A Phase III, Randomized, Open-Label, Multicenter Study of Lurbinectedin in Combination With Atezolizumab Compared With Atezolizumab as Maintenance Therapy in Participants With Extensive-Stage Small-Cell Lung Cancer (ES-SCLC) Following First-Line Induction Therapy With Carboplatin, Etoposide and Atezolizumab
Phase: PHASE3
Conditions: Small-Cell Lung Cancer
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase III, Randomized, Open-Label, Multicenter Study of 
Lurbinectedin in Combination with Atezolizumab Compared with 
Atezolizumab as Maintenance Therapy in Participants with 
Extensive-Stage Small-Cell Lung Cancer (ES-SCLC) Following First-
Line Induction Therapy with Carboplatin, Etoposide and Atezolizumab 
NCT Number: 
NCT05091567 
Document Date: 
Protocol Amendment Version 8: 05-Mar-2025 

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unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore, is 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. 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol GO43104, Version 8 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL, 
MULTICENTER STUDY OF LURBINECTEDIN IN 
COMBINATION WITH ATEZOLIZUMAB 
COMPARED WITH ATEZOLIZUMAB AS 
MAINTENANCE THERAPY IN PARTICIPANTS 
WITH EXTENSIVE-STAGE SMALL-CELL LUNG 
CANCER (ES-SCLC) FOLLOWING FIRST-LINE 
INDUCTION THERAPY WITH CARBOPLATIN, 
ETOPOSIDE AND ATEZOLIZUMAB 
PROTOCOL NUMBER: 
GO43104 
STUDY NAME: 
IMforte 
VERSION NUMBER: 
8 
TEST COMPOUNDS: 
Lurbinectedin (PM01183/JZP712) 
Atezolizumab (RO5541267) 
STUDY PHASE: 
Phase III 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS:  
IND Number:  156,531 
EudraCT Number:  2021-001930-20 
EU CT Number:  2023-503868-16-00 
NCT Number:  NCT05091567 
SPONSOR'S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4058 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the 
final page of this document. 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GO43104, Version 8 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
8 
See electronic date stamp on the final page of this 
document. 
7 
27 November 2023 
6 
23 February 2023 
5 
19 September 2022 
4 
18 February 2022 
3 
3 December 2021 
2 
22 September 2021 
1 
11 August 2021 
  
 
 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GO43104, Version 8 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol GO43104 has been amended to align the risks and management guidelines 
with the Atezolizumab Investigator's Brochure, Version 21.  In addition, given that the 
clinical cut-off date for the final overall survival analysis has been reached and some 
study analyses are now complete, certain changes as outlined below have been 
implemented to alleviate the burden on participants and sites. 
Substantive changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
 
 
 
 
 
 
 
Collection of demographic data, including information on race and ethnicity, is of 
importance to the future interpretation of results from the clinical trial.  A rationale 
has been provided in Section 4.2.7. 
 
The estimated length of the study from first participant screened for enrollment into 
the induction phase to last participant, last visit has been updated from 
approximately 60 months to approximately 90 months (Section 4.4). 
 
Text in Section 6.6 has been modified to align with updates to the Roche Global 
Policy on Continued Access to Investigational Medicinal Products. 
 
The responsibilities of the investigator and the role of the Medical Monitor in study 
conduct have been clarified (Section 7.1). 
 
The Sponsor's policy on trade secrets has been described in Section A1-10 to 
increase transparency. 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 21 (Section A6-2.4.2). 
 
The adverse event management guidelines have been streamlined by removing 
standard of care information and restructured, for consistency with regulatory 
guidelines and industry standards (Section A6-2.4.2). 
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. 
 
 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol GO43104, Version 8 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
1. 
PROTOCOL SUMMARY ............................................................... 12 
1.1 
Synopsis .................................................................................. 12 
1.2 
Study Schema ......................................................................... 17 
1.3 
Schedule of Activities and Sample Collection Schedule .......... 18 
2. 
INTRODUCTION ........................................................................... 32 
2.1 
Study Rationale ....................................................................... 32 
2.2 
Background.............................................................................. 32 
2.2.1 
Background on Lung Cancer ................................................... 32 
2.2.2 
Current Standard Treatment for Extensive-Stage Small-
Cell Lung Cancer ..................................................................... 33 
2.2.3 
Background on Lurbinectedin .................................................. 34 
2.2.4 
Background on Atezolizumab .................................................. 35 
2.3 
Benefit–Risk Assessment ........................................................ 36 
2.3.1 
COVID-19 Benefit–Risk Assessment ....................................... 38 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 39 
4. 
STUDY DESIGN ........................................................................... 43 
4.1 
Overall Design ......................................................................... 43 
4.2 
Rationale for Study Design ...................................................... 44 
4.2.1 
Rationale for Study Population ................................................ 45 
4.2.2 
Rationale for Control Group ..................................................... 46 
.................. 47 
4.2.4 
Rationale for the Collection of Tumor Specimens 
Post-Induction and Prior to Maintenance Therapy and at 
Radiographic Progression........................................................ 48 
4.2.5 
Rationale for Choice of Stratification Factors ........................... 48 
4.2.6 
Rationale for Primary Endpoint Selection ................................ 49 
4.2.7 
Rationale for Collection of Information on Race and 
Ethnicity .................................................................................. 49 
4.3 
Justification for Dose and Schedule ......................................... 50 
4.3.1 
Rationale for Lurbinectedin Dose and Schedule ...................... 50 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol GO43104, Version 8 
4.3.2 
Rationale for Atezolizumab Dose and Schedule ...................... 50 
4.3.3 
Rationale for Atezolizumab Dose and Schedule in 
Combination with Carboplatin and Etoposide .......................... 50 
4.3.4 
Rationale for Lurbinectedin in Combination with 
Atezolizumab Dose and Schedule ........................................... 50 
4.3.5 
Rationale for Use of Primary Granulocyte 
ColonyStimulating Factor Prophylaxis for Lurbinectedin ........ 51 
4.4 
End of Study Definition ............................................................ 51 
4.5 
Duration of Participation .......................................................... 51 
5. 
STUDY POPULATION .................................................................. 52 
5.1 
Inclusion Criteria ...................................................................... 52 
5.1.1 
Inclusion Criteria for the Induction Phase ................................ 52 
5.1.2 
Inclusion Criteria for the Maintenance Phase .......................... 55 
5.2 
Exclusion Criteria ..................................................................... 57 
5.2.1 
Exclusion Criteria for the Induction Phase ............................... 57 
5.2.2 
Exclusion Criteria for the Maintenance Phase ......................... 59 
5.3 
Lifestyle Considerations ........................................................... 61 
5.3.1 
Meals and Dietary Restrictions ................................................ 61 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................... 61 
5.3.3 
Activity ..................................................................................... 61 
5.3.4 
Contraception Requirements ................................................... 61 
5.4 
Screen Failures ........................................................................ 62 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY ........... 62 
6.1 
Study Treatments Administered ............................................... 62 
6.1.1 
Study Treatment in the Induction Phase .................................. 65 
6.1.2 
Study Treatment in the Maintenance Phase ............................ 65 
6.1.2.1 
Arm A:  Atezolizumab  Lurbinectedin ..................................... 65 
6.1.2.2 
Arm B:  Atezolizumab .............................................................. 68 
6.1.3 
Prophylactic Medications ......................................................... 69 
6.2 
Preparation, Handling, Storage, and Accountability ................. 71 
6.3 
Treatment Assignment ............................................................. 72 
6.4 
Study Treatment Compliance .................................................. 72 
6.5 
Dose Modification .................................................................... 73 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Protocol GO43104, Version 8 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 73 
6.7 
Treatment of Overdose ............................................................ 74 
6.8 
Concomitant Therapy .............................................................. 74 
6.8.1 
Permitted Therapy ................................................................... 75 
6.8.2 
Cautionary Therapy ................................................................. 76 
6.8.2.1 
Cautionary Therapy for Atezolizumab-Treated Participants .... 76 
6.8.2.2 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes ...................................................................... 76 
6.8.2.3 
Herbal Therapies ..................................................................... 77 
6.8.3 
Prohibited Therapy .................................................................. 77 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............ 77 
7.1 
Discontinuation of Study Treatment ......................................... 78 
7.1.1 
Liver Chemistry Stopping Criteria ............................................ 79 
7.2 
Participant Discontinuation or Withdrawal from the Study ....... 79 
7.3 
Participants Lost to Follow-Up ................................................. 79 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 80 
8.1 
Efficacy Assessments .............................................................. 81 
8.1.1 
Tumor and Response Evaluations ........................................... 81 
8.1.1.1 
Radiographic Assessments ..................................................... 82 
8.1.1.2 
Response Evaluation ............................................................... 84 
8.2 
Safety Assessments ................................................................ 84 
8.2.1 
Physical Examinations ............................................................. 84 
8.2.2 
Vital Signs ................................................................................ 84 
8.2.3 
Electrocardiograms .................................................................. 84 
8.2.4 
Clinical Safety Laboratory Tests .............................................. 85 
8.2.5 
Pregnancy Testing ................................................................... 85 
8.3 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 86 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 86 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 87 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol GO43104, Version 8 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 87 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 87 
8.3.5 
Pregnancy................................................................................ 88 
8.3.6 
Cardiovascular and Death Events ........................................... 88 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting ..... 88 
8.3.8 
Adverse Events of Special Interest .......................................... 89 
8.3.9 
Medical Monitors and Emergency Medical Contacts ............... 90 
8.4 
Pharmacokinetics .................................................................... 90 
8.5 
Pharmacodynamics ................................................................. 90 
8.6 
Genetics .................................................................................. 90 
........................................................ 90 
8.8 
Immunogenicity Assessments ................................................. 92 
8.9 
Health Economics .................................................................... 92 
8.10 
Clinical Outcome Assessments ............................................... 93 
8.10.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 93 
8.10.2 
Description of Clinical Outcome Assessment Instruments ....... 94 
8.10.2.1 
EORTC Quality of Life QuestionnaireCore 30 ....................... 94 
8.10.2.2 
EORTC Quality of Life QuestionnaireLung Cancer 
Module ..................................................................................... 94 
8.10.2.3 
EORTC Item List 46 ................................................................. 94 
8.10.2.4 
EuroQol EQ-5D-5L .................................................................. 95 
8.10.2.5 
PRO-CTCAE ............................................................................ 95 
8.11 
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ........................................................ 95 
8.11.1 
Optional Tumor Biopsies (Participants Providing Separate 
Consent) .................................................................................. 95 
8.11.2 
Optional Samples for Research Biosample Repository 
(Participants Providing Separate Consent at Participating 
Sites) ....................................................................................... 96 
8.11.2.1 
Overview of the Research Biosample Repository .................... 96 
8.11.2.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 97 
8.11.2.3 
Sample Collection .................................................................... 97 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol GO43104, Version 8 
 
LIST OF TABLES 
Table 1 
Schedule of Activities during the Induction Phase ...................... 18 
Table 2 
Schedule of Activities during the Maintenance Phase ................ 22 
................. 30 
Table 4 
Primary Objectives and Estimand Definition for Randomized 
Participants ................................................................................. 40 
Table 5 
Secondary and Exploratory Objectives and Endpoints for 
Randomized Participants ............................................................ 41 
Table 6 
Study Treatment Description during the Induction Phase ........... 63 
Table 7 
Study Treatment Description during the Maintenance Phase ..... 64 
Table 8 
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 67 
Table 9 
Administration of First and Subsequent Infusions of 
Lurbinectedin .............................................................................. 68 
Table 10 
Description of Participant Analysis Sets .................................... 102 
 .............................................. 108 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 17 
Figure 2 
Order of Administration of Study Treatment and Prophylactic 
Medications in Arm A .................................................................. 70 
 
 ........................................... 100 
 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ......... 115 
Appendix 2 
Clinical Laboratory Tests .......................................................... 122 
Appendix 3 
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ....................................... 123 
Appendix 4 
Contraceptive and Barrier Guidance ......................................... 144 
Appendix 5 
Genetics:  Use and Analysis of DNA ......................................... 147 
Appendix 6 
Safety Plan:  Management of Identified and Potential Risks ..... 148 
Appendix 7 
Anaphylaxis Precautions ........................................................... 186 
Appendix 8 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) ........................................................................... 187 
Appendix 9 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 199 
Appendix 10 
EuroQol EQ-5D-5L .................................................................... 200 

Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GO43104, Version 8 
Appendix 11 
European Organisation for Research and Treatment of 
Cancer Quality of LifeCore 30 Questionnaire 
(EORTC QLQC30) .................................................................. 202 
Appendix 12 
European Organisation for Research and Treatment of 
Cancer Quality of LifeLung Cancer Module 
(EORTC QLQLC13) ................................................................ 204 
Appendix 13 
European Organisation for Research and Treatment of 
Cancer  Item List 46 .............................................................. 205 
Appendix 14 
Patient-Reported Outcome Common Terminology Criteria for 
Adverse Events ......................................................................... 206 
Appendix 15 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 209 
Appendix 16 
Cytochrome P450 3A Inhibitors and Inducers ........................... 210 
Appendix 17 
Veterans Administration Lung Study Group Staging System 
for Small-cell Lung Cancer ........................................................ 212 
Appendix 18 
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ....................................... 213 
Appendix 19 
Protocol Amendment History .................................................... 215 
Appendix 20 
Abbreviations ............................................................................ 223 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol GO43104, Version 8 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL, 
MULTICENTER STUDY OF LURBINECTEDIN IN 
COMBINATION WITH ATEZOLIZUMAB 
COMPARED WITH ATEZOLIZUMAB AS 
MAINTENANCE THERAPY IN PARTICIPANTS WITH 
EXTENSIVE-STAGE SMALL-CELL LUNG CANCER 
(ES-SCLC) FOLLOWING FIRST-LINE INDUCTION 
THERAPY WITH CARBOPLATIN, ETOPOSIDE AND 
ATEZOLIZUMAB 
PROTOCOL NUMBER: GO43104 
STUDY NAME: 
IMforte 
VERSION NUMBER: 
8 
TEST COMPOUNDS: 
Lurbinectedin (PM01183/JZP712) 
Atezolizumab (RO5541267) 
SPONSOR NAME: 
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.

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol GO43104, Version 8 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL, MULTICENTER 
STUDY OF LURBINECTEDIN IN COMBINATION WITH 
ATEZOLIZUMAB COMPARED WITH ATEZOLIZUMAB AS 
MAINTENANCE THERAPY IN PARTICIPANTS WITH 
EXTENSIVE-STAGE SMALL-CELL LUNG CANCER (ES-SCLC) 
FOLLOWING FIRST-LINE INDUCTION THERAPY WITH 
CARBOPLATIN, ETOPOSIDE AND ATEZOLIZUMAB 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  156,531 
EudraCT Number: 2021-001930-20 
EU CT Number:  2023-503868-16-00 
NCT Number:  NCT05091567 
  
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of lurbinectedin, an alkylating drug 
that binds guanine residues in the minor groove of DNA, in combination with atezolizumab for 
the maintenance treatment of extensive-stage small-cell lung cancer (ES-SCLC) in participants 
whose disease has not progressed after first-line induction therapy with atezolizumab, 
carboplatin, and etoposide. 
Despite the improved efficacy observed with programmed death-ligand 1 (PD-L1) inhibitors in 
combination with platinum-based chemotherapy in first-line ES-SCLC, most patients eventually 
experience disease progression and upon relapse, their prognosis is poor.  Therefore, novel 
combination strategies are needed to deliver better long-term outcomes. 
The early introduction of other agents active in small-cell lung cancer (SCLC), and with a 
complementing pathway to the current treatment approach, is an appealing strategy to further 
improve the prognosis of patients with advanced SCLC. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Corresponding Endpoints 
 To evaluate the efficacy 
of lurbinectedin in 
combination with 
atezolizumab compared 
with atezolizumab 
 Population:  individuals with ES-SCLC who have ongoing CR, 
PR, or SD after completion of 4 cycles of carboplatin, etoposide, 
and atezolizumab first-line induction treatment, as defined 
through the inclusion and exclusion criteria for the maintenance 
phase 
 Endpoint: IRF-assessed PFS after randomization, defined as the 
time from randomization to the date of first documented disease 
progression (as assessed by the IRF according to RECIST v1.1) 
or death, whichever occurs first 
 Treatments: 
– 
Experimental arm: atezolizumab 1200 mg 
IV  lurbinectedin 3.2 mg/m2 IV on Day 1 of each 21-day 
cycle 
– 
Control arm: atezolizumab 1200 mg IV on Day 1 of each 
21-day cycle 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol GO43104, Version 8 
 
 Intercurrent events and handling strategies: 
– 
Early discontinuation from study treatment for any reason:  
treatment policy strategy 
– 
Start of non-protocol anti-cancer therapy prior to the 
respective event of interest:  treatment policy strategy 
 Population-level summary:  hazard ratio for IRF-assessed PFS 
 Population:  as defined above 
 Endpoint:  OS after randomization, defined as the time from 
randomization to the date of death from any cause 
 Treatments:  as defined above 
 Intercurrent events and handling strategies:  as defined above 
 Population-level summary:  hazard ratio for OS  
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy 
of lurbinectedin in 
combination with 
atezolizumab compared 
with atezolizumab 
 Investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of disease progression as 
determined by the investigator according to RECIST v1.1, or 
death from any cause, whichever occurs first 
 Confirmed ORR, defined as the proportion of randomized 
participants with a CR or PR on two consecutive occasions 
 4 weeks apart after randomization, as determined by the IRF 
according to RECIST v1.1 
 Confirmed ORR, defined as the proportion of randomized 
participants with a CR or PR on two consecutive 
occasions    4 weeks apart after randomization, as determined 
by the investigator according to RECIST v1.1 
 DOR, defined as the time from the first occurrence of a 
documented confirmed objective response after randomization 
until disease progression as determined by the IRF according to 
RECIST v1.1, or death from any cause, whichever occurs first 
 DOR, defined as the time from the first occurrence of a 
documented confirmed objective response after randomization 
until disease progression as determined by the investigator 
according to RECIST v1.1, or death from any cause, 
whichever occurs first 
 PFS rates at 6 months and 12 months, defined as the proportion 
of participants who have not experienced disease progression or 
death from any cause at 6 months and 12 months after 
randomization, as determined by the IRF according to 
RECIST v1.1 
 PFS rates at 6 months and 12 months, defined as the proportion 
of participants who have not experienced disease progression or 
death from any cause at 6 months and 12 months after 
randomization, as determined by the investigator according to 
RECIST v1.1 
 OS rates at 12 months and 24 months, defined as the proportion 
of participants who have not experienced death from any cause 
at 12 months and 24 months after randomization 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol GO43104, Version 8 
 To evaluate the safety of 
lurbinectedin in 
combination with 
atezolizumab compared 
with atezolizumab 
 Incidence and severity of adverse events, including serious 
adverse events and adverse events of special interest, with 
severity determined according to NCI CTCAE v5.0 
 To evaluate the 
immunogenicity of 
atezolizumab with and 
without lurbinectedin 
 Prevalence of ADAs to atezolizumab at induction phase baseline 
and incidence of ADAs to atezolizumab after drug administration 
 To evaluate the health-
related quality of life of 
participants treated with 
lurbinectedin in 
combination with 
atezolizumab compared 
with atezolizumab 
 TTCD from randomization in patient-reported physical functioning 
and global health status as measured by the EORTC QLQ-C30 
ADA  anti-drug antibody; CR  complete response; DOR  duration of response; 
EORTC  European Organisation for Research and Treatment of Cancer; 
HRQoL    health-related quality of life; IRF  Independent Review Facility; 
NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5; ORR  objective response rate; OS  overall survival; PFS  progression-free survival; 
PR  partial response; PRO    Patient-Reported Outcome; QLQ-C30  Quality of Life 
QuestionnaireCore 30; RECIST  Response Evaluation Criteria in Solid Tumor; SD    stable 
disease; TTCD  time to confirmed deterioration. 
 
 
OVERALL DESIGN AND STUDY POPULATION 
Study GO43104 is a Phase III, randomized, open-label, multicenter study of lurbinectedin in 
combination with atezolizumab compared with atezolizumab alone administered as 
maintenance therapy in participants with ES-SCLC after first-line induction therapy with 
carboplatin, etoposide, and atezolizumab.  Participants are required to have an ongoing 
response or SD per the Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 after 
completion of 4 cycles of carboplatin, etoposide, and atezolizumab induction treatment in order 
to be considered for eligibility screening for the maintenance phase. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
15/Protocol GO43104, Version 8 
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: 
ES-SCLC 
Interventional 
Model: 
Single group induction 
phase, parallel group 
maintenance phase 
Population Age: 
  18 years 
Test Compounds: 
Lurbinectedin, 
Atezolizumab 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator: Atezolizumab 
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Induction phase: 
approximately 690 
Maintenance phase: 
approximately 
 
ES-SCLC   extensive-stage small-cell lung cancer. 
 
