Clinical trial NCT04471428
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Hoffmann-La Roche
Start date: 2020-10-01; Completion date: 2025-01-17
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab given in combination with cabozantinib compared with docetaxel monotherapy in patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK translocation, who have progressed following treatment with platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or sequentially.

Detailed description:

Arms: arm 1: Participants received atezolizumab on Day 1 of each 21-day cycle and cabozantinib orally once daily on Days 1-21 of each cycle. arm 2: Participants received docetaxel on Day 1 of each 21-day cycle.
Interventions: intervention 1: Cabozantinib intervention 2: Atezolizumab intervention 3: Docetaxel
Intervention descriptions: intervention 1: Cabozantinib will be administered orally, once daily at a dose of 40 mg on Days 1-21 of each cycle. intervention 2: Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. intervention 3: Docetaxel will be administered by IV infusion at a starting dose of 75mg/m2 on Day 1 of each 21-day cycle.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Open-Label, Controlled Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of 
Atezolizumab Given in Combination With Cabozantinib Versus 
Docetaxel Monotherapy in Patients With Metastatic Non-Small Cell 
Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody 
and Platinum-Containing Chemotherapy 
NCT Number: 
NCT04471428 
Document Date: 
Protocol Amendment Version 5: 22-March-2023 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol GO41892, Version 5 
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-
LABEL, CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
ATEZOLIZUMAB GIVEN IN COMBINATION WITH 
CABOZANTINIB VERSUS DOCETAXEL 
MONOTHERAPY IN PATIENTS WITH METASTATIC 
NONSMALL CELL LUNG CANCER PREVIOUSLY 
TREATED WITH AN ANTIPD-L1/PD-1 ANTIBODY AND 
PLATINUM-CONTAINING CHEMOTHERAPY 
PROTOCOL NUMBER: 
GO41892 
VERSION NUMBER: 
5  
TEST PRODUCTS: 
Atezolizumab (RO5541267) and cabozantinib (XL184) 
STUDY PHASE 
Phase III 
REGULATORY AGENCY 
IDENTIFIER NUMBERS 
IND Number:  146261 
EudraCT Number:  2020-000100-11 
NCT Number:  NCT04471428 
SPONSOR’S NAME AND 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GO41892, Version 5 
 
PROTOCOL HISTORY 
 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
5 
See electronic date 
stamp on the final 
page of this document 
France 
4 
To be determined 
4 
10 March 2022 
France 
3 
25 March 2022 
3 
18 March 2021 
France 
2 
26 April 2021 
2 
29 June 2020 
France 
1 
14 October 2020 
1 
27 February 2020 
 
 
 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GO41892, Version 5 
 
PROTOCOL AMENDMENT, VERSION 5 
RATIONALE 
Protocol GO41892, Version 5, has been amended primarily to update the adverse event 
management guidelines to align with the recent Atezolizumab Investigator's Brochure, 
Version 19, and Cabozantinib Investigator’s Brochure, Version 18. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Two newly approved indications for cabozantinib have been added to align with the 
Cabozantinib Investigator’s Brochure, Version 18 (Section 1.3). 
 
A note has been added that the completion of patient-reported outcome (PRO) 
questionnaires will no longer be required after the final overall survival (OS) analysis 
(Sections 3.1, 4.5.9, 4.6.1.1, and Appendix 1). 
 
The duration of follow-up after the completion of final OS analysis has been 
specified as 6 months after patient’s last dose of study treatment (Sections 3.1, 
4.5.6, 4.6.1.1, and Appendix 1). 
 
The end-of-study definition has been updated to include the additional criteria of 
when the last data point required for safety follow-up has been received (if it occurs 
later than the required number of deaths for the final analysis OS), and the last 
patient’s last visit has occurred.  Patients may continue on study treatment until the 
development of progressive disease, unacceptable toxicity, patient consent 
withdrawal, or Sponsor’s decision to terminate the study, whichever occurs first.  
The Sponsor will provide a written notification to investigators in the event that the 
study has terminated and the investigators, in consultation with the Medical Monitor, 
may offer suitable patients with potential enrollment to the continued access 
program or another study for continued access to study treatment (Section 3.2).   
 
The medical term “Wegener granulomatosis” has been replaced by the term 
“granulomatosis with polyangiitis” to align with the updated preferred term in Medical 
Dictionary for Regulatory Activities (Section 4.1.2 and Appendix 4). 
 
Text has been added to clarify that the number of pharmacokinetic (PK) and anti-
drug antibody (ADA) samples may be reduced or sample collection may cease 
altogether based on emerging safety, activity, or efficacy data.  These collected 
samples may not be analyzed if not warranted.  Furthermore, after final OS analysis 
is conducted, the Sponsor may decide to no longer collect additional biomarker 
samples.  The existing collected samples may still be used for exploratory analysis. 
(Section 4.5.7, and Appendices 1 and 2). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.10.6). 
 
The list of identified risks for atezolizumab has been revised to include pericardial 
disorders, myelitis, and facial paresis.  In addition, hemophagocytic 
lymphohistiocytosis (HLH) has been updated from a potential risk to an identified 
risk associated with atezolizumab and language has been revised accordingly 
(Section 5.1.1). 


Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol GO41892, Version 5 
 
 
The list of identified risks for cabozantinib has been revised to include venous and 
arterial thrombotic events, angioedema, and musculoskeletal disorders 
(Section 5.1.2). 
 
The list of adverse events of special interest has been revised to include myelitis 
and facial paresis (Section 5.2.3). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol.  Medical Monitor contact information 
has been replaced with a sentence indicating that this information will be provided 
separately to sites (Section 5.4.1). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.6). 
 
Guidance has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a pericardial 
disorder while receiving another immunostimulatory anti-cancer agent.  Autoimmune 
myelitis has also been added to the table of autoimmune diseases (Appendix 4). 
 
The adverse event management guidelines for risks associated with atezolizumab 
have been updated to align with the Atezolizumab Investigator's Brochure, 
Version 19, as well as Addendum 1 and 2 to the Atezolizumab Investigator's 
Brochure, Version 19.  Management guidelines for pericardial disorders, myelitis, 
and facial paresis have been included, and HLH has been updated from a potential 
risk to an identified risk (Appendix 6). 
 
The adverse event management guidelines for risks associated with cabozantinib 
have been updated to align with the Cabozantinib Investigator’s Brochure, 
Version 18 (Appendix 7). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol GO41892, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on NonSmall Cell Lung Cancer.......................... 21 
1.2 
Background on Atezolizumab .................................................. 22 
1.3 
Background on Cabozantinib ................................................... 23 
1.4 
Ongoing Clinical Study with Atezolizumab and 
Cabozantinib ............................................................................ 25 
1.5 
Study Rationale and Benefit-Risk Assessment ........................ 26 
1.5.1 
Study Rationale ....................................................................... 26 
1.5.2 
Overall BenefitRisk Assessment ............................................ 27 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 29 
2.1 
Efficacy Objectives .................................................................. 29 
2.1.1 
Primary Efficacy Objective ....................................................... 29 
2.1.2 
Secondary Efficacy Objective .................................................. 29 
2.1.3 
Exploratory Efficacy Objective ................................................. 30 
2.2 
Safety Objectives ..................................................................... 30 
2.3 
Pharmacokinetic Objective ...................................................... 31 
2.4 
Immunogenicity Objectives ...................................................... 31 
2.5 
Exploratory Biomarker Objective ............................................. 31 
2.6 
Health Status Utility Objective .................................................. 31 
3. 
STUDY DESIGN ........................................................................... 32 
3.1 
Description of the Study ........................................................... 32 
3.1.1 
Independent Data Monitoring Committee ................................ 36 
3.2 
End of Study and Length of Study ........................................... 36 
3.3 
Rationale for Study Design ...................................................... 37 
3.3.1 
Rationale for Evaluating Cabozantinib in Combination with 
Atezolizumab in Metastatic NSCLC after Progression on 
Prior Platinum-Containing Chemotherapy and AntiPD-
L1/PD-1 Antibody ..................................................................... 37 
3.3.2 
Rationale for Control Arm ........................................................ 38 


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3.3.3 
Rationale for Study Treatment Dose Selection and 
Treatment Schedule ................................................................ 38 
3.3.3.1 
Rationale for Atezolizumab Dose and Schedule ...................... 38 
3.3.3.2 
Rationale for Cabozantinib Dose and Schedule ...................... 39 
3.3.4 
Rationale for Patient Population and Analysis Groups ............ 39 
3.3.5 
Rationale for Open-Label Study ............................................... 40 
3.3.6 
Rationale for Treatment beyond Initial Radiographic 
Progression per RECIST v1.1.................................................. 40 
3.3.7 
Rationale for Biomarker Assessments ..................................... 40 
3.3.8 
Rationale for Patient-Reported Assessments .......................... 42 
3.3.9 
Rationale for Stratification Factors ........................................... 42 
4. 
MATERIALS AND METHODS ...................................................... 44 
4.1 
Patients .................................................................................... 44 
4.1.1 
Inclusion Criteria ...................................................................... 44 
4.1.2 
Exclusion Criteria ..................................................................... 47 
4.2 
Method of Treatment Assignment and Blinding ....................... 52 
4.2.1 
Treatment Assignment ............................................................. 52 
4.2.2 
Blinding .................................................................................... 53 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 53 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 53 
4.3.1.1 
Atezolizumab ........................................................................... 53 
4.3.1.2 
Cabozantinib ............................................................................ 53 
4.3.1.3 
Docetaxel ................................................................................. 54 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 54 
4.3.2.1 
Experimental Arm .................................................................... 55 
4.3.2.2 
Control Arm .............................................................................. 57 
4.3.3 
Investigational Medicinal Product Accountability ..................... 57 
4.3.4 
Continued Access to Atezolizumab and Cabozantinib ............. 58 
4.4 
Concomitant Therapy .............................................................. 58 
4.4.1 
Permitted Therapy ................................................................... 58 
4.4.2 
Cautionary Therapy for All Patients ......................................... 60 
4.4.2.1 
Herbal Therapies ..................................................................... 60 


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4.4.3 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 60 
4.4.3.1 
Corticosteroids, Immunosuppressive Medications, and 
TNF- Inhibitors ....................................................................... 60 
4.4.4 
Cautionary Therapy for Cabozantinib Treated Patients ........... 61 
4.4.4.1 
Cytochrome P450 .................................................................... 61 
4.4.4.2 
Protein Binding ........................................................................ 62 
4.4.4.3 
Other Interactions .................................................................... 62 
4.4.5 
Cautionary Therapy for Docetaxel-Treated Patients ................ 63 
4.4.6 
Prohibited Therapies for All Patients ........................................ 63 
4.4.7 
Prohibited Therapies for Atezolizumab-Treated and 
Cabozantinib-Treated Patients ................................................ 64 
4.4.8 
Prohibited Food for Cabozantinib-Treated Patients ................. 64 
4.5 
Study Assessments ................................................................. 64 
4.5.1 
Informed Consent Forms and Screening Log .......................... 65 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 65 
4.5.3 
Physical Examinations ............................................................. 65 
4.5.4 
Vital Signs ................................................................................ 66 
4.5.5 
Tumor and Response Evaluations ........................................... 66 
4.5.6 
Survival Assessments .............................................................. 69 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 69 
4.5.8 
Electrocardiograms .................................................................. 73 
4.5.9 
Patient-Reported Outcome Assessments ................................ 73 
4.5.9.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments ........................................................................... 74 
4.5.9.2 
Description of Patient-Reported Outcome Assessment 
Questionnaires ......................................................................... 75 
4.5.10 
Optional Tumor Biopsies and Blood Samples.......................... 76 
4.5.10.1 
Overview of the Research Biosample Repository .................... 77 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 77 
4.5.10.3 
Sample Collection .................................................................... 77 
4.5.10.4 
Confidentiality .......................................................................... 78 
4.5.10.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 79 


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8/Protocol GO41892, Version 5 
4.5.10.6
Withdrawal from the Research Biosample Repository ............. 79
4.5.10.7
Monitoring and Oversight ......................................................... 79
4.6
Treatment, Patient, Study, and Site Discontinuation ................ 80
4.6.1
Study Treatment Discontinuation ............................................. 80
4.6.1.1
Post-Treatment Assessments .................................................. 80
4.6.2
Patient Discontinuation from the Study .................................... 81
4.6.3
Study Discontinuation .............................................................. 82
4.6.4
Site Discontinuation ................................................................. 82
5.
ASSESSMENT OF SAFETY ......................................................... 82
5.1
Safety Plan .............................................................................. 82
5.1.1
Risks Associated with Atezolizumab ........................................ 83
5.1.2
Risks Associated with Cabozantinib ........................................ 83
5.1.3
Risks Associated with Docetaxel ............................................. 83
5.1.4
Management of Patients Who Experience Adverse Events 
and Potential Overlapping Toxicities ........................................ 84
5.1.4.1
Dose Modifications .................................................................. 84
5.1.4.2
Treatment Interruption ............................................................. 86
5.2
Safety Parameters and Definitions .......................................... 87
5.2.1
Adverse Events ........................................................................ 88
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 88
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 89
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 90
5.3.1
Adverse Event Reporting Period .............................................. 90
5.3.2
Eliciting Adverse Event Information ......................................... 90
5.3.3
Assessment of Severity of Adverse Events ............................. 90
5.3.4
Assessment of Causality of Adverse Events............................ 91
5.3.5
Procedures for Recording Adverse Events .............................. 92
5.3.5.1
Infusion-Related Reactions ...................................................... 92
5.3.5.2
Diagnosis versus Signs and Symptoms ................................... 92
5.3.5.3
Adverse Events That Are Secondary to Other Events ............. 93
5.3.5.4
Persistent or Recurrent Adverse Events .................................. 93


Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol GO41892, Version 5 
 
5.3.5.5 
Abnormal Laboratory Values ................................................... 94 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 94 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 95 
5.3.5.8 
Deaths ..................................................................................... 95 
5.3.5.9 
Preexisting Medical Conditions ................................................ 96 
5.3.5.10 
Lack of Efficacy or Worsening of NonSmall Cell Lung 
Cancer ..................................................................................... 96 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 96 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 97 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 99 
5.3.5.14 
Safety Biomarker Data ............................................................. 99 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 99 
5.4.1 
Emergency Medical Contacts ................................................ 100 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 100 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ........... 100 
5.4.2.2 
Events That Occur after Study Treatment Initiation ............... 100 
5.4.3 
Reporting Requirements for Pregnancies .............................. 101 
5.4.3.1 
Pregnancies in Female Patients ............................................ 101 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 101 
5.4.3.3 
Abortions................................................................................ 102 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 102 
5.5 
Follow-Up of Patients after Adverse Events........................... 102 
5.5.1 
Investigator Follow-Up ........................................................... 102 
5.5.2 
Sponsor Follow-Up ................................................................ 103 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 103 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 103 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 104 
6.1 
Determination of Sample Size ............................................... 104 
6.2 
Summaries of Conduct of Study ............................................ 105 


Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GO41892, Version 5 
 
6.3 
Summaries of Treatment Group Comparability ...................... 105 
6.4 
Efficacy Analysis .................................................................... 106 
6.4.1 
Primary Efficacy Endpoint ...................................................... 106 
6.4.2 
Secondary Efficacy Endpoints ............................................... 106 
 
 
 
 
 
 
 
  
 
6.4.2.2 
Objective Response Rate as Assessed by the Investigator ... 107 
6.4.2.3 
Duration of Response as Assessed by the Investigator ......... 107 
6.4.2.4 
Time to Confirmed Physical Function or Health-Related 
Quality of Life Deterioration ................................................... 107 
6.4.2.5 
Progression-Free Survival Assessed by Investigator at 
Landmark Timepoints ............................................................ 108 
6.4.2.6 
Overall Survival Rate at Landmark Timepoints ...................... 108 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 108 
6.5 
Safety Analyses ..................................................................... 108 
6.5.1 
Exploratory Analyses of Patient-Reported Outcome Data ..... 109 
6.6 
Pharmacokinetic Analyses ..................................................... 109 
6.7 
Immunogenicity Analyses ...................................................... 109 
6.8 
Biomarker Analyses ............................................................... 110 
6.9 
Health Status Utility Analyses ................................................ 110 
6.10 
INTERIM ANALYSES ............................................................ 110 
6.10.1 
Planned Interim Analyses ...................................................... 110 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 111 
7.1 
Data Quality Assurance ......................................................... 111 
7.2 
Electronic Case Report Forms ............................................... 112 
7.3 
Source Data Documentation .................................................. 112 
7.4 
Use of Computerized Systems .............................................. 113 
7.5 
Retention of Records ............................................................. 113 
8. 
ETHICAL CONSIDERATIONS .................................................... 113 
8.1 
Compliance with Laws and Regulations ................................ 113 
8.2 
Informed Consent .................................................................. 114 
8.3 
Institutional Review Board or Ethics Committee .................... 115 
8.4 
Confidentiality ........................................................................ 115 
8.5 
Financial Disclosure ............................................................... 116 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 116 
9.1 
Study Documentation ............................................................ 116 
9.2 
Protocol Deviations ................................................................ 116 
9.3 
Management of Study Quality ................................................ 117 
9.4 
Administrative Structure ......................................................... 117 
9.5 
Site Inspections ..................................................................... 117 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 118 
9.7 
Protocol Amendments ........................................................... 119 
10. 
REFERENCES............................................................................ 120 
LIST OF TABLES 
Table 1 
Cabozantinib Tablet Components and Composition ................... 54 
Table 2 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 55 
Table 3 
Dose Reduction Levels of Cabozantinib (Oral Dosing) ............... 85 
Table 4 
Dose Modifications for Cabozantinib-Related Adverse 
Events ......................................................................................... 86 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 91 
Table 6 
Causal Attribution Guidance ....................................................... 92 
Table 7 
Analysis Timing and Stopping Boundaries for Interim and 
Final Analyses for Primary Endpoint - Overall Survival ............. 111 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 33 
Figure 2 
Scan Frequency .......................................................................... 68 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 127 
Appendix 2 
 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 134 
Appendix 3 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 137 
Appendix 4 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 146 
Appendix 5 
 Anaphylaxis Precautions .......................................................... 147 
Appendix 6 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 148 
Appendix 7 
 Risks Associated with Cabozantinib and Guidelines for 
Management of Adverse Events Associated with 
Cabozantinib ............................................................................. 180 


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Appendix 8
 Highly Effective Methods of Contraception .............................. 196
Appendix 9
 European Organisation for Research and Treatment of 
Cancer Quality of Life–Core 30 Questionnaire:  EORTC 
QLQ-C30................................................................................... 199
Appendix 10
 European Organisation for Research and Treatment of 
Cancer Quality of Life–Lung Cancer 13-Item Questionnaire: 
EORTC QLQ-LC13 ................................................................... 201
Appendix 11
 EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) ...... 203
Appendix 12
 Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) .......... 206
Appendix 13  European Organisation for Research and Treatment of 
Cancer Item List 17 Questionnaire:  EORTC IL17 .................... 208


Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol GO41892, Version 5 
 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL, CONTROLLED STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF ATEZOLIZUMAB GIVEN IN COMBINATION WITH 
CABOZANTINIB VERSUS DOCETAXEL 
MONOTHERAPY IN PATIENTS WITH METASTATIC 
NONSMALL CELL LUNG CANCER PREVIOUSLY 
TREATED WITH AN ANTIPD-L1/PD-1 ANTIBODY AND 
PLATINUM-CONTAINING CHEMOTHERAPY 
PROTOCOL NUMBER: 
GO41892 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Atezolizumab (RO5541267) and cabozantinib (XL184) 
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. 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol GO41892, Version 5 
 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL, 
CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND PHARMACOKINETICS OF ATEZOLIZUMAB GIVEN IN 
COMBINATION WITH CABOZANTINIB VERSUS DOCETAXEL 
MONOTHERAPY IN PATIENTS WITH METASTATIC NONSMALL 
CELL LUNG CANCER PREVIOUSLY TREATED WITH AN 
ANTIPD-L1/PD-1 ANTIBODY AND PLATINUM-CONTAINING 
CHEMOTHERAPY 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS 
IND Number:  146261 
EudraCT Number:  2020-000100-11 
NCT Number:  NCT04471428 
 
STUDY RATIONALE 
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab when 
given in combination with cabozantinib (Atezo  + Cabo) compared with docetaxel monotherapy 
in patients with metastatic non-small cell lung cancer (NSCLC), with no sensitizing 
epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinas (ALK) 
translocation, who have progressed on prior treatment with both anti-PD-L1/PD-1 antibody 
and platinum-containing chemotherapy.  Specific objectives and corresponding endpoints for 
the study are outlined below. 
 
OBJECTIVES AND ENDPOINTS 
EFFICACY OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is to evaluate the efficacy of Atezo  Cabo 
compared with docetaxel monotherapy on the basis of the following endpoint: 
 
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 Atezo  Cabo 
compared with docetaxel monotherapy on the basis of the following endpoints:  
 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression, as determined by the investigator according to 
Response Evaluation Criteria in Solid Tumor, Version 1.1. (RECIST v1.1), or death from 
any cause (whichever occurs first) 
 
Confirmed objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) on two consecutive occasions  4 weeks 
apart, as determined by the investigator according to RECIST v1.1 
 
Duration of response (DOR) for patients with confirmed ORR, defined as the time from the 
first occurrence of a documented objective response to disease progression, as determined 
by the investigator according to RECIST v1.1, or death from any cause (whichever occurs 
first) 


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 
Time to confirmed deterioration in patientreported Physical Function (PF) and global 
health status (GHS) as measured by the corresponding scores from the European 
Organisation for the Research and Treatment of Cancer Quality of LifeCore 30 (EORTC 
QLQ-C30) 
 
PFS rates assessed by the investigator at 6 months and at 1 year  
 
OS rates at 1 and 2 years  
 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of Atezo  Cabo compared with 
docetaxel monotherapy on the basis of the following endpoint: 
 
Incidence and severity of adverse events with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI 
CTCAE v5.0) 
 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
Atezo  Cabo on the basis of the following endpoints: 
 
Serum concentration of atezolizumab at specified timepoints 
 
Plasma concentration of cabozantinib at specified timepoints 
 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to Atezo  Cabo 
on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of 
ADAs to atezolizumab after treatment 
 
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy, safety, and pharmacokinetics of atezolizumab given in combination with cabozantinib 
compared with docetaxel monotherapy in patients with metastatic NSCLC, with no sensitizing 
EGFR mutation or ALK translocation, who have progressed following treatment with 
platinum-containing chemotherapy and antiPD-L1/PD-1 antibody, administered concurrently 
or sequentially.  
Several key aspects of the study design and study population are summarized below.  
Phase: 
Phase III 
Population Type: 
Adult patients 
Control Method: 
Active comparator 
Population Diagnosis 
or Condition: 
Metastatic non-small 
cell lung cancer 
Interventional 
Model: 
Parallel group 
Population Age: 
 18 years 
Test Compound{s}: 
Atezolizumab and 
cabozantinib 
Site Distribution: 
Multi-site and multi-
region 
Active Comparator: Docetaxel 
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of 
Participants to Be 
Enrolled: 
Approximately 350 
 
 
 


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In the experimental arm:  Atezolizumab and cabozantinib treatment will continue until 
unacceptable toxicity, 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).  During study treatment, patients who meet criteria for disease 
progression per RECIST v1.1 and show evidence for clinical benefit may continue atezolizumab 
and/or cabozantinib treatment at the investigator’s discretion provided that the patients meet all 
of the following criteria:   
 
Evidence of clinical benefit, as assessed by the investigator 
 
Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease 
 
No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status that can 
be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 
Patients 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 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) for this study are atezolizumab, cabozantinib, and 
docetaxel. 
TEST PRODUCTS (INVESTIGATIONAL DRUG) 
Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg on 
Day 1 of each 21-day cycle. 
Cabozantinib will be administered orally, once a day at a dose of 40 mg (2  20-mg tablets) on 
Days 121 of each cycle. 
COMPARATOR 
Docetaxel will be administered by IV infusion at a starting dose of 75 mg/m2 every 3 weeks 
according to the locally approved label. 
 
END OF STUDY 
The end of this study will occur when all of the following criteria have been met: 
 
The required number of deaths for the final analysis of OS has been observed or the last 
data point required for safety follow-up is received, whichever occurs later. 
 
The last patient’s last visit has occurred. 
 
In addition, the Sponsor may decide to terminate the study at any time and provide a written 
notification to investigators.  Patients may continue study treatment until the development of 
progressive disease, unacceptable toxicity, patient consent withdrawal, or Sponsor’s decision 
to terminate the study, whichever occurs first.  If the Sponsor decides to end the study, 
patients still receiving study treatment may be offered participation in the continued access 
program or enrollment into another study for continued access to study treatment, if, in the 
opinion of the investigator and in consultation with the Medical Monitor, the patient would 
potentially benefit from continuing therapy and the patient cannot reasonably obtain 
treatment outside of the program.   
 
 


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LENGTH OF STUDY 
The approximate total length of the study, from screening of the first patient to the end of the 
study, is expected to be approximately 47 months. 
 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee 
Other Committees: 
Not applicable 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody, also known as anti-therapeutic 
antibody 
ALK 
anaplastic lymphoma kinase 
AUC 
area under the plasma concentrationtime curve 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRS 
cytokine-release syndrome 
CSR 
Clinical Study Report 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DTC 
differentiated thyroid carcinoma 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EORTC IL46 
European Organisation for Research and Treatment of 
Cancer Item List 46 
EORTC IL17 
European Organisation for Research and Treatment of 
Cancer Item List 17 
EQ-5D-5L 
EuroQol 5-Dimension, 5-Level Questionnaire 
ESMO 
European Society for Medical Oncology 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
GHS 
global health status 
HBV 
hepatitis B virus 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 


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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
ICI 
immune checkpoint inhibitor 
iDMC 
independent Data Monitoring Committee 
IFN 
interferon 
IL 
interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITT 
intent-to-treat (analysis or population) 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LMWH 
low-molecular-weight heparin 
MET 
mesenchymalepithelial transition 
MN 
mobile nursing 
MRI 
magnetic resonance imaging 
MRP2 
multidrug resistance-associated protein 2 
NCCN 
National Comprehensive Cancer Network® 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NSCLC 
nonsmall cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD(L)1 
PD-L1/PD-1 
PF 
Physical Function 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 


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Abbreviation 
Definition 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
QD 
once a day 
QLQ-C30 
Quality of LifeCore 30 Questionnaire 
QLQ-LC13 
Quality of LifeLung Cancer 13-Item Questionnaire 
QOD 
every other day 
QoL 
quality of life 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
RAI 
radioactive iodine 
RBR 
Research Biosample Repository 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RET 
rearranged during transfection 
RF 
Role Function 
RTK 
receptor tyrosine kinase 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SE 
standard error 
SITC 
Society for Immunotherapy of Cancer 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
T3 
free triiodothyronine 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor 
TNF- 
tumor necrosis factor 
TPS 
tumor proportion score 
ULN 
upper limit of normal 
USPI 
U.S. Package Insert 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 
VEGFR2 
vascular endothelial growth factor receptor 2 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON NONSMALL CELL LUNG CANCER 
Lung cancer is one of the most frequently diagnosed cancers worldwide and is also the 
leading cause of cancer deaths in developed countries.  In the United States, it was 
estimated that 228,150 new cases (116,440 in men and 111,710 in women) were 
diagnosed in 2019, while more than 142,670 deaths will occur (76,650 in men and 
66,020 in women; Torre et al. 2016; Seigel et al. 2019).  In Europe, 470,000 new cases 
of lung cancer in 2018 have been estimated (311,800 in men and 158,200 in women), 
while 387,900 deaths were expected to occur (267,300 in men and 120,600 in women; 
Ferlay et al. 2018). 
Nonsmall cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 84% of all lung cancer cases (Howlader et al. 2015).  
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma.  Adenocarcinoma histology accounts for more than half of all NSCLC, 
while squamous cell histology accounts for approximately 25% of NSCLC (Langer et al. 
2010).  The remaining cases of NSCLC are represented by large cell carcinoma, 
neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated histology. 
The overall 5-year survival rate for NSCLC is 23% but drops to as low as 6% for 
metastatic NSCLC (Cancer.Net 2019).  Poor prognostic factors for survival in patients with 
NSCLC include advanced stage of disease at the time of initial diagnosis, poor 
performance status, and a history of unintentional weight loss.  More than half of the 
patients with NSCLC are diagnosed with distant disease, which directly contributes to poor 
survival prospects. 
Treatment options for patients with Stage IV NSCLC are informed by the presence or 
absence of genetic alterations.  Current treatment guidelines recommend testing for the 
genetic abnormalities including epidermal growth factor receptor (EGFR) mutations, 
anaplastic lymphoma kinase (ALK) rearrangements, ROS1 rearrangements, and NTRK 
fusions and BRAF mutations; as well as the presence or absence of PD-L1 expression 
on tumor or tumor-infiltrating immune cells.  There are several other targets that are 
being tested for, including mesenchymal-epithelial transition (MET) alterations, 
rearranged during transfection (RET) rearrangements, and HER2 mutation.  The 
introduction of tyrosine kinase inhibitor (TKI)-based therapy has transformed treatment 
approaches for many of these patients. 
Platinum-containing chemotherapy with or without vascular endothelial growth factor 
(VEGF) targeted therapy (bevacizumab) has been the standard of care front-line therapy 
in patients with advanced NSCLC who do not have genetic markers that can be 
selectively targeted.  Recently, immune checkpoint inhibitors (ICIs) targeting the 
PD-L1/PD-1 signaling pathway have become a new treatment choice in patients with 


