabo versus Cabo and its 95% CI will be 
presented for each subgroup in a Forest plot.  
5.8 
INTERIM ANALYSES  
5.8.1 
Planned Interim Analyses 
There are no planned interim analyses for the primary endpoint of IRF-PFS.  
A total of three analyses of OS will be performed, including two interim analyses and 
one final analysis.  The boundary for statistical significance at each OS analysis will be 
determined based on the Lan-DeMets implementation of the O’Brien-Fleming (OBF) 
function (DeMets and Lan 1994) to maintain the overall type I error rate 
(Hung et al. 2007; Glimm et al. 2010) at either 0.03 or 0.05 level, depending on whether 
primary endpoint of IRF-PFS is significant at 0.02 level.  The OBF boundary for 
statistical significance is provided in Table 3.  The OS endpoint will be considered 
positive in the ITT population if statistical significance is achieved in favor of the 
Atezo+Cabo arm for any of the two OS interim analyses or the final analysis. 
Table 3 
Analysis Timing and Stopping Boundaries for Overall Survival 
Interim and Final Analyses  
 
OS Interim Analysis 1 OS Interim Analysis 2 
Final OS 
Percent Informationa 
53% 
175 events 
80% 
260 events 
100% 
325 events 
Timing from FPI 
27 monthsb 
 
39 months 
52 months 
OBF Boundary when 
α = 0.03 (α = 0.05) 
0.0019 (0.0045) 
0.0125 (0.0231) 
0.0259 (0.0424) 
MDD when α = 0.03 
(α = 0.05) 
HR ≤ 0.62 
(HR ≤ 0.65) 
HR ≤ 0.73 
(HR ≤ 0.75) 
HR ≤ 0.78 
(HR ≤ 0.80) 
FPI = first patient in; HR = hazard ratio; MDD = minimum detectable difference; 
OBF = O’Brien-Fleming; OS = overall survival; PFS = progression-free survival. 
a Corresponds to the number of death events required for the final analysis of OS  
b At the time of PFS primary analysis 
  
The first interim analysis of OS will be performed at the time of the PFS primary analysis.  
A total of 175 OS events are expected at the first interim analysis of OS, which 
corresponds to 53% of the events information required for the final analysis of OS in the 
ITT population.  Statistical significance will be declared if p < 0.0019.  If there are 
significantly fewer (< 160) OS events than the expected 175 OS events, then the first 
interim analysis will be delayed until 175 OS events occur.  An administrative α of 


 
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0.000001 (negligible impact on overall type I error rate) will be spent on the OS 
hypothesis at the time of the planned PFS. 
The second interim analysis of OS will be performed when approximately 260 deaths 
have occurred, which corresponds to approximately 80% of the events information 
required for the final analysis of OS in the ITT population.  Statistical significance will be 
declared if p < 0.0125. 
The final analysis of OS will be performed when 325 deaths (65% of 500 patients in the 
ITT population) have occurred.  Statistical significance will be declared if p < 0.0259 when 
exactly 325 deaths have occurred at the time of the final OS analysis. 
The actual OBF boundary will be calculated at the time of analysis based on actual 
number of events observed. 
6. 
SUPPORTING DOCUMENTATION 
This section is not applicable since there is no additional supporting document. 
7. 
REFERENCES 
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009;28:586−604. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Burman CF, Sonesson C, Guilbaud O, et al. A recycling framework for the construction 
of Bonferroni-based multiple tests. Stat Med 2009;28:739-61. 
DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341-52. 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med 2010;29:291-28. 
Hung HM, Wang SJ, O’Neil R. Statistical considerations for testing multiple endpoints in 
group sequential or adaptive clinical trials. J Biopharm Stat 2007;17:1201-10. 
 


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