 
STUDY TREATMENT 
STUDY TREATMENT IN THE INDUCTION PHASE 
Once participants are screened for the induction phase and have been determined to be 
eligible, participants will be enrolled to receive 4 cycles of standard of care treatment with 
carboplatin, etoposide and atezolizumab unless unacceptable toxicity, disease progression or a 
participant's decision to discontinue occur, with each cycle being 3 weeks (21 days) in length.  
All participants will receive a fixed dose of 1200 mg atezolizumab administered by IV infusion on 
Day 1 of each 21-day cycle. 
STUDY TREATMENT IN THE MAINTENANCE PHASE 
Arm A:  Atezolizumab  Lurbinectedin 
Atezolizumab and lurbinectedin will be administered in the following order for Arm A: 
Atezolizumab → Lurbinectedin 
 
Atezolizumab 1200 mg IV  Lurbinectedin 3.2 mg/m2 IV on Day 1 of each 21-day cycle. 
Prophylactic anti-emetic medication and primary prophylaxis with pegylated G-CSF will be 
administered. 
 
All participants will receive atezolizumab administered by IV infusion at a fixed dose of 1200 mg 
on Day 1 of each 21-day cycle until unacceptable toxicity, disease progression per 
RECIST v1.1, or any other discontinuation criterion has been met.  The atezolizumab dose is 
fixed and is not dependent on body weight or body surface area.  There will be no dose 
modifications such as dose reductions, for atezolizumab.  Treatment with atezolizumab may be 
temporarily suspended as appropriate for management of adverse events. 
All participants in Arm A will receive 3.2 mg/m2 lurbinectedin administered by IV infusion on 
Day 1 of each 21-day cycle.  The lurbinectedin dose is dependent on body surface area (BSA).  
It is recommended to calculate BSA using the DuBois formula. 
The dose of lurbinectedin will be based on the participant's maintenance baseline weight 
(measured  28 days prior to randomization into the maintenance phase) and will remain the 
same throughout the study unless the participant's weight changes by  10% relative to the 
weight recorded at the time of the previous dose calculation.  However, treating physicians may 
choose to re-calculate the dose of lurbinectedin based on the actual weight assessed prior to 
each dosing. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
16/Protocol GO43104, Version 8 
Up to 2 lurbinectedin dose reductions will be allowed (first dose reduction:  2.6 mg/m2 Q3W; 
second dose reduction:  2 mg/m2 Q3W).  Once the dose has been reduced for an individual 
participant, it must not be re-escalated again.  If the participant receives a lurbinectedin dose of 
2 mg/m2 and experiences a toxicity that would warrant a lurbinectedin dose reduction, treatment 
with lurbinectedin must be permanently discontinued. 
If study treatment has to be temporarily interrupted or permanently discontinued to manage 
toxicity, atezolizumab and lurbinectedin can be interrupted or discontinued independently from 
each other (i.e., an interruption or discontinuation of lurbinectedin does not necessarily result in 
a simultaneous interruption or discontinuation of atezolizumab; an interruption or discontinuation 
of atezolizumab does not necessarily result in a simultaneous interruption or discontinuation of 
lurbinectedin), depending on the toxicity and suspected causality. 
 
Arm B:  Atezolizumab 
Atezolizumab will be administered to participants in Arm B: 
Atezolizumab 1200 mg IV on Day 1 of each 21-day cycle 
 
Prophylactic anti-emetic medication and primary G-CSF prophylaxis is not required for 
atezolizumab administered alone. 
Prophylactic Medications 
All participants in the atezolizumab  lurbinectedin arm (Arm A) will receive the following anti-
emetic and G-CSF prophylactic medication for lurbinectedin treatment: 
 
Anti-emetic treatment on Day 1 of the first cycle will be administered as per local standard 
practice (before or after infusion of atezolizumab, but at least 1530 minutes before the 
infusion of lurbinectedin): 
– 
Corticosteroids (dexamethasone 8 mg IV or equivalent) 
AND 
– 
5-HT3 antagonists (Zofran [ondansetron hydrochloride] 8 mg IV or equivalent), with or 
without metoclopramide 10 mg IV or equivalent 
 
Other possible additional prophylactic medications: 
 
Extended treatment with oral prednisone not exceeding 10 mg/day or equivalent and/or oral 
ondansetron 48 mg or equivalent, at the investigator's discretion if required 
 
Additional anti-emetics may be used, if required 
 
Aprepitant and equivalent agents (e.g., fosaprepitant) are not permitted in participants treated 
with lurbinectedin.  The requirement for premedication for anti-emetic prophylaxis for the 
subsequent cycles (i.e., Day 1, Cycle 2 and subsequent cycles) should be evaluated on an 
individual basis, and its administration left to the investigator's judgment, taking into account the 
potential impact of corticosteroids on the beneficial immunologic effects of treatment with 
atezolizumab. 
Primary prophylaxis with pegylated G-CSF is mandated in participants receiving lurbinectedin.  
It is strongly recommended to use pegylated instead of non-pegylated G-CSF; however, if 
pegylated G-CSF cannot be obtained at the site, the use of non-pegylated G-CSF is permitted.  
Type, dose, and scheme may vary according to institutional standard practices or guidelines.  
Home self-administration of G-CSF is permitted according to institutional standard practice.  
A mandatory window of at least 24 hours to up to 48 hours from lurbinectedin administration 
must be allowed until G-CSF prophylaxis is started. 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 1 day to 
more than 2 years. 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee 
 

Table 1 
Schedule of Activities during the Induction Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
20/Protocol GO43104, Version 8 
a Assessments should be performed before study treatment infusion unless otherwise noted. 
b Enrolled participants will receive their first dose of study treatment the day of enrollment, if possible.  Cycle 1 must be performed within 5 days 
after the participant is enrolled.  Screening assessments performed  4 days before Cycle 1, Day 1 are not required to be repeated for Cycle 1, 
Day 1.  Day 1 dose administrations are to be performed within a  3-day window, unless treatment is delayed or on hold to manage adverse 
events.  If the scheduled dose administration coincides with a weekend or holiday that precludes administration, administration should be 
performed as soon as possible but within 7 days following the scheduled D1 dose administration. 
c 
d Vital signs include pulse rate, respiratory rate, blood pressure, and temperature.  Vital signs should be recorded as described in Section 8.2.2. 
e Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils) and platelet count. 
f At screening, the participant must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days 
prior to enrollment.  See Section 5.1 for details. 
g Local laboratory assessments may be obtained  4 days before Day 1 of each cycle. 
h For participants at participating sites who have signed Informed Consent to take part in mobile nursing visits, this assessment or procedure may 
be performed by a trained nursing professional at the participant's home or another suitable location. 
i Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide, sodium, potassium, magnesium, chloride, glucose, BUN 
or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH.  A CPK assessment is required 
at screening. 
j A serum pregnancy test is required within 14 days prior to enrollment.  On Day 1 of each cycle, a urine pregnancy test is required. 
k TSH, free T3 (or total T3 for sites where free T3 is not preferred), and free T4 can be assessed after enrollment but must be assessed before 
drug administration on Day 1 of Cycle 1. 
l All participants will be tested for HIV prior to inclusion into the study.  Participants who have a negative HIV test at screening are eligible.  
Participants with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count  200/L, and 
have an undetectable viral load.  Participants with active HBV (chronic or acute; defined as having a positive HBsAg test result at screening) will 
be excluded from the study.  Participants with past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are 
eligible; HBV DNA should be obtained in these participants prior to randomization.  Participants with active HCV will be excluded from the study; 
participants who test positive for HCV antibody are eligible only if a PCR test is negative for HCV RNA. 

Table 1 
Schedule of Activities during the Induction Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
21/Protocol GO43104, Version 8 
m For atezolizumab, the initial dose will be administered over 60 ( 15) minutes.  If the first infusion is well-tolerated, subsequent infusions may be 
administered over 30 ( 10) minutes (see Section 6.1.1).  The order of infusions should be as per local standard of care.  Atezolizumab 
and carboplatin will be administered on Day 1 of each induction treatment cycle, etoposide will be administered on Day 1, Day 2, and Day 3 
of each induction treatment cycle. 
n CT scans (with IV contrast unless contraindicated and oral contrast as appropriate per institutional standards) of the chest, abdomen and pelvis.  
A CT (with contrast) or MRI scan of the head is required to evaluate CNS metastasis in all participants.  Target and non-target lesions must be 
assigned to allow tumor response assessments per RECIST v1.1.  See Section 8.1.1.1 for details. 
o Please see requirements for tumor assessment scans at maintenance screening in Table 2. 
p The optional RBR whole blood sample requires an additional Informed Consent signature. If the optional blood sample for the RBR was not 
collected on Day 1 of Cycle 1 of the induction phase, it can be collected at any other time during the study after the RBR optional consent has 
been signed. 
q 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.  After initiation of study treatment, 
all adverse events must be reported.  Please see Section 8.3.1 for the adverse event reporting period. 
r From 7 days prior to enrollment until the treatment discontinuation visit.  All such medications must be recorded on the Concomitant Medications 
eCRF. 
s EORTC QLQ-C30, EORTC QLQ-LC13, EORTC IL46, PRO-CTCAE (select items), and the EQ-5D-5L questionnaires will be completed by the 
participants at the start of the clinic visit before discussion of the participant's health state, laboratory results, or health record; before 
administration of study treatment; and/or prior to the performance of any other study assessments that could bias the participant's responses.  In 
scenarios where laboratory assessments (e.g., blood draws) are done in a different clinic than the one providing treatment or when they are 
done on a different day than study treatment administration, laboratory assessments can be completed before the completion of PROs as long 
as results have not been discussed with the participant.  If the participant comes to the clinic for study drug administration, completes the PRO 
questionnaires and then does not receive study treatment (i.e., a decision is made that study treatment cannot be administered on that day due 
to the participant's health status), the collected PROs should be kept and questionnaires for this timepoint should not be re-administered on the 
day of the delayed study drug administration.  All questionnaires will be completed during the induction phase on Cycle 1, Day 1 only.  The PRO 
instruments will be self-administered by the participant via electronic PRO device at the investigational site. 
 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
23/Protocol GO43104, Version 8 
Procedure 
Maintenance 
Screening a 
Maintenance Phase (21-Day Cycles) b 
Treatment 
Discontinuation 
Visit 
Post-Treatment 
Follow-Up e 
Days 28 to 1 
Day 1 ( 3 Days) c 
Day 10 ( 3 Days) of 
Maintenance Cycles 1 
and 2 only 
 30 Days after the 
Last Dose of 
Study Treatment d 
Maintenance treatment administration r 
Arm A:  atezolizumab  lurbinectedin 
Arm B:  atezolizumab 
 
x 
 
 
 
Tumor assessment 
x s 
x t 
 
 
x u 
Optional tumor biopsy after 
induction/prior to maintenance 
treatment v 
(if participant signs the Consent Form 
and if clinically feasible) 
x 
 
 
 
 
Optional tumor biopsy at the time of 
radiographic disease progression v 
(if the participant signs the 
Consent Form and if clinically feasible) 
 
At the time of radiographic disease progression 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
25/Protocol GO43104, Version 8 
Events; QLQ-C30  Quality of Life QuestionnaireCore 30; QLQ-LC13  Quality of Life QuestionnaireLung Cancer Module; RBR  Research 
Biosample Repository; RECIST  Response Evaluation Criteria in Solid Tumors. 
a Maintenance screening can be started as early as all Cycle 4 induction treatment administrations have been completed.  The maintenance 
screening window is up to 28 days.  Randomization must occur within 5 weeks (35 days) from the day of the administration of the last dose 
of induction treatment with atezolizumab, carboplatin, and/or etoposide (whichever occurs last), but Cycle 1, Day 1 of the maintenance phase 
must not be administered less than 3 weeks (21 days) from Cycle 4, Day 1 of the induction treatment phase.  Participants receiving PCI must be 
randomized within 9 weeks (63 days) from the last dose of induction treatment with atezolizumab, carboplatin, and/or etoposide 
(whichever occurs last). 
b Assessments should be performed before study treatment infusion unless otherwise noted. 
c Randomized participants will receive their first dose of study treatment the day of randomization into the maintenance phase, if possible.  Cycle 1 
must be performed within 5 days after randomization.  Screening assessments performed  4 days before Cycle 1, Day 1, do not need to be 
repeated for Cycle 1, Day 1.  Day 1 dose administrations are to be performed within a  3-day window, unless treatment is delayed or on hold to 
manage adverse events.  If the scheduled dose administration coincides with a weekend or holiday that precludes administration, administration 
should be performed as soon as possible but within 7 days following the scheduled D1 dose administration.  For Arm A, should one study drug 
be temporarily interrupted because of toxicity caused by lurbinectedin or atezolizumab, treatment will be restarted such that the administration of 
both study drugs remains synchronized. 
d The treatment discontinuation visit is to be performed within 30 days of the last study treatment administration or within 30 days from the date the 
decision was made to permanently discontinue all study treatment. 
e The follow-up period starts from the day of the treatment discontinuation visit. All participants will enter the follow-up period, regardless of the 
reason for treatment discontinuation.  Participants will remain in follow-up until the end of the study, withdrawal of consent, loss to follow-up, 
death, or study termination by the Sponsor. 
f Vital signs include pulse rate, respiratory rate, blood pressure, and temperature.  Vital signs should be recorded as described in Section 8.2.2. 
g Symptom-directed physical examinations; see Section 8.2.1 for details. 
h May be obtained  4 days before Day 1 of each cycle. 
i Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils) and platelet count. 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
26/Protocol GO43104, Version 8 
j At screening, the participant must have adequate hematologic and end-organ function defined by laboratory test results obtained within 7 days 
prior to randomization.  See Section 5.1.2  for details. 
k For participants at participating sites who have signed Informed Consent to take part in mobile nursing visits, this assessment or procedure may 
be performed by a trained nursing professional at the participant's home or another suitable location. 
l Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide, sodium, potassium, magnesium, chloride, glucose, BUN 
or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, CPK and LDH.  For participants entering 
the maintenance phase with asymptomatic amylase and/or lipase elevation up to 2.0  ULN with no abdominal pain and no characteristic 
CT findings, weekly monitoring of blood amylase and lipase is required until complete or partial resolution (Grade  1). 
m Serum pregnancy test within 14 days prior to randomization. 
n During the maintenance phase of the study, urine pregnancy tests will be performed on Day 1 of every cycle.  After study treatment 
discontinuation, a urine pregnancy test will be performed at either 6 months ( 30 days) after the final dose of carboplatin or etoposide 
or lurbinectedin, or at 5 months ( 30 days) after the final dose of atezolizumab, whichever is later.  If a urine pregnancy test result is positive, 
it must be confirmed by a serum pregnancy test. 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
27/Protocol GO43104, Version 8 
o TSH, free T3 (or total T3 for sites where free T3 is not preferred), and free T4 will be assessed during the maintenance phase on or  4 days 
before Day 1 of Cycles 5, 9, 13, and every fourth cycle thereafter. 
p Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.  Urinalysis is required at screening and thereafter will be 
obtained if clinically indicated. 
q One blood sample for the evaluation of AGP will be collected prior to the start of maintenance treatment on Cycle 1 Day 1; AGP will be collected 
and analyzed by the central laboratory only for participants randomized to the experimental arm. 
r Atezolizumab will be administered over 60 ( 15) minutes, unless previous infusions during the induction phase have been well-tolerated in which 
case atezolizumab may be administered over 30 ( 10) minutes (see Section 6.1.2.2).  Infusions should be given in the following order for the 
experimental arm:  atezolizumab → lurbinectedin.  Lurbinectedin will be administered over 1 hour (see Section 6.1.2.1).  For treatment 
continuation criteria for Arm A, please see Table A6-2. 
s CT scans (with IV contrast unless contraindicated and oral contrast as appropriate per institutional standards) of the chest, abdomen and pelvis.  
An MRI scan or CT with contrast of the head is required to evaluate CNS metastasis in all participants.  For participants for whom imaging of the 
brain was performed after the end of induction treatment and who subsequently received PCI, brain imaging does not need to be repeated after 
PCI before randomization.  See Section 8.1.1.1 for details.  The maintenance baseline tumor scans are to evaluate tumor response per 
RECIST v1.1 against the induction baseline scans as only participants with complete or partial response, or with stable disease are eligible for 
maintenance treatment.  However, note that the scans performed during maintenance screening will become the new baseline scans to compare 
against for all subsequent tumor assessments and reassignment of target and non-target lesions is required.  See Appendix 8 for more details. 
t Perform CT scans (with contrast) of the chest and abdomen, and any other known or suspected site of disease.  Perform MRI or CT scans of the 
head as surveillance as per local practice, or as clinically indicated.  Perform tumor assessments every 6 weeks ( 7 days) for 48 weeks following 
Cycle 1, Day 1 of the maintenance phase and every 9 weeks ( 7 days) thereafter, 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.  Tumor assessments 
are to be scheduled based on the date of the previously performed tumor assessment.  Participants without any radiographic evidence of 
disease progression 2 years after Cycle 1, Day 1 of the maintenance phase may undergo tumor assessments every 3 months ( 7 days) or more 
frequently if required per local standard of care until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  Note that all tumor assessments performed during the maintenance phase are to be 
compared against the maintenance baseline scans (or nadir) and are not to be compared against the scans performed before or during induction 
treatment.  See Appendix 8 for more details. 
u If the participant discontinues study treatment for any reason prior to radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration), tumor assessments will continue at the same frequency as would have been followed if the participant had remained 
on study treatment until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first, even if the participant starts a new anti-cancer therapy after study treatment discontinuation.  See Section 7.1 for details. 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
28/Protocol GO43104, Version 8 
v The optional tumor biopsy after induction and prior to maintenance should be collected if clinically feasible after the last cycle of the induction 
treatment and prior to the start maintenance treatment.  Optional tumor biopsy at radiographic disease progression, if clinically feasible, 
preferably within 40 days after radiographic progression or prior to the start of the next anti-cancer therapy, whichever occurs sooner. 
w All serious adverse events, regardless of relationship to study drug, will be reported until 90 days after the last dose of study drug or until 
initiation of a new systemic anti-cancer therapy, whichever occurs first.  Serious adverse events believed to be related to prior exposure to study 
treatment are to be reported indefinitely.  Adverse events of special interest, regardless of relationship to study drug, will continue to be reported 
until 90 days after the final dose of study treatment or until initiation of a new systemic anti-cancer therapy, whichever occurs first.  Adverse 
events of special interest believed to be related to prior exposure to study treatment are to be reported indefinitely.  All other adverse events, 
regardless of relationship to study drug, will be reported until 30 days after the last dose of study drug or until initiation of a new systemic anti-
cancer therapy, whichever occurs first. 
x From 7 days prior to the initiation of study treatment until the treatment discontinuation visit.  All such medications should be recorded on 
the Concomitant Medications eCRF. 
y PRO questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30, EORTC IL46, and EQ-5D-5L) will be completed by the participants at the start 
of the clinic visit before discussion of the participant's health state, laboratory results, or health record; before administration of study treatment; 
and/or prior to the performance of any other study assessments that could bias the participant's responses.  In scenarios where laboratory 
assessments (e.g., blood draws) are done in a different clinic than the one providing treatment or when they are done on a different day than 
study treatment administration, laboratory assessments can be completed before the completion of PROs as long as results have not been 
discussed with the participant.  If the participant comes to the clinic for study drug administration, completes the PRO questionnaires and then 
does not receive study treatment (i.e., a decision is made that study treatment cannot be administered on that day due to the participant's health 
status), the collected PROs should be kept and questionnaires for this timepoint should not be re-administered on the day of the delayed study 
drug administration.  The questionnaires will be completed on Cycle 1, Day 1 (baseline); Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1, and 
Cycle 5, Day 1.  From Cycle 6 onwards, the questionnaires will be completed at every other study treatment cycle prior to the administration of 
study drug (i.e., on Cycle 6, Day 1; Cycle 8, Day 1; Cycle 10, Day 1; etc.).  PROs will be collected during the treatment period and at the study 
treatment discontinuation visit.  During follow-up, PROs (EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L) will be completed at 3 months 
( 30 days) and 6 months ( 30 days).  The PRO instruments will be self-administered by the participant via ePRO device or may be collected 
remotely on non-visiting dates (e.g., during follow-up or in exceptional circumstances). 

Table 2 
Schedule of Activities during the Maintenance Phase (cont.) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
29/Protocol GO43104, Version 8 
z PRO questionnaires (PRO-CTCAE [select items]) will be completed by the participants at the start of the clinic visit before discussion of 
the participant's health state, laboratory results, or health record; before administration of study treatment; and/or prior to the performance of any 
other study assessments that could bias the participant's responses.  In scenarios where laboratory assessments (e.g., blood draws) are done in 
a different clinic than the one providing treatment or when they are done on a different day than study treatment administration, laboratory 
assessments can be completed before the completion of PROs as long as results have not been discussed with the participant.  If the participant 
comes to the clinic for study drug administration, completes the PRO questionnaires and then does not receive study treatment (i.e., a decision 
is made that study treatment cannot be administered on that day due to the participant's health status), the collected PROs should be kept and 
questionnaires for this timepoint should not be re-administered on the day of the delayed study drug administration.  The questionnaires will be 
completed on Cycle 1, Day 1 (baseline); Cycle 1, Day 10; Cycle 2, Day 1; Cycle 2, Day 10; Cycle 3, Day 1; Cycle 4, Day 1, and Cycle 5, Day 1.  
From Cycle 6 onwards, the questionnaires will be completed at every other study treatment cycle prior to the administration of study drug (i.e., on 
Cycle 6, Day 1; Cycle 8, Day 1; Cycle 10, Day 1; etc.).  PROs will be collected during the treatment period and at the study treatment 
discontinuation visit.  The PRO instrument will be self-administered by the participant via ePRO device or may be collected remotely on non-
visiting dates (e.g., for Day 10 assessments or in exceptional circumstances). 
aa After radiographic disease progression per RECIST v1.1 and discontinuation of study treatment, survival follow-up information will be collected 
by telephone, participant medical records, and/or clinic visits every 3 months or more frequently ( 30 days) until death, loss to follow-up, 
withdrawal of consent, or study termination by the Sponsor, whichever occurs first.  All participants will be periodically contacted for survival 
and new anti-cancer therapy information unless the participant requests to be withdrawn from follow-up (this request must be documented in the 
source documents and signed by the investigator).  If the participant withdraws from the study, study staff may use a public information source 
(e.g., county records), when permissible, to obtain information about survival status only. 
  