 
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metastatic NSCLC by improving overall survival (OS) and progression-free survival 
(PFS) compared with standard chemotherapy (Reck et al. 2016; Gandhi et al. 2018; 
Socinski et al. 2018; Reck et al. 2019).  Currently, several antibody plus chemotherapy 
combinations are approved as first-line treatment of patients with metastatic 
nonsquamous NSCLC:  1) atezolizumab (antiPD-L1 antibody) in combination with 
bevacizumab, paclitaxel, and carboplatin; 2) atezolizumab in combination with 
carboplatin and paclitaxel protein-bound; and 3) pembrolizumab (antiPD-1 antibody) in 
combination with pemetrexed and platinum-containing chemotherapy (Tecentriq U.S. 
Package Insert [USPI] and European Medicines Agency [EMA] Summary of Product 
Characteristics [SmPC]; Keytruda USPI and EMA SmPC).  Additionally, pembrolizumab 
in combination with carboplatin and either paclitaxel or paclitaxel protein-bound is 
approved as first-line treatment of patients with metastatic squamous NSCLC (Keytruda 
USPI and EMA SmPC).  Pembrolizumab is also approved as a monotherapy for the 
first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 with 
no EGFR or ALK translocations (Keytruda USPI and EMA SmPC). 
In addition, several antiPD-L1/PD-1 antibodies have been approved by regulatory 
agencies as a single-agent therapy in patients with NSCLC after prior 
platinum-containing therapy.  These include atezolizumab (Tecentriq USPI and EMA 
SmPC), nivolumab (Opdivo USPI and EMA SmPC), and pembrolizumab (Keytruda 
USPI and EMA SmPC).  The use of an antiPD-L1/PD-1 antibody earlier in the 
treatment paradigm has created a high unmet medical need for antiPD-L1/PD-1 ICI and 
platinum-refractory patients in second and third lines of therapy.  
For patients who progress on an antiPD-L1/PD-1 antibody and platinum-containing 
chemotherapy given sequentially or in combination, additional treatment options include 
single-agent chemotherapy, such as docetaxel and pemetrexed (Planchard et al. 2018).  
The activity of single-agent chemotherapy following platinum-containing first-line therapy 
is modest with objective response rate (ORR) of  10% and median PFS and OS ranging 
from 23 months and 89 months, respectively (Hanna et al. 2004; Garon et al. 2014).  
Although higher response rates have been reported for salvage chemotherapy following 
antiPD-L1/PD-1 ICI therapy, the median PFS and OS appear to be similar in antiPD-
L1/PD-1 ICI-pretreated and antiPD-L1/PD-1 ICI-naive patients who have previously 
received platinum-containing chemotherapy (Grigg et al. 2017; Schvartsman et al. 2017; 
Park et al. 2018).  Another treatment option for patients who progress on or after 
platinum-containing treatment is the combination of an anti-VEGF receptor 2 (VEGFR2) 
antibody, ramucirumab, with docetaxel.  Compared with docetaxel alone, this 
combination demonstrated a modest increase in median PFS (4.5 vs. 3.0 months) and 
median OS (10.5 vs. 9.1 months; Garon et al. 2014). 
1.2 
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), 


 
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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 cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
As noted above, atezolizumab is approved as a combination therapy with either 
bevacizumab, paclitaxel, and carboplatin; or with carboplatin and paclitaxel 
protein-bound for the first-line treatment of patients with metastatic nonsquamous 
NSCLC (Tecentriq USPI, Tecentriq EMA SmPC).  Atezolizumab monotherapy is 
approved as first-line treatment for patients with metastatic NSCLC whose tumors have 
high PD-L1 expression (PD-L1 stained  50% of tumor cells [TC   50%] or PD-L1 stained 
tumor-infiltrating immune cells [IC] (Tecentriq USPI).  Atezolizumab monotherapy is also 
approved for patients who have disease progression during or following platinum-
containing chemotherapy (Tecentriq USPI, Tecentriq EMA SmPC).  Additionally, 
atezolizumab is also approved for the treatment of urothelial carcinoma, small-cell lung 
cancer, triple-negative breast cancer, hepatocellular carcinoma, and melanoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.3 
BACKGROUND ON CABOZANTINIB 
Cabozantinib (XL184) is a potent, orally bioavailable inhibitor of multiple receptor 
tyrosine kinases (RTKs) known to play important roles in tumor cell proliferation and/or 
tumor neovascularization, including the VEGFR2, MET, and RET.  Cabozantinib targets 
also include TYRO3, AXL, and MER (TAM family kinases) and are implicated in 
promoting suppression of an anti-tumor immune response.  Preclinical studies (Kwilas 
et al. 2014; Song et al. 2015; Lu et al. 2017) and clinical observations on circulating 
immune suppressive cells and immune effector cells in cancer patients (Apolo et al. 
2014) suggest that cabozantinib promotes an immune-permissive environment, which 
might present an opportunity for synergistic effects from combination treatment with ICIs 
independent of PD-L1 expression.  
Cabozantinib (60 mg, tablets) is approved as single agent for patients with advanced 
renal cell carcinoma (RCC) and in combination with nivolumab as first-line treatment for 
patients with advanced RCC (Cabometyx USPI), for adult patients with advanced RCC 


 
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after prior VEGF-targeted therapy or treatment-naïve adult patients with intermediate or 
poor risk RCC (Cabometyx EMA 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.  
Cabozantinib (40 mg or 60 mg tablets, depending on body surface area) is also approved 
for the treatment of adult and pediatric patients 12 years of age and older with locally 
advanced or metastatic differentiated thyroid carcinoma (DTC) that has progressed 
following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-
refractory or ineligible (Cabometyx USPI).  Additionally, the use of cabozantinib is 
approved in the European Union and other regions as a second-line treatment in 
RAI-refractory DTC in adult patients.  
Cabozantinib once a day (QD) has been evaluated as a single agent and in combination 
in several early stage clinical trials in ICI-naive patients with advanced NSCLC.  In an 
open-label, randomized Phase II study sponsored by National Cancer Institute (NCI), 
125 patients with nonsquamous NSCLC without EGFR genetic alterations received 
cabozantinib (60 mg QD), erlotinib (150 mg QD), or both agents in combination (erlotinib 
150 mg QD  cabozantinib 40 mg QD) as second- or third-line (post-platinum-containing 
chemotherapy) treatment (Neal et al. 2016).  Compared with erlotinib alone, the primary 
endpoint of PFS was significantly improved in patients receiving cabozantinib as single 
agent (4.3 vs. 1.8 months; hazard ratio [HR]  0.39; p  0.0003) and in combination with 
erlotinib (4.7 vs. 1.8 months; HR  0.37; p  0.0003).  The estimated median OS for 
patients treated with cabozantinib alone was 9.2 months (95% CI: 5.1 to 15.0), for 
cabozantinib with erlotinib was 13.3 months (95% CI: 7.6 to NR), and for erlotinib alone 
was 5.1 months (95% CI: 3.3 to 9.3).  The ORR for patients treated with cabozantinib 
alone was 11%.  Notably, progression as best response was reported for 23%24% for 
patients treated with cabozantinib alone or in combination with erlotinib, and 66% for 
patients treated with erlotinib alone.  The most common Grade 3 or 4 adverse events for 
single-agent cabozantinib were hypertension (25%), fatigue (15%), oral mucositis (10%), 
diarrhea (8%), and thromboembolic events (8%).  One death due to respiratory failure 
assessed as possibly related to study drug occurred in the cabozantinib arm, and one 
death due to pneumonitis assessed as related to either study drug or the combination 
occurred in the erlotinib plus cabozantinib arm. 
In a Phase II randomized discontinuation trial in 526 patients across 9 disease cohorts, 
60 patients with advanced NSCLC of nonsquamous (n  43) or squamous cell (n  17) 
histology received cabozantinib 100 mg QD as a single agent (Schöffski et al. 2017; 
Hellerstedt et al. 2019).  The ORR at Week 12 (primary endpoint) was 10% in the 
NSCLC cohort, 6 patients had a confirmed partial response (PR), and no patients had a 
complete response (CR).  Overall disease-control rate (ORR  stable disease [SD]) at 


 
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Week 12 was 38%.  Tumor regression was observed in 30 of 47 patients (64%) with at 
least one postbaseline radiographic tumor assessment.  Median PFS during the 
randomized stage was 2.4 months for the cabozantinib arm (median PFS during the 
entire treatment period from the start of the study was 4.2 months for all treated 
patients).  The most frequently reported Grade 3 or 4 adverse events were fatigue 
(13%), palmar-plantar erythrodysesthesia [PPE] (10%), diarrhea (7%), hypertension 
(7%), and asthenia (5%).  One treatment-related Grade 5 hemorrhage was reported; 
however, based on a retrospective review of the baseline tumor assessment, this patient 
should have been excluded from the study at screening as there was a tumor mass 
infiltrating the pulmonary artery, which was one of the exclusion criteria. 
Refer to the Cabozantinib Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.4 
ONGOING CLINICAL STUDY WITH ATEZOLIZUMAB AND 
CABOZANTINIB 
Cabozantinib in combination with atezolizumab is currently being evaluated in a 
multi-cohort Phase Ib study in patients with locally advanced or metastatic solid tumors 
(COSMIC-021; NCT03170960).  In the dose-escalation portion of this study, 12 patients 
with treatment-naive advanced RCC were treated at 2 dose levels of cabozantinib 
(6 patients each at 40 mg and 60 mg QD) with atezolizumab administered at 1200 mg 
intravenously (IV) every 3 weeks (Q3W) (Agarwal et al. 2018).  The ORR at the 40 mg 
QD level was 50% (3 of 6 patients), while at the 60 mg QD level it was 83% (5 of 
6 patients).  There were no dose-limiting toxicities (DLTs) or serious adverse events in 
either dose cohort.  Most adverse events, including immune-mediated adverse events, 
were Grade 1 or 2 in severity.  There were 3 patients (25%) who experienced Grade 3 
immune-mediated adverse events (one event each of ALT increased, AST increased, 
GGT increased, lipase increased, and myositis).  Other Grade 3 adverse events 
included five events of hypertension, two events each of diarrhea and 
hypophosphatemia, and one event each of lymphopenia, pulmonary embolism, nephritis, 
and hyperglycemia.  All adverse events were manageable by dose modifications 
including dose reductions and dose delays as well as supportive care.  There were no 
Grade 4 or 5 adverse events.  
Because of a more favorable safety profile of the 40-mg cabozantinib dose level over a 
prolonged time on study treatment with less frequent dose reductions and encouraging 
preliminary efficacy, the cabozantinib dose of 40 mg QD combined with atezolizumab at 
1200 mg Q3W was selected by the Cohort Review Committee as the recommended 
dose for expansion stage in multiple solid tumor expansion cohorts in the COSMIC-021 
study.  One expansion cohort (Cohort 7) is currently enrolling patients with Stage IV 
nonsquamous NSCLC who have radiographically progressed on or after treatment with 
one prior antiPD-1 or antiPD-L1 ICI and platinum-containing chemotherapy for 


 
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metastatic disease.  This cohort has completed initial enrollment of 30 patients, and per 
protocol, has been allowed to enroll up to 50 additional patients.   
As of 21 August 2019, 33 patients have been enrolled and treated in the expansion 
Cohort 7, of whom 27 patients were evaluable for efficacy.  Preliminary clinical activity is 
encouraging:  8 patients with a best response of PR (6 confirmed PRs and 
2 unconfirmed PRs) and 15 patients with a best response of SD.  The most common 
adverse events of any grade regardless of causality in the 33 patients who were 
evaluable for safety comprised diarrhea (45%), fatigue (33%), constipation (30%), 
decreased appetite (27%), asthenia (24%), nausea (24%), hypertension (21%), and 
vomiting (21%).  Grade 4 adverse events comprised neutrophil count decrease (n  1), 
hyponatremia (n  1), dehydration (n  1), atrial thrombosis (n  1), and white blood cell 
count decreased (n  1).  There were five serious adverse events considered to be 
related to study treatment (Grade 3 nausea, Grade 3 PPE, Grade 4 atrial thrombosis, 
Grade 4 dyspnea and subsequent death in one patient).  Grade 5 adverse events 
observed were disease progression (n  2), death (n  2), completed suicide (n  1), 
sepsis secondary to disease progression (n  1), and general physical health 
deterioration (n  1).  Only one of these Grade 5 events (death) is considered related to 
study treatment by the investigator.  This patient had Grade 5 events considered related 
to atezolizumab (interstitial lung disease, myocarditis, and death). 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.5.1 
Study Rationale 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The use of antiPD-L1/PD-1 antibody in the first-line setting has shifted the treatment 
landscape creating a high unmet medical need for antiPD-L1/PD-1 ICI-refractory 
patients in second and third lines of therapy.  
For patients who progress on antiPD-L1/PD-1 antibody and platinum-containing 
chemotherapy given sequentially or in combination, additional treatment options include 
single-agent chemotherapy, such as docetaxel and pemetrexed (NCCN 2019; European 
Society for Medical Oncology [ESMO] guidelines for metastatic NSCLC, Planchard et al. 
2018).  Given the modest activity of these agents, there is a significant unmet need for 
novel treatment options in patients with NSCLC who have progressed on or after prior 
platinum-containing chemotherapy and antiPD-L1/PD-1 therapies. 
The combination of atezolizumab and cabozantinib has shown encouraging preliminary 
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on or after treatment with one prior anti-PD-1 or anti-PD-L1 ICI and platinum-containing 
chemotherapy for metastatic disease (see Section 1.4).  
This is a Phase III, multicenter, randomized, open-label study to evaluate the efficacy 
and safety of atezolizumab given in combination with cabozantinib versus docetaxel 
monotherapy, in patients with metastatic NSCLC who have progressed following prior 
treatment with antiPD-L1/PD-1 antibody and platinum-containing chemotherapy.  
Evaluation of single-agent cabozantinib is being performed within the Phase Ib study 
(COSMIC-021), in which a single-agent cabozantinib cohort is enrolling a similar patient 
population as this Phase III study.  This allows for an evaluation of the contribution of the 
cabozantinib component of the combination  
1.5.2 
Overall BenefitRisk Assessment 
There is a significant unmet need in patients with metastatic NSCLC who have 
progressed following prior platinum-containing chemotherapy and antiPD-L1/PD-1 
antibody.  Currently, single-agent docetaxel is the most frequently used treatment option 
available to these patients. 
This randomized, open-label, Phase III study evaluates the efficacy and safety of 
atezolizumab in combination with cabozantinib compared with docetaxel monotherapy in 
patients with metastatic NSCLC who have progressed on prior platinum-containing 
chemotherapy and antiPD-L1/PD-1 antibody.  Preliminary clinical data with the 
combination of these two agents in the NSCLC cohort (Cohort 7) in the ongoing 
Phase Ib study (COSMIC-021) have shown improved efficacy and long-term tolerability 
in patients who have radiographically progressed on or after treatment with one prior 
anti-PD-1 or anti-PD-L1 ICI and platinum-containing chemotherapy for metastatic 
disease.  The combination of atezolizumab and cabozantinib has not been evaluated in 
squamous NSCLC.  However, single-agent activity of atezolizumab (Rittmeyer et al. 
2017; Section 1.2) and cabozantinib (Schöffski et al. 2017; Section 1.3) has been 
demonstrated in studies that evaluated both nonsquamous and squamous NSCLC 
where a similar treatment effect was observed with both histologies.  Atezolizumab and 
cabozantinib have each demonstrated single-agent clinical activity in previously treated 
patients with NSCLC (Sections 1.2 and 1.3).  The safety profile of each of the 
constituents of the combination is well-defined, and the combination has been studied in 
previous clinical trials with manageable safety profile.  Dose management guidelines are 
included in the current study protocol for the most important risks.  
Thus, the overall benefitrisk assessment is deemed favorable. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
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syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade is 
associated with serious exacerbation of inflammation in the setting of acute (as opposed 
to chronic) viral infection with lymphocytic choriomeningitis virus (Clone 13) (Frebel et al. 
2012).  However, there are insufficient and inconsistent clinical data to assess if 
outcome from SARS-CoV-2 infection is altered by cancer immunotherapy. 
Severe SARS-CoV-2 infection is associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- 
(Merad and Martin 2020).  While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute SARS-
CoV-2 infection while receiving atezolizumab.  At this time, there is insufficient evidence 
for causal association between atezolizumab and an increased risk of severe outcomes 
from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2 related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including ICIs), with the understanding 
that there are limited safety and efficacy data in such patients (NCCN 2021).  Given the 
lack of clinical data, currently no recommendations can be made regarding the optimal 
sequence of COVID-19 vaccination in patients who are receiving cancer immunotherapy 
(SITC 2020).  For patients enrolling in this study and receiving atezolizumab and 
cabozantinib treatment, a decision to administer the vaccine to a patient should be made 
on an individual basis by the investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
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receive COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection 
and potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab when 
given in combination with cabozantinib (Atezo  Cabo) compared with docetaxel 
monotherapy in patients with metastatic NSCLC, with no sensitizing EGFR mutation or 
ALK translocation, who have progressed on prior treatment with both antiPD-L1/PD-1 
antibody and platinum-containing chemotherapy.  Specific objectives and corresponding 
endpoints for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of Atezo  Cabo 
compared with docetaxel monotherapy on the basis of the following endpoint: 
 
OS, 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 Atezo  Cabo 
compared with docetaxel monotherapy on the basis of the following endpoints:  
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator according to Response Evaluation 
Criteria in Solid Tumor, Version 1.1. (RECIST v1.1), or death from any cause 
(whichever occurs first) 
 
Confirmed ORR, defined as the proportion of patients with a CR or PR on two 
consecutive occasions  4 weeks apart, as determined by the investigator according 
to RECIST v1.1 
 
Duration of response (DOR) for patients with confirmed ORR, defined as the time 
from the first occurrence of a documented objective response to disease 
progression, as determined by the investigator according to RECIST v1.1, or death 
from any cause (whichever occurs first) 
 
Time to confirmed deterioration in patient-reported Physical Function (PF) and 
global health status (GHS) as measured by the corresponding scores from the 


 
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European Organisation for Research and Treatment of Cancer Quality of LifeCore 
30 Questionnaire (EORTC QLQ-C30) 
 
PFS rates assessed by the investigator at 6 months and at 1 year  
 
OS rates at 1 and 2 years  
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of 
Atezo  Cabo compared with docetaxel monotherapy on the basis of the following 
endpoint: 
 
Change from baseline and proportion of patients who report deterioration, 
improvement, or no change in their symptoms and functioning including quality of 
life (QoL) as measured by the EORTC Quality of LifeLung Cancer 13-Item 
Questionnaire (EORTC QLQ-LC13) symptom scores (cough, dyspnea, chest pain, 
arm/shoulder pain, or fatigue) and EORTC QLQ-C30 functioning scores (PF, Role 
Function [RF], GHS) 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of Atezo  Cabo compared 
with docetaxel monotherapy on the basis of the following endpoint: 
 
Incidence and severity of adverse events with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 
 
The exploratory safety objective for this study is to evaluate the safety of Atezo  Cabo 
compared with docetaxel monotherapy from the patient's perspective on the basis of the 
following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of selected symptoms frequently reported with the intake of 
atezolizumab, cabozantinib, or docetaxel, as determined through the use of the NCI 
Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) (see Appendix 12) 
 
Change from baseline in selected symptoms frequently reported with the intake of 
atezolizumab, cabozantinib, or docetaxel, as assessed through use of the 
PRO-CTCAE 
 
Frequency of patients’ response of the degree they are troubled with treatment 
symptoms, as assessed through use of the single item EORTC Item List 46 
(EORTC IL46) 
 
 


 
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2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
Atezo  Cabo on the basis of the following endpoints: 
 
Serum concentration of atezolizumab at specified timepoints 
 
Plasma concentration of cabozantinib at specified timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
Atezo  Cabo on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and 
incidence of ADAs to atezolizumab after treatment 
 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs to atezolizumab on the basis of the following endpoint: 
 
Relationship between atezolizumab ADA status and efficacy, safety, or PK 
endpoints 
 
2.5 
EXPLORATORY BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to Atezo  Cabo (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 
Atezo  Cabo, can provide evidence of Atezo  Cabo activity (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 peripheral blood mononuclear cells (PBMC), 
plasma, serum, and tumor tissue (including, but not limited to, PD-L1, PD-1, somatic 
mutations, and others) 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 Atezo  Cabo compared with docetaxel monotherapy 
to inform pharmacoeconomic modeling on the basis of the following endpoints: 
 
Health utility scores from the EuroQol 5-Dimension Questionnaire (5-level version; 
EQ-5D-5L) index-based at each timepoint  
 
Change from baseline at each timepoint using the EQ-5D-5L visual analog scale 
(VAS) scores 
 


 
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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, safety, and pharmacokinetics of atezolizumab given in combination with 
cabozantinib compared with docetaxel monotherapy in patients with metastatic NSCLC, 
with no sensitizing EGFR mutation or ALK translocation, who have progressed following 
treatment with platinum-containing chemotherapy and antiPD-L1/PD-1 antibody, 
administered concurrently or sequentially.  
Approximately 350 eligible patients will be randomized in a 1:1 ratio at approximately 
125 global sites in this trial.  
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 
 
Ab  antibody; NSCLC  nonsmall cell lung cancer; NSQ  nonsquamous; PO  by mouth; 
QD  once a day; Q3W  every 3 weeks; RECIST v1.1  Response Evaluation Criteria in Solid 
Tumors, Version 1.1; SQ  squamous. 
  
After providing informed consent, patients will undergo screening procedures as outlined 
in the schedule of activities in Appendix 1.  Patients who do not meet the criteria for 
participation in this study (screen failure) may qualify for one re-screening opportunity 
(for a total of two screenings per participant) at the investigator's discretion.  Patients are 
not required to re-sign the consent form.  The investigator will record reasons for screen 
failure in the screening log (see Section 4.5.1).  Screening period may be extended per 
investigators discretion based on extenuating circumstances (i.e., delayed laboratory 
results). 
Patients with tumors of nonsquamous histology with unknown EGFR or ALK mutational 
status will be required to be tested either locally using a validated health 


 
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authorityapproved test or via central laboratory prior to enrollment (see specific 
exclusion Section 4.1.2).  Patients with tumors of squamous histology who have an 
unknown EGFR or ALK mutational status will not be required to be tested (see specific 
exclusion criteria in Section 4.1.2). 
Eligible patients will be in a randomized 1:1 ratio to receive either atezolizumab plus 
cabozantinib or docetaxel monotherapy.  Randomization will be stratified by: 
 
Histology: nonsquamous versus squamous  
 
Prior NSCLC treatment regimen(s) at the following four levels: 
1. 
Concurrent platinum-containing chemotherapy and antiPD-L1/PD-1 antibody 
combination 
2. 
Platinum-containing chemotherapy first, disease progression occurs, followed 
by antiPD-L1/PD-1 antibody 
3. 
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by platinum-containing chemotherapy without antiPD-L1/PD-1 
antibody 
4. 
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by continued anti-PD-L1/PD-1 antibody in combination with platinum-
containing chemotherapy added on  
 
In the experimental arm, atezolizumab (fixed dose of 1200 mg) will be administered by 
IV infusion on Day 1 of each 21-day cycle.  Cabozantinib (40 mg) will be administered 
orally in tablet form (two tablets of 20 mg each) QD on Days 121 of each cycle.  In the 
control arm, docetaxel (75 mg/m2) will be administered by IV on Day 1 of each 21-day 
cycle. 
In the experimental arm:  Atezolizumab and cabozantinib treatment will continue until 
unacceptable toxicity, 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).  During study treatment, patients who 
meet criteria for disease progression per RECIST v1.1 and show evidence for clinical 
benefit may continue atezolizumab and/or cabozantinib treatment at the investigator’s 
discretion provided that the patients meet all of the following criteria:   
 
Evidence of clinical benefit, as assessed by the investigator 
 
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease 
 
No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
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 
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 and/or standard therapies exist must 
provide written consent to acknowledge deferring these treatment options in favor of 
continuing study treatment at the time of progression 
 
Patients randomized to the experimental arm may be allowed to discontinue one 
component of the combination study treatment but continue to receive the other 
component.  
In the control arm:  Docetaxel treatment will continue until unacceptable toxicity or 
disease progression as assessed by the investigator per RECIST v1.1. 
Crossover from the control-arm to the experimental-arm will not be allowed.  
Patients will undergo tumor assessments at baseline, every 6 weeks ( 7 days) for the 
first 48 weeks following Day 1 of Cycle 1, and every 9 weeks ( 7 days) after completion 
of the Week 48 tumor assessment regardless of treatment delays.  Patients will continue 
scanning regardless of treatment delays until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for patients who continue study treatment after 
disease progression per RECIST v1.1), withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  
Patients in the experimental arm who are treated beyond disease progression per 
RECIST v1.1 will undergo tumor assessments at the frequency described above 
(i.e., every 6 weeks [ 7 days] for the first 48 weeks and every 9 weeks [ 7 days] after 
48 weeks) until study treatment is discontinued. 
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.  In the absence of radiographic 
disease progression per RECIST v1.1, tumor assessments should continue regardless 
of whether a patient starts a new anti-cancer therapy.  
Response will be assessed according to RECIST v1.1 (see Appendix 3). 
During the study, patients will be asked to complete patient-reported outcome (PRO) 
surveys at the beginning of the study (i.e., Day 1 of Cycle 1), on Day 1 of each cycle 
after Day 1 of Cycle 1, at treatment discontinuation, and during survival follow-up at 
3 and 6 months (see Section 4.5.9 and Appendix 1).  Completion of PRO questionnaires 
will no longer be required after the final OS analysis. 


 
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After study treatment discontinuation, survival follow-up information will be collected by 
means of telephone calls, patient medical records, and/or clinic visits approximately 
every 3 months or more frequently until death, loss to follow-up, or study termination by 
the Sponsor, whichever occurs first (see Section 4.6.1).  All patients will be periodically 
contacted for survival and new anti-cancer therapy information unless the patient 
requests to be withdrawn from survival follow-up (this request must be documented in 
the source documents and signed by the investigator).  After completion of final OS 
analysis, patients will only need to be followed for 6 months after the last dose of study 
treatment and information on new anti-cancer therapy will no longer be required.  If the 
patient withdraws from the study, study staff may use a public information source (e.g., 
county records) when permissible to obtain information about survival status. 
3.1.1 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will evaluate safety data and will 
review the interim analysis for OS.  Sponsor affiliates will be excluded from iDMC 
membership.  The iDMC will follow a charter that outlines the iDMC roles and 
responsibilities and meeting frequencies. 
Unblinded safety data will be reviewed on a periodic basis, approximately every 
6 months or as needed from the time of enrollment of the first patient.  Unblinded 
efficacy data will be reviewed as part of an interim analysis for OS (see Section 6.10).  
All summaries and analyses for the iDMC review will be prepared by an external 
independent Data Coordinating Center. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  For the interim analysis of OS, the iDMC will review the 
analysis results provided by the iDCC and will recommend or not recommend to unblind 
the study to the Sponsor.  Final decisions will rest with the Sponsor.  Details will be 
specified in the iDMC charter. 
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 (IRBs/ECs). 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study will occur when all of the following criteria have been met: 
 
The required number of deaths for the final analysis of OS has been observed 
(see Section 6.4.1) or the last data point required for safety follow-up is received, 
whichever occurs later. 
 
The last patient’s last visit has occurred. 
 


 
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In addition, the Sponsor may decide to terminate the study at any time and provide a 
written notification to investigators.  Patients may continue study treatment until the 
development of progressive disease, unacceptable toxicity, patient consent withdrawal, 
or Sponsor’s decision to terminate the study, whichever occurs first.  If the Sponsor 
decides to end the study, patients still receiving study treatment may be offered 
participation in the continued access program or enrollment into another study for 
continued access to study treatment, if, in the opinion of the investigator and in 
consultation with the Medical Monitor, the patient would potentially benefit from 
continuing therapy and the patient cannot reasonably access the treatment outside of 
the program.   
The approximate total length of the study, from screening of the first patient to the end of 
the study, is expected to be approximately 47 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Evaluating Cabozantinib in Combination with 
Atezolizumab in Metastatic NSCLC after Progression on Prior 
Platinum-Containing Chemotherapy and AntiPD-L1/PD-1 
Antibody 
As outlined in Section 1.3, in addition to multiple RTKs such as VEGFR2, MET, and 
RET, cabozantinib also inhibits TYRO3, AXL, and MER (TAM family kinases).  The latter 
are implicated in promoting suppression of an antitumor immune response.  Preclinical 
studies (Kwilas et al. 2014; Song et al. 2015; Lu et al. 2017) and clinical observations on 
circulating immune suppressive cells and immune effector cells in patients with cancer 
(Apolo et al. 2014) suggest that cabozantinib promotes an immune-permissive 
environment, which might present an opportunity for synergistic effects from combination 
treatment with antiPD-L1/PD-1 ICIs independent of PD-L1 expression.  
Cabozantinib in combination with atezolizumab is currently being evaluated in a 
multi-cohort Phase Ib study in patients with locally advanced or metastatic solid tumors 
(COSMIC-021) (see the Cabozantinib Investigator's Brochure for more information).  In 
Study COSMIC-021, encouraging clinical activity and tolerability of this combination was 
observed.  Thus, this combination holds promise as a potential new treatment 
opportunity in patients with metastatic NSCLC who have limited treatment options after 
failure of antiPD-L1/PD-1 antibody and platinum-containing chemotherapy.   
This randomized, open-label, Phase III study of the efficacy and safety of atezolizumab 
in combination with cabozantinib versus docetaxel monotherapy in patients with 
metastatic NSCLC who have progressed on prior platinum-containing chemotherapy and 
antiPD-L1/PD-1 antibody will test this hypothesis. 