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
32/Protocol GO43104, Version 8 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of lurbinectedin, an 
alkylating drug that binds guanine residues in the minor groove of DNA, in combination 
with atezolizumab for the maintenance treatment of extensive-stage small-cell lung 
cancer (ES-SCLC) in participants whose disease has not progressed after first-line 
induction therapy with atezolizumab, carboplatin, and etoposide. 
Despite the improved efficacy observed with programmed death-ligand 1 (PD-L1) 
inhibitors in combination with platinum-based chemotherapy in first-line ES-SCLC, most 
patients eventually experience disease progression and upon relapse, their prognosis is 
poor.  Therefore, novel combination strategies are needed to deliver better long-term 
outcomes. 
The early introduction of other agents active in small-cell lung cancer (SCLC), and with a 
complementing pathway to the current treatment approach, is an appealing strategy to 
further improve the prognosis of patients with advanced SCLC. 
2.2 
BACKGROUND 
2.2.1 
Background on Lung Cancer 
Lung cancer remains the leading cause of cancer deaths worldwide.  In 2020 in the 
United States, it was estimated that there will be 228,820 new cases of lung cancer 
(116,300 cases in men and 112,520 cases in women) and 142,670 lung cancer deaths 
(Siegel et al. 2020).  According to the European Cancer Information System 
(ECIS) 2020, lung cancer is the most common cause of cancer-related deaths in Europe 
with approximately 384,176 deaths occurring in 2020, accounting for 19.8% of all cancer 
deaths (ECIS 2020). 
Nonsmall-cell lung cancer (NSCLC) accounts for approximately 85% of all cases 
of lung cancer (Molina et al. 2008; Howlader et al. 2015).  SCLC accounts for 
approximately 15% of all cases and is distinguished from NSCLC by its rapid growth rate 
and early development of metastatic disease (Govindan et al. 2006). 
Patients with limited-stage SCLC can be treated with chemotherapy and radiation with 
the potential for long-term survival (Stinchcombe and Gore 2010), though a majority of 
patients will experience disease relapse.  The majority (approximately 70%) of patients 
with SCLC are diagnosed with ES-SCLC.  Chemotherapy alone can palliate symptoms 
and prolong survival for patients with ES-SCLC; however, long-term survival is rare 
(Johnson and Jänne 2004; Demedts et al. 2010).  SCLC has a very high rate of attrition 
with fewer patients eligible for therapy in later treatment lines (Armstrong and Liu 2019). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
33/Protocol GO43104, Version 8 
2.2.2 
Current Standard Treatment for Extensive-Stage Small-Cell 
Lung Cancer 
SCLC is a very aggressive disease characterized by poor survival, with little progress 
made in the development of novel treatments for over 2 decades.  However, advances 
with immunotherapies have opened new therapeutic avenues. 
Regulatory approval has been granted for atezolizumab in combination with carboplatin 
and etoposide for the treatment of first-line ES-SCLC in the United States and the 
European Union based on Study GO30081 (IMpower133).  In Study GO30081, 
201 participants were randomly assigned to the atezolizumab and carboplatin/etoposide 
combination therapy group, and 202 participants to the placebo and 
carboplatin/etoposide combination therapy group.  Induction therapy with 
atezolizumab/placebo and carboplatin and etoposide was given for 4 cycles and 
followed by maintenance therapy with atezolizumab or placebo until loss of clinical 
benefit or unacceptable toxicity.  At a median follow-up of 13.9 months, the median 
overall survival (OS) was 12.3 months in the atezolizumab combination therapy group 
and 10.3 months in the placebo combination therapy group (hazard ratio [HR] for 
death  0.70; 95% CI: 0.54 to 0.91; p  0.007).  The median progression-free survival 
(PFS) was 5.2 months and 4.3 months, respectively (HR for disease progression or 
death  0.77; 95% CI: 0.62 to 0.96; p  0.02).  The safety profile of atezolizumab in 
combination with carboplatin/etoposide followed by atezolizumab monotherapy was 
consistent with the previously reported safety profile of the individual agents, with no 
new findings observed (Horn et al. 2018). 
In an exploratory analysis of Study GO30081, the benefit of atezolizumab versus 
placebo in patients who reached the maintenance phase was assessed.  About 80% of 
the intent-to-treat (ITT) population received at least 1 cycle of maintenance treatment 
with atezolizumab or placebo.  The median OS from the start of maintenance treatment 
observed in this maintenance population was 12.5 months for patients receiving 
atezolizumab versus 8.4 months in the control arm (HR for OS from start of 
maintenance  0.59).  Median PFS from the start of maintenance treatment was 
2.6 months for the atezolizumab arm versus 1.8 months in the control arm in the 
maintenance population (HR  0.64; Reck et al. 2020). 
In the United States and the European Union, the currently recommended treatment for 
first-line ES-SCLC is atezolizumab in combination with carboplatin and etoposide 
administered as induction therapy, followed by atezolizumab maintenance therapy, or 
durvalumab in combination with platinum (cisplatin or carboplatin) and etoposide as 
induction therapy, followed by durvalumab maintenance therapy 
(National Comprehensive Cancer Network [NCCN] 2021a; ESMO 2021). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
34/Protocol GO43104, Version 8 
2.2.3 
Background on Lurbinectedin 
Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of 
DNA, forming adducts and resulting in a bending of the DNA helix towards the major 
groove.  Adduct formation triggers a cascade of events that can affect the subsequent 
activity of DNA binding proteins, including some transcription factors and DNA repair 
pathways, resulting in perturbation of the cell cycle and cell death. 
In nonclinical studies, lurbinectedin downregulated cytokine production in the tumor 
microenvironment and inhibited tumor-associated macrophage (TAM) functions and/or 
reduced the number of TAMs in the tumor microenvironment (Céspedes et al. 2016; 
Belgiovine et al. 2017).  Lurbinectedin has also shown synergy with immune checkpoint 
inhibitors (Xie et al. 2019). 
Lurbinectedin is approved in the United States under accelerated approval for the 
treatment of patients with metastatic SCLC with disease progression during or after 
receiving treatment with platinum-based chemotherapy.  This accelerated approval is 
based on the Phase II Study B-005, in which the activity of lurbinectedin monotherapy 
was studied in different tumor types, including SCLC.  In the cohort with SCLC, 
105 participants with an Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) of 02, who had received 1 prior line of platinum-based chemotherapy and 
had no CNS metastases at the time of study entry, were treated with lurbinectedin 
3.2 mg/m2 every 3 weeks (Q3W; Trigo et al. 2020).  The results of the objective 
response rate (ORR) and the duration of response (DOR) by the investigator and 
blinded Independent Review Committee (IRC) assessments were consistent and 
clinically meaningful; the high rate of ORR was associated with durable responses and a 
trend for prolonged OS in responding participants.  By investigator assessment, the 
ORR (all partial responses [PRs]) was 35% with a median duration of 5.3 months.  The 
ORR by IRC assessment was 30% with a median duration of 5.1 months.  Participants 
considered to be platinum-sensitive (chemotherapy-free interval [CTFI]  90 days) had 
favorable outcomes compared with participants considered to be platinum-resistant 
(CTFI  90 days).  Median PFS by investigator assessment was 3.5 months (95% CI: 2.6 
to 4.3 months) in the overall population, and 4.6 months and 2.6 months in the 
platinum-sensitive and in the platinum-resistant participant populations, respectively.  
With a median follow-up of 17.1 months, median OS was 9.3 months (95% CI: 6.3 to 
11.8 months) in the overall population, 11.9 months in the platinum-sensitive participant 
population, and 5.0 months in the platinum-resistant participant population.  
Participants received a median of 4 doses of lurbinectedin at a relative dose intensity of 
97%.  Fifty-nine percent (59%) of participants experienced Grade  3 adverse events, 
34.3% of participants experienced serious adverse events, and 2 participants (1.9%) 
died due to an adverse event (dyspnea [due to disease progression]).  Discontinuation of 
treatment with lurbinectedin due to an adverse event occurred in 4.8% of participants, 
and 24.8% of participants had lurbinectedin dose reductions to manage adverse events.  
The most common non-hematological treatment-related (or with unknown causality) 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
35/Protocol GO43104, Version 8 
adverse events (occurring in  10% of participants) were fatigue (59.0%); gastrointestinal 
events, including constipation (9.5%); diarrhea (13.3%), nausea (32.4%), and vomiting 
(18.1%); and decreased appetite (21.0%).  The most common treatment-related 
Grade  3 adverse events were fatigue (7.6%) and febrile neutropenia (4.8%).  
Hematologic toxicities included anemia (95.2% all Grades, 9.5% Grade  3); 
lymphopenia (85.7% all Grades, 43.8% Grade  3); leukopenia (79.0% all Grades, 28.6% 
Grade  3); neutropenia (71.4% all Grades, 45.7% Grade  3); and thrombocytopenia 
(43.8% all Grades, 6.7% Grade  3).  The most common serious adverse events were 
hematological events:  febrile neutropenia (4.8%), neutropenia/decreased ANC (5.7%), 
thrombocytopenia/platelets decreased (3.8%), and anemia/RBC decreased (3.8%).  
All events were considered to be treatment-related.  Infections occurring in the presence 
of febrile neutropenia/neutropenic sepsis were analyzed as adverse events of special 
interest.  Infections in the presence of Grade 3 or Grade 4 neutropenia were observed in 
8.6% of participants and were mostly respiratory disorders (Preferred Terms that 
occurred in  2 participants were pneumonia [2.9%], upper respiratory tract infection 
[1.0%], and respiratory tract infection [1.0%]).  These infections had a median onset of 
10 days after lurbinectedin administration and lasted a median of 67 days. 
See the Lurbinectedin Investigator's Brochure for details on nonclinical and clinical 
studies. 
2.2.4 
Background on Atezolizumab 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  
Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the 
magnitude and quality of tumor-specific T-cell responses, resulting in improved 
anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has 
minimal binding to fragment crystallizable (Fc) receptors, thus eliminating detectable 
Fc-effector function and associated antibody-mediated clearance of activated effector 
T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, NSCLC, SCLC, 
triple-negative breast cancer, hepatocellular carcinoma, melanoma, and alveolar soft 
part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
36/Protocol GO43104, Version 8 
2.3 
BENEFIT–RISK ASSESSMENT 
There is a significant unmet need in patients with ES-SCLC.  Despite the improved 
efficacy observed with first-line PD-L1 inhibitors administered in combination with 
platinum-based chemotherapy, most patients with ES-SCLC experience disease 
progression, and upon relapse, their prognosis is poor. 
The purpose of this study is to assess the efficacy and safety of lurbinectedin in 
combination with atezolizumab for the maintenance treatment of ES-SCLC in 
participants whose disease has not progressed after first-line induction therapy with 
atezolizumab, carboplatin, and etoposide.  The addition of atezolizumab to carboplatin 
and etoposide for the first-line treatment of ES-SCLC led to an improvement in PFS and 
OS, leading to the approval of atezolizumab as part of a first-line therapy for ES-SCLC 
(Armstrong and Liu 2019).  However, as evident from studies with PD-L1 inhibitors and 
chemotherapy in the first-line treatment ES-SCLC, many patients rapidly progress after 
the end of 4 cycles of induction therapy (Horn et al. 2018; Paz-Ares et al. 2019; 
Reck et al. 2020).  Given the aggressive nature of SCLC, the combination of an 
immune-checkpoint inhibitor with a novel transcription inhibitor lurbinectedin, may benefit 
patients in this setting.  Lurbinectedin has shown clinical benefit in participants with 
SCLC as a single agent in Study B-005.  As demonstrated in nonclinical studies, 
lurbinectedin downregulated cytokine production in the tumor microenvironment and 
inhibited TAM functions.  A combination of lurbinectedin with the PD-L1 inhibitor 
atezolizumab, could enhance the anti-tumor immune response by reducing the number 
of TAMs and their immune inhibitory activity.  Furthermore, this combination may 
eliminate the checkpoint signaling that PD-L1 elicits upon binding to PD-1 in cytotoxic 
T cells, resulting in greater anti-tumor activity than either agent provides alone. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
37/Protocol GO43104, Version 8 
 
primary G-CSF 
prophylaxis will be implemented for the experimental arm in Study GO43104 to mitigate 
expected hematological abnormalities.  Furthermore, based on the safety profile for 
lurbinectedin, additional premedication will be implemented to mitigate gastrointestinal 
toxicities such as nausea and vomiting. 
Immune-mediated adverse events observed with atezolizumab are well known, 
manageable and/or reversible.  The Sponsor does not foresee treatment with 
lurbinectedin to impact immune-mediated adverse events.  Currently, considering the 
different mechanisms of action of lurbinectedin and atezolizumab and the initial safety 
profile from Study ML40908, overlapping toxicities are expected to be limited, and no 
exacerbations are anticipated. 
Overall, the safety profile of each of the components of the combination is well-defined, 
generally transient, and manageable.  In addition, the preliminary data from the 
Phase III Study ML40908 suggest that the combination of lurbinectedin and 
atezolizumab has a manageable safety profile at the planned doses for Study GO43104.  
Thus, the overall benefitrisk assessment is deemed favorable. 
See Appendix 6 for information on anticipated risks for lurbinectedin and atezolizumab 
and risk mitigation measures, including guidelines for managing adverse events 
associated with lurbinectedin and atezolizumab. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
38/Protocol GO43104, Version 8 
More detailed information about the known and expected risks and reasonably expected 
adverse events of lurbinectedin and atezolizumab may be found in the lurbinectedin and 
atezolizumab Investigator's Brochures. 
2.3.1 
COVID-19 Benefit–Risk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, participants with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
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 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13; Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)- (Merad and Martin 2020).  
 
 
  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. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in participants receiving atezolizumab in combination with 
chemotherapy. 
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). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Protocol GO43104, Version 8 
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 immune checkpoint inhibitors), 
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 participants enrolling in this study 
and receiving atezolizumab treatment, a decision to administer the vaccine to a 
participant should be made on an individual basis by the investigator in consultation with 
the participant. 
With regards to administering COVID-19 vaccines in participants receiving lurbinectedin, 
the specific patient population for this trial, mode of action of lurbinectedin and potential 
risks and benefits to participants have been considered, and no known risks have been 
identified to date.  Standard safety surveillance processes are being followed.  No 
recommendations can be made regarding the optimal sequence of COVID-19 
vaccination in participants receiving lurbinectedin.  To date, there is no documented risk 
associated with the combined use of lurbinectedin and COVID-19 vaccination. 
For participants enrolling in this study and receiving atezolizumab with or without 
lurbinectedin treatment, a decision to administer the vaccine to a participant should be 
made on an individual basis by the investigator in consultation with the participant. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab with or without lurbinectedin 
treatment to 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. 
The 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 6.8). 
3. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of lurbinectedin when 
administered in combination with atezolizumab compared with atezolizumab 
monotherapy in participants with ES-SCLC, who have an ongoing response or stable 
disease (SD) after completion of 4 cycles of carboplatin, etoposide, and atezolizumab 
induction treatment.  Table 4 presents the primary objectives for the study expressed 
using the estimand framework in accordance with the International Council for 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Protocol GO43104, Version 8 
Harmonisation (ICH) E9(R1) statistical principles for clinical trials (ICH 2020).  Table 5 
presents the secondary and exploratory objectives and corresponding endpoints. 
The term "study treatment" refers to all protocol-mandated treatments and includes 
atezolizumab in combination with carboplatin and etoposide during the induction phase, 
and atezolizumab, lurbinectedin, and protocol-mandated prophylactic medications 
(e.g., G-CSF, anti-emetics) during the maintenance phase. 
Most endpoints described in Table 4 and Table 5 will be analyzed in randomized 
participants and therefore, the term "baseline" refers to the time of randomization into 
the maintenance phase, unless otherwise specified. 
Table 4 
Primary Objectives and Estimand Definition for Randomized 
Participants 
Primary Objective 
Estimand Definition 
 To evaluate the 
efficacy of 
lurbinectedin in 
combination with 
atezolizumab 
compared with 
atezolizumab 
 Population:  individuals with ES-SCLC who have ongoing CR, PR, or 
SD after completion of 4 cycles of carboplatin, etoposide, and 
atezolizumab first-line induction treatment, as defined through the 
inclusion and exclusion criteria for the maintenance phase (see 
Sections 5.1.2 and Section 5.2.2, respectively) 
 Endpoint: IRF-assessed PFS after randomization, defined as the time 
from randomization to the date of first documented disease 
progression (as assessed by the IRF according to RECIST v1.1) or 
death, whichever occurs first 
 Treatments: 
– 
Experimental arm: atezolizumab 1200 mg IV    lurbinectedin 
3.2 mg/m2 IV on Day 1 of each 21-day cycle 
– 
Control arm: atezolizumab 1200 mg IV on Day 1 of each 
21-day cycle 
 Intercurrent events and handling strategies: 
– 
Early discontinuation from study treatment for any reason:  
treatment policy strategy 
– 
Start of non-protocol anti-cancer therapy prior to the 
respective event of interest: treatment policy strategy 
 Population-level summary:  hazard ratio for IRF-assessed PFS 
 To evaluate the 
efficacy of 
lurbinectedin in 
combination with 
atezolizumab 
compared with 
atezolizumab 
 Population:  as defined above 
 Endpoint:  OS after randomization, defined as the time from 
randomization to the date of death from any cause 
 Treatments:  as defined above 
 Intercurrent events and handling strategies:  as defined above 
 Population-level summary:  hazard ratio for OS  
IRF  independent review facility; OS overall survival; PFS  progression-free survival. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
41/Protocol GO43104, Version 8 
Table 5 
Secondary and Exploratory Objectives and Endpoints for 
Randomized Participants 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of 
lurbinectedin in combination 
with atezolizumab compared 
with atezolizumab 
 Investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of disease 
progression as determined by the investigator according 
to RECIST v1.1, or death from any cause, 
whichever occurs first 
 Confirmed ORR, defined as the proportion of randomized 
participants with a CR or PR on two consecutive 
occasions  4 weeks apart after randomization, as 
determined by the IRF according to RECIST v1.1 
 Confirmed ORR, defined as the proportion of randomized 
participants with a CR or PR on two consecutive 
occasions    4 weeks apart after randomization, as 
determined by the investigator according to RECIST v1.1 
 DOR, defined as the time from the first occurrence of a 
documented confirmed objective response after 
randomization until disease progression as determined by 
the IRF according to RECIST v1.1, or death from any 
cause, whichever occurs first 
 DOR, defined as the time from the first occurrence of a 
documented confirmed objective response after 
randomization until disease progression as determined by 
the investigator according to RECIST v1.1, or death from 
any cause, whichever occurs first 
 PFS rates at 6 months and 12 months, defined as the 
proportion of participants who have not experienced 
disease progression or death from any cause at 6 months 
and 12 months after randomization, as determined by the 
IRF according to RECIST v1.1 
 PFS rates at 6 months and 12 months, defined as the 
proportion of participants who have not experienced 
disease progression or death from any cause at 6 months 
and 12 months after randomization, as determined by the 
investigator according to RECIST v1.1 
 OS rates at 12 months and 24 months, defined as the 
proportion of participants who have not experienced death 
from any cause at 12 months and 24 months after 
randomization 
 To evaluate the safety of 
lurbinectedin in combination 
with atezolizumab compared 
with atezolizumab 
 Incidence and severity of adverse events, including 
serious adverse events and adverse events of special 
interest, with severity determined according to 
NCI CTCAE v5.0 
 To evaluate the 
immunogenicity of 
atezolizumab with and without 
lurbinectedin 
 Prevalence of ADAs to atezolizumab at induction phase 
baseline and incidence of ADAs to atezolizumab after 
drug administration 
  