 
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3.3.2 
Rationale for Control Arm  
For patients with metastatic NSCLC, after failure of initial systemic chemotherapy and 
antiPD-L1/PD-1 treatment (either sequentially or concurrently), subsequent treatment 
options based on NCCN or ESMO guidelines include a) docetaxel; b) pemetrexed; and 
c) docetaxel and ramucirumab.  Of these options, docetaxel is the most frequently used 
treatment option in this setting globally.  
Docetaxel is approved in the United States as a single agent for locally advanced or 
metastatic NSCLC after platinum therapy failure and with cisplatin for unresectable, 
locally advanced or metastatic untreated NSCLC (Taxotere USPI) and also approved in 
the European Union for the treatment of patients with locally advanced or metastatic 
NSCLC after failure of prior chemotherapy (Taxotere EMA SmPC).   
More recently, the combination of docetaxel and ramucirumab was approved in the 
United States and the European Union for the second- and third-line treatment of 
metastatic NSCLC, based on the results of a large Phase III study comparing docetaxel 
and ramucirumab versus docetaxel monotherapy (n  1253 patients).  The study 
demonstrated a modest increase in median PFS (4.5 vs. 3.0 months) and median OS 
(10.5 vs. 9.1 months) (Garon et al. 2014).  This modest improvement in efficacy was 
seen in both squamous and nonsquamous histologies.  
Currently, docetaxel monotherapy continues to be widely used in this patient population.  
Several recent randomized Phase III trials in NSCLC in second- and third-line treatment 
of patients with metastatic NSCLC have been designed with docetaxel as the active 
control arm (Borghaei et al. 2015; Herbst et al. 2016; Rittmeyer et al. 2017).  Thus, 
based on the global treatment landscape, docetaxel will be used as the comparator in 
this study.  
3.3.3 
Rationale for Study Treatment Dose Selection and Treatment 
Schedule 
3.3.3.1 
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 dose regimen for atezolizumab 
(Tecentriq USPI) in NSCLC, and this atezolizumab dose regimen is also currently being 
evaluated in the Phase Ib study (COSMIC-021) of atezolizumab and cabozantinib.  
Anti-tumor activity has been observed across doses ranging from 1 mg/kg to 20 mg/kg 
Q3W.  In Study PCD4989g, the maximum tolerated dose of atezolizumab was not 
reached and no DLTs were observed at any dose.  The fixed dose of 1200 mg Q3W 
(equivalent to an average body weight-based dose of 15 mg/kg Q3W) was selected on 
the basis of both nonclinical studies (Deng et al. 2016) and available clinical PK, 
efficacy, and safety data (refer to the Atezolizumab Investigator's Brochure for details). 


 
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3.3.3.2 
Rationale for Cabozantinib Dose and Schedule 
In this Phase III study, the starting cabozantinib dose will be 40 mg QD based on results 
from the ongoing Phase Ib study (COSMIC-021) evaluating atezolizumab in combination 
with cabozantinib (Section 1.4).  In the Phase Ib study, a total of 12 patients with 
advanced RCC were evaluated in the dose-escalation stage at the 40-mg or 60-mg 
cabozantinib dose level (6 patients each) plus the standard dose of atezolizumab.  After 
reviewing all available safety and efficacy data of the dose-escalation stage, the Cohort 
Review Committee determined that cabozantinib 40 mg QD orally in combination with 
1200 mg atezolizumab Q3W IV is the recommended dose for the expansion-stage 
combination-therapy cohorts.  The Cohort Review Committee decision was based on the 
favorable safety profile of the 40-mg cabozantinib dose level over a prolonged time on 
study treatment with less frequent dose reductions and encouraging preliminary efficacy, 
which was deemed to optimize the benefitrisk of the combination therapy in multiple 
solid tumor expansion cohorts including an NSCLC cohort. 
The lower 40-mg dose of cabozantinib in combination with atezolizumab is further 
supported by an exposure-response analysis of safety and efficacy endpoints from 
cabozantinib monotherapy data in the METEOR trial in 2L RCC evaluating 60-mg 
cabozantinib versus everolimus (Lacy et al. 2018).  Dose reductions to 40 mg and then 
20 mg were allowed and occurred in 62% of patients in the cabozantinib group.  The 
60-mg exposure was associated with a higher risk for selected adverse events including 
PPE (Grade  1), fatigue/asthenia (Grade  3), hypertension (systolic blood 
pressure  160 mmHg or diastolic blood pressure  100 mmHg), and diarrhea 
(Grade  3), with predicted HRs of 1.49, 1.42, 1.36, and 1.33, respectively, relative to the 
predicted average steady-state cabozantinib concentration for a 40-mg starting dose.  
While the efficacy was somewhat lower with a 40-mg monotherapy dose compared to 
the 60-mg dose (higher risk of disease progression/death (HR  1.1), lower maximal 
median reduction in tumor size (9.1% vs. 11.9%) and lower ORR (15.6% vs. 19.1%), 
the benefitrisk in combination with atezolizumab based on the dose-escalation stage of 
the COSMIC-021 Phase Ib study favored the lower 40-mg cabozantinib dose, 
considering the potential overlapping adverse events of the two agents. 
3.3.4 
Rationale for Patient Population and Analysis Groups 
There is a significant unmet need in patients with metastatic NSCLC who have 
progressed following prior platinum-containing chemotherapy and antiPD-L1/PD-1 
antibody either in combination or in sequence.  Currently, single-agent chemotherapy is 
the main treatment option available to these patients but has modest activity as 
described above.  Both atezolizumab and cabozantinib have shown single-agent activity 
in multiple tumor types, including NSCLC.  Moreover, atezolizumab is approved as 
monotherapy for patients with metastatic NSCLC who have disease progression during 
or following platinum-containing chemotherapy (Tecentriq USPI), or as monotherapy for 
the treatment of adult patients with locally advanced or metastatic NSCLC after prior 
chemotherapy (Tecentriq SmPC).  The encouraging observed clinical activity and 


 
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tolerability of this combination hold promise as a potential new treatment opportunity in 
patients with metastatic NSCLC who have progressed on prior platinum-containing 
chemotherapy and antiPD-L1/PD-1 antibody.  This randomized, open-label, Phase III 
study of the efficacy and safety of atezolizumab in combination with cabozantinib versus 
docetaxel monotherapy in patients with metastatic NSCLC who have progressed on 
prior platinum-containing chemotherapy and antiPD-L1/PD-1 antibody will test this 
hypothesis.  Patients whose tumors have EGFR mutations or ALK translocation for 
which targeted therapy is approved are excluded irrespective of whether such therapy 
has previously been given.  
3.3.5 
Rationale for Open-Label Study  
An open-label study design was chosen for this trial, and this allows for adequate side 
effect management given the different toxicity profiles associated with each study drug.  
Furthermore, a blinded study would require administration of IV placebo, which could 
pose additional burden to patients.  Finally, because of the potential for 
pseudoprogression in patients randomized to the experimental arm, a blinded study 
would require all patients to continue treatment until loss of clinical benefit regardless of 
the arm to which they are randomized.  This could then delay subsequent treatment with 
approved therapies, as well as increase the complexity of treatment decisions for 
patients on the docetaxel arm. 
3.3.6 
Rationale for Treatment beyond Initial Radiographic 
Progression per RECIST v1.1 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (PD) (by initial radiographic 
evaluation) may not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression and/or tumor immune infiltration, this study will allow patients 
randomized to receive atezolizumab plus cabozantinib to continue to receive study 
treatment after apparent radiographic progression, provided the benefitrisk ratio is 
judged to be favorable (see criteria in Section 3.1).  Patients should be discontinued for 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data, 
biopsy results (if available), and clinical status. 
3.3.7 
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 will 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 
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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.  Methods for the 
biomarker analysis may also include, but are not limited to, digital polymerase chain 
reaction (PCR), quantitative reverse transcriptionPCR, and proteomics-based 
approaches. 
Fresh tumor biopsy, when clinically feasible, is preferred.  Tumor tissue will also be 
collected at the time of first evidence of radiographic disease progression per 
RECIST v1.1, if deemed clinically feasible by the investigator, to enable analysis of 
tumor tissue biomarkers related to resistance, disease progression, and clinical benefit 
of atezolizumab. 
Blood-based biomarkers (including, but not limited to, circulating tumor DNA [ctDNA]) 
may be also evaluated and correlated with Atezo  Cabo efficacy and evaluated as 
surrogate markers of efficacy.  This evaluation of blood-based markers may provide 
evidence for biologic activity of Atezo  Cabo in patients with NSCLC, help to identify 
patients who may benefit most from Atezo  Cabo, 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 samples will be collected in order to better understand the changes in 
blood-based 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 Atezo  Cabo or the 
pathogenesis of NSCLC.  
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.  WES 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 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. 


 
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3.3.8 
Rationale for Patient-Reported Assessments  
In the treatment of lung cancer, it is important to both increase survival and minimize 
symptoms by delaying progression because symptoms have negative impacts on 
patients’ functioning including health-related quality of life (HRQoL) (Hyde and Hyde 
1974; Hopwood and Stephens 1995; Sarna et al. 2004).  Patients are uniquely qualified 
to report their symptom severity and how it impacts their daily functioning and overall 
QoL.  Therefore, PROs will complement traditional evaluation of survival and tumor 
progression (see Section 2.1.2).  In addition, many of the most frequent adverse events 
attributed to atezolizumab, cabozantinib, or docetaxel (e.g., fatigue, rash, nausea) are 
symptoms directly reportable by patients; therefore, patients’ reporting of their 
experience with these symptoms will complement the evaluation of treatment tolerability 
(King-Kallimanis et al. 2019).  
This study includes use of validated patient-reported measures of symptom severity and 
symptom impact on functioning including HRQoL:  the EORTC QLQ-C30; its 
lung-specific module EORTC QLQ-LC13; and selected scales from the PRO-CTCAE 
item library to reflect known experience receiving atezolizumab, cabozantinib, and 
docetaxel, including one-item EORTC IL46 to document overall treatment burden.  Data 
generated from these questionnaires will inform patients’ experience with disease 
burden and treatment tolerability as part of the totality of evidence generated to inform 
the riskbenefit of atezolizumab and cabozantinib. 
Although the patients will not be blinded to their treatment, to date, upon examination of 
open-label studies, there is no empirical evidence that assessor bias is of such 
magnitude as to alter the findings particularly when ratings are on specific concepts as 
symptoms severity and symptoms interference with daily functioning (Atkinson et al. 
2017; Roydhouse et al. 2019).  
The EQ-5D-5L is also included in this study to generate utility scores for use in economic 
models for reimbursement.   
3.3.9 
Rationale for Stratification Factors 
To balance key clinical risk factors between the two treatment arms, randomization will 
be stratified as follows: 
 
Histology:  squamous vs. nonsquamous 
 
Prior NSCLC treatment regimen(s) at the following four levels: 
1. Patients who have received concurrent platinum-containing chemotherapy and 
antiPD-L1/PD-1 antibody combination 
2. Patients who have received platinum-containing chemotherapy first, disease 
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3. Patients who have received antiPD-L1/PD-1 antibody monotherapy first, 
disease progression occurs, followed by platinum-containing chemotherapy 
without anti-PD-L1/PD-1 antibody 
4. Patients who have received antiPD-L1/PD-1 antibody monotherapy first, 
disease progression occurs, followed by continued anti-PD-L1/PD-1 antibody in 
combination with platinum-containing chemotherapy added on  
 
The rationale for including each of these stratification factors is described below. 
Histology 
Since antiPD-L1/PD-1 antibodies appear to be equally efficacious in both squamous 
and nonsquamous histologies, this study will allow patients with either squamous or 
nonsquamous NSCLC to be enrolled.  However, it is well documented that median OS is 
shorter in patients with metastatic NSCLC with squamous histology than nonsquamous 
histology.  Therefore, histology is selected as a stratification factor to minimize any 
imbalance in these subgroups. 
Prior NSCLC Treatment Regimens 
A number of factors relating to prior NSCLC regimen may be associated with differing 
clinical outcomes, including the number, order of prior lines of therapy, and last type of 
therapy type received.   
For example, patients who have progressed on platinum-containing chemotherapy 
followed by antiPD-L1/PD-1 antibody (two prior lines of therapy) may have poorer 
outcomes than patients who have progressed on prior antiPD-L1/PD-1 antibody and 
platinum-containing chemotherapy in combination (i.e., one prior line of therapy) on the 
basis of having failed more lines of treatment.  For example, in the 2L/3L NSCLC OAK 
study (Rittmeyer et al. 2017), 2L patients had better OS outcome than 3L patients (OS 
HR of 0.71 in 2L vs. 0.80 in 3L, in favor of atezolizumab).   
In addition to the number of prior regimens, proximity to last antiPD-L1/PD-1 antibody 
treatment may correlate with outcomes as any intervening therapy may impact observed 
efficacy associated with re-challenge.   
Given the uncertainty regarding the underlying biology including mechanisms of 
resistance for antiPD-L1/PD-1 antibody refractory versus antiPD-L1/PD-1 antibody 
resistant NSCLC, sequencing of therapy, and last type of therapy; a multi-factor 
stratification factor will be used to maintain balance between study arms. 
Stratification on all permutations of when and in what combination prior antiPD-L1/PD-1 
antibody was received will minimize potential imbalances that may impact efficacy with 
re-challenge with an antiPD-L1/PD-1 antibody. 


 
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4. 
MATERIALS AND METHODS 
4.1 
PATIENTS  
Approximately 350 patients with metastatic NSCLC will be enrolled during the global 
enrollment phase of this study.  
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for entry into the study: 
 
Signed informed consent form 
 
Age  18 years old or meeting country definition of adult, whichever is older, on the 
day of consent 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Histologically or cytologically confirmed metastatic NSCLC 
 
Documented radiographic disease progression during or following treatment with 
platinum-containing chemotherapy and antiPD-L1/PD-1 antibody, administered 
concurrently or sequentially for metastatic NSCLC 
If antiPD-L1/PD-1 antibody and platinum-containing chemotherapy are given 
concurrently as the first-line treatment for metastatic NSCLC, no further lines of 
systemic anti-cancer therapy are allowed.  
If antiPD-L1/PD-1 antibody and platinum-containing chemotherapy are given 
sequentially as first and second lines, respectively, for metastatic NSCLC, no 
further lines of systemic anti-cancer therapy are allowed.  
Combination therapies with other agents are allowed with antiPD-L1/PD-1 
and/or platinum-containing chemotherapy (see exclusion criteria for 
exceptions). 
 
Measurable disease per RECIST v1.1 outside CNS as assessed by investigator  
Previously irradiated lesions can be considered as measurable disease only if PD 
has been unequivocally documented at that site since radiation. 
 
Known PD-L1 status or availability of tumor tissue for central PD-L1 testing: 
− 
Availability of representative fresh and archival tumor specimens suitable for 
determination of PD-L1 status via central testing (see Section 4.5.7 for tissue 
requirements).  Results of central PD-L1 testing are not required for patient to 
be randomized into the study. 
If obtaining representative fresh tumor is not clinically feasible, 
representative archival tumor specimen is acceptable. 
− 
If no tissue specimen (fresh or archival) is available, documentation of known 
PD-L1 status as established by a health authorityapproved PD-L1 assay is 
required.  
 
ECOG Performance Status score of 0 or 1  


 
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 
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 on 
supportive therapy in the opinion of the investigator 
Grade 2 alopecia is allowed for study participation.  
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to randomization: 
− 
ANC  1500/µL ( 1.5  109/L) without granulocyte colony-stimulating factor 
support within 14 days of laboratory sample collection 
− 
Lymphocyte count  0.5  109/L (500/L) 
− 
Platelets ≥ 100,000/µL ( 100  109/L) without transfusion within 14 days of 
laboratory sample collection 
− 
Hemoglobin  9 g/dL ( 90 g/L) without transfusion within 14 days of laboratory 
sample collection 
− 
Serum bilirubin  1.0  upper limit of normal (ULN) 
− 
Liver function tests meeting one of the following criteria: 
ALT and AST  2.5  ULN with ALP  2.5  ULN, 
OR 
ALT and AST  1.5  ULN with ALP  2.5  ULN 
− 
Serum creatinine  1.5  ULN or calculated creatinine clearance  40 mL/min 
(using the Cockcroft-Gault equation): 
For males:  (140 – age)  weight (kg)/(serum creatinine [mg/dL]  72) 
For females:  Multiply above value by 0.85. 
− 
Albumin  25 g/L (2.5 g/dL) 
− 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  1.5  ULN 
− 
Urine protein/creatinine ratio  1 mg/mg ( 113.2 mg/mmol) or 24-hour urine 
protein  1 g 
 
Negative HIV test at screening 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening 
The HBV DNA test will be performed only for patients who have a 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. 


 
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 
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 two methods of contraception, including 
at least one method with a failure rate of  1% per year, during the treatment 
with atezolizumab in combination with cabozantinib in the experimental arm or 
during the treatment with docetaxel in the control arm, and for 5 months after 
the final dose of atezolizumab and/or 4 months after the final dose of 
cabozantinib, whichever is later.  Women must refrain from donating eggs 
during this same period. 
A woman is considered to be of childbearing potential if she is 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).  Per this definition, a woman with a tubal ligation is 
considered to be of childbearing potential.  The definition of childbearing 
potential may be adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  The recommended highly effective methods of contraception are 
defined in Appendix 8. 
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 contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of  1% per 
year during the treatment with atezolizumab in combination with cabozantinib in 
the experimental arm or during the treatment with docetaxel in the control arm, 
and for 4 months after the final dose of cabozantinib, or for 6 months after the 
final dose of docetaxel.  Men must refrain from donating sperm during this 
same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment with atezolizumab in combination with cabozantinib in the 


 
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experimental arm or during the treatment with docetaxel in the control arm, and 
for 4 months after the final dose of cabozantinib to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and 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. 
 
Prior therapy with the following agents for NSCLC: 
− 
Cabozantinib 
− 
Docetaxel 
− 
Combination of an antiPD-L1/PD-1 antibody concurrently with a 
VEGFR-targeting TKI  
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Documentation of known sensitizing mutation in the EGFR gene or ALK fusion 
oncogene  
− Patients with nonsquamous NSCLC who have an unknown EGFR or ALK status 
will be required to be tested at screening. 
− Patients with squamous NSCLC who have an unknown EGFR or ALK status are 
eligible and will not be required to be tested at screening. 
− EGFR and/or ALK status may be assessed locally or at a central laboratory. 
EGFR status assessed locally must be performed on tissue or cytology using 
a validated health authorityapproved test that detects mutations in 
exons 1821. 
If samples are submitted for central EGFR and/or ALK testing, additional 
slides must be provided (see Section 4.5.7 for details). 
 
Patients with known ROS1 rearrangements, BRAF V600E mutations, or other 
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 
Symptomatic, untreated, or actively progressing CNS metastases 
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. 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met: 
− Measurable disease, per RECIST v1.1 as assessed by investigator, must 
be present outside the CNS. 
− The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage. 
− The patient has not undergone stereotactic radiotherapy within 7 days prior 
to initiation of study treatment, whole-brain radiotherapy within 14 days prior 
to initiation of study treatment, or neurosurgical resection within 28 days 
prior to initiation of study treatment. 
− The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.   
− 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 (if administered) and initiation of study treatment. 
– 
If the patient is receiving anticonvulsant therapy, the dose is considered stable. 
 
History of leptomeningeal disease 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There 
is no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (more frequently than once monthly) 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
 
Severe hepatic impairment (Child-Pugh B or C)  
 
Uncontrolled or symptomatic hypercalcemia  
 
Any other active malignancy at the time of initiation of study treatment or diagnosis 
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requires active treatment, except for locally curable cancers that have been 
apparently cured, such as basal or squamous cell skin cancer, incidental prostate 
cancer, or carcinoma in situ of the prostate, cervix, or breast 
 
Stroke, transient ischemic attack (TIA), myocardial infarction or other symptomatic 
ischemic events within 6 months of initiation of study treatment 
 
Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring 
surgical repair or recent peripheral arterial thrombosis) within 6 months of initiation of 
study treatment 
 
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 
 
Active tuberculosis  
 
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 therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease [COPD] exacerbation) are 
eligible for the study. 
 
Current treatment with anti-viral therapy for HBV 
 
Major surgical procedure, other than for diagnosis (e.g., gastrointestinal [GI] 
surgery, removal or biopsy of brain metastasis), within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the 
study 
Minor surgeries are not allowed within 10 days prior to initiation of study 
treatment.  Patients must have complete wound healing from major surgery or 
minor surgery before initiation of study treatment.  Patients with clinically 
relevant ongoing complications from prior surgery are not eligible. 
 
Pregnant or lactating females, or intention of becoming pregnant during the 
treatment with atezolizumab in combination with cabozantinib in the experimental 
arm or during the treatment with docetaxel in the control arm, or within 5 months 
after the final dose of atezolizumab and/or 4 months after the final dose of 
cabozantinib, whichever is later.   
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 
Ongoing Grade  2 sensory or motor neuropathy 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
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antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis (see Appendix 4 for a more comprehensive 
list of autoimmune diseases and immune deficiencies), with the following 
exceptions: 
Patients with a history of autoimmune-mediated hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus 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 (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Administration of 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 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tumor necrosis factorTNF- agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or 
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corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
Known allergy or hypersensitivity to any component of the cabozantinib formulation 
 
History of severe hypersensitivity to docetaxel or to other drugs formulated with 
polysorbate 80 
 
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 anti-coagulants allowed in this study: 
In addition to prophylactic use of low-dose aspirin for cardio-protection (per 
local applicable guidelines) and low-dose (prophylactic) low–molecular-weight 
heparins (LMWH), prophylactic dose of direct factor Xa inhibitors, rivaroxaban, 
edoxaban, or apixaban are permitted.  
Therapeutic doses of LMWHs or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed in patients without known 
brain metastases who are on a stable dose of the anticoagulant for at least 1 
week before randomization without clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor 
 
Thromboembolic event (e.g., deep vein thrombosis [DVT], pulmonary embolism) 
within 6 months before initiation of study treatment 
Patients with a diagnosis of DVT within 6 months are allowed if stable and 
treated with LMWH or direct factor Xa inhibitors, rivaroxaban, edoxaban, or 
apixaban for at least 1 week before initiation of study treatment. 
 
History of risk factors for torsades de pointes (e.g., long QT syndrome) 
 
Corrected QT interval corrected through use of Fridericia's formula (QTcF)  480 ms 
per ECG within 14 days before initiation of study treatment 
If a single ECG shows a QTcF with an absolute value  480 ms, two additional 
ECGs at intervals of approximately 3 minutes must be performed within 
30 minutes after the initial ECG, and the average of the three consecutive 
results for QTcF must be  480 ms for the patient to be eligible.  
 
Uncontrolled hypertension defined as systolic blood pressure  150 mm Hg or 
diastolic BP  90 mm Hg despite optimal antihypertensive treatment 


 
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 
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) 
 
Abdominal fistula, bowel obstruction, 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. 
 
Known cavitating pulmonary lesion(s) or known endobronchial disease 
manifestation 
 
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 wound/ulcer/bone fracture 
 
Malabsorption syndrome 
 
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency, or glucose-galactose malabsorption are also excluded. 
 
Requirement for hemodialysis or peritoneal dialysis 
 
Inability to swallow tablets  
 
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, the study site will access the interactive voice or web-based response system 
(IxRS) to obtain the patient screening number.  After all screening procedures and 
assessments have been completed, and eligibility has been established for a patient, the 
study site will obtain the patient's enrollment identification number and treatment 
assignment from IxRS. 
Patients will be randomly assigned to one of two treatment arms:  Experimental arm 
(atezolizumab 1200 mg IV Q3W  cabozantinib 40 mg PO QD) or control arm (docetaxel 
75 mg/m² IV Q3W).  Randomization will occur in a 1:1 ratio using a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified by the following factors: 
 
Histology (nonsquamous vs. squamous)  
 
Prior NSCLC treatment regimen(s) at the following four levels: 
1. 
Concurrent platinum-containing chemotherapy and antiPD-L1/PD-1 antibody 
combination 


 
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2. 
Platinum-containing chemotherapy first, disease progression occurs, followed 
by antiPD-L1/PD-1 antibody  
3. 
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by platinum-containing chemotherapy without anti-PD-L1/PD-1 
antibody 
4. 
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by continued anti-PD-L1/PD-1 antibody in combination with platinum-
containing chemotherapy added on  
 
Patients should receive their first dose of study drug on the day of randomization if 
possible. If this is not possible, the first dose should occur within 3 days after 
randomization. 
4.2.2 
Blinding 
Although this is an open label study, the study team at the Sponsor consisting of clinical, 
statistical, statistical programming, data management, and other study personnel, will be 
blinded to the randomized treatment assignment by IxRS.  
The study team will not be allowed to perform analyses or summaries generated by 
randomized treatment assignment and/or actual treatment received before the 
randomized treatment assignment for all randomized patients is disclosed to the study 
team for the prespecified analysis. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab, 
cabozantinib, and docetaxel. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
4.3.1.2 
Cabozantinib 
Cabozantinib will be supplied by the Sponsor as 20-mg yellow film-coated round tablets.  
Doses of 40 mg will comprise two 20-mg tablets.  The components of the tablets are 
listed in Table 1. 


 
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Table 1 
Cabozantinib Tablet Components and Composition  
Ingredient 
Function 
% w/wa 
Cabozantinib drug substance (25% drug load as free base) 
Active ingredient 
31.68 
Microcrystalline cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose anhydrous (60M)  
Filler 
19.42 
Hydroxypropyl cellulose (EXF)  
Binder 
3.00 
Croscarmellose sodium (Ac-Di-Sol®)  
Disintegrant 
6.00 
Colloidal silicon dioxide  
Glidant 
0.30 
Magnesium stearate  
Lubricant 
0.75 
Opadry® yellow film coating, which includes HPMC 
2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron 
oxide yellow  
Film coating 
4.00 
HPMC  hydroxypropyl methylcellulose. 
a 
Weight fraction, expressed in percentage. 
  
For information on the formulation and handling of cabozantinib, see the pharmacy 
manual and/or the Cabozantinib Investigator's Brochure. 
4.3.1.3 
Docetaxel 
Docetaxel will be used in commercially available formulation, packaging, and handling.  
Docetaxel will be provided by the Sponsor where it is considered an IMP by local 
regulations (see Section 4.3.3). 
For information on the formulation, packaging, and handling of docetaxel, see the local 
prescribing information. 
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.  
Patients in the experimental treatment arm will receive atezolizumab 1200 mg IV on 
Day 1 of each 21-day cycle and 40 mg of cabozantinib (two tablets of 20 mg each) orally 
QD on Days 121 of each cycle. 
Patients in the control arm will receive docetaxel 75 mg/m² IV Q3W. 
Administration of atezolizumab and docetaxel 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.  In addition, the first dose of 
cabozantinib is to be administered at the clinic.  For anaphylaxis precautions, see 
Appendix 5. 


 
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Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose, medication error, drug 
abuse, or drug misuse, along with any associated adverse events, should be reported as 
described in Section 5.3.5.12. 
4.3.2.1 
Experimental Arm 
Atezolizumab will be administered first on days when both atezolizumab and 
cabozantinib are to be given.  
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle.  For Cycle 1, premedication administered for atezolizumab is not 
permitted.  Atezolizumab infusions will be administered per the instructions outlined in 
Table 2. 
Table 2 
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 
and after the infusion of atezolizumab, but 
prior to the administration of cabozantinib. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during 
the infusion and at 30 ( 10) minutes after 
the infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-
related reaction, or 60 ( 15) minutes if 
the patient experienced an infusion-
related reaction with the previous 
infusion. 
 
If the patient experienced an infusion-
related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be measured every 
15 ( 5) minutes during the infusion and 
at 30 ( 10) minutes after the infusion. 
  
Guidelines for medical management of infusion-related reactions are provided in 
Appendix 6.  


 
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No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation for patients who experience adverse events are provided in 
Appendix 6. 
Cabozantinib  
Cabozantinib will be administered orally, QD at a dose of 40 mg (2  20-mg tablets) on 
Days 121 of each cycle. 
First Dose of Cabozantinib 
Cabozantinib will be administered after completion of atezolizumab infusion.  Patients 
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 continue to fast for an 
additional 1 hour.  
If the patient develops an infusion reaction during or after atezolizumab infusion, the 
administration of oral cabozantinib will be delayed or interrupted until the patient has 
recovered and the investigator believes that it is safe to administer cabozantinib. 
Subsequent Doses of Cabozantinib 
Patients should take cabozantinib outside the clinic at approximately the same time 
every day, preferentially before going to bed.  
Patients will 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 food 
intake for one more hours postdose.  If the patient’s schedule requires taking 
cabozantinib during the day, the patient is to be instructed to follow the same fasting 
recommendations.  
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 of oral study treatment 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 two doses to make 
up for the one the patient missed. 
Any unused oral study treatment must be returned to the study site for drug 
accountability and disposal.  


 
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Guidelines for dosage modification, treatment interruption or discontinuation for patients 
who experience adverse events with cabozantinib are provided in Appendix 7. 
4.3.2.2 
Control Arm 
Docetaxel will be administered by IV infusion at a starting dose of 75 mg/m2 Q3W 
according to the locally approved label. 
All patients randomized to receive docetaxel should be pre-medicated with 
corticosteroids according to local practice (e.g., oral dexamethasone at 16 mg per day 
[administered as 8 mg twice daily], for 3 days starting a day prior to docetaxel 
administration) to reduce the incidence and severity of fluid retention, as well as the 
severity of hypersensitivity reactions.  Anti-emetic prophylaxis may be administered at 
the treating physician’s discretion according to local practice. 
Vital signs will be collected for docetaxel infusions according to Section 4.5.4.  
Guidelines for dosage modification, treatment interruption or discontinuation for patients 
who experience adverse events with docetaxel are provided in Section 5. 
4.3.3 
Investigational Medicinal Product Accountability 
The IMPs for this study are atezolizumab, cabozantinib, and docetaxel.  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 using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor 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/or cabozantinib after completing the 
study if all of the following conditions are met: 
 
The patients’ underlying disease is life-threatening 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/or 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 
would not 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 NSCLC. 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
NSCLC. 
 
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: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the treatment discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year (see Section 4.1.1) 
 
Hormone replacement 


 
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 
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable 
guidelines) 
 
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 LMWH 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 subject has no evidence of brain metastasis, has 
been on a stable dose of the anticoagulant 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.  For management of thromboembolic complications 
while on study, refer to Appendix 7.  
Accepted clinical guidelines regarding appropriate management while receiving 
any kind of anticoagulation therapy must be followed.  This includes, but is not 
limited to, subject 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 gastrointestinal cancers, urothelial cancers, gastrointestinal 
mucosal abnormality (e.g., mucositis), renal or hepatic impairment, 
thrombocytopenia, arterial hypertension, or prior history of gastrointestinal 
bleed.  For direct factor Xa inhibitors, the potential for drug-drug interaction with 
other concomitant medications, as well as gastrointestinal absorption, should be 
considered.  Aspirin and nonsteroidal anti-inflammatory drugs should not 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 reassessed on a regular basis.  For more information regarding the 
use of anticoagulants, refer to the prescribing information of the anticoagulant 
and accepted clinical practice guidelines.  
 
Vaccinations (such as influenza, SARS-CoV-2) 
o Live, attenuated vaccines are not permitted (see Section 4.4.7) 


 
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 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab, 
cabozantinib, and docetaxel may be continued during palliative radiotherapy. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2  4.4.7) 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 5). 
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 


 
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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 (refer to Appendix 6 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 plasma concentrationtime curve (AUC) of co-administered 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]/Ki 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 μM).  
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 co-administration 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 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.  Co-administration 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 


 
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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.  
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/drug-interactions-labeling/drug-development-and-drug-
interactions. 
 
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 co-administered highly protein-bound drug (and a corresponding 
increase in pharmacologic effect). 
4.4.4.3 
Other Interactions 
Food may increase exposure levels of cabozantinib by 57%; fasting recommendations 
(see Section 4.3.2.1) should be followed.  In vitro data suggest that cabozantinib is 
unlikely to be a substrate for P-glycoprotein, but it does appear to have the potential to 
inhibit the P-glycoprotein transport activity.  Therefore, cabozantinib may have the 
potential to increase plasma concentrations of co-administered substrates of 
P-glycoprotein.  Patients should be cautioned against taking a P-glycoprotein substrate 
(e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, 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 investigator brochure. 
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. 
Administration of the proton-pump inhibitor esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers.  Therefore, concomitant 
use of gastric pH modifying agents (i.e., proton-pump inhibitors, H2 receptor antagonists, 
and antacids) is not contraindicated in patients administered cabozantinib. 


 
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Additional details regarding potential drug interactions with cabozantinib can be found in 
the Cabozantinib Investigator’s Brochure. 
4.4.5 
Cautionary Therapy for Docetaxel-Treated Patients 
Docetaxel is a CYP3A4 substrate.  Patients randomized to receive docetaxel must avoid 
using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin and voriconazole).  There are no clinical data with a dose adjustment in 
patients receiving strong CYP3A4 inhibitors.  
In addition, concomitant treatment with CYP3A4 inducers may decrease plasma 
concentrations of docetaxel.  Therefore, concomitant medications that are CYP3A4 
inducers should be used with caution.  
Granulocyte colony-stimulating factor treatment is permitted for patients in the docetaxel 
arm.  The primary prophylaxis should be administered per the American Society of 
Clinical Oncology, EORTC, and ESMO guidelines; namely, in patients who 
are   60 years of age and/or with comorbidities (Smith et al. 2006; Crawford et al. 2009; 
Aapro et al. 2011).  
Anti-emetics, anti-allergic measures, and other treatments for concomitant docetaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the Summary of Product Characteristics.  
See the Summary of Product Characteristics for docetaxel for all boxed warnings and 
contraindications.  
4.4.6 
Prohibited Therapies 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 4.4), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment (see Section 4.6.2, with the 
exception of palliative radiotherapy).  
 
Any investigational therapy or investigational medical device is prohibited within 
4 weeks prior to initiation of study treatment and during study treatment. 
 


 
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4.4.7 
Prohibited Therapies 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, intranasal influenza, measles, mumps, 
rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) are 
prohibited within 4 weeks prior to initiation of study treatment, during atezolizumab 
treatment, and for 5 months after the final dose of atezolizumab.  
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 
 
Oral anti-coagulation 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 cardioprotection per local 
applicable guidelines), until 4 weeks after cabozantinib has been permanently 
discontinued (for permitted anti-coagulants, refer to Section 4.4.1. 
 
Concomitant medications known to prolong the QTc interval should be avoided in 
patients who receive cabozantinib until they have permanently discontinued 
cabozantinib treatment (refer to http://www.qtdrugs.org for a list of drugs which have 
the potential to prolong the QTc interval). 
 
4.4.8 
Prohibited Food for Cabozantinib-Treated Patients  
Use of the following foods is prohibited as described below: 
 
Consumption of grapefruit or grapefruit juice and potent CYP3A4 enzyme inhibitors 
is prohibited during the treatment with cabozantinib. 
 
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. 
At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional at the patient's home to improve access and convenience for patients 
participating in the study.  The Sponsor will select a healthcare company that will be 
responsible for providing MN services for participating sites (the MN vendor).  The MN 
vendor is responsible for ensuring that all MN professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks 
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services are appropriate for a patient and the patient gives written informed consent to 
participate in MN visits, the MN network will communicate with the patient and the 
patient's site.  MN visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the MN professional, but will not include study drug 
infusions, which must be performed at the study site.  The schedules of activities (see 
Appendix 1 and Appendix 2) will specify the assessments that may be performed by an 
MN professional for patients in either arm.  Investigators should ensure adequate clinical 
oversight. 
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 
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 and use of alcohol and drugs of abuse, will be recorded at baseline.  Prior PD-L1 
testing and results will also be recorded in the eCRF.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded. 
Demographic data will include age at informed consent, sex, and self-reported 
race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
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cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, blood and 
lymphatic, 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 predose at 
specified postbaseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
Refer to Appendix 1 for the schedule of physical examination and performance status 
assessments.   
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
For the first infusion, vital signs should be measured within 60 minutes prior to each 
atezolizumab and docetaxel infusion, after the infusion of atezolizumab but prior to the 
administration of cabozantinib, and, if clinically indicated, during or after the infusion as 
indicated in the schedule of activities (Appendix 1).  If the patient experienced an 
infusion-related reaction with the previous infusion or if clinically indicated, vital signs 
should be measured every 15 ( 5) minutes during the infusion and at 30 ( 10) minutes 
after the infusion.  In addition, vital signs should be measured at other specified 
timepoints as outlined in the schedule of activities (see Appendix 1).   
4.5.5 
Tumor and Response Evaluations 
Screening assessments and subsequent tumor assessments must include CT scans 
(with oral or IV contrast) of chest, abdomen, and pelvis.  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 magnetic resonance imaging (MRI) scans of the 
abdomen and pelvis should be performed.   
A CT scan with contrast or MRI scan of the head must also 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 screening.   
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 
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Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days of Day 1 of Cycle 1 may be used rather than repeating tests.  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.  At 
subsequent (post-screening) tumor assessments, patients with a history of irradiated 
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. 
Patients will undergo tumor assessments at baseline, every 6 weeks ( 7 days) for the 
first 48 weeks following Day 1 of Cycle 1, and every 9 weeks ( 7 days) after completion 
of the Week 48 tumor assessment regardless of treatment delays.  Patients will continue 
scanning regardless of treatment delays until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for patients who continue study treatment after 
disease progression per RECIST v1.1), withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  At the investigator’s discretion, 
scans may be performed at any time if PD or loss of clinical benefit is suspected.  
Patients in the experimental arm who are treated beyond disease progression per 
RECIST v1.1 will continue to undergo tumor assessments at the frequency described 
above (i.e., every 6 weeks ( 7 days) for the first 48 weeks and every 9 weeks ( 7 days) 
after 48 weeks) until study treatment is discontinued.  
See Figure 2 for representation of on-study scan frequency




 
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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.  In the absence of radiographic 
disease progression per RECIST v1.1, tumor assessments should continue regardless 
of whether a patient starts a new anti-cancer therapy.   
A RECIST v1.1 PD-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 in the experimental arm.  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 at all subsequent assessments.  
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.  
4.5.6 
Survival Assessments 
OS follow-up information will be collected via telephone calls, patient medical records, 
and/or clinic visits every 3 months (every 12 weeks [ 7 days]) 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 and new anti-cancer therapy 
information 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).  
After completion of final OS analysis, patients will only need to be followed for 
6 months after the last dose of study treatment and information on new anti-cancer 
therapy information will no longer be required.  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 
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chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, 
calcium, total bilirubin, ALP, ALT, AST, and LDH 
 
Coagulation:  INR and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as free 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.  HBV 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, at treatment discontinuation, and as clinically indicated.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a woman with a tubal ligation is 
considered to be of childbearing potential.  The definition of childbearing 
potential may be adapted for alignment with local guidelines or regulations.  
 
Urine Chemistry (Protein [spot urine or 24-hour collection; fully quantitative]; 
Creatinine [spot urine; fully quantitative]; Urine protein/creatinine ratio [spot urine]) 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
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 
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 
Blood, plasma, and serum samples for exploratory biomarker research, including 
biomarker assay development 
Blood samples may be processed to obtain plasma, serum, PBMCs, and other 
derivatives (e.g., RNA, DNA, etc.).  
 
Representative fresh and archival tumor tissue sample obtained at baseline for 
exploratory research on biomarkers (e.g., PD-L1 status via central testing), including 
biomarker assay development.  Tumor tissue samples should be submitted before 
or within 4 weeks of randomization.   
If obtaining representative fresh tumor is not clinically feasible, representative 
archival tumor specimen is acceptable. 
Representative formalin-fixed, paraffin-embedded tumor specimens in a 
paraffin block (preferred) or slides (preferably 15 or more) containing unstained, 
freshly cut, serial sections should be submitted along with an associated 
pathology report.  If 15 slides are not available, fewer can be submitted.  A 
minimum of 5 slides is required for central PD-L1 testing.  
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 3, embedded in 
a single paraffin block), or excisional, incisional, punch, or forceps biopsy 
are acceptable.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  Tumor tissue from bone metastases that have been decalcified is 
not acceptable.  
 
For patients with nonsquamous NSCLC, if EGFR and/or ALK status is unknown, 
these must be assessed locally using a validated health authorityapproved test or 
at a central laboratory (see Section 4.1.2 for exclusion criteria).  If samples are 
submitted for central testing, an additional 5 unstained slides must be provided (see 
additional details in the laboratory manual).  
 
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. 
 
Exploratory biomarker research in tumor tissue and blood 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, 
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extraction of DNA, ctDNA, or RNA, analysis of somatic mutations, and use of NGS 
(including but not limited to WES). 
On the basis of emerging safety, activity, or efficacy data, the number of PK and ADA 
samples may be reduced or sample collection may cease altogether.  Additionally, these 
collected samples may not be analyzed if not warranted.  After final OS analysis is 
conducted, the Sponsor may decide to no longer collect additional biomarker samples.  
The existing collected samples may still be used for exploratory analysis. 
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 4.5.10), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Serum and plasma samples collected for PK or 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, or earlier depending on 
local regulations. 
 
Blood 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). 
 
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 
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4.5.8 
Electrocardiograms 
At screening and during the study, single ECG assessments will be performed with 
standard 12-lead ECG equipment according to standard procedures to determine the 
corrected QT interval calculated using the Fridericia formula (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, two additional ECGs at intervals of approximately 3 minutes 
must be performed within 30 minutes after the initial ECG, and the average of these 
three consecutive results for QTcF will be used as the value assessed (see Appendix 7).  
ECGs will be performed at the timepoints as indicated in the schedule of activities 
(Appendix 1).  ECGs for each patient should be obtained from the same machine 
wherever possible.  Lead placement should be as consistent as possible.  ECG 
recordings must be performed after the patient has been resting in a supine position for 
at least 10 minutes.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
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 
defining them as serious, they must be reported as serious adverse events 
(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) 
  
4.5.9 
Patient-Reported Outcome Assessments 
PRO questionnaires will be completed to more fully characterize the clinical profile of 
atezolizumab and cabozantinib to complement traditional endpoints of survival, tumor 
progression and tolerability.  In addition, PRO questionnaires will enable the capture of 
each patient's direct experience with atezolizumab and cabozantinib. 
PROs of symptom severity and functioning, including HRQoL, will be collected through 
use of the EORTC library, including the generic QoL questionnaires for cancer (EORTC 


 
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QLQ-C30), selected scales from the EORTC QLQ-C30 (EORTC IL17), its lung-specific 
module (EORTC QLQ-LC13), one item (IL46) documenting overall treatment burden, 
and selected items from the PRO-CTCAE library to inform symptoms commonly 
experienced while receiving atezolizumab, cabozantinib, or docetaxel. 
In addition, the EQ-5D-5L will be used in this study for economic modeling.  
Patients will be requested to complete EQ-5D-5L, the EORTC QLQ-C30, EORTC QLQ-
LC13, EORTC IL46, and PRO-CTCAE items at baseline (i.e., Day 1 of Cycle 1) and on 
Day 1 of each cycle thereafter (see Appendix 1), until and including the study treatment 
discontinuation visit.   
During the survival follow-up, once all treatments are discontinued, all patients will 
complete only the EORTC IL17 and EQ-5D-5L questionnaires at 3 and 6 months.  
Completion of PRO questionnaires will no longer be required after the final OS 
analysis. 
4.5.9.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments 
PRO questionnaire will be self-administered on paper or interviewer-administered (as 
appropriate) at the clinic at specified timepoints during the study (see schedule of 
activities in Appendix 1).  At the clinic, questionnaires will be administered before the 
patient receives any information on disease status, prior to the performance of non-PRO 
assessments that might bias patients’ ratings, and prior to the administration of study 
treatment.  For patients who are unable to come into the clinic due to government 
restrictions or personal safety, PROs may be completed via telephone call; source 
documentation should be obtained which includes, among other information, that the 
questionnaires were administered via telephone. 
PRO questionnaires, translated into the local language as appropriate, will be completed 
on paper questionnaires provided by the Sponsor.  During clinic visits, PRO 
questionnaires should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
questionnaires. 
 
Sites must administer the official version of each questionnaire, as provided by the 
Sponsor. Questionnaires must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the questionnaires. 
 
Sites should administer the questionnaires in a quiet area with minimal distractions 
and disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
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 
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 questionnaires. 
 
Site staff should review all completed questionnaires 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. 
 
If any of the questionnaires are not completed for any reason, the site staff should 
report the reason for non-completion in the eCRF. 
 
4.5.9.2 
Description of Patient-Reported Outcome Assessment 
Questionnaires 
 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999) (see Appendix 9).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of the previous week.  Scale scores can be obtained for 
the multi-item scales.  The functioning and symptoms items are scored on a 4-point 
scale that ranges from "not at all" to "very much," and the GHS and QoL items are 
scored on a 7-point scale that ranges from "very poor" to "excellent."  The EORTC 
QLQ-C30 module takes approximately 10 minutes to complete.  Selected scales 
(EORTC IL17) will be collected during survival follow up (see Appendix 13). 
EORTC QLQ-LC13 
The EORTC QLQ-LC13 is a modular supplement to the EORTC QoL questionnaire for 
use in lung cancer (see Appendix 10).  This module incorporates one multiple-item scale 
to assess dyspnea and a series of single item scales assessing pain, coughing, 
sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  All items are 
using a 4-point scale previously described.  The QLQ-LC13 module takes approximately 
5 minutes to complete. 
Selected Items from EORTC Item Library  
In addition, one-item EORTC IL46 will be collected to assess overall side effect impact.  
The item “To what extent have you been troubled with side-effects from your treatment?” 
uses the same rating scale of 4 points previously described (see Appendix 10).  
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 


 
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Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; see Appendix 11).  
There are two components to the EQ-5D-5L:  a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a 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. 
PRO-CTCAE 
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015).  The PRO-CTCAE contains 124 questions that are rated either dichotomously (for 
determination of presence vs. absence) or on a 5-point Likert scale (for determination of 
frequency of occurrence, severity, and interference with daily function).  Treatment 
toxicities can occur with observable signs (e.g., vomiting) or non-observable symptoms 
(e.g., nausea).  The standard PRO-CTCAE recall period is the previous 7 days.  Items 
from the PRO-CTCAE were selected based on their relevance to capture symptoms 
commonly reported with atezolizumab, cabozantinib, or docetaxel intake and not 
captured by the EORTC QLQ-C30 and QLQ-LC13.  These items capture rash, itching, 
chills (for IR), musculoskeletal pain, abdominal pain, dysgeusia and neuropathic pain 
(see Appendix 12). 
4.5.10 
Optional Tumor Biopsies and Blood Samples  
Consenting patients may undergo additional on-treatment biopsies at any other 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).  Samples collected via resection, core-needle biopsy (at least 
three cores preferred, embedded in a single paraffin block), 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 Tissue Biopsy 
Sample Informed Consent eCRF. 
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.  Refer to 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.  


 
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4.5.10.1 
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.  RBR 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 
 
For more information on collection of RBR samples see Appendix 2.  
4.5.10.2 
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 Institutional 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 will not 
be applicable at that site. 
4.5.10.3 
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, docetaxel, diseases, or drug safety:  
 
Blood samples collected predose on Day 1 of Cycle 1.   
Although strongly preferred, if sample collection is not feasible predose on Day 
1 of Cycle 1, then blood samples may be collected predose on Day 1 of any 
subsequent cycle visit.  
 
Leftover blood, serum, plasma, PBMC, 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 
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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 whole genome sequencing (WGS), WES, or other genomic analysis 
methods.  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 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.   
RBR 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). 
4.5.10.4 
Confidentiality 
RBR 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. 
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. 


 
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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. 
4.5.10.5 
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. 
4.5.10.6 
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 email 
address: 
global.rcr-withdrawal@roche.com 
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. 
4.5.10.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
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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 (Atezo  Cabo) are allowed to discontinue one 
component of the study treatment but continue to receive the other component as long 
as the patient is experiencing clinical benefit as determined by the investigator.  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 
 
Patients receiving atezolizumab and cabozantinib:  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 4.5.5 for details).   
 
Patients receiving docetaxel:  Radiographic disease progression per RECIST v1.1 
or symptomatic deterioration attributed to disease progression 
For equivocal findings of progression (e.g., very small or uncertain new lesions or 
lymph nodes), treatment may be continued until the next scheduled assessment. 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.1.1 
Post-Treatment Assessments  
Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment (see Appendix 1).  The visit at which response assessment 
shows PD may be used as the treatment discontinuation visit.  Patients who discontinue 


 
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study treatment (for any reason) in the absence of radiographic progression (per 
RECIST v.1.1) will continue to undergo tumor response assessments as outlined in the 
schedule of activities (see Appendix 1).   
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected by means of telephone calls, patient medical records, and/or 
clinic visits approximately every 3 months or more frequently until death (unless the 
patient withdraws consent for follow-up or the Sponsor terminates the study) (see 
Appendix 1).  After completion of final OS analysis, patients will only need to be 
followed for 6 months after the last dose of study treatment and information on new 
anti-cancer therapy will no longer be required.  Completion of PRO questionnaires will 
also no longer be required after the final OS analysis. 
If a patient is discontinued from study treatment because of an adverse event (including 
adverse events of special interest; see Section 5.2.3) considered to be related to study 
treatment and the event is ongoing 30 days after the final dose of study treatment, the 
event must be followed until resolution or determination by the investigator that the event 
has become stable or irreversible. 
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 
 
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 (i.e., survival 
follow-up), 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. 


 
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4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and cabozantinib in completed and/or ongoing studies and the most 
current prescribing information for docetaxel.  The anticipated important safety risks are 
outlined below (see Sections 5.1.1, 5.1.2, and 5.1.3). 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Section 4.1) and close 
monitoring of patients during the study as indicated below.  Administration of 
atezolizumab, docetaxel, 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 4.3.2.1).  Guidelines for 
managing patients who experience anticipated adverse events, including criteria for 
dosage modification and treatment interruption or discontinuation, are provided in 
Appendix 6 for atezolizumab, Appendix 7 for cabozantinib, and local prescribing 
information for docetaxel.  Refer to Sections 5.4  5.7 for details on safety reporting 
(e.g., adverse events, pregnancies) for this study. 


 
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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 ESMO). 
Severe SARS-CoV-2 infection 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 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  Infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to Appendix 6 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.  
5.1.2 
Risks Associated with Cabozantinib 
Cabozantinib has been associated with risks such as the following:  GI disorders, non-GI 
fistula formation, hemorrhage, venous and arterial thrombotic events, hypertension, 
stomatitis and mucositis, skin disorders, osteonecrosis, proteinuria, nervous system 
disorders, angioedema, hepatocellular toxicity, infections and infestations, blood system 
disorders, fatigue, weight loss, QTc prolongation, electrolyte disorders, endocrine 
disorders, musculoskeletal disorders, and respiratory disorders.  Refer to Appendix 7 of 
this protocol and Section 6 of the Cabozantinib Investigator's Brochure for a detailed 
description of anticipated safety risks and guidelines for the management of these 
adverse events associated with cabozantinib. 
5.1.3 
Risks Associated with Docetaxel 
The most common side effects of docetaxel used as a single agent in patients with 
NSCLC include infections, neutropenia, anemia, thrombocytopenia, peripheral sensory 
neuropathy, anorexia, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, 
stomatitis, alopecia, and skin reactions. 


 
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For more details regarding the safety profile and management guidelines for adverse 
events associated with docetaxel, refer to the local docetaxel prescribing information.  
The investigator may use discretion in adhering to the guidelines, as well as local 
hospital or clinical practice, considering the severity of the event and benefit versus risk 
for the patient, with the goal of maximizing patient compliance and access to supportive 
care.   
5.1.4 
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 overlap.  These overlapping adverse 
events include, but are not limited to, hepatotoxic, endocrine, gastrointestinal, 
dermatologic, neurologic, renal, and pulmonary events, as well as sign 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 administrated as a combination treatment and warrant diagnostic 
investigation.   
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 recommendation in Appendix 6 (atezolizumab) and Appendix 7 
(cabozantinib), applied to the component of the study treatment judged to be the primary 
cause.  If individual component causality for adverse events cannot be adequately 
determined, conservative management recommendation should be followed to include 
dose modification/interruption of both agents. 
5.1.4.1 
Dose Modifications  
Atezolizumab 
There will be no dose modifications, including dose reductions for atezolizumab in this 
study. 
Cabozantinib 
Dose modifications for cabozantinib are as follows: 
 
Two dose reduction levels of cabozantinib (20 mg daily, and 20 mg every other day 
[QOD]) are permitted on the experimental combination arm (see Table 3). 
 
Dose modification criteria for treatment-related adverse events of cabozantinib are 
shown in Table 4.  
 
Dose re-institution and re-escalation after dose interruptions and/or reductions:  
If the patient recovers from his or her toxicities to  Grade 1 per NCI CTCAE 
v.5.0 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.  


 
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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 4).  Patients who initiated treatment with cabozantinib at 40 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.  
Patients receiving a dose of 20 mg QOD on the experimental combination arm 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 QOD 
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). 
 
For patients concurrently taking a strong CYP3A4 inhibitor, reduce the daily 
cabozantinib dose by 20 mg (e.g., from 40 mg to 20 mg daily).  Resume the dose 
that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation 
of the strong inhibitor. 
 
For patients concurrently taking a strong CYP3A4 inducer, increase the daily 
cabozantinib dose by 20 mg (e.g., from 40 mg to 60 mg daily or from 20 mg to 40 mg 
daily) as tolerated.  Resume the dose that was used prior to initiating the CYP3A4 
inducer 2 to 3 days after discontinuation of the strong inducer.  The daily dose of 
cabozantinib should not exceed 60 mg. 
 
Table 3 
Dose Reduction Levels of Cabozantinib (Oral Dosing) 
Assigned Starting 
Dose 
First Dose Level 
Reduction 
Second Dose Level 
Reduction 
Third Dose Level 
Reduction 
40 mg QD 
(Experimental arm) 
20 mg QD 
20 mg QOD a 
No dose reduction 
permitted 
QD  once a day; QOD  once every other day 
a Cabozantinib will be discontinued if a dose of 20-mg cabozantinib every other day is not 
tolerated.  
 
 
 


 
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Table 4 
Dose Modifications for Cabozantinib-Related Adverse Events 
CTCAE v.5 Grade 
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. 
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.  
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. 
  
For guidelines on dose modifications to manage specific adverse events associated 
cabozantinib treatment, see Appendix 7. 
Docetaxel 
A single dose reduction of docetaxel is permitted for management of drug-related 
toxicities (refer to the local docetaxel prescribing information for the recommended dose 
reduction).  After dose reduction, the dose will not be escalated during subsequent 
administrations.  If further dose reduction is indicated, the patient must discontinue 
docetaxel. 
5.1.4.2 
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 are interrupted more than 12 weeks, the Sponsor 
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Patients on the experimental arm (Atezo  Cabo) 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 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 patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
For guidelines on treatment interruption to manage specific adverse events associated 
with atezolizumab and cabozantinib, see Appendix 6 for atezolizumab and Appendix 7 
for cabozantinib.   
Docetaxel treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study treatment.  For guidelines on treatment interruption to 
manage specific adverse events associated with docetaxel, please refer to the local 
docetaxel prescribing information. 
Dose interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed after consultation with the Medical Monitor.  The investigator 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 
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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 patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 


 
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see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
below 
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, macrophage activating 
syndrome, hemophagocytic lymphohistiocytosis  
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Grade  3 diarrhea 
 
Myelitis 
 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 - 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be 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 5 will be used for assessing severity for 
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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 6): 
 
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 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after treatment administration and 
are judged to be related to study treatment infusion (atezolizumab or docetaxel) should 
be captured as a diagnosis (e.g., "infusion-related reaction") on the Adverse Event 
eCRF.  If possible, avoid ambiguous terms such as "systemic reaction."  Associated 
signs and symptoms should be recorded on the dedicated Infusion-Related Reaction 
eCRF.  If a patient experiences both a local and systemic reaction to the same dose of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with signs and symptoms also recorded separately on the dedicated Infusion-
Related Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 


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


 
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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 blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
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 lung cancer should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 5.4.2).  The iDMC 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 one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 


 
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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of NonSmall Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on 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 
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 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of 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. 
 
Note: Special situations are not in themselves adverse events but may result in adverse 
events.   
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
or qualifies as an adverse event of special interest, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 


 
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Section 5.4.2).  For atezolizumab and 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. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
In addition, all special situations associated with atezolizumab and 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. 


 
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 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data (from EORTC, PRO-CTCAE 
items, and EQ-5D-5L questionnaires), and safety analyses will not be performed using 
PRO data.  However, if any PRO responses suggestive of a possible adverse event are 
identified during site review of the PRO data, the investigator will determine whether the 
criteria for an adverse event have been met and, if so, will report the event on the 
Adverse Event eCRF. 
5.3.5.14 
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) 


 
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 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to Medical Monitors is available 24 hours 
per day, 7 days per week.  An Emergency Medical Call Center will also be available 
24 hours per day, 7 days per week.  The Emergency Medical Call Center will connect 
the investigator with an Emergency Medical Contact, provide medical translation 
service if necessary, and track all calls.  Contact information, including toll-free 
numbers for the Emergency Medical Call Center, will be distributed to 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 Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
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 (see 
Section 5.3.1) or until initiation of new systemic anti-cancer therapy, whichever occurs 
first.  Investigators should record all case details that can be gathered immediately 


 
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(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the 
treatment with atezolizumab in combination with cabozantinib in the experimental arm or 
during the treatment with docetaxel in the control arm, and for 5 months after the final 
dose of atezolizumab and/or 4 months after the final dose of cabozantinib, whichever is 
later.  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, and the infant should 
have follow up for at least 6 months after birth.   
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  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 treatment with 
atezolizumab in combination with cabozantinib in the experimental arm or during the 
treatment with docetaxel in the control arm, or 4 months after the final dose of 
cabozantinib, or 6 months after the final dose of docetaxel.  The investigator should 


 
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report the pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit 
the form to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to study treatment.  When permitted by the site, the pregnant 
partner would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy and the infant for at least 6 months 
after birth.  If the authorization has been signed, the investigator should submit a Clinical 
Trial Pregnancy Reporting Form with additional information on the pregnant partner and 
the course and outcome of the pregnancy as it becomes available.  An investigator who 
is contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 


 
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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). 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.   
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
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 
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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 
Docetaxel 
Taxotere EMA SmPC  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy, safety, and pharmacokinetics of Atezo  Cabo compared with docetaxel 
monotherapy in patients with metastatic NSCLC, with no sensitizing EGFR mutation or 
ALK translocation, who have progressed following treatment with platinum-containing 
chemotherapy and antiPD-L1/PD-1 antibody, administered concurrently or sequentially.  
Efficacy analyses will be performed on the intent-to-treat (ITT) population (i.e., all 
randomized patients), with patients grouped according to the treatment assigned at 
randomization, regardless of whether they received any assigned study drug.   
Safety analyses will be performed on all randomized patients who received any amount 
of study drug, with patients grouped according to the actual treatment received.  
Specifically, a patient will be included in the Atezo  Cabo arm in the safety analyses if 
the patient receives any amount of atezolizumab or cabozantinib, regardless of the initial 
treatment assignment at randomization. 
Details of the planned analyses will be provided in a separate Statistical Analysis Plan 
(SAP) that will be finalized before any analysis of the primary endpoint is performed. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The study is designed to test the hypothesis that atezolizumab in combination with 
cabozantinib prolongs the duration of OS compared to the control arm (docetaxel) in the 
ITT population. 