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
43/Protocol GO43104, Version 8 
4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Study GO43104 is a Phase III, randomized, open-label, multicenter study of 
lurbinectedin in combination with atezolizumab compared with atezolizumab alone 
administered as maintenance therapy in participants with ES-SCLC after first-line 
induction therapy with carboplatin, etoposide, and atezolizumab.  Participants are 
required to have an ongoing response or SD per the Response Evaluation Criteria in 
Solid Tumor (RECIST) v1.1 after completion of 4 cycles of carboplatin, etoposide, and 
atezolizumab induction treatment in order to be considered for eligibility screening for the 
maintenance phase. 
The study consists of 2 phases:  an induction phase and a maintenance phase. 
Participants who have been diagnosed with ES-SCLC and are treatment-naïve for their 
extensive-stage disease have to provide written informed consent prior to entering 
screening for the induction phase (induction screening).  Participants who fulfill the 
eligibility criteria (see Sections 5.1 and 5.2) will be enrolled to receive 4 cycles of 
carboplatin, etoposide, and atezolizumab induction treatment.  The diagnosis of 
ES-SCLC will be based on the Veterans Administration Lung Study Group (VALG) 
staging system (Appendix 17).  Participants will receive 4 cycles of induction treatment 
unless they experience unacceptable toxicity or disease progression or they withdraw 
consent. 
Participants must fulfill the eligibility criteria for the maintenance phase 
(see Sections 5.1.2 and 5.2.2) prior to randomization (maintenance screening).  
Participants who have received fewer than 4 or more than 4 cycles of carboplatin, 
etoposide and atezolizumab as induction treatment, or experience progressive disease 
(PD) during the induction phase will not be eligible for the maintenance phase. 
Following the induction therapy but before randomization, participants may receive 
prophylactic cranial irradiation (PCI) at the investigator's discretion per local standard.  
In accordance with NCCN guidelines magnetic resonance imaging (MRI) surveillance 
can be considered as an alternative option to PCI (NCCN 2021a) 
Participants who receive consolidative thoracic radiation with curative intent or the intent 
to eliminate residual disease or participants with lesions that require palliative 
radiotherapy are not eligible for the maintenance phase of this study. 
Randomization must occur within 5 weeks (35 days) from the day of the administration 
of the last dose of atezolizumab, carboplatin and/or etoposide (whichever occurs last). 
Participants receiving PCI must be randomized within 9 weeks (63 days) from the 
last dose of atezolizumab, carboplatin and/or etoposide (whichever occurs last). 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
44/Protocol GO43104, Version 8 
In order not to confound the evaluation of OS, crossover will not be allowed from Arm B 
(atezolizumab) to Arm A (atezolizumab in combination with lurbinectedin). 
A study schema is provided in Section 1.2 (see Figure 1).  A schedule of activities and a 
sample collection schedule are provided in Section 1.3 (see Table 1 [induction phase], 
Table 2 [maintenance phase], and Table 3 [sample collection schedule]). 
An independent review facility (IRF) will perform a centralized, independent central 
review of images, and other clinical data as needed, prior to the efficacy analyses.  
Independent review facility membership and procedures will be detailed in an 
IRF charter. 
4.2 
RATIONALE FOR STUDY DESIGN 
An open-label design was chosen for this study.  Given the known hematological 
(e.g., neutropenia) and gastrointestinal (e.g., nausea, vomiting) toxicities associated with 
lurbinectedin therapy, physicians as well as participants assigned to the 
lurbinectedin-containing arm, may be capable of identifying treatment assignment in a 
blinded study.  In addition, given the safety profile of lurbinectedin, in this study, primary 
G-CSF use as well as the use of anti-emetics are mandatory for participants assigned to 
the lurbinectedin-containing arm only, while participants in Arm B 
(atezolizumab monotherapy) will not require mandatory primary G-CSF prophylaxis or 
anti-emetic treatment.  Thus, the physician must know which arm the participant is 
randomized to in order to use required prophylactic medication. 
A blinded study would require, in addition to the administration of a lurbinectedin 
placebo, placebos for the mandatory prophylactic medication with G-CSF and 
anti-emetics (e.g., steroids, serotonin [5-HT3] receptor antagonist), which would pose a 
significant burden to participants and site staff. 
Adequate steps have been taken to ensure the validity of data in an open-label study 
design.  This includes defining progression with use of the established RECIST v1.1, 
performing tumor assessments at the same frequency in both arms, assessment of PFS 
by an IRF, and determining the strategy for the final analysis of the primary endpoint 
prior to database lock for the primary efficacy analyses, including predefined methods for 
handling missing data and censoring rules.  Efficacy analyses will be performed only at 
the pre-specified analysis timepoints in the protocol.  In addition, primary endpoints of 
PFS and OS were chosen for this study. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
45/Protocol GO43104, Version 8 
4.2.1 
Rationale for Study Population 
SCLC is initially highly responsive to chemotherapy with or without cancer 
immunotherapy, with response rates ranging between 50%70% (Horn et al. 2018; Paz-
Ares et al. 2019).  In Study GO30081, around 60% of participants achieved a complete 
response or PR, and an additional 21% of participants had SD after receiving 
atezolizumab in combination with chemotherapy (Horn et al. 2018).  After induction 
therapy with carboplatin, etoposide with atezolizumab or placebo, about 80% of 
participants received at least 1 cycle of maintenance treatment with atezolizumab or 
placebo (Study GO30081 maintenance population).  Participants in the maintenance 
population had a median OS of 12.5 months from the start of maintenance treatment 
with atezolizumab versus a median OS of 8.4 months in the control arm (HR for OS from 
start of maintenance  0.59).  Median PFS from the start of maintenance was 2.6 months 
for the atezolizumab arm versus 1.8 months in the control arm of the maintenance 
population (HR  0.64; Reck et al. 2020). 
In Study B-005, lurbinectedin as second-line therapy demonstrated better efficacy in 
terms of ORR, PFS, and OS in the participants with platinum-sensitive SCLC 
(CTFI  90 days) compared with the overall population.  Thus, selection of participants 
with SD or an objective response after induction chemotherapy for maintenance 
treatment with lurbinectedin added to atezolizumab may enrich the response for 
participants who could benefit most. 
Participants who show disease progression at the last tumor assessment prior to 
randomization are not considered eligible for Study GO43104, as they progress onto 
second-line therapy. 
Since there is a lack of predictive biomarkers for PD-L1 inhibitors and lurbinectedin in 
ES-SCLC, the target population will be a biomarker-unselected ES-SCLC population 
with an ongoing response or SD after completion of 4 cycles of carboplatin, etoposide, 
and atezolizumab induction treatment. 
Controversial results exist regarding the benefit of PCI in patients with ES-SCLC 
compared with MRI surveillance in the brain, leading to decreased utilization of PCI in 
clinical practice (Gjyshi et al. 2019).  In recent Phase III trials of PD-L1 inhibitors in 
first-line ES-SCLC, only around 10% of participants received PCI (Horn et al. 2018; 
Paz-Ares et al. 2019).  Study GO43104 permits participants to receive PCI after 
induction treatment as per the investigator's decision before randomization. 
Given the highly aggressive nature of the disease, participants will be randomized within 
5 weeks of the last induction therapy administration, or within 9 weeks of the last 
induction therapy administration, if radiotherapy (e.g., PCI) after induction therapy is 
used. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
46/Protocol GO43104, Version 8 
Atezolizumab is approved for the first-line treatment of ES-SCLC by the U.S. Food and 
Drug Administration (FDA) and in the European Union in combination with carboplatin 
and etoposide.  Based on real-world data, the proportion of cisplatin use plus etoposide 
and atezolizumab is low (2%; McCune et al. 2019) and is only considered in individual 
cases.  Given the lack of regulatory approval for atezolizumab in combination with 
etoposide and cisplatin, carboplatin may not be replaced by cisplatin in this study. 
Participants with a history of CNS metastases are excluded from the study given the 
current lack of robust data for lurbinectedin in participants with CNS metastases due to 
their exclusion in the Phase II Study B-005 (Trigo et al. 2020) and overall lack of 
meaningful CNS penetration by the molecule based on nonclinical data (data on file). 
4.2.2 
Rationale for Control Group 
The current standard treatment for participants with first-line ES-SCLC is atezolizumab 
in combination with carboplatin and etoposide, as induction therapy, followed by 
atezolizumab maintenance therapy, or durvalumab in combination with platinum 
(cisplatin or carboplatin) and etoposide as induction therapy, followed by durvalumab 
maintenance therapy (NCCN 2021a; ESMO 2021). 
Regulatory approval has been granted for atezolizumab in combination with carboplatin 
and etoposide for the treatment of first-line ES-SCLC in the United States and European 
Union, based on Study GO30081 results.  In Study GO30081, 201 participants were 
randomly assigned to the atezolizumab and carboplatin/etoposide combination arm and 
202 participants to the placebo and carboplatin/etoposide combination arm.  At a median 
follow-up of 13.9 months, the median OS was 12.3 months in the atezolizumab arm and 
10.3 months in the placebo arm (OS HR  0.70; 95% CI: 0.54 to 0.91; p  0.007).  
The median PFS was 5.2 months and 4.3 months, respectively (PFS HR  0.77; 
95% CI: 0.62 to 0.96; p  0.02).  The safety profile of atezolizumab in combination with 
chemotherapy followed by atezolizumab monotherapy was consistent with the previously 
reported safety profile of the individual agents, with no new findings observed 
(Horn et al. 2018). 
Participants who started maintenance treatment in Study GO30081 
(maintenance population) and received at least 1 cycle of atezolizumab had a 
median OS of 12.5 months from the start of maintenance treatment versus a median OS 
of 8.4 months in the control arm (OS HR from start of maintenance  0.59; 
Reck et al. 2020).  PFS was also longer for the atezolizumab arm (median PFS from 
start of maintenance:  2.6 months vs. 1.8 months; PFS HR  0.64). 
Based on the results of Study GO30081, atezolizumab maintenance therapy was 
chosen as the comparator in Study GO43104 for participants with non-progressing 
ES-SCLC after induction therapy with atezolizumab and chemotherapy. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
48/Protocol GO43104, Version 8 
 
 
 
 
 
  
 
 
 
4.2.4 
Rationale for the Collection of Tumor Specimens 
Post-Induction and Prior to Maintenance Therapy and at 
Radiographic Progression 
If clinically feasible, it is recommended that a tumor biopsy be performed post-induction 
and prior to maintenance therapy and at the time of radiographic disease progression in 
order to better understand the biological changes with the combination of chemotherapy 
and atezolizumab during induction therapy and changes that drive the increase in size of 
the radiographically progressing lesion
 
 
 
 
 
 
 
4.2.5 
Rationale for Choice of Stratification Factors 
Participants eligible for randomization in this study will be stratified by ECOG PS at 
maintenance baseline (0 vs. 1), LDH at maintenance baseline ( upper limit of normal 
[ULN] vs.  ULN) via local laboratory test, presence of liver metastases at induction 
baseline (yes vs. no), and prior receipt of PCI (yes vs. no). 
Poor prognostic factors for survival in participants with SCLC include extensive-stage 
disease, poor ECOG PS, weight loss, and markers associated with excessive bulk of 
disease such as LDH (Yip et al. 2000; Foster et al. 2009).  Among these, disease stage, 
clinical ECOG PS, and LDH are considered the most important prognostic factors in 
SCLC (Hermes et al. 2010). 
Furthermore, recent Phase III trials investigating cancer immunotherapy have shown the 
presence of liver metastases to be an additional strong prognostic factor in 
extensive-stage SCLC (Horn et al. 2018; Owonikoko et al. 2019). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
49/Protocol GO43104, Version 8 
PCI has been reported to decrease the incidence of brain metastases (Slotman et al. 
2007), while the evidence regarding the impact of PCI on OS versus MRI surveillance for 
extensive-stage SCLC is currently inconclusive (Slotman et al. 2007; Takahashi et al. 
2017). 
4.2.6 
Rationale for Primary Endpoint Selection 
In Study GO43104, the primary efficacy endpoints are PFS, as assessed by the IRF (per 
RECIST v1.1), and OS. 
Improvement in OS is generally accepted as the best measure of clinical benefit for 
participants with advanced lung cancer, and is an endpoint that is objective and easily 
measured.  Recent data also suggest that OS may be a sensitive endpoint for cancer 
immunotherapy (Fehrenbacher et al. 2016).  For these reasons, OS is a primary 
endpoint in this study. 
PFS is a commonly used endpoint in oncology trials because it can reflect tumor growth, 
may correlate with patient symptom control (De Marinis et al. 2008; Griebsch et al. 
2014), and may be assessed before the evaluation of a survival benefit.  Additionally, its 
assessment is generally not confounded by subsequent therapies as can be the case for 
OS.  PFS can be considered a good measure of clinical benefit for participants with 
cancer, especially if the magnitude of effect is large and the treatment has an acceptable 
benefit–risk profile compared with available therapies (European Medicines 
Agency Guideline 2012; FDA Guidance for Industry 2018).  Furthermore, individual 
participant data analysis has demonstrated PFS to be a strong surrogate for OS in 
SCLC (Foster et al. 2015).  As such, PFS as a primary endpoint may enable an earlier 
indication of benefit and may potentially make this new treatment combination available 
to patients more quickly. 
4.2.7 
Rationale for Collection of Information on Race and 
Ethnicity 
Data pertaining to participant race and ethnicity represents a component of the broad 
demographic profile of the study population.  Collection of demographic data, including 
information on race and ethnicity, is of importance to the future interpretation of 
results from the clinical trial, including identification of potential differences in 
efficacy, safety, and pharmacokinetics among participants.  Collection of race and 
ethnicity data may enable investigation of potential relationships between biomarkers 
and race or ethnicity, including determination of whether race or ethnicity could be a 
prognostic factor.  Collection of these data may also contribute to a better 
understanding of the distribution of ES-SCLC according to race or ethnicity. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
50/Protocol GO43104, Version 8 
4.3 
JUSTIFICATION FOR DOSE AND SCHEDULE 
4.3.1 
Rationale for Lurbinectedin Dose and Schedule 
Lurbinectedin has received accelerated approval from the FDA for the treatment of adult 
patients with metastatic SCLC with disease progression while on or after receiving 
platinum-based chemotherapy.  The approved dosing regimen is 3.2 mg/m2 Q3W 
(3.2 mg/m2 on Day 1 of each 21-day cycle) administered as a 1-hour IV infusion.  In an 
exposure-response analysis for lurbinectedin, the recommended lurbinectedin dosing 
regimen of 3.2 mg/m² Q3W provided maximum benefit in participants with SCLC who 
had experienced disease progression while on or after receiving platinum-based 
chemotherapy with a manageable risk of Grade 4 neutropenia.  Lowering the dose 
resulted in reduced efficacy, whereas increasing it led to a higher incidence of severe 
hematological toxicity without improvement of efficacy (Fudio et al. 2020). 
4.3.2 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab, as outlined in the 
prescribing information (Tecentriq U.S. Prescribing Information [USPI]).  Anti-tumor 
activity has been observed across doses ranging from 120 mg/kg Q3W.  
In Study PCD4989g, the maximum tolerated dose of atezolizumab was not reached and 
no DLTs were observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an 
average body weight-based dose of 15 mg/kg for a person weighing 80 kg) was selected 
based on both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic (PK), efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).  The 3-week dosing schedule has been chosen as it aligns with the 
schedule of lurbinectedin administration. 
4.3.3 
Rationale for Atezolizumab Dose and Schedule in Combination 
with Carboplatin and Etoposide 
An approved dosage regimen for atezolizumab plus carboplatin and etoposide for the 
first-line treatment of patients with ES-SCLC is 1200 mg Q3W administered IV over 
60 ( 15) minutes for the first infusion and shortening to 30 [ 10] minutes for subsequent 
infusions (Tecentriq USPI; Tecentriq Summary of Product Characteristics [SmPC]). 
4.3.4 
Rationale for Lurbinectedin in Combination with Atezolizumab 
Dose and Schedule 
The combination of lurbinectedin and atezolizumab is being investigated in the ongoing 
investigator-sponsored Phase I/II Study ML40908.  Preliminary data from this study 
suggest that lurbinectedin and atezolizumab can be combined at the doses of 
3.2 mg/m2 Q3W and 1200 mg Q3W, respectively 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
51/Protocol GO43104, Version 8 
4.3.5 
Rationale for Use of Primary Granulocyte ColonyStimulating 
Factor Prophylaxis for Lurbinectedin 
In clinical studies of 554 participants with advanced solid tumors receiving lurbinectedin, 
Grade 3 or 4 neutropenia occurred in 41% of participants, with a median time to onset of 
15 days and a median duration of 7 days.  Febrile neutropenia occurred in 7% of 
participants (ZEPZELCA USPI). 
In Study B-005, neutropenia was the most common cause of dose administration delays 
(13 participants [12%]) and dose reductions (17 participants [16%]) for lurbinectedin in 
participants with SCLC (Trigo et al. 2020). 
Dose intensity is an important consideration for treatment effect from lurbinectedin 
(Fudio et al. 2020).  The development of chemotherapy-induced febrile neutropenia or 
severe neutropenia can lead to dose reductions, delays, or discontinuation of treatment, 
which may negatively impact patient outcomes (Aapro et al. 2006; 
Kelly and Wheatley 2009).  Primary prophylactic treatment with G-CSFs may prevent 
febrile neutropenia or reduce the duration of severe neutropenia. 
Given the risk factors for participants in Study GO43104 to develop febrile or high-grade 
neutropenia when receiving lurbinectedin treatment following 4 cycles of 
myelosuppressive agents (carboplatin and etoposide), together with the expected 
median age of participants, primary prophylaxis with pegylated G-CSF has been 
implemented for the experimental arm in this study. 
4.4 
END OF STUDY DEFINITION 
The end of this study is defined as the date of the last participant, last visit (LPLV) or the 
date at which the last data point required for statistical analysis (i.e., final OS analysis) or 
safety follow-up is received from the last participant, whichever occurs later.  The total 
length of the study, from screening of the first participant for the induction phase to the 
end of the study, is expected to be approximately 90 months. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.5 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 
1 day to more than 2 years. 
Study treatment with induction therapy and maintenance therapy will continue until 
disease progression per RECIST v1.1, unacceptable toxicity, or a participant's decision 
to discontinue, whichever occurs first.  Randomized participants who discontinue study 
treatment will enter the study follow-up phase.  Participants who are not eligible for the 
maintenance phase of the study will not enter the study follow-up phase. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
52/Protocol GO43104, Version 8 
5. 
STUDY POPULATION 
Approximately 690 participants are expected to be enrolled into the induction phase of 
this study.  Approximately 
 participants with ES-SCLC, who have an ongoing 
response or SD after completion of 4 cycles of carboplatin, etoposide, and atezolizumab 
induction treatment, and who meet the eligibility criteria for the maintenance phase, will 
be randomized into the maintenance phase of this study.  The number of participants in 
the induction phase of the study will be adjusted as necessary based on the actual 
screen failure rate for entering the maintenance phase to achieve the required number of 
approximately 
 participants in the maintenance phase of the study. 
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
5.1.1 
Inclusion Criteria for the Induction Phase 
Potential participants are eligible to be included in the induction phase of the study only if 
all of the following criteria apply: 
 
Signed Informed Consent Form 
 
 18 years at the time of signing the Informed Consent Form 
 
ECOG PS of 0 or 1 
 
Histologically or cytologically confirmed ES-SCLC (per the VALG staging system, 
Appendix 17) 
 
No prior systemic treatment for ES-SCLC 
For potential participants who have received prior chemoradiotherapy for 
limited-stage SCLC:  must have had treatment with curative intent and a 
treatment-free interval of at least 6 months between the last dose/cycle of 
chemotherapy, thoracic radiotherapy, or chemoradiotherapy and the diagnosis of 
ES-SCLC. 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to enrollment into the induction phase: 
– 
ANC  1.5  109/L (1500/L) for participants of non-African descent or 
ANC  1.3  109/L (1300/L) for participants of African descent without G-CSF 
support 
– 
Lymphocyte count  0.5  109/L (500/L) 
– 
Platelet count  100  109/L (100,000/L) without transfusion 
– 
Hemoglobin  90 g/L (9 g/dL) 
Potential participants may be transfused to meet this criterion. 
– 
AST, ALT, and ALP  2.5  ULN, with the following exceptions: 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
53/Protocol GO43104, Version 8 
Potential participants with documented liver metastases:  AST and ALT 
 5  ULN. 
Potential participants with documented liver or bone metastases:  
ALP  5  ULN. 
– 
Total bilirubin  1.5  ULN with the following exception: 
Potential participants with known Gilbert disease:  total bilirubin  3  ULN. 
– 
Creatinine  1.5  ULN or creatinine clearance  30 mL/min (calculated through 
use of the Cockcroft-Gault formula) 
– 
Creatine phosphokinase  2.5  ULN ( 5.0  ULN is acceptable if elevation is 
disease-related) 
– 
Albumin  30 g/L (3.0 g/dL) 
 
For potential participants not receiving therapeutic anticoagulation:  INR and aPTT 
 1.5  ULN 
For potential participants receiving therapeutic anticoagulation:  a stable 
anticoagulant regimen. 
 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if 
(1) disease progression has been unequivocally documented at that site since 
radiation therapy, and 
(2) the previously irradiated lesion is not the only site of measurable disease. 
 
Submission of pre-induction therapy tumor sample for exploratory biomarker 
research 
– 
 
 
– 
 
 
 
 
Negative HIV test at screening, with the following exception:  participants with a 
positive HIV test at screening are eligible provided they are stable on anti-retroviral 
therapy, have a CD4 count  200/L, and have an undetectable viral load 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb), or a positive total HBcAb test 
followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA 
test at screening 
– 
The HBV DNA test must be performed for individuals who have a negative 
HBsAg test, and a positive HBcAb test 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
54/Protocol GO43104, Version 8 
 
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 must be performed for participants who have a positive 
HCV antibody test 
 
For female participants of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraception, and agree to refrain 
from donating eggs, as defined below: 
Female participants must remain abstinent or use contraceptive methods with a 
failure rate of  1% per year during the treatment period and for 5 months after 
the final dose of atezolizumab, for 6 months after the final dose of carboplatin or 
etoposide, and for 7 months after the final dose of lurbinectedin, whichever 
occurs last. 
Female participants must refrain from donating eggs during this same period. 
A female participant 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 female participant 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 reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual.  
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. 
– 
Female participants who would like to become pregnant after study 
treatment discontinuation should seek advice on oocyte cryopreservation prior 
to initiation of study treatment because of the possibility of irreversible infertility 
due to treatment with carboplatin, etoposide and/or lurbinectedin. 
 