 
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The sample size determination is based on the number of events required to 
demonstrate efficacy with regard to OS (as defined in Section 6.4.1) in the ITT 
population.  The estimate of the number of events required is based on the following 
assumptions:  
 
1:1 randomization ratio 
 
OS curve that follows the exponential distributions 
 
Two-sided significance level of 0.05 for the comparison of OS 
 
90% power to detect an HR of 0.64 in OS in the ITT population, corresponding to an 
improvement in median OS from 9 to 14.1 months  
 
One planned interim analysis of OS 
The interim analysis of OS is to be performed when approximately 83% 
of the total number of OS events required for the final analysis are 
expected to have occurred.  Crossing boundaries are determined based on 
the Hwang-Shih-DeCani alpha spending function with the gamma parameter 
of 2.5 (Hwang et al. 1990).   
 
Accrual duration of approximately 16 months 
 
Dropout rate of 5% per 24 months for each treatment arm for OS 
 
With these assumptions, approximately 350 patients (approximately 175 per arm) in total 
will be randomized into the study.  The interim OS analysis will be conducted after 
approximately 182 OS events have occurred.  The final OS analysis will be conducted 
when approximately 220 OS events have occurred, which is expected to occur 
approximately 28 months after the first patient is enrolled.  This number of final OS 
events corresponds to a minimum detectable difference corresponding to an HR of 
approximately 0.757. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study drug administration, reasons for discontinuation from the study 
drug, and reasons for study termination will be summarized by treatment arm.  Major 
protocol deviations, including major deviations of inclusion/exclusion criteria, will be 
reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status, smoking status), will be summarized by 
treatment arms.  Descriptive statistics (mean, median, standard deviation, and range) 
will be presented for continuous data, and frequencies and percentages will be 
presented for categorical data. 
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of study drug, unless otherwise noted. 


 
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6.4 
EFFICACY ANALYSIS 
The analysis population for the efficacy analyses will consist of all randomized patients 
(i.e., the ITT population), with patients grouped according to their assigned treatment. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is OS. 
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are not reported as having died at the time of analysis will be censored at the date 
when they were last known to be alive.  Data for patients who do not have postbaseline 
information will be censored at the date of randomization.  The primary endpoint of OS 
will be compared between treatment arms with the use of the stratified log-rank test.  If 
the estimate of the HR is  1 and the two-sided p-value corresponding to the stratified 
log-rank test is less than the specified  level, then the null hypothesis will be rejected, 
and it will be concluded that the combination of Atezo  Cabo prolongs the duration of 
OS relative to the control treatment.  The HR and associated 95% CI will be estimated 
using a stratified Cox proportional hazard model.  The stratification factors will be the 
same as those recorded in the IxRS at randomization (Section 3.1).  Results from an 
unstratified analysis will also be provided. 
Kaplan-Meier methodology will be used to estimate the median OS for each treatment 
arm, and Kaplan-Meier curves will be constructed to provide a visual description of the 
difference between treatment arms.  Brookmeyer-Crowley methodology will be used to 
construct the 95% CI of the median OS for each treatment arm (Brookmeyer and 
Crowley 1982).   
One interim analysis is planned for OS.  The timing and stopping boundaries of the OS 
analyses are described in the sections of sample size determination (Section 6.1) and 
planned interim analyses (Section 6.10.1).   
To assess the consistency of the study results in subgroups defined by demographic 
(e.g., age, sex, and race/ethnicity) and baseline characteristics (e.g., ECOG 
Performance Status, histology, and PD-L1 status), the primary efficacy endpoint in 
these subgroups will be examined.  Additional analyses may be performed to evaluate 
the potential effect of nonprotocol-specified anti-cancer therapy on OS.  Details of 
these analyses will be provided in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 
Progression-Free Survival as Assessed by the Investigator 
PFS is defined as time from randomization to the first occurrence of disease progression 
as determined by investigator per RECIST v1.1 or death from any cause (whichever 
occurs first).  Patients who are alive and have not experienced disease progression at 


 
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the time of analysis will be censored at the time of last tumor assessment.  Patients with 
no postbaseline tumor assessment will be censored at the date of randomization. 
Additional analyses may be performed to assess the potential impact of intercurrent 
events (e.g., missing scheduled tumor assessments) on PFS.  Details of these analyses 
will be provided in the SAP. 
The methodologies outlined for the primary analysis of OS will be used for the analyses 
of PFS by the investigator. 
6.4.2.2 
Objective Response Rate as Assessed by the Investigator 
ORR, defined as the proportion of patients with a CR or PR on two consecutive 
occasions  4 weeks apart, as determined by the investigator according to RECIST v1.1.  
Patients not meeting these criteria, including patients without any postbaseline tumor 
assessment, will be considered non-responders.  ORR will be analyzed in the 
randomized patients with measurable disease at baseline. 
An estimate of ORR and its 95% CI will be calculated using the Clopper Pearson method 
for each treatment arm.  CIs for the difference in ORRs between the two treatment arms 
will be determined using the normal approximation to the binomial distribution.  The ORR 
will be compared between the two arms using the stratified Cochran-Mantel-Haenszel 
test, stratified by the same factors used in the primary OS analysis (see Section 6.4.1). 
6.4.2.3 
Duration of Response as Assessed by the Investigator 
DOR will be assessed in patients who had a confirmed objective response as 
determined by the investigator using RECIST v1.1.  DOR is defined as the time from the 
date of the first occurrence of a confirmed CR or PR (whichever status is recorded first) 
until the first date that PD or death is documented, whichever occurs first.  Patients who 
have not progressed and who have not died at the time of analysis will be censored at 
the time of last tumor assessment date.  If no tumor assessments were performed after 
the date of the first occurrence of a CR or PR, DOR will be censored at the date of the 
first occurrence of a CR or PR.  DOR is based on a non-randomized subset of patients 
(specifically, patients who achieved an objective response); therefore, formal hypothesis 
testing will not be performed for this endpoint.  Comparisons between treatment arms 
will be made for descriptive purposes.  The methodologies detailed for the OS analysis 
will be used for the DOR analysis. 
6.4.2.4 
Time to Confirmed Physical Function or Health-Related Quality 
of Life Deterioration 
Time to confirmed PF or HRQoL deterioration or worsening is defined as the time from 
the date of randomization to the first date of 10-point or more decrease on either the 
EORTC QLQ-C30 PF or GHS scale scores (range, 0100) held for two consecutive 
assessments, or a 10-point or more score decrease followed by death (any cause) within 
21 days or within time till next tumor assessment, whichever occurs first.  Confirmed 


 
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function or HRQoL deterioration was selected as the event in order to increase the 
specificity of the endpoints in capturing clinical deterioration due to tumor progression 
rather than experience of early adverse events that could transiently impact these two 
concepts. 
Patients who do not have a ≥10-point score decrease will be censored at the last 
assessment date.  Patients without a baseline or postbaseline PRO assessment will be 
censored at the randomization date. 
All randomized patients will be included in this time to confirmed deterioration analyses. 
The methodologies outlined for the analysis of OS will be used for these analyses. 
6.4.2.5 
Progression-Free Survival Assessed by Investigator at 
Landmark Timepoints 
The PFS rates at 6 months and 1 year assessed by investigator will be estimated using 
Kaplan-Meier methodology for each treatment arm, along with 95% CIs calculated using 
the standard error derived from Greenwood’s formula.  The 95% CI for the difference in 
PFS rates between the two treatment arms will be estimated using the normal 
approximation method. 
6.4.2.6 
Overall Survival Rate at Landmark Timepoints 
The OS rates at 1 and 2 years will be estimated using Kaplan-Meier methodology for 
each treatment arm, along with 95% CIs calculated using the standard error derived 
from Greenwood’s formula.  The 95% CI for the difference in OS rates between the 
two treatment arms will be estimated using the normal approximation method. 
6.4.3 
Exploratory Efficacy Endpoints 
Exploratory analyses of patient-reported function, symptoms, and functions will be 
detailed in the SAP and will include documentation of scales completion compliance, 
longitudinal analyses of mean changes in score from baseline, and proportion of patients 
reporting meaningful changes on each score at each assessment visit, end of treatment, 
tumor progression, or clinical progression and will be presented by treatment arm.  
Analyses will be performed in the ITT population. 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed on the safety-evaluable population, which is defined 
as all randomized patients who receive any amount of the study drug.  Specifically, a 
patient will be included in the Atezo  Cabo 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 


 
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adverse events of special interest, and clinical laboratory results following the 
administration of study drugs.  Drug exposure will be summarized, including duration, 
dosage, and dose intensity.  Verbatim description of adverse events will be mapped to 
the MedDRA thesaurus terms and graded according 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 occurrence 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.  
6.5.1 
Exploratory Analyses of Patient-Reported Outcome Data 
Analyses using PRO data (collected through selected items from the PRO-CTCAE item 
library and the overall tolerability item) will be descriptive, with a focus on characterizing 
the pattern of symptomatic treatment toxicities over the course of the study.  Results 
from these exploratory analyses will be presented separately from the other safety 
analyses.  PRO data will be analyzed at the item level.   
PRO data will be summarized over time including the number and percentage of patients 
reporting each symptom and the change from baseline at each assessment timepoint, 
including end of treatment, by treatment arm.  In addition, the maximum postbaseline 
score and change from baseline will be summarized by treatment arm.  Details of these 
analyses will be described in the SAP. 
6.6 
PHARMACOKINETIC ANALYSES  
PK samples will be collected in this study as outlined in Appendix 2.  Atezolizumab 
serum concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and standard deviations, as appropriate. 
Plasma concentrations of cabozantinib will be collected in this study as outlined in 
Appendix 2.  The concentrations of cabozantinib will be summarized using descriptive 
statistics as described above.  
Additional PK analyses, including population PK and exploratory exposure response 
analysis, may be conducted, as appropriate, based on the availability of data. 
6.7 
IMMUNOGENICITY ANALYSES  
The immunogenicity analysis population will consist of all patients 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 (postbaseline incidence) will be summarized.  Summary of baseline 
prevalence will be based on patients with at least one evaluable baseline ADA 


 
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assessment; summary of postbaseline incidence will be based on treated patients with 
at least one evaluable postbaseline ADA assessment.  Patients will be grouped 
according to treatment received. 
When determining postbaseline 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 postbaseline 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 post-treatment ADA negative if they are ADA 
negative or have missing data at baseline and all postbaseline samples are negative, or 
if they are ADA positive at baseline but do not have any postbaseline 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, and PK 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.  Results from these exploratory biomarker analyses may be reported separately 
from the CSR. 
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 and will inform pharmacoeconomic models.  As such, 
the data will not be reported in the CSR. 
6.10 
INTERIM ANALYSES 
6.10.1 
Planned Interim Analyses 
One interim analysis is planned for OS.  To control the type I error for OS at two-sided 
alpha of 0.05, the stopping boundaries for OS interim and final analyses are to be 
computed with use of the Hwang-Shih-DeCani alpha spending function with the gamma 
parameter of 2.5 as shown in Table 7.   
 
 


 
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Table 7 
Analysis Timing and Stopping Boundaries for Interim and Final 
Analyses for Primary Endpoint - Overall Survival 
Analysis 
Time from 
FPI 
(Months) 
Information 
Fraction a 
(No. of Events) 
Stopping Boundary 
HR (p-value b) 
OS IA 
23 
83% (182) 
HR  0.726 
(p  0.0310) 
OS FA 
28 
100% (220) 
HR  0.757 
(p  0.0396) 
FA  final analysis; FPI  first patient in; HR  hazard ratio; IA  interim analysis; No.  number; 
OS  overall survival;  
a The proportion of target number of events at each look given the total target number of events. 
b Two-sided p-value. 
  
Due to logistical considerations in event ascertainment and operational planning and 
conduct, the actual analyses may include more or fewer events than the target 
information fractions.  The actual critical values employed at the interim and final 
analyses of OS will depend upon the actual information fraction at the time of the 
analyses.  
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. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO questionnaires will be completed on paper questionnaires provided by the 
Sponsor.  Sites are responsible to ensure that the self- or interviewer-administered 
questionnaires are complete and accurate and administered prior to receipt of any 
information that might bias patients’ ratings, and prior to the administration of study 
treatment.  If any of the questionnaires is not completed when scheduled for completion, 


 
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then the site should report the reason for non-completion in the eCRF.  Site will enter the 
data via EDC system. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, 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, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration 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), the General Data Protection Regulation (2016/679), 
and applicable local, regional, and national laws. 


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


 
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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. 
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 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique 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. 


 
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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 
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 


 
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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 
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 
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 125 sites globally will participate to randomize approximately 
350 patients.  Screening, enrollment, and treatment assignment 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 and will review the interim analysis for 
OS.  Tumor response and progression will be evaluated by investigators.  
9.5 
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. 


 
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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/or other summaries of clinical study results may be available in 
health authority databases for public access, as required by local regulation, and will be 
made available upon request.  For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
The results of this study may be published or presented at scientific congresses.  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, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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9.7 
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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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
antiPD-1 antibody in cancer. N Engl J Med 2012;366:244354. 
Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016;893:119. 
Xalkori (crizotinib) Summary of Product Characteristics, Pfizer Europe MA EEIG. 22 
January 2020 [cited 26 February 2020]. Available from: 
https://www.ema.europa.eu/en/documents/product-information/xalkori-epar-
product-information_en.pdf. 


 
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Xalkori (crizotinib) U.S. Package Insert, Pfizer. 2016 [cited 26 February 2020]. Available 
from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202570s016lbl.pdf. 
Ye Y, Li A, Liu L, et al. A group sequential Holm procedure with multiple primary 
endpoints. Stat Med 2013;32:111224. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Appendix 1 Schedule of Activities 
Assessments 
Screening a 
Treatment  
Post-Treatment Follow-Up 
Days 28 to 1 
Day 1 (every 21 days) 
( 3 days) 
 30 Days after 
Final Dose 
Survival 
Follow-Up 
Informed consent 
x b 
 
 
 
Tumor tissue specimens c 
x 
 
 
 
Demographic data 
x 
 
 
 
Medical history, including NSCLC history, PD-L1 
status (if available), and baseline conditions d 
x 
 
 
 
ALK and/or EGFR assessment if status is unknown 
(may be done locally or centrally) e 
x 
 
 
 
Viral serology f 
x 
 
 
 
C-reactive protein 
x 
 
 
 
Height 
x 
 
 
 
Vital signs g 
x 
x gg 
x gg 
 
Weight 
x 
x  
x 
 
Complete physical examination h 
x 
 
x 
 
Limited physical examination i 
 
x j 
 
 
ECOG Performance Status 
x 
x j 
x 
 
ECG (12-lead)  
x k,i 
x j, k 
 
 
Hematology m 
x l 
x j, gg 
x gg 
 
Chemistry n 
x l 
x j, gg 
x gg 
 
Pregnancy test o 
x l 
x j, gg 
x gg 
 
Coagulation (INR, aPTT) 
x l 
 
x gg 
 
TSH, free T3 (or total T3), free T4 p 
x 
x j, p, gg 
x gg 
 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol GO41892, Version 5 
 
Assessments 
Screening a 
Treatment  
Post-Treatment Follow-Up 
Days 28 to 1 
Day 1 (every 21 days) 
( 3 days) 
 30 Days after 
Final Dose 
Survival 
Follow-Up 
Urine chemistry including UPCR or 24-hour urine 
protein 
x l 
x j 
x 
 
Urinalysis r 
x  
x q 
x 
 
Concomitant medications s 
x  
x gg 
x gg 
 
Adverse events t 
x 
x gg 
x gg 
x 
Atezolizumab administration u 
 
x 
 
 
Cabozantinib dispensing/reconciliation v 
 
x 
 
 
Docetaxel administration w 
 
x 
 
 
Patient-reported outcomes x 
 
x y 
x z 
x z 
Plasma PK samples for cabozantinib hh 
 
See Appendix 2. 
 
Serum PK samples for atezolizumab hh 
 
See Appendix 2. 
 
Serum ADA samples for atezolizumab hh 
 
See Appendix 2. 
 
PBMC, plasma, and serum samples for biomarkers 
(central laboratory) gg, hh 
 
See Appendix 2. 
 
Tumor biopsy, if clinically feasible 
 
At time of radiographic progression aa 
Optional tumor biopsy at other timepoints bb 
 
Any time during study treatment, observation FU or 
survival FU (at investigator's discretion) 
Tumor response assessments  
x cc 
x dd, ee 
Anti-cancer treatment information ff 
 
 
x 
x ff 
Survival follow-up  
 
 
 
x ff 
 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol GO41892, Version 5 
 
 
ADA  anti-drug antibody; Atezo  atezolizumab; Cabo  cabozantinib; CT  computed tomography (scan); ECOG  Eastern 
Cooperative Oncology Group; EORTC  European Organisation for Research and Treatment of Cancer; EQ-5D-
5L  EuroQol 5-Dimension, 5-Level Questionnaire; FFPE  formalin-fixed, paraffin-embedded; FU  follow-up; GHS  global 
health status; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; 
HCV  hepatitis C virus; IL46  Item List 46; NSCLC  nonsmall cell lung cancer; MRI  magnetic resonance imaging; 
OS  overall survival; PBMC  peripheral blood mononuclear cell; PD  progressive disease; PK  pharmacokinetic; 
PRO  patient-reported outcome;  QLQ-C30  Quality of LifeCore 30 Questionnaire, Version 1.1; QLQ-LC13  Quality of 
LifeLung Cancer 13-Item Questionnaire; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
T3  triiodothyronine; T4  thyroxine; 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 Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior 
to Day 1 may be used; such tests do not need to be repeated for screening. 
b Informed consent must be documented before any study-specific screening procedure is performed and may be obtained 
more than 28 days before initiation of study treatment. 
c Representative fresh and archival tumor tissue sample obtained at baseline for exploratory research on biomarkers (e.g., 
PD-L1 status via central testing), including biomarker assay development.  Tumor tissue samples should be submitted 
before or within 4 weeks of randomization.   
d If no tissue specimen is available, known PD-L1 status, as defined by a health authorityapproved PD-L1 assay, is 
required. 
e For patients with nonsquamous NSCLC histology with unknown EGFR and/or ALK status, test results are required at 
screening.  EGFR and/or ALK status must be assessed locally or at a central laboratory.  If samples are submitted for 
central testing, additional tissue sample is required.  See laboratory manual for details. 
f 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.   
g Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion, after the infusion of atezolizumab 
but prior to the administration of cabozantinib, and, if clinically indicated, every 15 ( 5) minutes during the infusion and at 
30 ( 10) minutes after the infusion.  For subsequent infusions of atezolizumab, vital signs should be measured within 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol GO41892, Version 5 
 
60 minutes prior to the infusion, and, if clinically indicated or if symptoms occurred during the previous infusion, every 
15 ( 5) minutes during the infusion and at 30 ( 10) minutes after the infusion.  Vital signs should be measured prior to 
docetaxel infusions. 
h Includes evaluation of the skin, head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, blood and lymphatic, and neurologic systems. 
i Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. 
j If screening assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated for 
Day 1 of Cycle 1.  At all cycles subsequent to Day 1 of Cycle 1, laboratory assessments, ECOG Performance Status, 
ECG (through Cycle 5), and limited physical examination must be performed within 96 hours prior to administration of 
drug. 
k ECG recordings will be obtained during screening (within 14 days before initiation of study treatment), on Day 1 of every 
cycle through Cycle 5, and then as clinically indicated at other timepoints.  Patients should be resting in a supine position 
for at least 10 minutes prior to ECG recording. 
l Specific screening laboratory test results must be obtained within 14 days prior to initiation of study treatment. 
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells [if applicable]). 
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, 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 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 TSH, 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 four cycles thereafter (i.e., Cycles 5, 9, 13, etc.). 
q Urinalysis should be performed as clinically indicated during study treatment. 
r Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol GO41892, Version 5 
 
s 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. 
t 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 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. 
u 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. 
v Cabozantinib tablets will be given on Day 1 of Cycle 1 after atezolizumab infusion.  Patients will take tablets once daily at 
home thereafter until study treatment is discontinued. 
w For docetaxel, study drug will be administered according to the local prescribing information, including premedication with 
steroids. 
x PRO assessments (EORTC QLQ-C30, EORTC IL17, EORTC QLQ-LC13, EORTC IL46, selected items from the PRO-
CTCAE 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 patients’ rating and the administration of study 
treatment.  Study personnel should confirm all questionnaires for completeness before the patient leaves the 
investigational site. 
y Patient-completed questionnaires should be completed by the patients prior to any assessments, tests or interactions 
that might bias patients’ view on their health status.   
z PRO assessments (EORTC QLQ-C30, EORTC QLQ-LC13, EORTC IL46, selected items from the PRO-CTCAE, and 
EQ-5D-5L) will be completed at the post treatment follow up visit.  Completion of PRO questionnaires will no longer be 
required after the final OS analysis.   
aa 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. 


Appendix 1: Schedule of Activities 
  
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bb 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 4.5.10 
for details. 
cc 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) of chest, abdomen, and pelvis, as 
wells as a CT scan (with oral or IV contrast) or MRI of the head.  If a CT scan with contrast is contraindicated (e.g., in 
patients with impaired renal clearance), a non-contrast CT scan of the chest must be performed and MRI scans of the 
abdomen, pelvis, and head must 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 irradiated 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 screening, if clinically indicated. 
dd All patients will undergo tumor assessments at baseline, every 6 weeks ( 7 days) for the first 48 weeks following Day 1 
of Cycle 1, and every 9 weeks ( 7 days) after completion of the Week 48 tumor assessment regardless of treatment 
delays. Patients will continue scanning regardless of treatment delays until radiographic disease progression per RECIST 
v1.1 (or loss of clinical benefit for patients who continue study treatment after disease progression per RECIST v1.1), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.  Patients in the experimental 
arm who are treated beyond disease progression per RECIST v1.1 will continue to undergo tumor assessments at the 
frequency described above until (i.e., every 6 weeks [ 7 days] for the first 48 weeks and every 9 weeks [  7 days] after 
48 weeks) until study treatment is discontinued. 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. In the absence of radiographic disease 
progression per RECIST v1.1, tumor assessments should continue regardless of whether a patient starts a new anti-
cancer therapy.  


Appendix 1: Schedule of Activities 
  
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133/Protocol GO41892, Version 5 
 
ee 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).  
ff 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 (every 12 weeks [ 7 days]) or more frequently until death (unless the patient withdraws consent or the Sponsor 
terminates the study).  After completion of final OS analysis, patients will only need to be followed for 6 months after 
the last dose of study treatment and information on new anti-cancer therapy will also no longer be required.  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. 
gg For patients in either arm at participating sites who have provided written informed consent to participate in mobile 
nursing visits, this assessment or procedure may be performed by a trained nursing professional at the patient's home or 
another suitable location. 
hh On the basis of emerging safety, activity, or efficacy data, the number of PK and ADA samples may be reduced or 
sample collection may cease altogether.  Additionally, collected samples may not be analyzed if not warranted.  After 
final OS analysis is conducted, the Sponsor may decide to no longer collect additional biomarker samples.  The 
existing collected samples may still be used for exploratory analysis. 
 
 
 


 
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Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
Visit 
Timepoint 
Experimental Arm 
(Atezo  Cabo) 
Control Arm 
(Docetaxel) 
Day 1 of Cycle 1 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Cabozantinib PK (plasma) 
 Atezolizumab ADA (serum)  
 Biomarker (PBMC, plasma, serum) 
 Biomarker (blood for RBR, optional a) 
 Biomarker (PBMC, plasma, serum) 
 Biomarker (blood for RBR, optional a) 
Day 1 of Cycle 1 
30 ( 10) minutes after end of 
atezolizumab infusion 
 Atezolizumab PK (serum) 
 
Day 1 of Cycle 2 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Cabozantinib PK (plasma) 
 Atezolizumab ADA (serum) 
 Biomarker (PBMC, plasma, serum) 
 Biomarker (PBMC, plasma, serum) 
Day 1 of Cycle 3 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Cabozantinib PK (plasma) 
 Atezolizumab ADA (serum) 
 Biomarker (plasma, serum) 
 Biomarker (plasma, serum) 
Day 1 of Cycle 4 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Cabozantinib PK (plasma) 
 Atezolizumab ADA (serum) 
 Biomarker (plasma, serum) 
 Biomarker (plasma, serum) 


Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol GO41892, Version 5 
 
Visit 
Timepoint 
Experimental Arm 
(Atezo  Cabo) 
Control Arm 
(Docetaxel) 
Day 1 of Cycle 5 
Predose (same day as 
treatment administration) 
 Cabozantinib PK (plasma) 
 
Day 1 of Cycle 8 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (plasma, serum) 
 Biomarker (plasma, serum) 
Day 1 of Cycle 12 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (plasma, serum) 
 
Biomarker (plasma, serum) 
Day 1 of Cycle 16 
Predose (same day as 
treatment administration) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (plasma, serum) 
 Biomarker (plasma, serum) 
Post-treatment follow-up 
visit (≤ 30 days after final 
dose)c 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (PBMC, plasma, serum) 
 Biomarker (PBMC, plasma, serum) 
Disease Progression c 
At time of radiographic 
progression per 
RECIST v1.1 b 
 Biomarker (PBMC, plasma, serum) 
 Biomarker (PBMC, plasma, serum) 
 


Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol GO41892, Version 5 
 
ADA  anti-drug antibody; Atezo  atezolizumab; Cabo  cabozantinib; eCRF  electronic Case Report Form; PBMC  peripheral blood mononuclear 
cell; PK  pharmacokinetic; RBR  Research Biosample Repository; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Notes:  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. 
On the basis of emerging safety, activity, or efficacy data, the number of PK and ADA samples may be reduced or sample collection may cease 
altogether.  Additionally, collected samples may not be analyzed if not warranted.  After final OS analysis is conducted, the Sponsor may decide 
to no longer collect additional biomarker samples.  The existing collected samples may still be used for exploratory analysis. 
Blood sampling for cabozantinib PK analyses:  After Day 1 of Cycle 1, PK samples should be collected approximately 8 or more hours after the 
previous dose of cabozantinib, and if cabozantinib will be administered on that day, PK samples should be collected prior to cabozantinib 
administration.  The investigator will ask the patient for the date and time of the most recent prior dose of cabozantinib, and this information will be 
recorded on the appropriate eCRF. 
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.  RBR samples are preferred to be collected on Day 1 of Cycle 1; however, they may be collected 
predose on Day 1 of any subsequent cycle visit. 
b Blood collections should be performed within 40 days after progression or prior to the next anti-cancer therapy, whichever is sooner. 
c For patients in either arm at participating sites who have provided written informed consent to participate in mobile nursing visits, collection of this 
sample may be performed by a trained nursing professional at the patient's home or another suitable location. 
 


 
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Appendix 3  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)  
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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138/Protocol GO41892, Version 5 
 
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. 
 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol GO41892, Version 5 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.   
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol GO41892, Version 5 
 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 


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sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 
 10 mm but  15 mm) should be considered non-target lesions.  Nodes that have a 
short axis of  10 mm are considered non-pathological and should not be recorded or 
followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 


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 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 


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 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 


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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. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 


 
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Appendix 4  
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-
mediated hypothyroidism on a stable dose of thyroid replacement hormone may be 
eligible for this study.  In addition, transient autoimmune manifestations of an acute 
infectious disease that resolved upon treatment of the infectious agent are not excluded 
(e.g., acute Lyme arthritis).  Caution should be used when considering atezolizumab for 
patients who have previously experienced a severe or lifethreatening skin adverse 
reaction or pericardial disorder while receiving another immunostimulatory anti-cancer 
agent.  The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions. 
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 myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease 
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular autoimmune 
syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Granulomatosis with 
polyangiitis 


 
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Appendix 5  
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 6  
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 following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and survival follow-up.  There should be a high level of suspicion that 
new symptoms are treatment related. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.51 mg/kg/day of prednisone or equivalent) may be administered.
 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (12 mg/kg/day prednisone or equivalent).  Corticosteroids should 
be tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours 
of high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab.  Resumption of atezolizumab may be 
considered in patients who are deriving benefit and have fully recovered from the 


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immune-mediated event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s assessment of the benefits and risks and 
documented by the investigator. The Medical Monitor is available to advise as 
needed. 
DOSE MODIFICATIONS 
For information on dose modification, see Section 5.1.4.1. 
TREATMENT INTERRUPTION 
For information on treatment interruption, see Section 5.1.4.2. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study 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.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  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. 
 For Grade 1 pneumonitis, consider withholding atezolizumab 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 


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Event 
Management 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c. d 
• For recurrent events or events with no improvement after 
48-72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. c, d 
• Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
• Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
BAL =  bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefit−risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 


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HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, 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. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits or to baseline 
values.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 


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Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
LFT  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.   
 
 
 


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GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  
Table 3 
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist   5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone.  If 
the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 


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


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


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 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be based on the investigator’s benefitrisk 
assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.   
 
 


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Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve, and glucose 
levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
 a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 


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Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis (pan-
hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.   
 


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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.   
 


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IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, 
and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  


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Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, 
Grades 2−4 
 
Immune-mediated 
pericardial 
disorders, Grades 
2−4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD or 
pericardiocentesis as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with of atezolizumab may receive premedication with antipyretic 
medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 


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onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs during Cycle 1 are provided in Table 7.  
For subsequent cycles, IRRs should be managed according to institutional guidelines. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
 
 


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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in 
patients with significant symptoms and/or comorbidities, consider 
managing as per Grade 2. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, 
and/or analgesics, and monitor closely for IRRs and/or CRS. 


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


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


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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level 
positive airway pressure; CAR = chimeric antigen receptor; CPAP = continuous positive 
airway pressure; CRS = cytokine-release syndrome; CTCAE = Common Terminology 
Criteria for Adverse Events; eCRF = electronic Case Report Form; HLH = hemophagocytic 
lymphohistiocytosis; ICU = intensive care unit; IRR = infusion-related reaction; 
MAS = macrophage activation syndrome; NCCN = National Cancer Comprehensive 
Network; NCI = National Cancer Institute. 
Note:  The management guidelines have been adapted from the NCCN guidelines for the 
management of CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or 
organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  In 
this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as 
oxygen delivered at > 6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's benefit−risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.  
For subsequent infusions, administer oral premedication with antihistamines, 
antipyretic medications, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be 
considered after consulting the Medical Monitor and considering the benefit−risk ratio. 
f Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
 
 


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PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8. 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator's benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed.   


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol GO41892, Version 5 
 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.   
 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol GO41892, Version 5 
 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limited, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson Syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
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. 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol GO41892, Version 5 
 
Event 
Management 
 Follow the applicable treatment and management guidelines 
above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
SJS  Stevens-Johnson syndrome; TEN  toxic epidermal necrolysis. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.   
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 10, with specific guidelines for myelitis provided in Table 11. 
Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume 
atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol GO41892, Version 5 
 
• For facial paresis: 
– 
If event resolves fully, resume atezolizumab. b 
– 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefit−risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.   
 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol GO41892, Version 5 
 
Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any 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 12. 
 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol GO41892, Version 5 
 
Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common 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 13. 
Table 13 Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values.  
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol GO41892, Version 5 
 
Table 13 Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 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 based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.   
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy. 
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 
 
 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol GO41892, Version 5 
 
Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a and contact the 
Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If corticosteroids are initiated and event does not improve within 48 hours 
after initiating corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator's benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.   


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol GO41892, Version 5 
 
Table 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Immune-
mediated 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a and contact 
the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if 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 the 
Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event.  Permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator's benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.  
 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol GO41892, Version 5 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
− Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
− Platelet count  100  109/L (100,000/L) 
− ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
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 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
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178/Protocol GO41892, Version 5 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 15. 
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). If event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
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Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 


Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management  
of Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol GO41892, Version 5 
 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 


 
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Appendix 7  
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).  Appendix 6 describes risks associated with atezolizumab and 
provides guidelines for management of patients who experience atezolizumab-associated 
IRRs and immune-mediated adverse events (e.g., pulmonary, hepatic, gastrointestinal, 
endocrine, ocular, myocarditis, pericardial disorders, pancreatic, dermatologic, 
neurologic, meningoencephalitis, renal, myositis, hemophagocytic lymphohistiocytosis). 
DOSE MODIFICATIONS 
For information on dose modification, see Section 5.1.4.1. 
TREATMENT INTERRUPTION 
For information on treatment interruption, see Section 5.1.4.2. 
MANAGEMENT GUIDELINES  
The most frequent adverse events experienced by  20% of patients treated with 
cabozantinib in descending order of frequency were diarrhea, fatigue, decreased 
appetite, nausea, palmar-plantar erythrodysesthesia syndrome, weight decreased, 
vomiting, hypertension, constipation, asthenia, dysphonia, and AST increased.  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 and venous 
thrombotic adverse events (e.g., DVT, pulmonary embolism, TIA, arterial aneurysm, and 
myocardial infarction), severe hemorrhagic events, proteinuria, wound healing 
complications, GI perforation, abscesses including intra-abdominal and pelvic abscess, 
GI and non-GI fistula formation, osteonecrosis, rhabdomyolysis, 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 AST 
increased, ALT increased, anemia, hypothyroidism, hypokalemia, hypomagnesemia, 
thrombocytopenia, hypocalcemia, proteinuria, hypophosphatemia, ALP increased, LDH 
increased, neutropenia, lipase increased, hyponatremia, platelet count decreased, GGT 
increased, hypoalbuminemia, leukopenia, and blood TSH increased. 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
of Adverse Events Associated with Cabozantinib 
  
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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 
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 5.1.4.1). 
Cabozantinib should be discontinued for the following adverse events:  visceral 
perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic 
events, nephrotic syndrome, hypertension with life-threatening consequences, persistent 
uncontrolled hypertension despite optimal medical management, serious and life-
threatening rhabdomyolysis, 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 antidiarrheal/anti-motility agents is recommended at the first sign of 
diarrhea as initial management.  Some patients may require concomitant treatment with 
more than one antidiarrheal agent.  When therapy with antidiarrheal agents does not 
control the diarrhea to tolerable levels, cabozantinib should be temporarily interrupted or 
dose reduced.  When the diarrhea is controlled, retreatment 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 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
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performed whenever diarrhea has occurred during treatment with cabozantinib. 
Infections of the perianal region should be treated per local guidelines. 
Table 1 
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 12 
(duration  48 h) 
 
Continue with study treatment and consider dose reduction. 
 
Initiate treatment with an antidiarrheal 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). 
 
Re-assess after 24 hours: 
− 
Diarrhea resolving to baseline bowel habits: gradually add 
solid foods and discontinue or decrease antidiarrheal 
treatment after 12 h diarrhea-free interval. 
− 
Diarrhea not resolving: Continue/resume antidiarrheal 
treatment. 
Intolerable Grade 2, 
Grade 2  48 h,  
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 h) 
 
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. 
 
Re-assess after 24 h 
− 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: 
consider restarting study treatment at reduced dose. 
− 
Diarrhea not resolving:  Start and or continue antidiarrheal 
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 antidiarrheal or referral 
to gastroenterologist. 
 
Nausea and vomiting:  Antiemetic 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.  Antiemetic medications should be assessed for potential drug interactions 
(see Section 4.4 for further details). 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
of Adverse Events Associated with Cabozantinib 
  
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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 on 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 (DVT) and 
pulmonary embolism (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.  Anticoagulation with warfarin or 
other coumarin-related agents, or the direct thrombin inhibitor dabigatran, or the direct 
factor Xa inhibitor betrixaban, or antiplatelet agents, or chronic use of aspirin above low 
dose levels for cardioprotection per local applicable guidelines is not allowed.  Refer to 
Sections 4.1.2 and 4.4.1 for detailed information regarding the use of anti-coagulants. 
Arterial thrombotic events (e.g., TIA, myocardial infarction) have been observed in 
studies with cabozantinib.  Further treatment with cabozantinib should be discontinued in 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
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patients who develop an acute myocardial infarction, cerebral infarction, or any other 
clinically significant arterial thromboembolic complication. 
The available cabozantinib data from clinical studies and postmarketing experience 
showed that arterial aneurysms and dissections may occur rarely during cabozantinib 
treatment.  These events appear to primarily occur in the presence of hypertension 
(which is a known risk factor for this condition); however, in some events the presence 
of hypertension was not documented.  Discontinuation of treatment with cabozantinib 
should be considered in subjects who develop aortic aneurysm and dissections. 
HYPERTENSION 
Table 2 provides treatment guidelines for hypertension deemed related to cabozantinib.  
Blood pressure 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 hypertension with life-threatening 
consequences or when urgent intervention is indicated, and appropriate medical 
management should be initiated. 
Table 2 
Management of Hypertension a Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
≥ 140 mm Hg (systolic) and < 160 mm Hg 
OR 
≥ 90 mm Hg (diastolic) and  < 100 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 < 140 mm Hg systolic or  < 90 mm Hg 
diastolic. 
• 
If patient is symptomatic, cabozantinib 
treatment should be interrupted and can 
only be restarted once symptoms have 
resolved and BP is < 140 mm Hg systolic 
and  < 90 mm Hg diastolic.  
 


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Table 2 
Management of Hypertension a Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
 160 mm Hg (systolic) 
OR 
 100 mm Hg (diastolic) 
 
Reduce cabozantinib by one dose level or 
interrupt cabozantinib treatment per 
Investigator discretion. 
 
Cabozantinib treatment should be dose 
interrupted if upper limits of systolic BP 
(≥ 160 mm Hg) are sustained and not 
adequately manageable or if systolic BP 
is   180 mm Hg or sustained diastolic BP 
 100 mm Hg, or if patient is symptomatic. 
 
Add new or additional anti-hypertensive 
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 
< 160 mm Hg systolic or < 100 mm Hg 
diastolic, cabozantinib treatment should be 
dose reduced further or interrupted. 
 
Restart cabozantinib treatment at the 
reduced dose and re-escalate only if BP 
falls to and is sustained at  140 mm Hg 
systolic and  90 mm Hg diastolic. 
Hypertension with life-threatening 
consequences (e.g., malignant 
hypertension, transient or permanent 
neurologic deficit, hypertensive crisis); 
urgent intervention indicated  
 
Discontinue cabozantinib treatment. 
 
Initiate appropriate medical management. 
BP  blood pressure. 
a The Investigator may decide to initiate or adjust antihypertensive treatment at a lower 
threshold than systolic BP >140 mm Hg or diastolic BP > 90 mm Hg based on their clinical 
judgment and assessment of the individual patient. 
 
 


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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. 
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 on 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. 


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Aggressive management of symptoms is recommended, including early dermatology 
referral.  Treatment recommendations in response to PPE are summarized in Table 3. 
Table 3 
Management of Hand-Foot Syndrome (PPE) Associated with 
Cabozantinib 
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. 
CTCAE  Common Terminology Criteria for Adverse Events; NSAID  non-steroidal 
anti-inflammatory drug; PPE  palmar-plantar erythrodysesthesia-. 
a Permitted dose levels are defined by individual protocols. 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
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ANGIOEDEMA 
Angioedema should be managed according to standard practice. The patient should be 
observed until symptoms resolve, with particular attention to maintaining an open 
airway. 
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. 
If ONJ occurs, cabozantinib treatment should be held and should not be restarted 
until the condition has sufficiently healed and the Sponsor has approved the re-
initiation of therapy. 
PROTEINURIA 
Proteinuria has been reported with cabozantinib.  Proteinuria should be monitored by 
measuring 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).  
 


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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-h protein assessment within 
7 days. 
 
No change in cabozantinib treatment required if UPCR 
≤ 2 mg/mg or urine protein ≤ 2 g/24 h on 24-h urine collection. 
 
Dose reduce or interrupt cabozantinib treatment if UPCR 
 2 mg/mg on repeat UPCR testing or urine protein  2 g/24 h 
on 24-h urine collection.  Continue cabozantinib on a reduced 
dose if repeated UPCR decreases to < 2 mg/mg.  Consider 
interrupting cabozantinib treatment if repeated 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 hold unless otherwise approved by 
Sponsor. 
 
Repeat UPCR within 7 days and once per week.  If UPCR 
 1 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).  
If UPCR remains  1 mg/mg and  2 mg/mg for 1 month or is 
determined to be stable ( 20% change) for 1 month, check 
urine protein/creatinine per protocol or as clinically 
indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
 
Hold cabozantinib treatment pending repeat UPCR monitoring 
within 7 days and/or 24-h urine protein.  
 
If   3.5 mg/mg on repeat UPCR monitoring, continue to hold 
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 urine protein/creatinine 
should continue weekly until the UPCR decreases to 
 1 mg/mg.  If UPCR remains  1 mg/mg and  2 mg/mg for 
1 month or is determined to be stable ( 20% change) for 
1 month, check urine protein/creatinine per protocol or as 
clinically indicated. 
Nephrotic syndrome 
 
Discontinue cabozantinib treatment. 
UPCR  urine protein/creatinine ratio. 
 
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 


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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. 
 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
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Table 5 
Management of Hepatotoxicity Associated with Cabozantinib 
Severity of Transaminase (ALT or AST) 
Elevations by 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 if lasting longer than 
1 week and consider more frequent 
monitoring of ALT, AST, and bilirubin. 
 
Restart cabozantinib, at the same dose or a 
reduced dose at Investigator discretion, after 
laboratory abnormalities have resolved to no 
higher than 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 
CTCAE Grade ≤ 1 or baseline grade. 
 
Discontinue if laboratory abnormalities 
cannot be reversed despite interruption of 
cabozantinib. 
ALT  alanine aminotransferase; AST  aspartate aminotransferase; CTCAE  Common 
Terminology Criteria for Adverse Events. 
 
Elevations of aminotransferases when hepatic metastases are present may not 
require dose modifications if there are no progressive changes in the 
aminotransferases (less than a doubling) and if there are no progressive elevations 
in serum bilirubin concentration or coagulation factors. 
The following condition requires discontinuation of cabozantinib: 
 
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 cancer patients.  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.  


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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 
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 to Table 3 in Section 5.1.4.1. 
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 QD on QTc interval was evaluated 
in a placebo-controlled study in patients with medullary thyroid cancer.  A mean increase 
in 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  500 ms.  Review of the larger safety 
database (approximately 11,000 patients exposed to cabozantinib in clinical trials and 


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more than 98,000 patients in the postmarketing setting) confirmed the absence of 
safety concerns associated with QT prolongation.  There were no events of torsades de 
pointes reported. 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may 
increase cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value  500 ms or an 
increase of  60 ms above baseline per the site’s ECG read, two additional ECGs must 
be performed with intervals not less than 3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is  500 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 
(http://www.qtdrugs.org). 
 
Repeat ECG triplicates hourly until the average QTcF is  500 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 
 
Cabozantinib treatment has been interrupted through a minimum of 1 week 
following the return of the QTcF to  500 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  


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
of Adverse Events Associated with Cabozantinib 
  
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194/Protocol GO41892, Version 5 
 
 
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. 
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 (confirmed by central ECG lab) after re-initiation 
of study treatment at a reduced dose 
 
ENDOCRINE DISORDERS 
Thyroid dysfunction, primarily hypothyroidism, has been observed with cabozantinib 
treatment. The underlying potential mechanism of thyroid dysfunction observed with 
cabozantinib treatment remains unclear. Routine monitoring of thyroid function and 
assessments for signs and symptoms associated with thyroid dysfunction is 
recommended before initiation and during treatment with cabozantinib.  Management 
of thyroid dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical 
practice guidelines. 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based 
on nonclinical GLP-compliant toxicology studies.  The development of new or 
progressive, unexplained musculoskeletal symptoms such as pain or weakness should be 
assessed for underlying causes.  
Rhabdomyolysis has been reported.  Cabozantinib should be discontinued in subjects 
with serious and life-threatening rhabdomyolysis and interrupted if less severe forms 
occur when there are no other clear causes.  Reinitiation of cabozantinib treatment 
must be discussed with and approved by the Sponsor.  Therapy of rhabdomyolysis 
should include supportive care and standard medical intervention. 
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 


Appendix 7: Risks Associated with Cabozantinib and Guidelines for Management  
of Adverse Events Associated with Cabozantinib 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol GO41892, Version 5 
 
treated with cabozantinib and should be considered as clinically indicated in subjects 
presenting with pulmonary symptoms. 
ELECTROLYTE DISORDERS 
Serum electrolyte imbalance including hypocalcemia, hypokalemia, hypomagnesemia, 
and hypophosphatemia has been reported during treatment with cabozantinib. In some 
cases, there have been Grade 3 or 4 and/or serious.  
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 5.1.4.1, Table 4) and may include oral or IV 
replacement. 
REFERENCES 
Turnage RH, Badgwell B. Abdominal wall, umbilicus, peritoenum, mesentery, omentum 
and retroperitoneum. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, 
editors. Sabiston Textbook of Surgery. 20th ed. 2016. 
 


 
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196/Protocol GO41892, Version 5 
 
Appendix 8  
Highly Effective Methods of Contraception 
In Inclusion Criteria (see Section 4.1.1), sexually active fertile patients and their partners 
must agree to use highly effective methods of contraception that alone or in combination 
result in a failure rate of less than 1% per year when used consistently and correctly 
during the course of the study and until the end of relevant systemic exposure, defined 
as 5 months after the final dose of atezolizumab and/or 4 months after the final dose of 
cabozantinib, whichever is later , for women, and 4 months after the final dose of 
cabozantinib, or for 6 months after the final dose of docetaxel. 
The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not 
been investigated.  Because oral contraceptives might possibly not be considered as 
“effective methods of contraception,” they should be used together with another method. 
Contraception guidance for female patients of childbearing potential 
One of the highly effective methods of contraception listed below, in combination with 
one acceptable barrier method below, is required during study duration and until the end 
of relevant systemic exposure, defined as 5 months after the final dose of atezolizumab 
and/or 4 months after the final dose of cabozantinib, whichever is later.  Local laws and 
regulations may require use of alternative and/or additional contraception methods.  
Highly effective contraceptive methods that are user dependent:  These methods have a 
failure rate of < 1% per year when used consistently and correctly.  Typical use failure 
rates may differ from those when used consistently and correctly.  Use should be 
consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− Oral, intravaginal, or transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
− Oral or injectable 
 
Highly effective contraceptive methods that are user independent: 
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
 
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants, and 
intrauterine hormone-releasing system 
 
Intrauterine device 
 
Bilateral tubal occlusion 
 


Appendix 8:   Highly Effective Methods of Contraception 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
197/Protocol GO41892, Version 5 
 
Vasectomized partner 
− A vasectomized partner is a highly effective contraception method provided that 
the partner is the sole male sexual partner of the female patient of childbearing 
potential and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used 
 
Sexual abstinence 
− Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study drug.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
It is not necessary to use any other method of contraception when 
complete abstinence is elected. 
Female patients of childbearing potential who choose complete abstinence 
must continue to have pregnancy tests per the protocol.  Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that any of these patients chooses to forego complete 
abstinence. 
 
Acceptable barrier methods for use in combination with a highly effective method: 
 
Male or female condom with or without spermicide 
 
Diaphragm with spermicide 
 
Cervical cap with spermicide 
 
Vaginal Sponge with spermicide 
 
Unacceptable as a Sole Method of Contraception: 
 
Male or female condom with or without spermicide. Male and female condoms 
cannot be used simultaneously 
 
Diaphragm with spermicide 
 
Cervical cap with spermicide 
 
Vaginal Sponge with spermicide 
 
Progestogen-only oral hormonal contraception of which inhibition of ovulation is not 
the primary mechanism of action 
 
Periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (e.g., coitus interruptus) 
 
Spermicide only 
 
Lactation amenorrhea method 
 


Appendix 8: Highly Effective Methods of Contraception 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
198/Protocol GO41892, Version 5 
 
Contraception guidance for male participants with partner(s) of 
childbearing potential  
Male patients with female partners of childbearing potential are eligible if they agree to 
the following during the course of study treatment and until the end of relevant systemic 
exposure, defined as 4 months after the final dose of cabozantinib, or for 6 months after 
the final dose of docetaxel. 
 
Inform any and all partner(s) of their participation in a clinical drug study and the 
need to comply with contraception instructions as directed by the investigator. 
 
Male patients must refrain from donation sperm and are required to use a condom 
to prevent transmission of study treatment in semen during the treatment period and 
for 4 months after the final dose of cabozantinib.  
Note: Male patients with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during 
each episode of penile during the treatment period and for 4 months after the 
final dose of cabozantinib. 
 
Docetaxel may alter male fertility.  Male patients randomly assigned to receive 
docetaxel should seek advice on conservation of sperm prior to treatment. 
 
 


 
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Appendix 9  
European Organisation for Research and Treatment of Cancer 
Quality of Life–Core 30 Questionnaire:  EORTC QLQ-C30 
 
 


Appendix 9: European Organisation for Research and Treatment of Cancer Quality of 
Life–Core 30 Questionnaire:  EORTC QLQ-C30 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol GO41892, Version 5 
 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
201/Protocol GO41892, Version 5 
Appendix 10  
European Organisation for Research and Treatment of Cancer 
Quality of Life–Lung Cancer 13-Item Questionnaire:  EORTC 
QLQ-LC13 
 


Appendix 10: European Organisation for Research and Treatment of Cancer Quality 
of Life–Lung Cancer 13-Item Questionnaire:  EORTC QLQ-LC13 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
202/Protocol GO41892, Version 5 
 
 
Additional item  
 
 
 
 
 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol GO41892, Version 5
Appendix 11
EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L)
English version for the USA


Appendix 11: EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
204/Protocol GO41892, Version 5 
 


Appendix 11: EuroQol 5- Dimension, 5-Level Questionnaire (EQ-5D-5L) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
205/Protocol GO41892, Version 5 
 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
206/Protocol GO41892, Version 5 
Appendix 12  
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) 
 
 
 
 
 


Appendix 12: Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) 
  
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207/Protocol GO41892, Version 5 
 
 
 
 
 
 


 
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208/Protocol GO41892, Version 5 
Appendix 13  
European Organisation for Research and Treatment of Cancer 
Item List 17 Questionnaire:  EORTC IL17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Signature Page for Protocol - GO41892 - TECENTRIQ - v5 - Global/Core - Published
System identifier: RIM-CLIN-473031
Approval Task
Company Signatory
22-Mar-2023 17:59:46 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Open-Label, Controlled Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of 
Atezolizumab Given in Combination With Cabozantinib Versus 
Docetaxel Monotherapy in Patients With Metastatic Non-Small Cell 
Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody 
and Platinum-Containing Chemotherapy 
NCT Number: 
NCT04471428 
Document Date: 
Statistical Analysis Plan (SAP) Version 1: 07-February-2022 
 
 
 


CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan GO41892
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL,
CONTROLLED STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF ATEZOLIZUMAB 
GIVEN IN COMBINATION WITH CABOZANTINIB VERSUS 
DOCETAXEL MONOTHERAPY IN PATIENTS WITH 
METASTATIC NON-SMALL CELL LUNG CANCER 
PREVIOUSLY TREATED WITH AN ANTI-PD-L1/PD-1
ANTIBODY AND PLATINUM-CONTAINING
CHEMOTHERAPY
PROTOCOL NUMBER:
GO41892
STUDY DRUG:
Atezolizumab (RO5541267) and Cabozantinib 
(XL184)
VERSION NUMBER:
1
IND NUMBER:
146261
EUDRACT NUMBER:
2020-000100-11
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
Company Signatory
07-Feb-2022 19:20:03
STATISTICAL ANALYSIS PLAN APPROVAL


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GO41892
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 8
2.2
Objectives and Endpoints........................................................ 8
2.2.1
Primary Efficacy Objective....................................................... 8
2.2.2
Secondary Efficacy Objective.................................................. 8
2.2.3
Exploratory Efficacy Objective................................................. 9
2.2.4
Pharmacokinetic Objective ...................................................... 9
2.2.5
Safety Objectives................................................................... 10
2.2.6
Immunogenicity Objectives.................................................... 10
2.2.7
Exploratory Biomarker Objective ........................................... 10
2.2.8
Health Status Utility Objective ............................................... 11
2.3
Determination of Sample Size ............................................... 11
2.4
Analysis Timing ..................................................................... 12
2.4.1
Interim and Final Analysis Timing for OS............................... 12
3.
STUDY CONDUCT..................................................................................... 13
3.1
Randomization....................................................................... 13
3.2
Data Monitoring ..................................................................... 13
4.
STATISTICAL METHODS .......................................................................... 13
4.1
Analysis Populations ............................................................. 14
4.1.1
Efficacy Analysis Population.................................................. 14
4.1.2
Pharmacokinetic-Evaluable Population ................................. 14
4.1.3
Safety Population .................................................................. 14
4.1.4
Immunogenicity Population.................................................... 14
4.2
Analysis of Study Conduct..................................................... 15
4.3
Analysis of Treatment Group Comparability .......................... 15
4.4
Efficacy Analysis.................................................................... 15
4.4.1
Primary Efficacy Endpoint...................................................... 15
4.4.2
Secondary Efficacy Endpoints............................................... 16
4.4.2.1
PFS in the ITT population...................................................... 16


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3/Statistical Analysis Plan GO41892
4.4.2.2
Objective Response Rate...................................................... 16
4.4.2.3
Duration of Response............................................................ 17
4.4.2.4
Time to Confirmed Deterioration in Patient-
Reported Physical Functioning and Global Health 
Status/Quality of Life ............................................................. 17
4.4.2.5
PFS Rate at the 6-Month and 1-Year Landmark 
Timepoints............................................................................. 18
4.4.2.6
OS Rate at the 1- and 2-Year Landmark 
Timepoints............................................................................. 18
4.4.3
Exploratory Efficacy Endpoints: Patient-Reported 
Outcomes .............................................................................. 18
4.4.3.1
Completion Rate.................................................................... 18
4.4.3.2
Visit Score Summary and Change from Baseline.................. 18
4.4.3.3
Proportion of Patients who Improved, Worsened, 
or Remained Stable............................................................... 18
4.4.4
Sensitivity Analyses............................................................... 19
4.4.4.1
Non-Protocol Specified Anti-Cancer Therapy........................ 19
4.4.4.2
Loss to Follow-up .................................................................. 19
4.4.5
Subgroup Analyses ............................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Safety Analyses..................................................................... 20
4.6.1
Exposure of Study Medication............................................... 20
4.6.2
Adverse Events ..................................................................... 20
4.6.3
Laboratory Data..................................................................... 21
4.6.4
Vital Signs.............................................................................. 21
4.6.5
Patient-Reported Outcome Data ........................................... 21
4.7
Immunogenicity Analyses...................................................... 21
4.8
Exploratory Biomarker Analyses............................................ 21
4.9
Health Status Utility Analyses................................................ 22
4.10
Missing Data.......................................................................... 22
5.
REFERENCES ........................................................................................... 23


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GO41892
LIST OF TABLES
Table 1
Analysis for Overall Survival ....................................................... 12
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 24
Appendix 2
Schedule of Activities.................................................................. 37
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples..................................................................... 44


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GO41892
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study GO41892 (CONTACT-01), a Phase III, multicenter, 
randomized, open-label, controlled study evaluating the efficacy and safety of 
atezolizumab (MPDL3280A, anti-programmed death-ligand 1 [PD-L1] antibody), in 
combination with cabozantinib (inhibitor of multiple receptor tyrosine kinase [RTKs], 
including vascular endothelial growth factor receptor 2 [VEGFR2], 
mesenchymal-epithelial transition [MET], rearranged during transfection [RET], and 
Tyro3-Axl-Mer [TAM] family kinases) compared with docetaxel monotherapy in patients 
with metastatic non-small cell lung cancer (NSCLC) previously treated with an 
anti-PD-L1/programmed death 1 (PD-1) antibody and platinum-containing 
chemotherapy. The background for the study can be found in the study protocol.
2.
STUDY DESIGN
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy, safety, and pharmacokinetics of atezolizumab given in combination with 
cabozantinib compared with docetaxel in approximately 350 patients with metastatic 
NSCLC, with no sensitizing epidermal growth factor receptor (EGFR) mutation or 
anaplastic lymphoma kinase (ALK) translocation, who have progressed following 
treatment with anti-PD-L1/PD-1 antibody and platinum-containing chemotherapy.
Eligible patients were stratified by tumor histology (non-squamous vs. squamous), and 
prior NSCLC treatment regimen(s) at the following four levels:
1.
Concurrent platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody 
combination
2.
Platinum-containing chemotherapy first, disease progression occurs, followed by 
anti-PD-L1/PD-1 antibody
3.
Anti-PD-L1/PD-1 antibody monotherapy first, disease progression occurs, followed 
by platinum-containing chemotherapy without anti-PD-L1/PD-1 antibody
4.
Anti-PD-L1/PD-1 antibody monotherapy first, disease progression occurs, followed 
by continued anti-PD-L1/PD-1 antibody in combination with platinum-containing 
chemotherapy added on
Eligible patients will be randomized in a 1:1 ratio to receive either atezolizumab plus 
cabozantinib (the experimental arm) or docetaxel monotherapy (the control arm).
In the experimental arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day
cycle, followed by 40 mg cabozantinib (220-mg tablets), administered orally once a 
day (QD) on Days 1-21 of each cycle.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan GO41892
In the control arm, patients will receive docetaxel at a starting dose of 75 mg/m2 Q3W, 
administered by IV infusion according to the locally approved label.
Treatment in the control arm will continue until unacceptable toxicity or disease 
progression as assessed by the investigator per Response Evaluation Criteria for Solid 
Tumors, Version 1.1 (RECIST v1.1). Treatment in the experimental arm will continue 
until unacceptable toxicity, 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). During the study
treatment, patients randomized to the experimental arm who meet the criteria for 
disease progression per RECIST v1.1 and show evidence for clinical benefit may 
continue study treatment (atezolizumab and/or cabozantinib) at the investigator’s 
discretion provided that the patients meet all of the criteria specified in study protocol 
Section 3.1 and provide written consent. Figure 1 illustrates the study design of which 
details can be found in the study protocol.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan GO41892
Figure 1
Study Schema
Abantibody; IVintravenous; NSCLCnon-small cell lung cancer; NSQ non-squamous; 
PD-L1/PD-1progressive disease-ligand 1; POby mouth; QDonce a day; Q3W every 
3 weeks; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; 
SQsquamous.
Patients will undergo tumor assessments at baseline and every 6 weeks (7 days) for 
48 weeks following Day 1 of Cycle 1 regardless of treatment delays (see study protocol 
Section 4.5.5 and Appendix 1). After the completion of the Week 48 tumor assessment, 
tumor assessments will be required every 9 weeks (7 days) regardless of treatment 
delays until radiographic disease progression per RECIST v1.1, withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first. Patients in the 
experimental arm who are treated beyond disease progression per RECIST v1.1 will 
undergo tumor assessments at the frequency described above until study treatment is 
discontinued. 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. In the absence of radiographic 