For male participants:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive methods, and agree to refrain from donating 
sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, male 
participants must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
55/Protocol GO43104, Version 8 
during the treatment period and for 4 months after the final dose of 
lurbinectedin and for 6 months after the final dose of carboplatin or etoposide, 
whichever occurs last.  Male participants must refrain from donating sperm 
during this same period. 
With a pregnant female partner, male participants must remain abstinent or use 
a condom during the treatment period and for 4 months after the final dose of 
lurbinectedin and for 6 months after the final dose of carboplatin or etoposide, 
whichever occurs last 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 individual.  
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. 
 
5.1.2 
Inclusion Criteria for the Maintenance Phase 
Potential participants must meet all of the following criteria to be eligible to be 
randomized to receive either lurbinectedin in combination with atezolizumab or 
atezolizumab after completion of the induction phase: 
 
Able to comply with the requirements and restrictions listed in the Informed Consent 
Form and the study protocol (there is no separate Informed Consent Form for 
entering the maintenance phase) 
 
ECOG PS of 0 or 1 
 
Have received 4 cycles of first-line treatment with carboplatin, etoposide and 
atezolizumab and must have an ongoing complete response (CR), partial response 
(PR), or SD by RECIST v1.1 after completion of the induction therapy 
– 
Radiographic tumor assessment must have occurred  28 days prior to 
randomization into the maintenance phase 
– 
Participants who have received  4 cycles or  4 cycles of induction therapy are 
not eligible 
 
Randomized within 5 weeks (35 days), from the day of the administration of the last 
dose of atezolizumab, carboplatin or etoposide (whichever occurs last).  
Participants receiving PCI must be randomized within 9 weeks (63 days) from the 
last dose of induction treatment. 
– 
Study treatment during the maintenance phase must not be administered 
 3 weeks (21 days) from Cycle 4, Day 1 of the induction treatment phase 
– 
Study treatment during the maintenance phase must not be administered 
 2 weeks (14 days) from the last dose of radiotherapy 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
56/Protocol GO43104, Version 8 
 
Toxicities attributed to prior induction anti-cancer therapy or PCI must have resolved 
to Grade 1 or better (according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) or baseline other than: 
– 
Adverse events that are clinically non-significant and/or stable on supportive 
therapy and are not expected to interfere with treatment in the study such as: 
Grade  2 alopecia, asthenia, dermatologic events. 
Grade  2 anemia if hemoglobin  90 g/L (9 g/dL). 
Asymptomatic amylase and/or lipase elevation up to 2.0  ULN with no 
abdominal pain and no characteristic CT findings.  However, weekly 
monitoring of amylase and lipase is required in this case. 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to randomization into the maintenance 
phase: 
– 
ANC  1.5  109/L (1500/L) for participants of non-African descent or 
ANC  1.3  109/L (1300/L) for participants of African descent without G-CSF 
support 
– 
Lymphocyte count  0.5  109/L (500/L) 
– 
Platelet count  100  109/L (100,000/L) without transfusion 
– 
Hemoglobin  90 g/L (9 g/dL) 
Participants may be transfused to meet this criterion. 
– 
AST, ALT, and ALP  2.5  ULN, with the following exceptions: 
Potential participants with documented liver metastases:  AST and ALT 
 5  ULN. 
Potential participants with documented liver or bone metastases:  
ALP  5  ULN. 
– 
Total bilirubin  1.5  ULN with the following exception: 
Potential participants with known Gilbert disease:  total bilirubin  3  ULN. 
– 
Creatinine  1.5  ULN or creatinine clearance  30 mL/min (calculated through 
use of the Cockcroft-Gault formula) 
– 
Creatine phosphokinase  2.5  ULN ( 5.0  ULN is acceptable if elevation is 
disease-related) 
– 
Albumin  30 g/L (3.0 g/dL) 
 
For potential participants not receiving therapeutic anticoagulation:  INR and aPTT 
 1.5  ULN 
For potential participants receiving therapeutic anticoagulation:  a stable 
anticoagulant regimen. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
57/Protocol GO43104, Version 8 
5.2 
EXCLUSION CRITERIA 
5.2.1 
Exclusion Criteria for the Induction Phase 
Potential participants are excluded from the study if any of the following criteria apply: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 7 months after the final dose of study treatment 
Potential female participants of childbearing potential must have a negative 
serum pregnancy test result within 14 days prior to enrollment. 
 
Presence or history of CNS metastases 
– 
A CT (with contrast) or MRI scan of the head is required at induction screening.  
A brain MRI scan is the preferred imaging method for evaluating CNS 
metastases. 
 
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for  1 week prior to enrollment 
 
Leptomeningeal disease 
 
Consolidative chest radiation is planned 
 
Uncontrolled tumor-related pain 
– 
Potential participants requiring pain medication must be on a stable regimen at 
study entry to be eligible 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
– 
Potential participants with indwelling catheters (e.g., PleurX) are allowed 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  ULN) 
 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse 
 
Active or a history of autoimmune disease or immune deficiency (for a full list of 
excluded conditions see Appendix 15), including, but not limited to, myasthenia 
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or 
multiple sclerosis, with the following exceptions: 
– 
History of autoimmune-related hypothyroidism who are on thyroid replacement 
hormone are eligible for the study 
– 
Controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
58/Protocol GO43104, Version 8 
– 
Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., participants with psoriatic arthritis are excluded) are 
eligible for the study provided all of following conditions are met: 
Rash must cover  10% of body surface area. 
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids. 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan 
– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
 
Active tuberculosis 
 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to enrollment, unstable arrhythmia, or unstable angina 
– 
Known coronary artery disease, congestive heart failure not meeting the above 
criteria, or left ventricular ejection fraction  50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation 
with a cardiologist if appropriate 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the participant at high risk from 
treatment complications 
 
Receiving current treatment with anti-viral therapy for HBV or HCV 
 
Receiving treatment with investigational therapy within 28 days prior to enrollment 
 
Received prior treatment with CD137 agonists or immune checkpoint blockade 
therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies 
 
Received prior treatment with lurbinectedin or trabectedin 
 
Received treatment with systemic immunostimulatory agents (including, but not 
limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives, 
whichever is longer, prior to enrollment 
 
Received treatment with systemic immunosuppressive medication (including, but 
not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and antiTNF- agents) within 1 week prior to enrollment, or 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
59/Protocol GO43104, Version 8 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions: 
– 
Received acute, low-dose systemic immunosuppressant medication, defined 
as  10 mg/day prednisone equivalent, or a one-time pulse dose of systemic 
immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast 
allergy) are eligible for the study 
– 
Received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose 
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or 
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are 
eligible for the study 
 
Known allergy or hypersensitivity to any component of the lurbinectedin formulation 
 
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 
 
History of allergic reactions to carboplatin or etoposide 
 
Received prior allogeneic stem cell or solid organ transplantation 
 
History of malignancies other than SCLC within 5 years prior to enrollment, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year 
OS rate  90%), such as adequately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, 
or Stage I uterine cancer 
 
Received treatment with a live, attenuated vaccine within 4 weeks prior to 
enrollment, or anticipation of need for such a vaccine during study treatment or 
within 5 months after the final dose of atezolizumab or within 2 weeks after the final 
dose of lurbinectedin, whichever is later 
 
5.2.2 
Exclusion Criteria for the Maintenance Phase 
Potential participants are excluded from randomization in the study if any of the following 
criteria apply after completion of the induction phase: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 7 months after the final dose of study treatment 
 
Presence or history of CNS metastases 
– 
A CT (with contrast) or MRI scan of the head is required at maintenance 
screening.  A brain MRI scan is the preferred imaging method for evaluating 
CNS metastases. 
 
Consolidative chest radiation are excluded 
 
Uncontrolled tumor-related pain 
– 
Potential participants requiring pain medication must be on a stable regimen at 
entry of maintenance phase to be eligible 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
60/Protocol GO43104, Version 8 
 
Lesions (e.g., bone metastases or metastases causing nerve impingement) 
requiring palliative radiotherapy are not eligible 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
– 
Potential participants with indwelling catheters (e.g., PleurX) are allowed 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  ULN) 
 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse 
 
Active or a history of autoimmune disease or immune deficiency (for a full list of 
excluded conditions see Appendix 15), including, but not limited to, myasthenia 
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or 
multiple sclerosis, with the following exceptions: 
– 
History of autoimmune-related hypothyroidism who are on thyroid replacement 
hormone are eligible for the study 
– 
Controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study 
– 
Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., participants with psoriatic arthritis are excluded) are 
eligible for the study provided all of following conditions are met: 
Rash must cover  10% of body surface area. 
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids. 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan 
– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
 
Active tuberculosis 
 
Undergone a major surgical procedure, other than for diagnosis, within 4 weeks 
prior to randomization into the maintenance phase, or anticipation of need for a 
major surgical procedure during the study 
 
Severe infection within 2 weeks prior to randomization into the maintenance phase, 
including, but not limited to, hospitalization for complications of infection, 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
61/Protocol GO43104, Version 8 
bacteremia, or severe pneumonia, or any active infection that could impact 
participant safety 
 
Receive treatment with therapeutic oral or IV antibiotics at the time of randomization 
– 
Potential participants receiving prophylactic antibiotics (e.g., to prevent a 
urinary tract infection or COPD exacerbation) are eligible for the study 
 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident), 
unstable arrhythmia, or unstable angina 
– 
Potential participants with known coronary artery disease, congestive heart 
failure not meeting the above criteria, or left ventricular ejection fraction  50% 
must be on a stable medical regimen that is optimized in the opinion of the 
treating physician, in consultation with a cardiologist if appropriate 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the participant at high risk from 
treatment complications 
 
Receiving current treatment with anti-viral therapy for HBV or HCV 
 
Known allergy or hypersensitivity to any component of the lurbinectedin formulation 
 
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 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
This study has the following meal and dietary restrictions: 
 
The lurbinectedin population PK model detected several covariates that affected 
lurbinectedin pharmacokinetics (refer to the Lurbinectedin Investigator's Brochure).  
Covariates detected included albumin, -1 acid glycoprotein, body surface area and 
the presence of CYP3A inhibitors.  Therefore, any food or fruit rich in containing 
CYP3A inhibitors or inducers (e.g., grapefruit, grapefruit juice, or Seville orange) 
should be avoided during lurbinectedin treatment. 
 
5.3.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, participants must use contraception or take other precautions as 
described in Section 5.1. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
62/Protocol GO43104, Version 8 
5.4 
SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of 2 screenings per individual) for the 
induction phase at the investigator's discretion.  Individuals are not required to re-sign 
the Consent Form if they are re-screened within 28 days after previously signing the 
Consent Form.  There is also 1 re-screening opportunity for the maintenance phase 
provided randomization occurs within 5 weeks from the last dose of induction therapy (or 
9 weeks for participants who received PCI).  The investigator will maintain a record of 
reasons for screen failure (see Section 8).  Participants are not required to sign a 
separate Informed Consent Form to enter the maintenance study phase. 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY 
Study treatment is defined as any investigational treatment, marketed product, placebo, 
or medical device intended to be administered to a study participant according to the 
study protocol. 
The investigational medicinal products (IMPs) for this study are lurbinectedin and 
atezolizumab.  Carboplatin and etoposide in the induction phase, and mandatory 
prophylactic medications (e.g., G-CSF, anti-emetics) in the maintenance phase are 
considered non-IMPs (NIMPs)/auxiliary medicinal products (AxMPs).  Appendix 18 
identifies all IMPs, AxMPs, and NIMPs for this study. 
6.1 
STUDY TREATMENTS ADMINISTERED 
Table 6 and Table 7 provide a description of the study treatments for this study. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
63/Protocol GO43104, Version 8 
Table 6 
Study Treatment Description during the Induction Phase 
Induction Phase (Cycles 14) 
 
Atezolizumab 
Carboplatin 
Etoposide 
Use 
Standard therapy 
Standard therapy 
Standard therapy 
Type of medicinal 
product 
Test product/Comparator 
Background therapy 
Background therapy 
Drug form 
Liquid concentrate 
Per local requirements 
Unit dose strength(s) 
60 mg/mL 
Per local requirements 
Dosage level(s) 
1200 mg Q3W on Day 1 
over 60 ( 15) minutes 
(for the first infusion and 
shortening to 
30 [ 10] minutes for 
subsequent infusions) 
Refer to local 
prescribing 
information 
 
Recommendation:  
Carboplatin AUC 5 
over 3060 minutes 
on Day 1 Q3W 
(after completion of 
atezolizumab) 
 
Carboplatin infusion 
times and dosing may 
be adapted in 
accordance with local 
standard of care 
Refer to local 
prescribing 
information 
 
Recommendation: 
Etoposide 100 mg/m2 
IV over 60 minutes 
on Day 1 
(following carboplatin 
administration), 
Day 2 and Day 3 
Q3W (or oral 
equivalent) 
 
Etoposide infusion 
times, route of 
administration and 
dosing may be 
adapted in 
accordance with local 
standard of care 
Packaging 
20-cc single-use glass 
vials 
Per local requirements 
Labeling 
Per local requirements 
Route of 
administration 
IV infusion 
IV infusion 
IV infusion (or oral) 
Source 
Sponsor 
Site 
Site 
AUC  area under the concentrationtime curve; Q3W  every 3 weeks. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
64/Protocol GO43104, Version 8 
Table 7 
Study Treatment Description during the Maintenance Phase 
 
Maintenance Phase 
Lurbinectedin 
Atezolizumab 
Ondansetron 
(or equivalent) a 
Corticosteroids a, b 
G-CSF a 
Use 
Experimental 
Standard therapy  
Prophylactic medication 
Prophylactic medication Prophylactic medication 
Type of medicinal 
product 
Test product 
Test 
product/Comparator 
Rescue medication 
Rescue medication 
Rescue medication 
Drug form 
Lyophilized powder 
Liquid concentrate 
Ondansetron 8 mg or 
equivalent 
 
Refer to local prescribing 
information 
Dexamethasone 8 mg IV 
or equivalent or at 
institutional doses 
 
Refer to local prescribing 
information 
Pegylated G-CSF c 
 
Refer to local 
prescribing information 
or institutional 
guidelines 
Unit Dose 
Strength(s) 
0.5 mg/mL 
60 mg/mL 
Dosage Level(s) 
3.2 mg/m2 Q3W 
1200 mg Q3W 
Formulation(s) 
Refer to pharmacy 
manual and 
Investigator's 
Brochure 
Refer to pharmacy 
manual and 
Investigator's 
Brochure 
Packaging 
4 mg single-dose 
vial 
20-cc single-use 
glass vials  
Labeling 
Per local requirements 
Route of 
administration 
IV Infusion 
IV infusion 
IV infusion or oral 
IV infusion or oral 
Subcutaneous injection 
Source 
Sponsor 
Sponsor 
Site 
Site 
Site 
G-CSF  granulocyte colony-stimulating factor. 
a See Section 6.1.3. 
b At the first cycle and afterwards per the investigator's decision. 
c It is strongly recommended to use pegylated instead of non-pegylated G-CSF; however, if pegylated G-CSF cannot be obtained at the site, the 
use of non-pegylated G-CSF is permitted.  Home self-administration of G-CSF is permitted according to institutional standard practice. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
65/Protocol GO43104, Version 8 
The treatment regimens are summarized in Section 4.3. 
Guidelines for dose modification (lurbinectedin only) and treatment interruption or 
discontinuation for participants who experience adverse events are provided in 
Appendix 6. 
6.1.1 
Study Treatment in the Induction Phase 
Once participants are screened for the induction phase and have been determined to be 
eligible, participants will be enrolled to receive 4 cycles of standard of care treatment 
with carboplatin, etoposide and atezolizumab unless unacceptable toxicity, disease 
progression or a participant's decision to discontinue occur, with each cycle being 
3 weeks (21 days) in length.  All participants will receive a fixed dose of 1200 mg 
atezolizumab administered by IV infusion on Day 1 of each 21-day cycle.  
Atezolizumab infusions will be administered per the instructions outlined in Table 8. 
The specifics of the chemotherapy regimen (carboplatin and etoposide) and prophylactic 
medication (e.g., anti-emetics) during the induction phase are at the discretion of the 
treating physician.  Recommendations are provided in Table 6 . 
6.1.2 
Study Treatment in the Maintenance Phase 
6.1.2.1 
Arm A:  Atezolizumab  Lurbinectedin 
Atezolizumab and lurbinectedin will be administered in the following order for Arm A: 
Atezolizumab → Lurbinectedin 
 
Atezolizumab 1200 mg IV  Lurbinectedin 3.2 mg/m2 IV on Day 1 of each 
21-day cycle 
 
Prophylactic anti-emetic medication and primary prophylaxis with pegylated G-CSF will 
be administered as described in Section 6.1.3. 
All participants will receive atezolizumab administered by IV infusion at a fixed dose of 
1200 mg on Day 1 of each 21-day cycle until unacceptable toxicity, disease progression 
per RECIST v1.1, or any other criterion as outlined in Section 7.1 have been met.  
The atezolizumab dose is fixed and is not dependent on body weight or body surface 
area.  There will be no dose modifications such as dose reductions, for atezolizumab.  
Treatment with atezolizumab may be temporarily suspended as appropriate for 
management of adverse events. 
All participants in Arm A will receive 3.2 mg/m2 lurbinectedin administered by IV infusion 
on Day 1 of each 21-day cycle.  The lurbinectedin dose is dependent on body surface 
area (BSA).  It is recommended to calculate BSA using the DuBois formula. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
66/Protocol GO43104, Version 8 
The dose of lurbinectedin will be based on the participant's maintenance baseline weight 
(measured  28 days prior to randomization into the maintenance phase) and will remain 
the same throughout the study unless the participant's weight changes by  10% relative 
to the maintenance baseline weight.  However, treating physicians may choose to 
re-calculate the dose of lurbinectedin based on the actual weight assessed prior to each 
dosing. 
Up to 2 lurbinectedin dose reductions will be allowed (first dose reduction:  2.6 mg/m2 
Q3W; second dose reduction:  2 mg/m2 Q3W).  Once the dose has been reduced for an 
individual participant, it must not be re-escalated again.  If the participant receives a 
lurbinectedin dose of 2 mg/m2 and experiences a toxicity that would warrant a 
lurbinectedin dose reduction, treatment with lurbinectedin must be permanently 
discontinued. 
If study treatment has to be temporarily interrupted or permanently discontinued to 
manage toxicity, atezolizumab and lurbinectedin can be interrupted or discontinued 
independently from each other (i.e., an interruption or discontinuation of lurbinectedin 
does not necessarily result in a simultaneous interruption or discontinuation of 
atezolizumab; an interruption or discontinuation of atezolizumab does not necessarily 
result in a simultaneous interruption or discontinuation of lurbinectedin), depending on 
the toxicity and suspected causality (see Appendix 6 for management guidelines).  
Should one study drug be temporarily interrupted because of toxicity caused by 
lurbinectedin or atezolizumab, treatment will be restarted such that the administration of 
both study drugs remains synchronized. 
Administration of lurbinectedin and atezolizumab will be performed in a monitored setting 
where there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions. 
Atezolizumab and lurbinectedin infusions and prophylactic medications will be 
administered per the instructions outlined in Table 8 and Table 9, respectively. 
Please see Figure 2 for an overview of the order and timing of administration of study 
treatment and prophylactic medications for Arm A. 
For anaphylaxis precautions, see Appendix 7.  Guidelines for medical management of 
infusion-related reactions are provided in Appendix 6. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
67/Protocol GO43104, Version 8 
Table 8 
Administration of First and Subsequent Infusions 
of Atezolizumab 
 
First Infusion 
(Induction Phase) 
Subsequent Infusions 
(Induction and Maintenance Phases) 
Atezolizumab 
infusion 
 No premedication is allowed for 
the first infusion of atezolizumab 
 Record the participant's vital 
signs (pulse rate, respiratory 
rate, blood pressure, and 
temperature) within 60 minutes 
prior to starting the infusion 
 Infuse atezolizumab over 
60 ( 15) minutes 
 If clinically indicated, record the 
participant's vital signs every 
15 ( 5) minutes during the 
infusion 
 If the participant experienced an IRR 
during any previous infusion of 
atezolizumab, premedication with an 
antihistamine and/or antipyretic may be 
administered for subsequent infusions at 
the discretion of the investigator 
 Record the participant's vital signs within 
60 minutes prior to starting the infusion 
 If the participant tolerated the previous 
infusion of atezolizumab well without an 
IRR, the next infusion of atezolizumab 
may be infused over 30 ( 10) minutes 
 If the participant experienced an IRR 
during the previous infusion, the next 
infusion of atezolizumab should be 
administered over 60 ( 15) minutes 
 Continue to record vital signs within 
60 minutes prior to the infusion 
 Record vital signs during the infusion of 
atezolizumab if clinically indicated 
Observation 
period after 
infusion of 
atezolizumab 
 After the infusion of 
atezolizumab, the participant 
begins a 30-minute observation 
period 
 Record the participant's vital 
signs at 30 ( 10) minutes after 
the end of the infusion of 
atezolizumab 
 Participants should be informed 
about the possibility of delayed 
post-infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms 
 After the infusion of atezolizumab, the 
participant begins a 30-minute 
observation period 
 If the participant experienced an IRR 
during the (previous) infusion, the 
observation period should be 60 minutes 
 If clinically indicated, record the 
participant's vital signs at 30 ( 10) 
minutes after the end of the infusion 
IRR  infusion-related reaction. 
  