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan GO41892
disease progression per RECIST v1.1, tumor assessments should continue regardless 
of whether a patient starts a new anti-cancer therapy.
In order not to confound the overall survival (OS) endpoint, crossover will not be allowed 
from the control arm (docetaxel monotherapy) to the experimental arm (atezolizumab 
plus cabozantinib).
The primary efficacy endpoint is OS. See Section 2.2 for details on primary endpoint, 
secondary endpoints, and other endpoints such as safety, pharmacokinetics (PK), and 
exploratory outcome measures. 
The primary analysis of all OS analyses will be performed on intent-to-treat (ITT) 
population (i.e., all randomized patients), with patients grouped according to the 
treatment assigned at randomization, regardless of whether they received any assigned 
study drug (See Section 4.1 for details on analysis populations).
There is one interim analysis planned for OS in this study. See Section 2.4 for detailed 
analysis timing. 
An external independent Data Monitoring Committee (iDMC) will be set up to evaluate 
safety data on an ongoing basis and to review the interim analysis for OS.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Activities in Appendix 2 and Appendix 3.
2.2
OBJECTIVES AND ENDPOINTS
2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
plus cabozantinib compared with docetaxel monotherapy on the basis of the following 
endpoint:

OS, defined as the time between the date of randomization and date of death from 
any cause in the ITT population
2.2.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
plus cabozantinib compared with docetaxel monotherapy on the basis of the following 
endpoints: 

Progression-free survival (PFS), defined as the time from randomization to the first
occurrence of the disease progression as determined by the investigator according 
to RECIST v1.1 or death from any cause, whichever occurs first, in the ITT 
population


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan GO41892

Confirmed objective response, defined as the proportion of patients with either a 
complete response (CR) or a partial response (PR), as determined by the 
investigator according to RECIST v1.1 on two consecutive occasions 4 weeks 
apart, in the ITT population with measurable disease at baseline

Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression, as determined by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs 
first, in the ITT population with confirmed objective response

Time to confirmed deterioration (TTCD) in patient-reported physical functioning (PF)
and global health status/quality of life (GHS/QoL) as measured by the 
corresponding scale scores from the European Organization for Research and 
Treatment of Cancer Quality of LifeCore 30 (EORTC QLQ-C30) questionnaire in 
the ITT population

PFS rates at 6 months and 1 year, defined as the proportion of patients alive and 
without progression as assessed by the investigator according to RECIST v1.1 at 
6 months and 1 year after randomization estimated using Kaplan-Meier (KM) 
methodology in the ITT population

OS rates at 1 and 2 years, defined as the proportion of patients alive at 1 and 
2 years after randomization estimated using KM methodology in the ITT population
2.2.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of 
atezolizumab plus cabozantinib compared with docetaxel monotherapy on the basis of 
the following endpoint:

Change from baseline and the proportion of patients who report deterioration, 
improvement or no change in their symptoms and function including quality of 
life (QoL) as measured by EORTC Quality of LifeLung Cancer 13-Item
Questionnaire (EORTC QLQ-LC13) and EORTC QLQ-C30
2.2.4
Pharmacokinetic Objective
The PK objective for this study is to characterize the PK profile of atezolizumab plus 
cabozantinib on the basis of the following endpoints:

Serum concentration of atezolizumab at specific timepoints

Plasma concentrations of cabozantinib at specific timepoints


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan GO41892
2.2.5
Safety Objectives
The safety objective for this study is to evaluate the safety of atezolizumab plus 
cabozantinib compared with docetaxel monotherapy on the basis of the following 
endpoint:

Incidence and severity of adverse events (AEs) with severity determined according 
to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)
The exploratory safety objective for this study is to evaluate the safety of 
atezolizumabcabozantinib compared with docetaxel monotherapy from the patient’s 
perspective on the basis of the following endpoints:

Presence, frequency of occurrence, severity and/or degree of interference with daily 
function of selected symptoms frequently reported with the intake of atezolizumab, 
cabozantinib, or docetaxel, as determined through the use of NCI Patient-Reported
Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Change from baseline in selected symptoms frequently reported with the intake of 
atezolizumab, cabozantinib, or docetaxel, as assessed through use of the 
PRO-CTCAE

Frequency of patients’ response of the degree they are troubled with treatment 
symptoms, as assessed through use of the single item EORTC Item 
List 46 (EORTC-IL46)
2.2.6
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab plus cabozantinib on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and 
incidence of ADAs to atezolizumab after treatment
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs to atezolizumab on the basis of the following endpoint:

Relationship between atezolizumab ADA status and efficacy, safety, or PK 
endpoints
2.2.7
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers on the basis of the following endpoint: 

Relationship between biomarkers in peripheral blood mononuclear cells (PBMC), 
plasma, serum, and tumor tissue (including, but not limited to, PD-L1, PD-1, 
prevalence of immune subsets, circulating factors, gene expression, gene 
expression signatures of tumor and immune biology, somatic mutations, tumor 
mutation burden, and others) and efficacy, PK, immunogenicity, or other endpoints






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3.
STUDY CONDUCT
3.1
RANDOMIZATION
Randomization to the treatment and control arms will occur in a 1:1 ratio using a 
permuted-block randomization method. Randomization will be stratified by the following 
factors:

Histology (nonsquamous vs. squamous)

Prior NSCLC treatment regimen(s) at the following four levels:
1. Concurrent platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody 
combination
2. Platinum-containing chemotherapy first, disease progression occurs, followed by 
anti-PD-L1/PD-1 antibody
3. Anti-PD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by platinum-containing chemotherapy without anti-PD-L1/PD-1 antibody
4. Anti-PD-L1/PD-1 antibody monotherapy first, disease progression occurs, 
followed by continued anti-PD-L1/PD-1 antibody in combination with 
platinum-containing chemotherapy added on
3.2
DATA MONITORING
An external iDMC will be used to evaluate safety data and review the interim analysis for 
OS. Unblinded safety data will be reviewed on a periodic basis, approximately every 
6 months from the point of first patient in until the time the database is locked.
Unblinded efficacy data will be reviewed as part of an interim analysis for OS. All 
summaries and analyses by treatment arm for the iDMC review will be prepared by an 
independent data coordinating center (iDCC).
Following the data review, the iDMC will provide a recommendation as to whether the 
study may continue, whether amendment(s) to the protocol should be implemented, or 
whether the study should be stopped. For the interim analysis of OS, the iDMC will 
review the analysis results provided by the iDCC and will recommend or not recommend 
to unblind the study to the Sponsor. The final decision will rest with the Sponsor.
Members of the iDMC will be external to the Sponsor and will follow a separate iDMC 
Charter to outline their roles and responsibilities, as well as a detailed monitoring plan.
4.
STATISTICAL METHODS
The analyses described in this SAP will supersede those specified in Protocol GO41892 
for the purposes of a regulatory filing.


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4.1
ANALYSIS POPULATIONS
4.1.1
Efficacy Analysis Population
The randomized population or ITT population is defined as all randomized patients, 
whether or not the patient received the assigned treatment.
The analyses of PFS and all OS analyses will be performed on the ITT population. 
Patients are grouped according to the treatment assigned at randomization, regardless 
of whether they received any assigned study drug.
Confirmed objective response rate (ORR) will be analyzed in the ITT population who 
have measurable disease as assessed by investigator at baseline.
DOR will be assessed in patients in the ITT population who have a confirmed objective 
response as determined by the investigator using RECIST v1.1.
Analyses of the EORTC QLQ-C30 and EORTC QLQ-LC13 data will be conducted in the 
ITT population.
PFS rate at the 6-month and 1-year landmark timepoints will be analyzed in the same 
population as defined for the PFS analysis.
OS rate at the 1- and 2-year landmark timepoints will be analyzed in the same 
population as defined for the OS analyses.
4.1.2
Pharmacokinetic-Evaluable Population
The pharmacokinetic-evaluable population is defined as all patients who received any 
dose of atezolizumab or cabozantinib and who have evaluable PK samples.
4.1.3
Safety Population
The safety population includes treated patients, defined as all randomized patients who 
receive any amount of study drug. Specifically, a patient will be included in the 
experimental arm in the safety analyses if the patient receives any amount of 
atezolizumab or cabozantinib, regardless of the initial treatment assignment at 
randomization.
Analyses of the PRO-CTCAE and the EORTC IL46 data will be conducted in the safety 
population.
4.1.4
Immunogenicity Population
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment for atezolizumab. Patients will be grouped according to the treatment 
received.


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4.2
ANALYSIS OF STUDY CONDUCT
Study enrollment, major protocol deviations, including major deviations from 
inclusion/exclusion criteria, and reasons for study termination will be summarized overall 
and by treatment arm for the ITT population. Study treatment administration and 
reasons for discontinuation from study treatment will be summarized for the safety 
population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, baseline disease 
characteristics (e.g., Eastern Cooperative Oncology Group [ECOG] performance status, 
smoking status), and stratification factors (histology, prior NSCLC treatment regimens) 
will be summarized by treatment arms. Descriptive statistics (mean, median, standard 
deviation, and range) will be presented for continuous data, and frequencies and 
percentages will be presented for categorical data.
Unless otherwise noted, baseline measurements are the last available data obtained 
prior to the patient receiving the first dose of any component of study drug on Cycle 1, 
Day 1.
4.4
EFFICACY ANALYSIS
Patients will be grouped for efficacy analyses according to the treatment assigned at 
randomization, whether or not the assigned treatment was received.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is OS. 
OS is defined as the time from randomization to death from any cause. Data for patients 
who are not reported as having died at the time of analysis will be censored at the date
when they were last known to be alive. Data for patients who do not have post-baseline 
information will be censored at the date of randomization.
The null (H0) and alternative (H1) hypotheses regarding OS in a population can be
phrased in terms of population hazard ratio (HR) between the atezolizumab plus 
cabozantinib arm (Arm A) and the docetaxel arm (Arm B):
H0: 1 versus H1:≠1
If the estimate of the HR, is and the two-sided p-value corresponding to the 
stratified log-rank test is less than the specified level, then the null hypothesis will be 
rejected, and it will be concluded that the combination of atezolizumab plus cabozantinib 
prolongs the duration of OS relative to the control treatment.


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The HR and associated 95% confidence interval (CI) will be estimated using a stratified 
Cox regression model with the same stratification variables used for stratified log-rank
test. Results from an unstratified analysis will also be provided. 
For OS analyses in the ITT population, the stratification factors will be histology, and 
prior NSCLC treatment regimens, as listed in Section 3.1. The stratification factors will 
be the same as those recorded in the interactive voice/web response system.
The analyses based on stratification factors as recorded on the electronic Case Report 
Form (eCRF) may also be provided. 
Treatment comparison will be conducted by comparing Arm A versus Arm B based on 
stratified log-rank test for primary endpoint of OS at the two-sided significance level as 
described in Section 2.4.1. Kaplan-Meier methodology will be used to estimate the 
median OS and to construct survival curves for each treatment arm for a visual 
description of the difference among arms. The Brookmeyer-Crowley methodology will 
be used to construct the 95% CI for the median OS (Brookmeyer and Crowley 1982).
Follow-up for OS, defined as the time from randomization to death or last known date 
alive, will be summarized for all patients included in the analysis (whether patient is alive 
or has died). Follow-up will be summarized using the KM method with data for patients 
who died censored at the date of death.
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
PFS in the ITT population
PFS is defined as time from randomization to the first occurrence of disease progression 
as determined by the investigator per RECIST v1.1 or death from any cause (whichever 
occurs first). Patients who are alive and have not experienced disease progression at 
the time of analysis will be censored at the time of last tumor assessment. Patients with 
no post-baseline tumor assessment will be censored at the date of randomization.
PFS by the investigator will be analyzed using the same method as the primary analysis 
of OS, described in Section 4.4.1.
4.4.2.2
Objective Response Rate 
ORR is defined as the proportion of patients with a CR or PR on two consecutive 
occasions 4 weeks apart, as determined by the investigator according to RECIST v1.1. 
Patients not meeting these criteria, including patients without any post-baseline tumor 
assessment, will be considered non-responders. ORR will be analyzed in patients with
measurable disease at baseline and compared between treatment arms using the 
stratified Cochran-Mantel-Haenszel test, stratified by the same factors used in the 
primary OS analysis (Section 4.4.1). 95% CIs for the difference in ORRs between the 
two treatment arms will be determined using the normal approximation to the binomial 


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distribution. An estimate of ORR and its 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.
4.4.2.3
Duration of Response 
DOR will be assessed in patients who achieved a confirmed objective response as 
determined by the investigator according to RECIST v1.1. DOR is defined as the time 
from the date of the first occurrence of a confirmed CR or PR (whichever status is 
recorded first) until the first date of progression disease as determined by the 
investigator according to RECIST v1.1 or death is documented, whichever occurs first.
Patients who have not progressed and who have not died at the time of analysis will be 
censored at the time of the last tumor assessment date. Because the determination of 
DOR is based on a non-randomized subset of patients, formal hypothesis testing will not 
be performed. DOR will be estimated using KM methodology.
4.4.2.4
Time to Confirmed Deterioration in Patient-Reported Physical 
Functioning and Global Health Status/Quality of Life
TTCD analyses will be performed for patient-reported physical functioning (items 1 to 5) 
and GHS/QoL (items 29 and 30) as measured by the EORTC QLQ-C30. Raw scores 
from both scales will be linearly transformed so that each score will range from 0 to 100.
High scores (i.e., closer to 100) represent high/healthy level of functioning and 
health-related quality of life.
TTCD is defined as the time from the date of randomization to the first confirmed 
clinically meaningful deterioration on each respective scale score. Confirmed clinically 
meaningful deterioration for physical functioning and GHS/QoL is defined as a clinically 
meaningful decrease from baseline in physical functioning or GHS/QoL score that must 
be held for at least two consecutive assessments or an initial clinically meaningful 
decrease from baseline followed by death from any cause within 21 days or until the 
next tumor assessment, whichever occurs first. A score change of 10 points on either 
the EORTC QLQ-C30 physical functioning or GHS/QoL scale scores is determined as 
being clinically meaningful (Osoba et al. 1998).
The TTCD analyses will be performed in the ITT population and will include all data 
collected through disease progression and survival follow up. The methodologies that 
are outlined for the analysis of OS (Section 4.4.1 ) will be used for the analyses. TTCD 
for physical functioning and GHS/QoL will be summarized using the KM method. 
Comparison of TTCD for physical functioning and GHS/QoL between treatment arms will 
be performed using the stratified log-rank test; the stratified HRs and 95% CIs will also 
be reported. If no baseline or post-baseline assessment is performed, patients will be 
censored at the randomization date. Patients without a confirmed deterioration at the 
time of analysis will be censored at the last time they were known to have not 
deteriorated. There will be no imputation for missing baseline or post-baseline data for 
TTCD analyses.


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4.4.2.5
PFS Rate at the 6-Month and 1-Year Landmark Timepoints
The PFS rates at 6 months and 1 year assessed by investigator will be estimated for 
each treatment arm using KM methodology, along with 95% CIs calculated using the 
standard error derived from Greenwood’s formula. The 95% CI for the difference in PFS 
rates between the two treatment arms will be estimated using the normal approximation 
method, with standard errors computed using the Greenwood method. 
4.4.2.6
OS Rate at the 1- and 2-Year Landmark Timepoints
The OS rate at the 1 and 2 years will be estimated for each treatment arm using 
KM methodology, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula. The 95% CI for the difference in OS rates between the two 
treatment arms will be estimated using the normal approximation method, with standard 
errors computed using the Greenwood method.
4.4.3
Exploratory Efficacy Endpoints: Patient-Reported Outcomes
4.4.3.1
Completion Rate
Completion rates will be summarized by the number and the proportion of patients who 
completed the patient-reported outcome (PRO) questionnaires among those expected to 
complete the questionnaires at each timepoint. Reasons for non-completion will also be 
summarized if available.
4.4.3.2
Visit Score Summary and Change from Baseline
Visit summary and change from baseline analyses will be performed for the 
EORTC QLQ-C30 and QLQ-LC13 scales.  Summary statistics (number of patients,
mean, standard deviation, median, minimum, maximum) of score(s) and score 
change(s) from baseline will be presented. The analyses will be performed at each visit, 
end of treatment tumor progression, or clinical progression and will be presented by 
each treatment arm.
4.4.3.3
Proportion of Patients who Improved, Worsened, or Remained 
Stable
The number and proportion of patients who improved, worsened, or remained stable
versus baseline on the EORTC QLQ-C30 and EORTC QLQ-LC13 scale scores will be 
summarized. For symptom scales, a decrease of 10 points from baseline will be 
considered an improvement, an increase of 10 points from baseline will be considered 
worsening, and a change of any other magnitude will be considered stabilization. For 
the functional and GHS/QoL scales, an increase of 10 points from baseline will be 
considered an improvement, a decrease of 10 points from baseline will be considered 
worsening, and a change of any other magnitude will be considered stabilization. The 
analyses will be performed at each visit, end of treatment tumor progression, or clinical 
progression and will be presented by each treatment arm.


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4.4.4
Sensitivity Analyses
4.4.4.1
Non-Protocol Specified Anti-Cancer Therapy
The impact of subsequent non-protocol specified anti-cancer therapy (NPT) on OS will 
be assessed depending on the number of patients who received NPT. If 10% of 
patients received a NPT in either treatment arm, the following analyses may be 
performed to compare treatment arms:

The discounted method uses a ‘discounted’ survival time after switching for patients 
who switch treatments based on a user-specified assumption for the effect in OS.
OS may be discounted according to a range of possible effects on OS of the 
subsequent NPT after treatment switching occurred (e.g., 10%, 20%, 30%, etc.).
4.4.4.2
Loss to Follow-up
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up. If 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis may be performed for the comparisons 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.
4.4.5
Subgroup Analyses
The consistency of OS results in subgroups will be examined. The subgroups are 
defined by the following: 

Demographics (e.g., age, sex, race/ethnicity)

Baseline characteristics (e.g., ECOG performance status, histology, prior NSCLC 
treatment regimens [as listed in Section 3.1] and PD-L1 status)
Summaries of OS, including the unstratified HR estimated from a Cox proportional 
hazards model and KM estimates of median OS, will be produced separately for each 
level of the subgroup for the comparisons between treatment arms and displayed in a 
forest plot (Lewis and Clarke 2001).
Summaries of PFS by subgroup will also be provided. 
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 3. 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, and standard deviations, as appropriate.
Plasma concentrations of cabozantinib will be collected in this study as outlined in
Appendix 3. The concentrations of cabozantinib will be summarized using descriptive
statistics as described above.


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Additional PK analyses may be conducted, as appropriate, based on the availability of 
data.
4.6
SAFETY ANALYSES
The safety population includes treated patients, defined as all randomized patients who 
receive any amount of the study drug. Specifically, a patient will be included in the 
atezolizumab plus cabozantinib experimental arm if the patient receives any amount of 
atezolizumab or cabozantinib, regardless of the initial treatment assignment at 
randomization.
4.6.1
Exposure of Study Medication
Study drug exposure, including treatment duration, dosage and dose intensity, will be 
summarized for each treatment arm with descriptive statistics.
4.6.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms. Severity of all AEs will be graded by the 
investigator in accordance with the NCI CTCAE v5.0.
Treatment-emergent adverse events will be summarized by mapped term, appropriate 
thesaurus level, NCI CTCAE grade (wherever applicable), and treatment arm. Multiple 
occurrence of the same event in same patient will be counted once at the maximum 
grade. Common AEs, treatment-related AEs, serious adverse events (SAEs).  AEs 
leading to study treatment discontinuation or interruption, Grade 3-4 AEs, fatal AEs 
(Grade 5) and immune-mediated AEs will be summarized accordingly. 
For the purpose of analyses, AEs of special interest (AESIs) will be identified by a set of 
comprehensive definitions using standardized MedDRA queries (SMQs), High-level
terms (HLTs), and Sponsor-defined adverse event grouped terms (AEGTs) from the 
clinical database and presented by medical concepts. AESIs will be summarized by 
treatment arm and NCI CTCAE grade. The medical concepts include 
atezolizumab-associated identified risks, potential risks and class effects reported with 
other immune-checkpoint inhibitors.
For the safety analyses, “treatment-emergent” is defined as AEs occurring on or after the 
first dose of study drug treatment or as a pre-existing condition that worsened on or after 
the first dose of the study treatment up to the data cutoff date. 
Listings of AEs will include all treatment-emergent AEs 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 deaths will be summarized 
by treatment arm.


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4.6.3
Laboratory Data
Laboratory data will be summarized by treatment arm. Laboratory data will be graded 
according to NCI CTCAE v5.0 and will be summarized descriptively. Shift tables from 
baseline to worst value post-baseline will also be presented.
4.6.4
Vital Signs
Changes in selected vital signs from baseline will be summarized by treatment arm.
4.6.5
Patient-Reported Outcome Data
Completion rates will be summarized by the number and the proportion of patients who 
completed the PRO questionnaires among those expected to complete the 
PRO questionnaires by treatment group at each timepoint. Reasons for non-completion
will also be summarized if available.
Analyses of the PRO data (collected through selected items from the PRO-CTCAE item 
library and the overall tolerability item in the EORTC IL46) will be primarily descriptive. 
PRO-CTCAE data will be analyzed at the item level in line with current 
NCI recommendations for data handling (Basch et al. 2014). The number (percentage) 
of patients reporting symptoms by “frequency,” “severity,” “interference,” and “presence”
will be reported at each visit by treatment arm. PRO-CTCAE scores, and change in 
frequency of responses by symptom will also be summarized at each visit by treatment 
arm. The worst post-baseline score and the shift from baseline to the worst 
post-baseline will be summarized by treatment arm. For the EORTC IL46, the frequency 
of patients’ response of the degree they are troubled with treatment symptoms will be 
analyzed by treatment group at each timepoint.
Results from these exploratory analyses will be presented separately from the other 
safety analyses.
4.7
IMMUNOGENICITY ANALYSES
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. The evaluation of PK, efficacy, and safety 
endpoints by ADA status may be analyzed and reported via descriptive statistics.
4.8
EXPLORATORY BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with response to study drug, including efficacy (PFS, OS, 
and/or ORR). The biomarkers include but are not limited to PD-1, prevalence of immune 
subsets, circulating factors, gene expression, gene expression signatures of tumor and 
immune biology, somatic mutations, tumor mutation burden in blood and/or tumor tissue. 
These and additional predictive, prognostic, and pharmacodynamics exploratory 


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biomarkers in archival and/or fresh tumor tissue and/or blood may be examined for their 
association with disease status and/or clinical outcomes. These exploratory analyses 
will not be included in the Clinical Study Report (CSR) for this study.
4.9
HEALTH STATUS UTILITY ANALYSES
The EQ-5D-5L questionnaire will also be collected to generate health-related quality of 
life and utility scores for use in economic models for reimbursement. The analyses will 
not be included in the CSR for this study.
4.10
MISSING DATA
Please refer to Section 4.4.1 and Section 4.4.2 for methods of handling missing data for 
the primary and secondary efficacy endpoints.


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5.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41.
Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s
patient-reported outcomes version of the common terminology criteria for adverse
events (PRO-CTCAE). J Natl Cancer Inst 2014;106:1-11.
Hwang IK, Shih WJ, deCani JS. Group sequential designs using a family of type I error
probability spending functions. Stat Med 1990;9:1439-1445.
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J clin oncol. 1998;16:139-44.


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL, 
CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND PHARMACOKINETICS OF ATEZOLIZUMAB GIVEN IN 
COMBINATION WITH CABOZANTINIB VERSUS DOCETAXEL 
MONOTHERAPY IN PATIENTS WITH METASTATIC NONSMALL 
CELL LUNG CANCER PREVIOUSLY TREATED WITH AN 
ANTIPD-L1/PD-1 ANTIBODY AND PLATINUM-CONTAINING 
CHEMOTHERAPY
PROTOCOL NUMBER:
GO41892
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000100-11
IND NUMBER:
146261
NCT NUMBER:
NCT04471428
TEST PRODUCT:
Atezolizumab (RO5541267) and cabozantinib (XL184)
PHASE:
III
INDICATION:
Nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab when given 
in combination with cabozantinib (Atezo Cabo) compared with docetaxel monotherapy in 
patients with metastatic nonsmall cell lung cancer (NSCLC), with no sensitizing epidermal 
growth factor receptor (EGFR) mutation or anaplastic lymphoma kinas (ALK) translocation, 
who have progressed on prior treatment with both antiPD-L1/PD-1 antibody and 
platinum-containing chemotherapy.  Specific objectives and corresponding endpoints for the 
study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of AtezoCabo 
compared with docetaxel monotherapy on the basis of the following endpoint:

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 AtezoCabo 
compared with docetaxel monotherapy on the basis of the following endpoints: 

Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression, as determined by the investigator according to 
Response Evaluation Criteria in Solid Tumor, Version 1.1. (RECIST v1.1), or death from 
any cause (whichever occurs first)


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
Confirmed objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) on two consecutive occasions 4 weeks 
apart, as determined by the investigator according to RECIST v1.1

Duration of response (DOR) for patients with confirmed ORR, defined as the time from the 
first occurrence of a documented objective response to disease progression, as determined 
by the investigator according to RECIST v1.1, or death from any cause (whichever occurs 
first)

Time to confirmed deterioration in patientreported Physical Function (PF) and global 
health status (GHS) as measured by the corresponding scores from the European 
Organisation for the Research and Treatment of Cancer Quality of LifeCore 30 (EORTC 
QLQ-C30)

PFS rates assessed by the investigator at 6 months and at 1 year 

OS rates at 1 and 2 years 
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of AtezoCabo 
compared with docetaxel monotherapy on the basis of the following endpoint:

Change from baseline and proportion of patients who report deterioration, improvement or 
no change in their symptoms and functioning including quality of life (QoL) as measured by 
the EORTC Quality of LifeLung Cancer 13-Item Questionnaire (EORTC QLQ-LC13) 
symptom scores (cough, dyspnea, chest pain, arm/shoulder pain, or fatigue) and EORTC 
QLQ-C30 functioning scores (PF, Role Function [RF], GHS)
Safety Objectives
The safety objective for this study is to evaluate the safety of AtezoCabo compared with 
docetaxel monotherapy on the basis of the following endpoint:

Incidence and severity of adverse events with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI 
CTCAE v5.0)
The exploratory safety objective for this study is to evaluate the safety of AtezoCabo 
compared with docetaxel monotherapy from the patient's perspective on the basis of the 
following endpoints:

Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptoms frequently reported with the intake of atezolizumab, 
cabozantinib, or docetaxel, as determined through the use of the NCI Patient-Reported 
Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Change from baseline in selected symptoms frequently reported with the intake of 
atezolizumab, cabozantinib, or docetaxel, as assessed through use of the PRO-CTCAE

Frequency of patients’ response of the degree they are troubled with treatment symptoms, 
as assessed through use of the single item EORTC Item List (EORTC IL46)
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
AtezoCabo on the basis of the following endpoints:

Serum concentration of atezolizumab at specified timepoints

Plasma concentration of cabozantinib at specified timepoints


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
26/Statistical Analysis Plan GO41892
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to Atezo Cabo 
on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of 
ADAs to atezolizumab after treatment
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
to atezolizumab on the basis of the following endpoint:

Relationship between atezolizumab ADA status and efficacy, safety, or PK endpoints
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to AtezoCabo (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 AtezoCabo, can provide evidence of 
AtezoCabo activity (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 peripheral blood mononuclear cells (PBMC), plasma, 
serum, and tumor tissue (including, but not limited to, PD-L1, PD-1, somatic mutations, and 
others) and efficacy, PK, immunogenicity, or other biomarker endpoints.
Health Status Utility Objectives
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with AtezoCabo compared with docetaxel monotherapy to inform 
pharmacoeconomic modeling on the basis of the following endpoints:

Health utility scores from the EuroQol 5-Dimension Questionnaire (5-level version; 
EQ-5D-5L) index-based at each timepoint 

Change from baseline at each timepoint using the EQ-5D-5L visual analog scale (VAS) 
scores
Study Design
Description of Study
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy, safety, and pharmacokinetics of atezolizumab given in combination with cabozantinib 
compared with docetaxel monotherapy in patients with metastatic NSCLC, with no sensitizing 
EGFR mutation or ALK translocation, who have progressed following treatment with 
platinum-containing chemotherapy and antiPD-L1/PD-1 antibody, administered concurrently 
or sequentially. 
Approximately 350 eligible patients will be randomized in a 1:1 ratio at approximately 125 global 
sites in this trial. 
After providing informed consent, patients will undergo screening procedures.  Patients who do 
not meet the criteria for participation in this study (screen failure) may qualify for one 
re-screening opportunity (for a total of two screenings per participant) at the investigator's 
discretion.  Patients are not required to re-sign the consent form.  The investigator will record 
reasons for screen failure in the screening log.  Screening period may be extended per Medical 
Monitor discretion based on extenuating circumstances (i.e., delayed laboratory results).
Patients with tumors of nonsquamous histology with unknown EGFR or ALK mutational status 
will be required to be tested either locally using a validated health authorityapproved test or via 
central laboratory prior to enrollment.  Patients with tumors of squamous histology who have an 
unknown EGFR or ALK mutational status will not be required to be tested.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
27/Statistical Analysis Plan GO41892
Eligible patients will be in a randomized 1:1 ratio to receive either atezolizumab plus 
cabozantinib or docetaxel monotherapy.  Randomization will be stratified by:

Histology: nonsquamous versus squamous 

Prior NSCLC treatment regimen(s) at the following four levels:
1.
Concurrent platinum-containing chemotherapy and antiPD-L1/PD-1 antibody 
combination
2.
Platinum-containing chemotherapy first, disease progression occurs, followed by 
antiPD-L1/PD-1 antibody
3.
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, followed by 
platinum-containing chemotherapy without anti-PD-L1/PD-1 antibody
4.
AntiPD-L1/PD-1 antibody monotherapy first, disease progression occurs, followed 
by continued anti-PD-L1/PD-1 antibody in combination with platinum-
containing chemotherapy added on 
In the experimental arm, atezolizumab (fixed dose of 1200 mg) will be administered by IV 
infusion on Day 1 of each 21-day cycle.  Cabozantinib (40 mg) will be administered orally in 
tablet form (two tablets of 20 mg each) once daily (QD) on Days 121 of each cycle.  In the 
control arm, docetaxel (75 mg/m2) will be administered by IV on Day 1 of each 21-day cycle.
In the experimental arm:  Atezolizumab and cabozantinib treatment will continue until 
unacceptable toxicity, 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).  During study treatment, patients who meet criteria for disease 
progression per RECIST v1.1 and show evidence for clinical benefit may continue atezolizumab 
and/or cabozantinib treatment at the investigator’s discretion provided that the patients meet all 
of the following criteria:  

Evidence of clinical benefit, as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status that can 
be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions

Patients 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
Patients randomized to the experimental arm may be allowed to discontinue one component of 
the combination study treatment but continue to receive the other component. 
In the control arm:  Docetaxel treatment will continue until unacceptable toxicity or disease 
progression as assessed by the investigator per RECIST v1.1.
Crossover from the control-arm to the experimental-arm will not be allowed. 
Patients will undergo tumor assessments at baseline, every 6 weeks (7 days) for the first 
48 weeks following Day 1 of Cycle 1, and every 9 weeks (7 days) after completion of the 
Week 48 tumor assessment regardless of treatment delays.  Patients will continue scanning 
regardless of treatment delays until radiographic disease progression per RECIST v1.1 (or loss 
of clinical benefit for patients who continue study treatment after disease progression per 
RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever 
occurs first. 
Patients in the experimental arm who are treated beyond disease progression per RECIST v1.1 
will undergo tumor assessments at the frequency described above (i.e., every 6 weeks 


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
28/Statistical Analysis Plan GO41892
[7 days] for the first 48 weeks and every 9 weeks [7 days] after 48 weeks) until study 
treatment is discontinued.
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. In the absence of radiographic disease progression per RECIST v1.1, tumor 
assessments should continue regardless of whether a patient starts a new anti-cancer therapy. 
Response will be assessed according to RECIST v1.1.
During the study, patients will be asked to complete patient-reported outcome surveys at the 
beginning of the study (i.e., Day 1 of Cycle 1), on Day 1 of each cycle after Day 1 of Cycle 1, at 
treatment discontinuation, and during survival follow-up at 3 and 6.
After study treatment discontinuation, survival follow-up information will be collected by means 
of telephone calls, patient medical records, and/or clinic visits approximately every 3 months 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 and new anti-cancer therapy 
information unless the patient requests to be withdrawn from survival follow-up (this request 
must be documented in the source documents and signed by the investigator).  If the patient 
withdraws from the study, study staff may use a public information source (e.g., county records) 
when permissible to obtain information about survival status.
Number of Patients
Approximately 350 patients with metastatic NSCLC will be enrolled during the global enrollment 
phase of this study. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed informed consent form

Age 18 years old or meeting country definition of adult, whichever is older, on the day of 
consent

Ability to comply with the study protocol, in the investigator's judgment

Histologically or cytologically confirmed metastatic NSCLC

Documented radiographic disease progression during or following treatment with 
platinum-containing chemotherapy and antiPD-L1/PD-1 antibody, administered 
concurrently or sequentially for metastatic NSCLC

If antiPD-L1/PD-1 antibody and platinum-containing chemotherapy are given 
concurrently as the first-line treatment for metastatic NSCLC, no further lines of 
systemic anti-cancer therapy are allowed. 