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
68/Protocol GO43104, Version 8 
Table 9 
Administration of First and Subsequent Infusions of 
Lurbinectedin 
 
First Infusion 
Subsequent Infusions 
Lurbinectedin 
infusion 
 Anti-emetic prophylaxis before 
infusion of lurbinectedin a: 
– Corticosteroids 
(dexamethasone 8 mg IV or 
equivalent). 
– 5-HT3 antagonists 
(ondansetron 8 mg IV or 
equivalent), with or without 
metoclopramide 10 mg IV or 
equivalent. 
– Other possible prophylactic 
medications: 
Extended oral prednisone 
not exceeding 10 mg/day 
and/or oral ondansetron 
48 mg or equivalent, at the 
investigator's discretion if 
required. 
Additional anti-emetics 
might be used, if required. 
 Infuse lurbinectedin over 1 hour 
 Extended use of anti-emetics is 
permitted for post-infusion nausea 
and vomiting 
 Primary prophylaxis with pegylated 
G-CSF:  A mandatory window of at 
least 24 hours and up to 48 hours 
must be allowed from lurbinectedin 
administration until G-CSF 
prophylaxis is started 
 The requirement for premedication 
for anti-emetic prophylaxis for the 
subsequent cycles (i.e., Day 1, 
Cycle 2 and subsequent cycles) 
should be evaluated on an individual 
basis, and its administration left to 
the investigator's judgment 
 Infuse lurbinectedin over 1 hour 
 Extended use of anti-emetics is 
permitted for post-infusion nausea 
and vomiting 
 Primary prophylaxis with pegylated 
G-CSF:  A mandatory window of at 
least 24 hours and up to 48 hours 
must be allowed from lurbinectedin 
administration until G-CSF 
prophylaxis is started 
Management 
of infusion site 
reactions 
 Infusion site reactions such as 
phlebitis 
– Increase the volume of diluent, 
and extend infusion time by at 
least 50% 
 Infusion site reactions such as 
phlebitis 
– Increase the volume of diluent, 
and extend infusion time by at 
least 50% 
5-HT3  serotonin; G-CSF  granulocyte colony-stimulating factor. 
a See Section 6.1.3 for more information on the timing of anti-emetic administration. 
  
6.1.2.2 
Arm B:  Atezolizumab 
Atezolizumab will be administered to participants in Arm B: 
Atezolizumab 1200 mg IV on Day 1 of each 21-day cycle 
 
Please follow the instructions for atezolizumab administration as described under 
Section 6.1.2.1.  Prophylactic anti-emetic medication and primary G-CSF prophylaxis is 
not required for atezolizumab administration alone. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
69/Protocol GO43104, Version 8 
6.1.3 
Prophylactic Medications 
All participants in the atezolizumab  lurbinectedin arm (Arm A) will receive the following 
anti-emetic and G-CSF prophylactic medication for lurbinectedin treatment: 
 
Anti-emetic treatment on Day 1 of the first cycle will be administered as per local 
standard practice (before or after infusion of atezolizumab, but at least 
1530 minutes before the infusion of lurbinectedin): 
– 
Corticosteroids (dexamethasone 8 mg IV or equivalent) 
AND 
– 
5-HT3 antagonists (Zofran [ondansetron hydrochloride] 8 mg IV or equivalent), 
with or without metoclopramide 10 mg IV or equivalent 
 
Other possible additional prophylactic medications: 
 
Extended treatment with oral prednisone not exceeding 10 mg/day or equivalent 
and/or oral ondansetron 48 mg or equivalent, at the investigator's discretion if 
required 
 
Additional anti-emetics may be used, if required 
 
Aprepitant and equivalent agents (e.g., fosaprepitant) are not permitted in participants 
treated with lurbinectedin.  The requirement for premedication for anti-emetic prophylaxis 
for the subsequent cycles (i.e., Day 1, Cycle 2 and subsequent cycles) should be 
evaluated on an individual basis, and its administration left to the investigator's 
judgment, taking into account the potential impact of corticosteroids on the immunologic 
effects of treatment with atezolizumab (see Section 6.8.2.1). 
Primary prophylaxis with pegylated G-CSF is mandated in participants receiving 
lurbinectedin.  It is strongly recommended to use pegylated instead of non-pegylated 
G-CSF; however, if pegylated G-CSF cannot be obtained at the site, the use of non-
pegylated G-CSF is permitted.  Type, dose, and scheme may vary according to 
institutional standard practices or guidelines.  Home self-administration of G-CSF is 
permitted according to institutional standard practice.  A mandatory window of at least 
24 hours to up to 48 hours from lurbinectedin administration must be allowed until 
G-CSF prophylaxis is started.  In circumstances in which participants did not tolerate 
prior G-CSF use, the investigator may choose not to administer primary G-CSF 
prophylaxis with close monitoring of hematologic values and any other supportive care 
according to local standard practice. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
71/Protocol GO43104, Version 8 
6.2 
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel, e.g., pharmacist) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each participant, and disposition or return of unused IMP, thus enabling reconciliation of 
all IMP received, and for ensuring that participants are provided with doses specified by 
the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor, with use of an 
interactive voice or Web-based response system (IxRS) to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  The investigator or 
designee must confirm that appropriate temperature conditions have been maintained 
during transit, 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. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
Investigational medicinal products will either be disposed of at the study site according to 
the study site's institutional standard operating procedure or be returned to the Sponsor 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual, the lurbinectedin and atezolizumab 
Investigator's Brochures, and/or local prescribing information for information on IMP 
preparation, storage, handling, and accountability. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
72/Protocol GO43104, Version 8 
6.3 
TREATMENT ASSIGNMENT 
This is a randomized, open-label study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a participant, the study site will obtain the participant's 
study identification number from the IxRS.  For those participants who are eligible for 
randomization into the maintenance phase of the study, the study site will obtain the 
participant's randomization number and treatment assignment from the IxRS once 
eligibility has been established during the maintenance screening phase. 
Participants will be randomly assigned to one of two treatment arms:  
A) atezolizumab  lurbinectedin or B) atezolizumab.  Randomization will occur in a 
1:1 ratio through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm.  Randomization will be stratified by: 
 
ECOG PS at maintenance baseline (0 vs. 1) 
 
LDH at maintenance baseline ( ULN vs  ULN) via local laboratory test 
 
Presence of liver metastases at induction baseline (yes vs. no) 
 
Prior receipt of PCI (yes vs. no) 
 
Although this is an open-label study, the randomized treatment assignments from the 
IxRS will be withheld from members of the Sponsor, including, but not limited to, the 
study's Medical Monitor, Study Statistician, Statistical Programmer, and Study Data 
Manager.  Members of the Sponsor are not permitted to perform analyses or summaries 
by randomized treatment assignment and/or actual treatment received before the 
randomized treatment assignments are disclosed to the study team for the pre-specified 
analysis. 
6.4 
STUDY TREATMENT COMPLIANCE 
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The dose of study treatment 
and the study participant's identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration electronic Case Report Form (eCRF).  
Cases of accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Appendix 3. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
73/Protocol GO43104, Version 8 
6.5 
DOSE MODIFICATION 
Up to 2 lurbinectedin dose reductions are allowed (first dose reduction:  2.6 mg/m2 Q3W; 
second dose reduction:  2 mg/m2 Q3W).  Once the dose has been reduced for an 
individual participant, it must not be re-escalated again.  If the participant receives a 
lurbinectedin dose of 2 mg/m2 and experiences a toxicity that would warrant a 
lurbinectedin dose reduction, treatment with lurbinectedin must be permanently 
discontinued (refer to Table A6-1 for more details on dose modification guidelines for 
lurbinectedin). 
Modification of the atezolizumab dose is not permitted. 
If study treatment has to be temporarily interrupted or permanently discontinued to 
manage toxicity, atezolizumab and lurbinectedin can be interrupted or discontinued 
independently from each other (i.e., an interruption or discontinuation of lurbinectedin 
does not necessarily result in a simultaneous interruption or discontinuation of 
atezolizumab; an interruption or discontinuation of atezolizumab does not necessarily 
result in a simultaneous interruption or discontinuation of lurbinectedin), depending on 
the toxicity and suspected causality (see Appendix 6 for management guidelines).  
Should one study drug be temporarily interrupted because of toxicity caused by 
lurbinectedin or atezolizumab, treatment will be restarted such that the administration of 
both study drugs remains synchronized. 
6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
The Sponsor will offer continued access to atezolizumab free of charge to eligible 
participants in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.  The Sponsor will evaluate whether 
to continue providing lurbinectedin in accordance with this policy. 
A participant will be eligible to receive atezolizumab and/or lurbinectedin after completing 
the study if all of the following conditions are met: 
 
The participant has a life-threatening or severe medical condition and requires 
continued treatment with atezolizumab and/or lurbinectedin for his or her well-being. 
 
There are no appropriate alternative treatments available to the participant. 
 
The participant and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A participant will not be eligible to receive atezolizumab and/or lurbinectedin after 
completing the study if any of the following conditions are met: 
 
Atezolizumab and/or lurbinectedin are commercially marketed in the participant's 
country and are reasonably accessible to the participant (e.g., is covered by the 
participant's insurance or wouldn't otherwise create a financial hardship for the 
participant). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
74/Protocol GO43104, Version 8 
 
The Sponsor has discontinued development of atezolizumab and/or lurbinectedin or 
data suggest that the treatment is not effective for ES-SCLC. 
 
The Sponsor has reasonable safety concerns regarding atezolizumab and/or 
lurbinectedin as a treatment for ES-SCLC. 
 
Provision of atezolizumab and/or lurbinectedin is not permitted under the laws and 
regulations of the participant's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
https://assets.roche.com/f/176343/x/1b18e080e0/2025-revision-
roche_global_policy_on_continued_access_to_investigational_interventions.pdf 
6.7 
TREATMENT OF OVERDOSE 
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose.  There is no known antidote for treating an overdose.  Cases of overdose, along 
with any associated adverse events, should be reported as described in Appendix 3. 
In the event of an overdose, the investigator should take the following steps: 
1. 
Contact the Medical Monitor immediately. 
2. 
Closely monitor the participant for any adverse event or serious adverse event and 
laboratory abnormalities. 
 
6.8 
CONCOMITANT THERAPY 
Any medication and/or vaccine, including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements used by a participant in addition to 
protocolmandated treatment from 7 days prior to enrollment until the treatment 
discontinuation visit must be recorded on the Concomitant Medications eCRF along with 
the following information: 
 
Reason for use (indication) 
 
Dates of administration, including start and end dates 
 
Dosage information, including dose and frequency 
 
For participants who discontinue study treatment for any reason other than disease 
progression, information on the administration of any COVID-19 vaccine will continue to 
be collected beyond the treatment discontinuation visit until radiographic disease 
progression per RECIST v1.1 has been confirmed.  This is due to the risk of 
lymphadenopathy as a result of a COVID-19 vaccine (see the respective information in 
Appendix 8). 
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
75/Protocol GO43104, Version 8 
6.8.1 
Permitted Therapy 
Participants are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year (see Section 5.1) 
 
Hormone replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccines (such as influenza, COVID-19) 
Live attenuated vaccines are not permitted (see Section 6.8.3) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
– 
Inhaled or low-dose corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
PCI administered after completion of induction treatment, per local standard of care; 
requirement to complete PCI before randomization into the maintenance phase 
 
Palliative radiotherapy (e.g., treatment of known bone metastases or symptomatic 
relief of pain): 
– 
Treatment with lurbinectedin must be withheld during palliative radiotherapy 
and lurbinectedin must not be restarted less than 2 weeks following the last 
dose of radiotherapy 
– 
Treatment with atezolizumab may be continued during palliative radiotherapy 
 
Blood products and transfusions, as clinically indicated 
 
Bisphosphonates 
 
Erythropoietin use according to local guidelines 
 
G-CSF 
 
In case of nausea or vomiting, prophylaxis and/or symptomatic treatment for emesis 
according to local guidelines 
 
Premedication with antihistamines, anti-pyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a participant's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section 6.8.2 and Section 6.8.3) as clinically indicated, per 
local standard practice.  Participants 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, 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
76/Protocol GO43104, Version 8 
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 6). 
6.8.2 
Cautionary Therapy 
6.8.2.1 
Cautionary Therapy for Atezolizumab-Treated Participants 
Corticosteroids, Immunosuppressive Medications, and TNF- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF- inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (see Appendix 6 for details). 
6.8.2.2 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
In vitro studies with human liver microsomes have shown that CYP3A4 is a major 
metabolic enzyme involved in the metabolism of lurbinectedin, followed by CYP2E1, 
CYP2D6, and CYP2C9.  The contribution of other CYP isoenzymes is negligible.  
Thus, concomitant medications which induce or inhibit CYP3A4 should be carefully 
monitored or avoided, whenever possible (see Appendix 16).  A significant interaction 
with aprepitant (CYP3A4 inhibitor) is suggested by Phase II data with lurbinectedin from 
participants with ovarian cancer and a Phase II Study PM1183-A-008-13 in participants 
with advanced solid tumors where lurbinectedin clearance was reduced by 
approximately 42% in the presence of aprepitant and participants experienced unusually 
long-lasting neutropenia, as well as thrombocytopenia.  Although all participants 
recovered from these events, the use of aprepitant and equivalent agents 
(e.g., fosaprepitant) is not permitted. 
Based on in vitro studies, lurbinectedin was shown to inhibit CYP2C8, CYP3A4 and 
CYP2B6.  However, according to guidelines from the European Medicines Agency and 
FDA, the calculated in vivo impact of lurbinectedin on those CYP isoenzymes was 
insignificant.  Therefore, no potential drug-drug interaction is expected between 
lurbinectedin and drugs which are metabolized by CYP3A4, CYP2C8, or CYP2B6 
(see Appendix 16). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
77/Protocol GO43104, Version 8 
The investigator should consult the prescribing information and Investigator's Brochures 
when determining whether a concomitant medication can be safely administered with 
study treatment.  In addition, the investigator should contact the Medical Monitor if 
questions arise regarding medications not listed above. 
6.8.2.3 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 6.8.3) may be used during the study at the discretion of the investigator. 
6.8.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 6.8.2), and during study treatment, until disease progression is 
documented and the participant has discontinued study treatment, with the 
exception of palliative radiotherapy and local therapy under certain circumstances 
 
Cisplatin instead of carboplatin in the induction phase 
 
Investigational therapy is prohibited within 28 days prior to enrollment and during 
study treatment 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
enrollment, during study treatment, and for 5 months after the final dose of 
atezolizumab or for 2 weeks after the final dose of lurbinectedin, whichever is later 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to enrollment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination 
with study treatment 
 
Systemic immunosuppressive medications other than corticosteroids as described 
in Section 6.8.2.1 (including, but not limited to, cyclophosphamide, azathioprine, 
methotrexate, and thalidomide) are prohibited during study treatment because these 
agents could potentially alter the efficacy and safety of study treatment 
 
Radiotherapy other than limited-field radiotherapy for pain control 
 
Aprepitant or other neurokinin-1 receptor (NK-1) antagonists (e.g., fosaprepitant) for 
participants receiving treatment with lurbinectedin 
 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
Study and site closure is described in Appendix 1. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
78/Protocol GO43104, Version 8 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
It may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study treatment.  If study treatment is definitively 
discontinued, the participant will remain in the study follow-up phase.  See the schedule 
of activities (see Section 1.3, Table 2) for data to be collected at the time of 
discontinuation of study treatment and for any further follow-up evaluations that need to 
be completed. 
Participants must permanently discontinue study treatment if any of the following criteria 
are met: 
 
Any medical condition that the investigator determines may jeopardize the 
participant's safety if the participant continues to receive study treatment 
 
Investigator determination that treatment discontinuation is in the best interest of the 
participant 
 
Pregnancy 
 
Disease progression per RECIST v1.1 
 
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) 
 
Use of any anti-cancer therapy not allowed per protocol or use of a prohibited 
therapy (see Section 6.8.3) 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual participant's potential response to therapy and severity of the 
event 
 
The primary reason for study treatment discontinuation must be documented on the 
appropriate eCRF. 
Participants will return to the clinic for a treatment discontinuation visit within 30 days 
after the final dose of study drug or within 30 days from the date the decision was made 
to permanently discontinue study treatment. 
See the schedule of activities in Section 1.3 (Table 2) for details on follow-up 
assessments to be performed for participants who permanently discontinue study 
treatment.  If a participant requests to be withdrawn from study treatment and/or 
follow-up, this request must be documented in the source documents and signed by the 
investigator. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
79/Protocol GO43104, Version 8 
7.1.1 
Liver Chemistry Stopping Criteria 
Discontinuation of study treatment is required by the investigator when a study 
participant meets abnormal liver tests as outlined in Section A37.7, or if the investigator 
believes that it is in best interest of the participant to discontinue. 
7.2 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM 
THE STUDY 
A participant may withdraw from the study at any time at his or her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a participant requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent.  Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) 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. 
If a participant withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status. 
7.3 
PARTICIPANTS LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule.  If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic, and determine if there are ways to support participant 
participation. 
 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing 
address or local equivalent methods).  These contact attempts should be 
documented in the participant's medical record. 
 
Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
80/Protocol GO43104, Version 8 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
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 individuals and for individuals who are not 
subsequently enrolled will be maintained at the study site. 
Study procedures and their timing are summarized in the schedule of activities 
(see Section 1.3 [Table 1 and Table 2]).  Protocol waivers or exemptions are not 
allowed. 
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a detailed record of 
all participants screened to document eligibility or record reasons for screening failure, 
as applicable. 
Procedures conducted as part of the participant's routine clinical management and 
obtained before signing of the Informed Consent Form may be utilized for screening or 
baseline purposes provided the procedures meet the protocol-specified criteria and are 
performed within the time frame defined in the schedule of activities. 
Medical history and baseline conditions, 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 induction baseline.  Any medication and/or vaccine 
(including over-the-counter or prescription medicines, vitamins, and herbal supplements) 
used by the participant within 7 days prior to enrollment will be recorded at induction 
baseline.  Demographic data, including age, sex, and self-reported race or ethnicity, will 
also be recorded.  At the time of each physical examination, an interval medical history 
should be obtained and any changes in medications and allergies should be recorded. 
Participants will be closely monitored for safety throughout the study.  
Participants should be assessed for toxicity prior to each dose; treatment will be 
administered only if the clinical assessment and local laboratory test values are 
acceptable.  Urgent safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
81/Protocol GO43104, Version 8 
At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional at the participant's home or another suitable location, such as a local 
practice, to improve access and convenience for participants in the study.  The Sponsor 
will evaluate and may select a health care company (the MN vendor) to provide 
MN services for participating sites.  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 have been performed.  If the 
investigator at a participating site determines that MN services are appropriate for a 
participant and the participant gives written informed consent to participate in MN visits, 
the MN vendor will communicate with the participant and the participant's site.  MN visits 
will be scheduled on specified visit days, to allow for relevant assessments to be 
performed by the MN professional.  The schedule of activities (see Section 1.3 [Table 1, 
Table 2, and Table 3]) will specify the assessments that may be performed by a MN 
professional. 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Tumor and Response Evaluations 
A tumor assessment is required at induction screening and at maintenance screening.  
Participants must have SD or partial or complete response per RECIST v1.1 at 
maintenance screening in order to be eligible for randomization into the maintenance 
phase.  Tumor assessments are to be performed during the maintenance phase 
every 6 weeks ( 7 days) for 48 weeks following Cycle 1, Day 1 of the maintenance 
phase and every 9 weeks ( 7 days) thereafter, 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.  Participants without any 
radiographic evidence of disease progression 2 years after Cycle 1, Day 1 of the 
maintenance phase may undergo tumor assessments every 3 months ( 7 days) or more 
frequently if required per local standard of care until radiographic disease progression 
per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first.  Thus, tumor assessments are to continue according to schedule 
in participants who discontinue treatment for reasons other than disease progression per 
RECIST v1.1, even if they start new non-protocol anti-cancer therapy.  At the 
investigator's discretion, tumor assessments may be repeated at any time if PD is 
suspected. 
All measurable and/or evaluable lesions should be assessed and documented at 
screening.  Tumor assessments performed as a standard of care prior to obtaining 
informed consent and within 28 days prior to enrollment do not have to be repeated at 
screening, so long as they meet criteria as per RECIST v1.1. 
Study treatment will be continued until radiographic disease progression according to 
RECIST v1.1, unacceptable toxicity, or a participant's decision to discontinue, whichever 
occurs first. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
82/Protocol GO43104, Version 8 
The tumor assessment performed during maintenance screening will serve as the 
baseline scan (maintenance baseline) for RECIST v1.1 assessment purposes 
post-randomization. 
The potential need for palliative radiotherapy should be considered, if possible, during 
the selection of target lesions as an irradiated target lesion renders the patient 
non-evaluable for RECIST v1.1 tumor response with the exception of the assessment of 
disease progression. 
8.1.1.1 
Radiographic Assessments 
Participants will undergo tumor assessments at induction screening and at maintenance 
screening.  The tumor assessment at induction screening will serve to determine 
whether participants have SD or partial or complete response following the completion of 
induction therapy at the time of screening for the maintenance phase.  The tumor 
assessment at maintenance screening will serve as the baseline to determine tumor 
response per RECIST v1.1 post-randomization. 
All participants in the maintenance phase will undergo tumor assessments 
every 6 weeks ( 7 days) for 48 weeks following Day 1 of Cycle 1 of maintenance 
therapy, regardless of treatment delays.  After completion of the Week 48 tumor 
assessment, tumor assessments are required every 9 weeks ( 7 days), regardless of 
treatment delays.  Participants without any radiographic evidence of disease progression 
2 years after Cycle 1, Day 1 of the maintenance phase may undergo tumor assessments 
every 3 months ( 7 days) or more frequently if required per local standard of care.  
Tumor assessments are to be performed until radiographic disease progression per 
RECIST v1.1 criteria, withdrawal of consent, study termination by the Sponsor, or death, 
whichever occurs first.  Magnetic resonance imaging surveillance of the brain (preferred) 
or brain CT with contrast every 34 months is recommended during Year 1, and every 
6 months during Year 2 independent of the use of PCI (NCCN 2021a). 
Additional tumor assessments during the induction and maintenance phases will be 
performed as per local standard of care and as clinically indicated and must also be 
reported in the study database as unscheduled visits. 
Tumor assessments at induction screening, maintenance screening, and subsequent 
assessments must include computed tomography (CT) scans (with IV contrast, unless 
contraindicated, and oral contrast as appropriate per institutional standards) of the chest 
and abdomen.  A CT scan, with contrast, of the pelvis is required at induction screening, 
maintenance screening, and as clinically indicated or as per local standard of care at 
subsequent response evaluations.  Magnetic resonance imaging scans with contrast of 
the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may be used in 
participants for whom CT scans with IV contrast are contraindicated (i.e., participants 
with iodine-based contrast allergy or impaired renal clearance). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
83/Protocol GO43104, Version 8 
An MRI scan or CT scan with contrast of the head must be done at induction screening 
and maintenance screening to evaluate CNS metastases in all participants.  
For participants for whom imaging of the brain was performed after induction and who 
subsequently received PCI, brain imaging does not need to be repeated after PCI before 
randomization.  A brain MRI scan is the preferred imaging method for evaluating 
CNS metastases as it is more sensitive than CT for identifying brain metastases; 
however, CT of the brain is acceptable if MRI is contraindicated.  If a CT scan with 
contrast is performed and the presence of brain metastases is considered equivocal, 
an MRI scan of the brain is required to confirm or refute the diagnosis of CNS 
metastases.  Participants with CNS metastases are not eligible for the study. 
All known or suspected sites of disease should be assessed at induction screening and 
maintenance screening and at subsequent assessments with use of the same imaging 
method and technique.  If more than one method is used at screening, then the most 
accurate method according to RECIST v1.1 should be used when recording data, and 
should again be used for all subsequent assessments. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full 
contrast diagnostic CT scan. 
For participants with bone lesions, bone scans, PET 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.  
Participants should undergo bone scans if bone disease cannot be assessed by another 
modality (e.g., CT scan). 
Further investigations (e.g., CT scans of the neck) should be performed as clinically 
indicated. 
Randomized participants who discontinue treatment for any reason prior to radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments at the same frequency as would have been 
followed if the participant had remained on study treatment, regardless of whether the 
participant starts a new non-protocol anti-cancer therapy. 
Radiographic images will be submitted to an IRF for a quality and completeness check, 
for independent central review, and for temporary storage prior to transferring images to 
the Sponsor for the long-term retention and eventual secondary/exploratory use. 
Radiographic images, whether reviewed locally or centrally, must be evaluated by a 
qualified, certified expert. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
84/Protocol GO43104, Version 8 
8.1.1.2 
Response Evaluation 
Objective response will be determined by the IRF and the investigator at specified 
timepoints according to RECIST v1.1 (see Appendix 8).  Assessments should be 
performed by the same individual, if possible, to ensure internal consistency across 
visits. 
Endpoints (e.g., confirmed ORR, PFS), will be calculated programmatically by the 
Sponsor on the basis of the IRF's and investigator's assessments of responses. 
8.2 
SAFETY ASSESSMENTS 
8.2.1 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at induction baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in participant notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
8.2.2 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at induction 
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. 
The measurement of vital signs during lurbinectedin infusion should be performed as 
clinically indicated. 
See Table 8 for details on the measurements of vital signs during atezolizumab 
infusions. 
In addition, vital signs should be assessed at other specified timepoints as outlined in the 
schedule of activities (see Section 1.3). 
8.2.3 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  Electrocardiograms for 
each participant should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  Electrocardiogram recordings 
must be performed after the participant has been resting in a supine position for at least 
10 minutes. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
85/Protocol GO43104, Version 8 
For safety monitoring purposes, the investigator must review, sign, and date all 
ECG reports.  Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site.  Any morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF. 
8.2.4 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and see the 
schedule of activities (see Section 1.3 [Table 1 and Table 2]) for the timing and 
frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the Adverse Event Case Report 
Form (CRF; see Appendix 3). 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 months of the final dose of atezolizumab or 30 days 
after the final dose of lurbinectedin treatment should be repeated until the values return 
to normal or baseline or are considered to be stable and no longer considered clinically 
significant by the investigator.  If such values do not return to normal or baseline within a 
period of time judged reasonable by the investigator, the etiology should be identified 
and the Sponsor notified. 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution's local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event, adverse 
event or requirement of a dose modification), the results must be recorded on the eCRF. 
Sample collection may be performed by a MN professional. 
Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final Clinical Study Report (CSR). 
8.2.5 
Pregnancy Testing 
The schedule for pregnancy testing for female participants of childbearing potential is 
outlined in Section 1.3 (Table 1 and Table 2) and will be conducted as outlined in 
Appendix 2. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
86/Protocol GO43104, Version 8 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
The definitions of adverse event and serious adverse event can be found in Appendix 3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are 
considered related to the study treatment or study procedures, or caused the participant 
to discontinue the study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
After informed consent has been obtained but prior to initiation of study drug, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (see Appendix 3).  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 e-mailing the form using the fax number or e-mail address 
provided to investigators.  All other medical occurrences that begin before the start of 
study treatment will be recorded on the General Medical History and Baseline Conditions 
eCRF, not the Adverse Event eCRF. 
All adverse events will be reported from the start of treatment until 30 days after the final 
dose of study treatment or until start of new systemic anti-cancer therapy, whichever 
occurs first.  Serious adverse events and adverse events of special interest will be 
reported from the start of study treatment until 90 days after the final dose of study 
treatment or until start of new systemic anti-cancer therapy, whichever occurs first.  
Serious adverse events and adverse events of special interest considered related to 
prior exposure to study treatment will be reported indefinitely. 
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation.  However, if the investigator learns of 
any serious adverse event, including a death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify the 
Sponsor. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
87/Protocol GO43104, Version 8 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 3. 
Care must be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about adverse event occurrences. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts.  
All adverse events will be followed until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the participant is lost to 
follow-up (as defined in Section 7.3), or the participant withdraws consent.  
Further information on follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification (i.e., within 24 hours of awareness) by the investigator to the Sponsor 
of a serious adverse event is essential so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety of 
a study treatment under clinical investigation.  The Sponsor will comply with regulatory 
requirements for expedited safety reporting to the regulatory authority (which include the 
use of applicable systems, such as EudraVigilance), Institutional Review Boards or 
Ethics Committees (IRBs/ECs), and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
To determine reporting requirements for serious 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 
Lurbinectedin 
Lurbinectedin Investigator's Brochure 
Atezolizumab 
Atezolizumab Investigator's Brochure 
  

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
88/Protocol GO43104, Version 8 
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 investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 
events) from the Sponsor will review and then file it along with the 
Investigator's Brochures and will notify the IRB/EC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed through the 
Informed Consent Form to immediately inform the investigator if they become pregnant 
during study treatment or within 5 months after the final dose of atezolizumab, or within 
6 months after the final dose of carboplatin and etoposide, or within 7 months after the 
final dose of lurbinectedin, whichever is later. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during their study treatment 
or within 4 months after the final dose of lurbinectedin, or within 6 months after the final 
dose of carboplatin or etoposide, whichever is later. 
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
The Sponsor or a designee may follow up by telephone, fax, e-mail, and/or a monitoring 
visit to obtain additional case details and outcome information (e.g., from hospital 
discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
8.3.6 
Cardiovascular and Death Events 
Information on cardiovascular events and reporting deaths is provided in Appendix 3. 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting 
Events not qualifying for expedited reporting will not be defined for this study. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
89/Protocol GO43104, Version 8 
8.3.8 
Adverse Events of Special Interest 
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 the investigator becomes aware 
of the event; see Section A35 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 A37.7) 
 
Suspected transmission of an infectious agent by a 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 participant exposed to a medicinal product.  This term applies only 
when a contamination of the study treatment is suspected. 
 
Hepatitis, including AST or ALT  10  ULN 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome (CRS), hemophagocytic lymphohistiocytosis, and macrophage activation 
syndrome 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis 
 
Descriptions of risks and management of the above-listed adverse events are provided 
in Appendix 6. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
90/Protocol GO43104, Version 8 
8.3.9 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study participants, access to the 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 investigators. 
8.4 
PHARMACOKINETICS 
 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples will be used to evaluate the pharmacokinetics of lurbinectedin and 
atezolizumab.  Samples collected for analyses of lurbinectedin and atezolizumab plasma 
and serum concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
Participant confidentiality will be maintained.  Pharmacokinetic samples will be destroyed 
no later than 5 years after the final CSR has been completed to allow for assay 
development and validation (if needed). 
8.5 
PHARMACODYNAMICS 
See Section 8.7 for information on pharmacodynamic biomarkers. 
8.6 
GENETICS 
See Section 8.7 and Appendix 5 for information on genetic biomarkers. 
 
 
 
 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
91/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
  
– 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
92/Protocol GO43104, Version 8 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
8.8 
IMMUNOGENICITY ASSESSMENTS 
 
 
 
 
 
 
 
Samples may be stored for a maximum of 5 years (or according to local regulations) 
after the final CSR has been completed at a facility selected by the Sponsor to enable 
further analysis of the immunogenicity of atezolizumab. 
8.9 
HEALTH ECONOMICS 
For all participants throughout the study, the investigator and study site personnel will 
collect data about health care resource utilization associated with medical encounters. 
The data collected will include the reasons and duration of hospitalizations and 
emergency room visits and exclude procedures, tests, and encounters mandated by the 
protocol. 
The Sponsor may use the collected data to conduct economic analyses. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
93/Protocol GO43104, Version 8 
8.10 
CLINICAL OUTCOME ASSESSMENTS 
Patient-reported outcome (PRO) instruments will be completed to assess the treatment 
benefit of the lurbinectedin and atezolizumab combination.  In addition, PRO instruments 
will enable the capture of each participant's direct experience with lurbinectedin and 
atezolizumab. 
Patient-reported outcomes data will be collected through use of the following 
instruments:  the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life QuestionnaireCore 30 (QLQ-C30), EORTC Quality of Life 
QuestionnaireLung Cancer Module (QLQ-LC13), EORTC IL46, Patient-Reported 
Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 
EQ-5D-5L. 
8.10.1 
Data Collection Methods for Clinical Outcome Assessments 
Patient-reported outcomes instruments will be self-administered at the clinic at specified 
timepoints during the study (see schedule of activities in Section 1.3 [Table 1 and 
Table 2]).  At the clinic, instruments will be administered before the participant receives 
any information on disease status, and prior to the administration of study treatment, 
unless otherwise specified. 
Patient-reported outcomes instruments, translated into the local language as 
appropriate, will be completed through use of an electronic device provided by the 
Sponsor.  The device will be pre-programmed to enable the appropriate instruments to 
be administered in the correct order at each specified timepoint.  The electronic device 
and instructions for completing the instruments electronically will be provided by the site 
staff.  The data will be transmitted to a centralized database maintained by the electronic 
device vendor.  The data will be available for access by appropriate study personnel 
only. 
Participants should be given the following instructions for completing PRO instruments at 
home: 
 
Participants should complete the instruments in a quiet area with minimal 
distractions and disruptions. 
 
Participants should answer questions to the best of their ability; there are no right or 
wrong answers. 
 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
During clinic visits and visits conducted by a MN professional, PRO instruments should 
be administered as outlined below: 
 
Participants' health status should not be discussed prior to administration of the 
instruments 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
94/Protocol GO43104, Version 8 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for participants to complete the instruments 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions 
 
Participants should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request 
 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments 
 
Patient-reported outcomes may be completed remotely during the maintenance phase 
on Cycle 1, Day 10 and Cycle 2, Day 10.  Additionally, remote data collection may occur 
during follow-up and in exceptional circumstances, if the participant cannot get to the 
site.  Source documentation should be obtained which includes, among other 
information, that the questionnaires were administered remotely. 
8.10.2 
Description of Clinical Outcome Assessment Instruments 
8.10.2.1 
EORTC Quality of Life QuestionnaireCore 30 
The QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; see Appendix 11).  It consists of 30 questions that assess 
five aspects of participant functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, and pain), global health status and 
quality of life (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 
global health status and QoL items are scored on a 7-point scale that ranges from 
"very poor" to "excellent."  The QLQ-C30 module takes approximately 10 minutes to 
complete. 
8.10.2.2 
EORTC Quality of Life QuestionnaireLung Cancer Module 
The EORTC QLQ-LC13 (Bergman et al. 1994; see Appendix 12) is composed of 13 lung 
cancer-specific items and includes 11 disease-specific scales and items (dyspnea, 
coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in 
chest, pain in arm or shoulder, pain in other parts, pain medication).  The QLQ-LC13 
takes approximately 7 minutes to complete. 
8.10.2.3 
EORTC Item List 46 
The single-item EORTC Item List 46 (IL 46) question assesses overall side-effect impact 
(Appendix 13). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
95/Protocol GO43104, Version 8 
8.10.2.4 
EuroQol EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; 
see  Appendix 10).  There are two components to the EQ-5D-5L:  a 5-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analog scale (VAS) that measures health state.  
The EQ-5D-5L is designed to capture the participant's current health status.  
Published weighting systems allow for creation of a single composite score of the 
participant's health status.  The EQ-5D-5L takes approximately 3 minutes to complete.  
It will be used in this study for informing pharmacoeconomic evaluations 
(see Section 8.9), scored according to its manual, and the results will be reported 
separately from the CSR. 
8.10.2.5 
PRO-CTCAE 
The PRO-CTCAE is a validated item library 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. 
A subset of 12 symptoms deemed most applicable to the current study treatments has 
been selected for this study (see Appendix 14).  Symptoms have been selected based 
on toxicities most commonly associated with lurbinectedin and atezolizumab. 
8.11 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
8.11.1 
Optional Tumor Biopsies (Participants Providing Separate 
Consent) 
Consenting participants will undergo an optional tumor biopsy (if deemed clinically 
feasible by the investigator) after the completion of induction treatment and/or at the time 
of radiographic disease progression (preferably within 40 days after radiographic 
progression or prior to start of the next anti-cancer treatment, whichever is sooner). 
Preferred sample types include FFPE samples prepared from resections, core needle, 
excisional, incisional, punch, or forceps biopsies.  If these sample types are not 
available, any type of specimen (including fine-needle aspiration, cell pellet specimens 
[e.g., from pleural effusion and lavage samples], preferably in cell blocks) is acceptable. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
96/Protocol GO43104, Version 8 
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of undergoing optional biopsies.  
Participants will be told that they are free to choose not to undergo optional biopsies and 
may withdraw their consent at any time and for any reason.  A separate, specific 
signature will be required to document a participant's agreement to undergo optional 
biopsies.  Participants who choose not to undergo optional biopsies will not provide a 
separate signature.  The investigator should document whether or not the participant has 
given consent to undergo optional biopsies and (if applicable) the date of consent, by 
completing the Sample Informed Consent/Withdrawal eCRF. 
Samples may be used for exploratory biomarker research as described in Section 8.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
 
 
8.11.2 
Optional Samples for Research Biosample Repository 
(Participants Providing Separate Consent at Participating 
Sites) 
8.11.2.1 
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 
 which may allow for 
individualized drug therapy for participants in the future. 
Samples for the RBR will be collected from participants 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 
 
 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
97/Protocol GO43104, Version 8 
8.11.2.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 8.11.2) 
will not be applicable at that site. 
8.11.2.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Research Biosample Repository samples are to be stored until they are no longer 
needed or until they are exhausted.  However, the RBR storage period will be in 
accordance with the IRB/ECapproved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
98/Protocol GO43104, Version 8 
8.11.2.4 
Confidentiality 
Research Biosample Repository samples and associated data will be labeled with a 
unique participant identification number. 
Participant 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 
participant, 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 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
8.11.2.5 
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 participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to choose not to provide optional RBR samples 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 participant's agreement to 
provide optional RBR samples.  Participants who choose not to provide optional 
RBR samples will not provide a separate signature.  The investigator should document 
whether or not the participant has given consent to provide optional RBR samples and 
(if applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal 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. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
99/Protocol GO43104, Version 8 
8.11.2.6 
Withdrawal from the Research Biosample Repository 
Participants 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.  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 
participant 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 participant's 
wishes through use of the appropriate RBR Subject Withdrawal Form and must enter the 
date of withdrawal on the Sample Informed Consent/Withdrawal eCRF.  If a participant 
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 e-mailing the study number and 
participant number to the following e-mail address: 
global.rcr-withdrawal@roche.com 
A participant's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a participant's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study. 
8.11.2.7 
Monitoring and Oversight 
Research Biosample Repository samples will be tracked in a manner consistent with 
Good Clinical Practice by a quality-controlled, auditable, and appropriately validated 
laboratory information management system, to ensure compliance with data 
confidentiality as well as adherence to authorized use of samples as specified in this 
protocol and in the Informed Consent Form.  Sponsor monitors and auditors will have 
direct access to appropriate parts of records relating to an individual's 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. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
The purpose of this study is hypothesis testing and estimation regarding the effect of 
lurbinectedin in combination with atezolizumab on the duration of IRF-assessed PFS 
and/or OS compared with atezolizumab alone.  The primary objective of this study is to 
evaluate the efficacy of lurbinectedin in combination with atezolizumab compared with 
atezolizumab.  The primary endpoints for this study are OS and IRF-assessed PFS in 
the full analysis set (FAS). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
100/Protocol GO43104, Version 8 
 
 
 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
Approximately 920 participants will be screened to achieve the enrollment of 
690 participants into the induction phase.  Approximately 
 participants will be 
randomized into this study for an estimated total of 
 participants per treatment group. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
101/Protocol GO43104, Version 8 
9.3 
ANALYSIS SETS 
The analysis sets are defined in Table 10. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
102/Protocol GO43104, Version 8 
Table 10 Description of Participant Analysis Sets 
Participant Analysis Set 
Description 
FAS 
All participants randomized into the maintenance phase 
regardless of whether or not the assigned study treatment is 
received: participants will be included in the analyses according 
to the treatment to which they were assigned by IxRS at 
randomization 
SAS 
All participants who are randomized into the maintenance phase 
and receive at least 1 dose of atezolizumab or lurbinectedin: 
participants will be analyzed according to the treatment that they 
received, i.e., participants who receive lurbinectedin in error will 
be analyzed in Arm A for the SAS 
Enrolled analysis set 
All participants who are enrolled in the induction phase, 
regardless of whether or not they receive induction treatment and 
regardless of whether they are subsequently randomized 
Enrolled SAS  
All enrolled participants who receive at least 1 dose of 
atezolizumab or carboplatin or etoposide, regardless of whether 
or not they are subsequently randomized 
FAS  Full Analysis Set; SAS  Safety Analysis Set. 
  