If antiPD-L1/PD-1 antibody and platinum-containing chemotherapy are given 
sequentially as first and second lines, respectively, for metastatic NSCLC, no further 
lines of systemic anti-cancer therapy are allowed. 

Combination therapies with other agents are allowed with antiPD-L1/PD-1 and/or 
platinum-containing chemotherapy (see exclusion criteria for exceptions).

Measurable disease per RECIST v1.1 outside CNS as assessed by investigator 

Previously irradiated lesions can be considered as measurable disease only if PD
has been unequivocally documented at that site since radiation.

Known PD-L1 status or availability of tumor tissue for central PD-L1 testing:
−
Availability of representative fresh and archival tumor specimens suitable for 
determination of PD-L1 status via central testing.  Results of central PD-L1 testing are 
not required for patient to be randomized into the study.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
29/Statistical Analysis Plan GO41892

If obtaining representative fresh tumor is not clinically feasible, representative 
archival tumor specimen is acceptable.
−
If no tissue specimen (fresh or archival) is available, documentation of known PD-L1 
status as established by a health authorityapproved PD-L1 assay is required.

ECOG Performance Status score of 0 or 1 

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 on supportive 
therapy in the opinion of the investigator

Grade 2 alopecia is allowed for study participation. 

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to randomization:
−
ANC 1500/µL (1.5109/L) without granulocyte colony-stimulating factor support 
within 14 days of laboratory sample collection
−
Lymphocyte count 0.5109/L (500/L)
−
Platelets 100,000/µL (100109/L) without transfusion within 14 days of laboratory 
sample collection
−
Hemoglobin 9 g/dL (90 g/L) without transfusion within 14 days of laboratory sample 
collection
−
Serum bilirubin 1.0upper limit of normal (ULN)
−
Liver function tests meeting one of the following criteria:

ALT and AST 2.5ULN with ALP 2.5ULN,

OR

ALT and AST 1.5ULN with ALP 2.5ULN
−
Serum creatinine 1.5ULN or calculated creatinine clearance 40 mL/min (using the 
Cockcroft-Gault equation):

For males:  (140 – age)weight (kg)/(serum creatinine [mg/dL]72)

For females:  Multiply above value by 0.85.
−
Albumin 25 g/L (2.5 g/dL)
−
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN
−
Urine protein/creatinine ratio 1 mg/mg (113.2 mg/mmol) or 24-hour urine 
protein 1 g

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening

The HBV DNA test will be performed only for patients who have a 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:


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan GO41892

Women must remain abstinent or use two methods of contraception, including at 
least one method with a failure rate of 1% per year, during the treatment with 
atezolizumab in combination with cabozantinib in the experimental arm or during the 
treatment with docetaxel in the control arm, and for 5 months after the final dose of 
atezolizumab and/or 4 months after the final dose of cabozantinib, whichever is later.  
Women must refrain from donating eggs during this same period.

A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis). The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.

Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  The 
recommended highly effective methods of contraception are defined in the protocol

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 
contraceptive methods, and agreement to refrain from donating sperm, as defined below:

With a female partner of childbearing potential who is not pregnant, men who are 
not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment with atezolizumab in combination with cabozantinib in the experimental arm 
or during the treatment with docetaxel in the control arm, and for 4 months after the 
final dose of cabozantinib, or for 6 months after the final dose of docetaxel.  Men must 
refrain from donating sperm during this same period.

With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment with atezolizumab in combination with cabozantinib in the 
experimental arm or during the treatment with docetaxel in the control arm, and for 4 
months after the final dose of cabozantinib.

The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.  If required per local 
guidelines or regulations, locally recognized acceptable methods of contraception and 
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.

Prior therapy with the following agents for NSCLC:
−
Cabozantinib
−
Docetaxel
−
Combination of an antiPD-L1/PD-1 antibody concurrently with a vascular endothelial 
growth factor (VEGF)R-targeting tyrosine kinase inhibitor (TKI)

Treatment with investigational therapy within 28 days prior to initiation of study treatment


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan GO41892

Documentation of known sensitizing mutation in the EGFR gene or ALK fusion oncogene 
−
Patients with nonsquamous NSCLC who have an unknown EGFR or ALK status will be 
required to be tested at screening.
−
Patients with squamous NSCLC who have an unknown EGFR or ALK status are 
eligible and will not be required to be tested at screening.
−
EGFR and/or ALK status may be assessed locally or at a central laboratory.

EGFR status assessed locally must be performed on tissue or cytology using 
a validated health authorityapproved test that detects mutations in exons 1821.

If samples are submitted for central EGFR and/or ALK testing, additional 
slides must be provided.

Patients with known ROS1 rearrangements, BRAF V600E mutations, or other 
actionable oncogenes with approved therapies if available 

Symptomatic, untreated, or actively progressing CNS metastases

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.

Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met:
−
Measurable disease, per RECIST v1.1 as assessed by investigator, must be 
present outside the CNS.
−
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
−
The patient has not undergone stereotactic radiotherapy within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment.
−
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted. 
−
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).
−
There is no evidence of interim progression between completion of CNS-directed 
therapy (if administered) and initiation of study treatment.
−
If the patient is receiving anti-convulsant therapy, the dose is considered 
stable.

History of leptomeningeal disease

Uncontrolled tumor-related pain

Patients requiring pain medication must be on a stable regimen at study entry.

Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to enrollment.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period.

Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (more frequently than once monthly)

Patients with indwelling catheters (e.g., PleurX®) are allowed.

Severe hepatic impairment (Child-Pugh C) 


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan GO41892

Uncontrolled or symptomatic hypercalcemia 

Any other active malignancy at the time of initiation of study treatment or diagnosis of 
another malignancy within 3 years prior to initiation of study treatment that requires active 
treatment, except for locally curable cancers that have been apparently cured, such as 
basal or squamous cell skin cancer, incidental prostate cancer, or carcinoma in situ of the 
prostate, cervix, or breast

Stroke, transient ischemic attack, myocardial infarction or other symptomatic ischemic events within 
6 months of initiation of study treatment

Significant vascular disease (e.g., aortic aneurysm or arterial dissection 
requiring surgical repair or recent peripheral arterial thrombosis) within 6 
months of initiation of study treatment

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, unstable arrhythmia, or unstable angina

Active tuberculosis 

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 on the investigator, could impact patient safety

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment

Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the 
study.

Current treatment with anti-viral therapy for HBV

Major surgical procedure, other than for diagnosis (e.g., gastrointestinal [GI] surgery, 
removal or biopsy of brain metastasis), within 4 weeks prior to initiation of study treatment, 
or anticipation of need for a major surgical procedure during the study

Minor surgeries are not allowed within 10 days prior to initiation of study 
treatment.  Patients must have complete wound healing from major surgery or minor 
surgery before initiation of study treatment.  Patients with clinically relevant ongoing 
complications from prior surgery are not eligible.

Pregnant or lactating females, or intention of becoming pregnant during the treatment with 
atezolizumab in combination with cabozantinib in the experimental arm or during the 
treatment with docetaxel in the control arm, or within 5 months after the final dose of 
atezolizumab and/or 4 months after the final dose of cabozantinib, whichever is later.

Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.

Ongoing Grade 2 sensory or motor neuropathy

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis 
(see protocol for a more comprehensive list of autoimmune diseases and immune 
deficiencies), with the following exceptions:

Patients with a history of autoimmune-mediated hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.

Patients with controlled Type 1 diabetes mellitus 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:


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan GO41892

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 (CT) scan

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Prior allogeneic stem cell of solid organ transplantation

Administration of 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 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-tumor 
necrosis factoragents) within 2 weeks prior to initiation of study treatment, or anticipation 
of need for systemic immunosuppressive medication during study treatment, with the 
following exceptions:

Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
confirmation has been obtained.

Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose 
systemic corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study.

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation

Known allergy or hypersensitivity to any component of the cabozantinib formulation

History of severe hypersensitivity to docetaxel or to other drugs formulated with 
polysorbate 80

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 anti-coagulants allowed in this study:

Prophylactic use of lowdose aspirin for cardio protection (per local applicable 
guidelines) and low dose (prophylactic), low-dose lowmolecular-weight heparins 
(LMWH) are permitted.

Therapeutic doses of LMWHs or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed in patients without known brain 
metastases who are on a stable dose of the anticoagulant for at least 1 week before 
randomization without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor


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34/Statistical Analysis Plan GO41892

Thromboembolic event (e.g., deep vein thrombosis [DVT], pulmonary embolism) within 
6 months before initiation of study treatment

Patients with a diagnosis of DVT within 6 months are allowed if stable and treated 
with LMWH for at least 1 week before initiation of study treatment.

History of risk factors for torsades de pointes (e.g., long QT syndrome)

Corrected QT interval corrected through use of Fridericia's formula (QTcF) 480 ms per 
ECG within 14 days before initiation of study treatment

If a single ECG shows a QTcF with an absolute value 480 ms, two additional 
ECGs at intervals of approximately 3 minutes must be performed within 30 minutes 
after the initial ECG, and the average of the three consecutive results for QTcF must 
be 480 ms for the patient to be eligible. 

Uncontrolled hypertension defined as systolic blood pressure 150 mm Hg or diastolic BP 
90 mm Hg 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)

Abdominal fistula, bowel obstruction, 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.

Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation

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 wound/ulcer/bone fracture

Malabsorption syndrome

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, 
or glucose-galactose malabsorption are also excluded.

Requirement for hemodialysis or peritoneal dialysis

Inability to swallow tablets 
Length of Study
The end of this study will occur when the required number of deaths for the final analysis of OS 
has been observed.
In addition, the Sponsor may decide to terminate the study at any time. 
The approximate total length of the study, from screening of the first patient to the end of the 
study, is expected to be approximately 47 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab, cabozantinib, and 
docetaxel.
Test Products (Investigational Drug)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle.
Cabozantinib will be administered orally, QD at a dose of 40 mg (2 20-mg tablets) on Days 
121 of each cycle.


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35/Statistical Analysis Plan GO41892
Comparator
Docetaxel will be administered by IV infusion at a starting dose of 75 mg/m2 every 3 weeks 
according to the locally approved label.
Statistical Methods
Primary Analysis
The analysis population for the efficacy analyses will consist of all randomized patients (i.e., the 
intent-to-treat [ITT] population), with patients grouped according to their assigned treatment.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is OS.
OS is defined as the time from randomization to death from any cause.  Data for patients who 
are not reported as having died at the time of analysis will be censored at the date when they 
were last known to be alive.  Data for patients who do not have postbaseline information will be 
censored at the date of randomization.  The primary endpoint of OS will be compared between 
treatment arms with the use of the stratified log-rank test.  If the estimate of the HR is 1 and 
the two-sided p-value corresponding to the stratified log-rank test is less than the specified 
level, then the null hypothesis will be rejected, and it will be concluded that the combination of 
Atezo Cabo prolongs the duration of OS relative to the control treatment.  The HR and 
associated 95% CI will be estimated using a stratified Cox proportional hazard model.  The 
stratification factors will be the same as those recorded in the interactive voice or web-based 
response system at randomization.  Results from an unstratified analysis will also be provided.
Kaplan-Meier methodology will be used to estimate the median OS for each treatment arm, and 
Kaplan-Meier curves will be constructed to provide a visual description of the difference 
between treatment arms.  Brookmeyer-Crowley methodology will be used to construct the 95% 
CI of the median OS for each treatment arm.
One interim analysis is planned for OS.  The timing and stopping boundaries of the OS 
analyses are described in the sections of sample size determination and planned interim 
analyses of the protocol.
To assess the consistency of the study results in subgroups defined by demographic (e.g., age, 
sex, and race/ethnicity) and baseline characteristics (e.g., ECOG Performance Status, 
histology, and PD-L1 status), the primary efficacy endpoint in these subgroups will be 
examined.  Additional analyses may be performed to evaluate the potential effect of 
nonprotocol-specified anti-cancer therapy on OS.  Details of these analyses will be provided in 
the SAP.
Determination of Sample Size
The study is designed to test the hypothesis that atezolizumab in combination with cabozantinib
prolongs the duration of OS compared to the control arm (docetaxel) in the ITT population. 
The sample size determination is based on the number of events required to demonstrate 
efficacy with regard to OS in the ITT population.  The estimate of the number of events required 
is based on the following assumptions: 

1:1 randomization ratio

OS curve that follows the exponential distributions

Two-sided significance level of 0.05 for the comparison of OS

90% power to detect an HR of 0.64 in OS in the ITT population, corresponding to an 
improvement in median OS from 9 to 14.1 months 

One planned interim analysis of OS

The interim analysis of OS is to be performed when approximately 83% 
of the total number of OS events required for the final analysis are expected to have 
occurred. Crossing boundaries are determined based on the Hwang-Shih-DeCani 
alpha spending function with the gamma parameter of 2.5.

Accrual duration of approximately 16 months

Dropout rate of 5% per 24 months for each treatment arm for OS


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36/Statistical Analysis Plan GO41892
With these assumptions, approximately 350 patients (approximately 175 per arm) in total will be 
randomized into the study.  The interim OS analysis will be conducted after approximately 
182 OS events have occurred.  The final OS analysis will be conducted when approximately 
220 OS events have occurred, which is expected to occur approximately 28 months after the 
first patient is enrolled.  This number of final OS events corresponds to a minimum detectable 
difference corresponding to an HR of approximately 0.757.
Interim Analyses
One interim analysis is planned for OS.  To control the type I error for OS at two-sided alpha of 
0.05, the stopping boundaries for OS interim and final analyses are to be computed with use of 
the Hwang-Shih-DeCani alpha spending function with the gamma parameter of 2.5.
Due to logistical considerations in event ascertainment and operational planning and conduct, 
the actual analyses may include more or fewer events than the target information fractions.  The 
actual critical values employed at the interim and final analyses of OS will depend upon the 
actual information fraction at the time of the analyses.


Appendix 2 Schedule of Activities
Assessments
Screening a
Treatment 
Post-Treatment Follow-Up
Days 28 to 1
Day 1 (every 21 days)
(3 days)
30 Days after 
Final Dose
Survival 
Follow-Up
Informed consent
x b
Tumor tissue specimens c
x
Demographic data
x
Medical history, including NSCLC history, PD-L1 
status (if available), and baseline conditions d
x
ALK and/or EGFR assessment if status is unknown 
(may be done locally or centrally) e
x
Viral serology f
x
C-reactive protein
x
Height
x
Vital signs g
x
x gg
x gg
Weight
x
x
x
Complete physical examination h
x
x
Limited physical examination i
x j
ECOG Performance Status
x
x j
x
ECG (12-lead)
x k
x j, k
Hematology m
x l
x j, gg
x gg
Chemistry n
x l
x j, gg
x gg
Pregnancy test o
x l
x j, gg
x gg
Coagulation (INR, aPTT)
x l
x gg
TSH, free T3 (or total T3), free T4 p
x
x j, p, gg
x gg
Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
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Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
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Appendix 2 Schedule of Activities (cont.)
Assessments
Screening a
Treatment 
Post-Treatment Follow-Up
Days 28 to 1
Day 1 (every 21 days)
(3 days)
30 Days after 
Final Dose
Survival 
Follow-Up
Urine chemistry including UPCR or 24-hour urine 
protein
x l
x j
x
Urinalysis r
x
x q
x
Concomitant medications s
x 
x gg
x gg
Adverse events t
x
x gg
x gg
x
Atezolizumab administration u
x
Cabozantinib dispensing/reconciliation v
x
Docetaxel administration w
x
Patient-reported outcomes x
x y
x z
x z
Plasma PK samples for cabozantinib
See Appendix 2
Serum PK samples for atezolizumab
See Appendix 2.
Serum ADA samples for atezolizumab
See Appendix 2.
PBMC, plasma, and serum samples for biomarkers 
(central laboratory)gg
See Appendix 2.
Tumor biopsy, if clinically feasible
At time of radiographic progression aa
Optional tumor biopsy at other timepoints bb
Any time during study treatment, observation FU or 
survival FU (at investigator's discretion)
Tumor response assessments
x cc
x dd, ee
Anti-cancer treatment information ff
x
x
Survival follow-up 
x ff


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Appendix 2 Schedule of Activities (cont.)
ADAanti-drug antibody; Atezoatezolizumab; Cabocabozantinib; CT computed tomography (scan); ECOG Eastern 
Cooperative Oncology Group; EORTCEuropean Organisation for Research and Treatment of Cancer; EQ-5D-
5LEuroQol 5-Dimension, 5-Level Questionnaire; FFPEformalin-fixed, paraffin-embedded; FUfollow-up; GHSglobal 
health status; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; 
HCVhepatitis C virus; IL46Item List 46; NSCLCnonsmall cell lung cancer; MRImagnetic resonance imaging; 
PBMCperipheral blood mononuclear cell; PDprogressive disease; PKpharmacokinetic; PRO patient-reported 
outcome; QLQ-C30Quality of LifeCore 30 Questionnaire, Version 1.1; QLQ-LC13Quality of LifeLung Cancer 13-Item 
Questionnaire; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; T3triiodothyronine; 
T4thyroxine; 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 Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior 
to Day 1 may be used; such tests do not need to be repeated for screening.
b Informed consent must be documented before any study-specific screening procedure is performed and may be obtained 
more than 28 days before initiation of study treatment.
c Representative fresh and archival tumor tissue sample obtained at baseline for exploratory research on biomarkers (e.g., 
PD-L1 status via central testing), including biomarker assay development. Tumor tissue samples should be submitted 
before or within 4 weeks of randomization.
d If no tissue specimen is available, known PD-L1 status, as defined by a health authorityapproved PD-L1 assay, is 
required.
e For patients with nonsquamous NSCLC histology with unknown EGFR and/or ALK status, test results are required at 
screening.  EGFR and/or ALK status must be assessed locally or at a central laboratory.  If samples are submitted for 
central testing, additional tissue sample is required.  See laboratory manual for details.
f
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.
g Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion, after the infusion of atezolizumab 


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
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Appendix 2 Schedule of Activities (cont.)
   but prior to the administration of cabozantinib, and, if clinically indicated, every 15 (5) minutes during the infusion and at 
30 (10) minutes after the infusion.  For subsequent infusions of atezolizumab, vital signs should be measured within
   60 minutes prior to the infusion, and, if clinically indicated or if symptoms occurred during the previous infusion, every 
15 (5) minutes during the infusion and at 30 (10) minutes after the infusion.  Vital signs should be measured prior 
to docetaxel infusions.
h Includes evaluation of the skin, head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, blood and lymphatic, and neurologic systems.
i
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.
j
If screening assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated for 
Day 1 of Cycle 1.  At all cycles subsequent to Day 1 of Cycle 1, laboratory assessments, ECOG Performance Status, 
ECG (through Cycle 5), and limited physical examination must be performed within 96 hours prior to administration of 
drug.
k ECG recordings will be obtained during screening, on Day 1 of every cycle through Cycle 5, and then as clinically 
indicated at other timepoints.  Patients should be resting in a supine position for at least 10 minutes prior to ECG 
recording.
l
Specific screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells [if applicable]).
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, 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 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 TSH, 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 four cycles thereafter (i.e., Cycles 5, 9, 13, etc.).
q Urinalysis should be performed as clinically indicated during study treatment.
r
Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan GO41892
Appendix 2 Schedule of Activities (cont.)
s 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.
t
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 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.
u 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.
v Cabozantinib tablets will be given on Day 1 of Cycle 1 after atezolizumab infusion. Patients will take tablets once daily at 
home thereafter until study treatment is discontinued.
w For docetaxel, study drug will be administered according to the local prescribing information, including premedication with 
steroids.
x PRO assessments (EORTC QLQ-C30, EORTC IL17, EORTC QLQ-LC13, EORTC IL46, selected items from the 
PRO-CTCAE 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 patients’ rating and the administration of 
study treatment.  Study personnel should confirm all questionnaires for completeness before the patient leaves the 
investigational site.
y Patient-completed questionnaires should be completed by the patients prior to any assessments, tests or interactions 
that might bias patients’ view on their health status.  
z PRO assessments (EORTC QLQ-C30, EORTC QLQ-LC13, EORTC IL46, selected items from the PRO-
CTCAE, and EQ-5D-5L) will be completed at the end-of-treatment visit.  Following treatment discontinuation, patients 
will complete selected scales from the EORTC QLQ-C30 (EORTC IL17) and the EQ-5D-5L questionnaires at the 
3-month (30 days) and 6-month (30 days) survival follow-up visits.  The questionnaires might be administered by 
the site over the telephone if patients are not coming in-person to the clinic.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
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Appendix 2 Schedule of Activities (cont.)
aa 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.
bb 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 4.5.10
for details.
cc 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) of chest, abdomen, and pelvis, as 
wells as a CT scan (with oral or IV contrast) or MRI of the head.  If a CT scan with contrast is contraindicated (e.g., in 
patients with impaired renal clearance), a non-contrast CT scan of the chest must be performed and MRI scans of the 
abdomen, pelvis, and head must 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 irradiated 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 screening, if clinically indicated.
dd All patients will undergo tumor assessments at baseline, every 6 weeks (7 days) for the first 48 weeks following Day 1 
of Cycle 1, and every 9 weeks (7 days) after completion of the Week 48 tumor assessment regardless of treatment 
delays. Patients will continue scanning regardless of treatment delays until radiographic disease progression per RECIST 
v1.1 (or loss of clinical benefit for patients who continue study treatment after disease progression per RECIST v1.1), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.  Patients in the experimental 
arm who are treated beyond disease progression per RECIST v1.1 will continue to undergo tumor assessments at the 
frequency described above until (i.e., every 6 weeks [7 days] for the first 48 weeks and every 9 weeks [7 days] after 
48 weeks) until study treatment is discontinued. 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 


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Appendix 2 Schedule of Activities (cont.)
consent, death, or study termination by the Sponsor, whichever occurs first. In the absence of radiographic disease 
progression per RECIST v1.1, tumor assessments should continue regardless of whether a patient starts a new anti-
cancer therapy.
ee 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).
ff 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 (every 12 weeks [7 days]) or more frequently until death (unless the patient withdraws consent or the 
Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in 
the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a 
public information source (e.g., county records) to obtain information about survival status only.
gg For patients in either arm at participating sites who have provided written informed consent to participate 
in mobile nursing visits, this assessment or procedure may be performed by a trained nursing professional 
at the patient's home or another suitable location.


Atezolizumab and cabozantinib—F. Hoffmann-La Roche Ltd
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Appendix 3 Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples
Visit
Timepoint
Experimental Arm
(AtezoCabo)
Control Arm
(Docetaxel)
Day 1 of Cycle 1
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Cabozantinib PK (plasma)

Atezolizumab ADA (serum) 

Biomarker (PBMC, plasma, serum)

Biomarker (blood for RBR, optional a)

Biomarker (PBMC, plasma, serum)

Biomarker (blood for RBR, optional a)
Day 1 of Cycle 1
30 (10) minutes after end of 
atezolizumab infusion

Atezolizumab PK (serum)
Day 1 of Cycle 2
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Cabozantinib PK (plasma)

Atezolizumab ADA (serum)

Biomarker (PBMC, plasma, serum)

Biomarker (PBMC, plasma, serum)
Day 1 of Cycle 3
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Cabozantinib PK (plasma)

Atezolizumab ADA (serum)

Biomarker (plasma, serum)

Biomarker (plasma, serum)
Day 1 of Cycle 4
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Cabozantinib PK (plasma)

Atezolizumab ADA (serum)

Biomarker (plasma, serum)

Biomarker (plasma, serum)


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Appendix 3 Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Visit
Timepoint
Experimental Arm
(AtezoCabo)
Control Arm
(Docetaxel)
Day 1 of Cycle 5
Predose (same day as 
treatment administration)

Cabozantinib PK (plasma)
Day 1 of Cycle 8
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (plasma, serum)

Biomarker (plasma, serum)
Day 1 of Cycle 12
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (plasma, serum)

Biomarker (plasma, serum)
Day 1 of Cycle 16
Predose (same day as 
treatment administration)

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (plasma, serum)

Biomarker (plasma, serum)
Post-treatment follow-up 
visit (≤ 30 days after final 
dose)c
At visit

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (PBMC, plasma, serum)

Biomarker (PBMC, plasma, serum)
Disease Progression c
At time of radiographic 
progression per 
RECIST v1.1 b

Biomarker (PBMC, plasma, serum)

Biomarker (PBMC, plasma, serum)


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Appendix 3 Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
ADA anti-drug antibody; Atezo atezolizumab; Cabo cabozantinib; eCRF electronic Case Report Form; PBMC peripheral blood mononuclear 
cell; PK pharmacokinetic; RBR Research Biosample Repository; RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Notes:  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.
Collection of PK samples may be halted early, or sampling frequency may be modified at the discretion of the Sponsor.
Blood sampling for cabozantinib PK analyses:  After Day 1 of Cycle 1, PK samples should be collected approximately 8 or more hours after the 
previous dose of cabozantinib, and if cabozantinib will be administered on that day, PK samples should be collected prior to cabozantinib 
administration.  The investigator will ask the patient for the date and time of the most recent prior dose of cabozantinib, and this information will be 
recorded on the appropriate eCRF.
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.  RBR samples are preferred to be collected on Day 1 of Cycle 1; however, they may be 
collected predose on Day 1 of any subsequent cycle visit.
b Blood collections should be performed within 40 days after progression or prior to the next anti-cancer therapy, whichever is sooner.
c
For patients in either arm at participating sites who have provided written informed consent to participate in mobile nursing 
visits, collection of this sample may be performed by a trained nursing professional at the patient's home or another suitable 
location.