9.4 
STATISTICAL ANALYSES 
The Statistical Analysis Plan will be finalized before the randomized treatment 
assignment information is disclosed to the study team for the pre-specified analyses, 
and it will include a more technical and detailed description of the statistical analyses 
described in this section.  This section is a summary of the planned statistical analyses 
of the most important endpoints, including primary and key secondary endpoints. 
9.4.1 
General Considerations 
All efficacy analyses will be performed in the FAS, unless otherwise specified.  
Participants will be analyzed according to the treatment assigned at randomization by 
IxRS. 
All safety analyses will be performed in the SAS, unless otherwise specified.  
Participants will be analyzed according to the treatment they actually received.  
Specifically, a participant will be included in the atezolizumab and lurbinectedin 
combination arm in the safety analyses if the participant receives any amount of 
lurbinectedin, regardless of the initial treatment assignment at randomization. 
Hypothesis tests will be 2-sided unless otherwise indicated. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
103/Protocol GO43104, Version 8 
9.4.2 
Estimation Methods for the Primary Estimands 
The primary objective for this study is to evaluate the efficacy of lurbinectedin when 
administered in combination with atezolizumab compared with atezolizumab 
monotherapy in participants with ES-SCLC, who have an ongoing response or SD after 
completion of 4 cycles of carboplatin, etoposide, and atezolizumab induction treatment 
on the basis of IRF-assessed PFS according to RECIST v1.1 and OS, as defined in 
Section 3 (see Table 4). 
9.4.2.1 
Main Analytical Approach for Primary Estimands 
For IRF-assessed PFS, participants who have not experienced disease progression and 
have not died by the clinical cutoff date will be censored at the time of the last tumor 
assessment.  Participants with no tumor assessment after baseline will be censored at 
the date of randomization. 
For OS, participants who are not reported as having died by the clinical cutoff date will 
be censored at the date when they were last known to be alive.  Participants who do not 
have information after baseline will be censored at the date of randomization. 
Each of the primary endpoints will be compared between two treatment arms based on 
the stratified log-rank test.  The HR will be estimated with use of a stratified Cox 
regression model, including two-sided 95% CIs.  The stratification factors will be those 
used for randomization.  The Kaplan-Meier methodology will be used to estimate the 
median IRF-assessed PFS and median OS for each treatment arm, and Kaplan-Meier 
curves will be constructed to provide a visual description of the difference between 
treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 
95% CIs for the median IRF-assessed PFS and median OS for each treatment arm 
(Brookmeyer and Crowley 1982).  Results from an unstratified analysis will also be 
provided. 
Further analysis details including sensitivity and supplemental analyses on the primary 
endpoints will be specified in the Statistical Analysis Plan. 
9.4.3 
Estimation Methods for the Secondary Endpoints 
9.4.3.1 
Investigator-Assessed PFS 
Investigator-assessed PFS is defined as the time from randomization to the date of first 
documented disease progression as assessed by the investigator according to 
RECIST v1.1 or death, whichever occurs first.  Participants who have not experienced 
disease progression and have not died by the clinical cutoff date will be censored at the 
time of the last tumor assessment.  Participants with no tumor assessment after baseline 
will be censored at the date of randomization. 
Investigator-assessed PFS will be analyzed through use of the same methods described 
for the IRF-assessed PFS analysis (see Section 9.4.2.1). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
104/Protocol GO43104, Version 8 
9.4.3.2 
Confirmed Objective Response Rate 
A confirmed objective response is defined as either a CR or a PR on two consecutive 
occasions  4 weeks apart after randomization, as determined by the IRF according to 
RECIST v1.1.  Participants not meeting these criteria, including participants without any 
post-baseline tumor assessment, will be considered non-responders. 
Confirmed ORR is defined as the proportion of participants who had a confirmed 
objective response after randomization.  The analysis set for confirmed ORR will be the 
FAS with measurable disease at baseline.  An estimate of confirmed ORR and its 95% 
CI will be calculated with use of the Clopper Pearson method for each treatment arm.  
Confidence intervals for the difference in confirmed ORRs between the two treatment 
arms will be determined with use of the normal approximation to the binomial 
distribution. 
Confirmed ORR as determined by the investigator according to RECIST v1.1 will also be 
analyzed through the same methods described above. 
9.4.3.3 
Duration of Response 
Duration of response will be assessed in participants who had a confirmed objective 
response as determined by IRF with use of RECIST v1.1 in the FAS.  Duration of 
response is defined as the time interval from the date of the first occurrence of a 
documented confirmed objective response until the first date that PD as determined by 
the IRF according to RECIST v1.1 or death is documented, whichever occurs first.  
Participants 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.  Duration of response is based 
on a non-randomized subset of participants (specifically, participants who achieved a 
confirmed objective response); therefore, formal hypothesis testing will not be performed 
for this endpoint.  Comparisons between treatment arms will be made for descriptive 
purposes. 
Duration of response (for patients with confirmed objective response), as determined by 
the investigator according to RECIST v1.1, will also be analyzed. 
The methodologies detailed for the PFS analysis will be used for the DOR analysis. 
9.4.3.4 
Progression-Free Survival and Overall Survival Rates at 
Landmark Timepoints 
The IRF-assessed and investigator-assessed PFS rates at 6 months and at 12 months 
after randomization will be estimated with use of the Kaplan-Meier methodology for each 
treatment arm, along with 95% CIs calculated with use of 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 with use of the normal approximation method. 
Similar analyses will be performed for the OS rates at 12 months and at 24 months after 
randomization. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
105/Protocol GO43104, Version 8 
9.4.3.5 
Incidence and Severity of Adverse Events 
The secondary safety objective will be assessed through summaries of the incidence 
and severity of adverse events in the SAS. 
Verbatim description of adverse events will be mapped to the MedDRA thesaurus terms.  
Severity for all adverse events will be graded by the investigator according to the 
NCI CTCAE v5.0.  Severity for CRS will also be graded by the investigator according to 
the American Society of Transplantation and Cellular Therapy (ASTCT) consensus 
grading scale.  All adverse events will be summarized by treatment arm and NCI CTCAE 
grade.  Cytokine release syndrome will also be summarized by treatment arm and the 
ASTCT consensus grade.  All adverse events, serious adverse events, adverse events 
leading to death, adverse events of special interest, and adverse events leading to study 
treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatmentemergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Multiple occurrences of the same event 
will be counted once at the maximum severity.  Deaths and cause of death will be 
summarized. 
9.4.3.6 
Time to Confirmed Deterioration 
Time to confirmed deterioration (TTCD) for physical functioning and global health status 
(GHS)/QoL using the EORTC QLQ-C30 is defined as the time from the date of 
randomization until the first confirmed clinically meaningful deterioration. 
Confirmed clinically meaningful deterioration for physical functioning and GHS/QoL is 
defined as a clinically meaningful decrease from baseline in physical functioning or GHS 
score that must be held for at least two consecutive assessments or an initial clinically 
meaningful decrease above baseline followed by death. 
A score change of  10-point change in GHS/QoL and functional subscale score is 
perceived by participants as clinically meaningful (Osoba et al. 1998). 
For TTCD, data for participants will be censored at the last time when they completed an 
assessment if they have not experienced a confirmed clinically meaningful deterioration 
at the clinical cutoff date.  If no baseline or post-baseline assessment is performed, 
participants will be censored at the randomization date.  Time to confirmed deterioration 
using the EORTC scale will be analyzed with use of the same methods as for PFS.  
Further details regarding the TTCD analysis for the EORTC measures will be described 
in the Statistical Analysis Plan. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
106/Protocol GO43104, Version 8 
 
 
 
 
 
9.4.4 
Other Safety Analyses 
Drug exposure will be summarized during the maintenance phase in the SAS, including 
duration, dosage, and dose intensity.  Laboratory data with values outside of the normal 
ranges will be identified.  Additionally, selected laboratory data may be summarized by 
treatment arm and grade.  Vital signs may also be summarized by treatment arm and 
visit. 
Additionally, drug exposure of atezolizumab and chemotherapy during the induction 
phase will be summarized to include number of doses and dose intensity with use of 
descriptive statistics for the enrolled SAS.  Adverse events, serious adverse events, and 
death (cause of death) during the induction phase will be summarized for the enrolled 
SAS. 
9.4.5 
Other Analyses 
9.4.5.1 
Summaries of Conduct of Study 
Study enrollment, study drug administration, reasons for discontinuation from the study 
treatment, and reasons for study discontinuation will be summarized for the enrolled 
analysis set, the enrolled SAS, the FAS, or the SAS by treatment arm as appropriate.  
Major protocol deviations, including major deviations of inclusion/exclusion criteria, will 
be reported and summarized for the enrolled analysis set and for the FAS by treatment 
arm. 
9.4.5.2 
Summaries of Demographics and Baseline Characteristics 
Demographics (e.g., sex, age) and baseline characteristics (e.g., ECOG PS, LDH) will 
be summarized for the FAS by treatment arm.  Baseline measurements are the last 
available data obtained prior to the participant receiving the first dose of any component 
of protocol treatment in the maintenance phase, unless otherwise noted.  Descriptive 
statistics (mean, standard deviation, median, and range) will be presented for continuous 
variables and counts and percentages will be presented for categorical variables. 
 
 
  
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
107/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
9.4.5.5 
Clinical Outcome Assessment Analyses 
Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and 
range) and the mean change from baseline of linear-transformed scores will be reported 
for all of the items and scales of the EORTC QLQ-C30 and EORTC QLQ-LC13 
(lung cancer-specific subset) questionnaires according to the EORTC scoring manual 
guidelines. 
Patient-reported outcome-CTCAE (tolerability as measured by severity, frequency 
and/or interference of relevant events) and EORTC IL46 (a single item for level of 
bothersome experienced from treatment) analyses will be conducted in the SAS.  
Analyses will be descriptive (frequency counts and percentages).  For the PRO-CTCAE, 
there will be a focus on characterizing the pattern of symptomatic treatment toxicities 
during the study.  The EORTC IL46 and PRO-CTCAE data will be summarized at the 
item level.  For each treatment arm, the number and percentage of participants reporting 
symptom by "frequency", "severity", "interference", and "presence" category will be 
reported at each assessment.  A summary table of the percentage of participants 
reporting severity of a symptom as 'severe' or 'very severe' over the course of the study 
by treatment arm will also be provided.  Change from baseline of severity for 
PROCTCAE selected items will be summarized.  Finally, a longitudinal analysis of 
change may be employed to understand how symptoms may have changed over the 
course of treatment.  Results from these exploratory analyses will be presented 
separately from other safety analyses.  EORTC IL46 will be summarized as frequencies 
by treatment arm and by timepoint. 
Completion rates of questionnaires will be summarized at each timepoint by treatment 
arm. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
108/Protocol GO43104, Version 8 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
109/Protocol GO43104, Version 8 
9.6 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (iDMC) will evaluate safety data during the 
study.  Sponsor affiliates will be excluded from iDMC membership.  The iDMC will follow 
a charter that outlines the iDMC's roles and responsibilities. 
Safety data will be reviewed on a periodic basis starting after approximately 
24 participants have completed 2 cycles of maintenance treatment or 6 months from the 
time of the first participant randomized into the maintenance phase, whichever is earlier, 
and approximately every 6 months thereafter until the randomized treatment assignment 
information is disclosed to the study team for the pre-specified analyses.  All summaries 
and analyses for the iDMC review will be prepared by an independent Data Coordinating 
Center. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor. 
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective IRBs/ECs.  
A detailed plan will be included in the iDMC Charter. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
110/Protocol GO43104, Version 8 
10. 
REFERENCES 
Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of 
chemotherapy-induced febrile neutropenia in adult patients with lymphomas and 
solid tumours. Eur J Cancer. 2006;42:243353. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organisation for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576. 
Armstrong SA, Liu SV. Immune checkpoint inhibitors in small-cell lung cancer: a partially 
realized potential. Adv Ther 2019;36:182632. 
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. 
Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated 
macrophages and the inflammatory tumour microenvironment in preclinical 
models. Br J Cancer 2017;117:62838. 
Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular 
supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in 
lung cancer clinical trials.  EORTC Study Group on Quality of Life. Eur J Cancer 
1994;30A:63542. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:2941. 
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372. 
Céspedes MV, Guillén MJ, López-Casas P, et al. Lurbinectedin induces depletion of 
tumor-associated macrophages, an essential component of its in vivo synergism 
with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech 
2016;9:146171. 
De Marinis F, Pereira JR, Fossella F, et al. Lung cancer symptom scale outcomes in 
relation to standard efficacy measures: an analysis of the phase III study of 
pemetrexed versus docetaxel in advanced nonsmall-cell lung cancer. J Thorac 
Oncol 2008;3:306. 
Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small-cell 
lung carcinoma: current status and future prospects. Eur Respir J 2010;35:20215. 
Deng R, Bumbaca D, Pastuskovas C, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of antiPD-L1 
monoclonal antibody, an immune checkpoint inhibitor. Mabs 2016;8:593603. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
111/Protocol GO43104, Version 8 
Dueck AC, Mendoza TR, Mitchell SA, et al. Validity and reliability of the U.S. National 
Cancer Institute's patient-reported outcomes version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol 2015;1:10519. 
ECIS  European Cancer Information System. European Commission [resource on the 
Internet]. 2020. Available from: 
https://ecis.jrc.ec.europa.eu. Accessed on 28 May 2021. 
European Medicines Agency. Guideline on the evaluation of anti-cancer medicinal 
products in man EMA/CHMP/205/95/Rev. 4 [resource on the Internet]. 2012. 
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
3/01/WC500137128.pdf. 
ESMO Guidelines Committee. Small-cell lung cancer: ESMO Clinical Practice 
Guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2021;32:83953. 
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208. 
FDA. Guidance for Industry. Clinical trial endpoints for the approval of cancer drugs and 
biologics. [resource on Internet] 2018. Available from: 
https://www.fda.gov/media/71195/download. 
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated nonsmall-cell lung cancer (POPLAR): a multicentre, 
open-label, phase 2 randomised controlled trial. Lancet 2016;387:183746. 
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease-specific quality 
of life (QoL) questionnaire module to supplement the EORTC core cancer QoL 
questionnaire, the QLQ-C30 in patients with pancreatic cancer.  EORTC Study 
Group on Quality of Life. Eur J Cancer 1999;35:93941. 
Foster NR, Renfro LA, Schild SE, et al. Multitrial evaluation of progression-free survival 
as a surrogate endpoint for overall survival in first-line extensive-stage small-cell 
lung cancer. J Thorac Oncol 2015;10:1099106. 
Foster NR, Mandrekar SJ, Schild SE, et al. Prognostic factors differ by tumor stage for 
small-cell lung cancer: a pooled analysis of North Central Cancer Treatment Group 
trials. Cancer 2009;115:272131. 
Frebel H, Nindl V, Schuepbach RA, et al. Programmed death 1 protects from fatal 
circulatory failure during systemic virus infection of mice. J Exp Med 
2012;209:248599. 
Fudio S. Exposure-response analyses and clinical utility index to justify the dosage of 
lurbinectedin in small-cell lung cancer [abstract]. 2020 World Conference on Lung 
Cancer Singapore. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
112/Protocol GO43104, Version 8 
Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung 
cancer in the United States over the last 30 years: analysis of the surveillance, 
epidemiologic, and end results database. J Clin Oncol 2006;24:453944. 
Griebsch I, Palmer M, Fayers PM, et al. Is progression-free survival associated with a 
better health-related quality of life in patients with lung cancer? Evidence from two 
randomised trials with afatinib. BMJ Open 2014;4:e005762. 
Gjyshi O, Ludmir EB, Pezzi TA, et al. Nationwide shift in patterns of prophylatic cranial 
irradiation utilization for extensive-stage small-cell lung cancer patients. J Clin 
Oncol 2019;37(Suppl 15). 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736. 
Hermes A, Gatzemeier U, Waschki B, et al. Lactate dehydrogenase as prognostic factor 
in limited and extensive disease stage small-cell lung cancer  a retrospective 
single institution analysis. Respir Med 2010;104:193742. 
Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in 
extensive-stage small-cell lung cancer. N Engl J Med 2018;379:22209. 
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 19752012. 
National Cancer Institute, 2015 [resource on the Internet]. Available from: 
https://seer.cancer.gov/csr/1975_2012/. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990;9:143945. 
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials, 17 February 2020. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727. 
Johnson BE, Jänne PA. Basic treatment considerations using chemotherapy for patients 
with small-cell lung cancer. Hematol Oncol Clin N Am 2004;18:30922. 
Kelly S, Wheatley D. Prevention of febrile neutropenia: use of granulocyte 
colony-stimulating factors. Br J Cancer 2009;101:S610. 
McCune S, Ton TG, Whipple S, et al. New treatment option for ES-SCLC: patient 
characteristics and use of an atezolizumab regimen in the real-world setting 
[abstract]. 2019 World Conference on Lung Cancer. 
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. 
Molina JR, Yang P, Cassivi SD, et al. Nonsmall-cell lung cancer: epidemiology, risk 
factors, treatment, and survivorship. Mayo Clin Proc 2008;83:58494. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
113/Protocol GO43104, Version 8 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in 
oncology. Small-cell lung cancer [resource on the Internet]. 2021a 
[updated 23 March 2021]. Version 3.2021. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf 
[NCCN] National Cancer Comprehensive Network. Recommendations of the NCCN 
COVID-19 Vaccination Advisory Committee [resource on the internet]. 2021b 
[cited: 28 May 2021]. Available from:  
https://www.nccn.org/docs/default-source/covid-19/2021_covid-
19_vaccination_guidance_v2-0.pdf?sfvrsn=b483da2b_2 
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. 
Owonikoko TK, Kim HR, Ramaswamy G, et al. Nivolumab plus ipilimumab, nivolumab, 
or placebo as maintenance therapy in patients with extensive disease small-cell 
lung cancer after first-line platinum-based chemotherapy: results from the 
double-blind, randomized phase 3 CheckMate 451 study [abstract]. 2019 
European Lung Cancer Virtual Congress. 
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus 
platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer 
(CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 
2019;394:192939. 
Ponce Aix S, Navarro A, Bernabe R, et al. 2SMALL (NCT04253145) phase I part: 
Lurbinectedin (LUR) in combination with Atezolizumab (ATZ) for second line 
Extensive Stage Small Cell Lung Cancer (ES-SCLC) patients (pts) [abstract]. 
2021 Society for Immunotherapy of Cancer Washington, D.C., US 
Reck M, Horn L, Mok TS, et al. IMpower133: exploratory analysis of maintenance 
therapy in patients with extensive-stage small-cell lung cancer [abstract]. 
2020 World Conference on Lung Cancer Singapore. 
Rosenberg JE, Hoffmann-Censits J, Powles T, et al. Atezolizumab in patients with 
locally advanced and metastatic urothelial carcinoma who have progressed 
folowing treatment with platinum-based chemotherapy: a single-arm, multicentre, 
phase 2 trial. Lancet 2016;387:190920. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2020. CA Cancer J Clin 2020;70:730. 
[SITC] Society for Immunotherapy of Cancer statement on SARS-CoV-2 vaccination and 
cancer Immunotherapy [resource on the internet]. Press release: 23 December 
2020 [cited: 28 May 2021]. Available from: 
https://www.sitcancer.org/aboutsitc/press-releases/2020/sitc-statement-sars-cov-2-
vaccination-cancer-immunotherapy. 
Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive 
small-cell lung cancer. N Engl J Med 2007;357:66472. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
114/Protocol GO43104, Version 8 
Stinchcombe TE, Gore EM. Limited-stage small-cell lung cancer: current 
chemoradiotherapy treatment paradigms. Oncologist 2010;15:18795. 
Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus 
observation in patients with extensive-disease small-cell lung cancer: 
a multicentre, randomised, open-label phase 3 trial. Lancet Oncoll 
2017;18:66371. 
Tecentriq (atezolizumab) U.S. Prescribing Information, Genentech. 
Tecentriq (atezolizumab) E.U. Summary of Product Characteristics, Genentech. 
Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients 
with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet 
Oncol 2020;21:64554. 
Xie W, Forveille S, Iribarren K, et al. Lurbinectedin synergizes with immune checkpoint 
blockade to generate anti-cancer immunity. Oncoimmunology 2019;8:e1656502. 
Ye Y, Li A, Liu L, et al. A group sequential Holm procedure with multiple primary 
endpoints. Stat Med 2012;111224. 
Yip D, Harper PG. Predictive and prognostic factors in small-cell lung cancer: current 
status. Lung Cancer 2000;28:17385. 
ZEPZELCA (lurbinectedin) injection, for intravenous use. U.S. Prescribing Information, 
Jazz Pharmaceuticals. 
Zofran (ondansetron hydrochloride) U.S. Prescribing Information, GlaxoSmithKline. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
115/Protocol GO43104, Version 8 
Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
TABLE OF CONTENTS 
A1–1 
Regulatory and Ethical Considerations .................................. 116 
A1–2 
Financial Disclosure ............................................................... 116 
A1–3 
Informed Consent Process .................................................... 117 
A1–4 
Data Protection ...................................................................... 117 
A1–5 
Administrative Structure ......................................................... 118 
A1–6 
Dissemination of Clinical Study Data ..................................... 118 
A1–7 
Data Quality Assurance ......................................................... 119 
A1–8 
Source Documents ................................................................ 120 
A1–9 
Study and Site Closure .......................................................... 120 
A1–10 
Publication Policy ................................................................... 121 
A1–11 
Protocol Deviations ................................................................ 121 
 
 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
116/Protocol GO43104, Version 8 
A1–1 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
 
Applicable laws and regulations 
 
The protocol, Informed Consent Form, Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board or 
Ethics Committee (IRB/EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 
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 
 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Clinical Trials Directive (2001/20/EC) or Clinical Trials 
Regulation (536/2014) (EEA sites only), and all other applicable local regulations 
  
A1–2 
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 
study and for 1 year after completion of the study (see definition of end of study in 
Section 4.4). 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
117/Protocol GO43104, Version 8 
A1–3 
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study, including the 
risks and benefits, to the participant or his or her legally authorized representative and 
answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a participant's willingness to continue in the 
study, the participant or the participant's legally authorized representative must 
re-consent by signing the most current version of the Informed Consent Form or the 
addendum, in accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the participant or the 
participant's legally authorized representative. 
A participant who is re-screened is not required to sign another Informed Consent Form 
if the re-screening occurs within 28 days from the previous Informed Consent Form 
signature date. 
A1–4 
DATA PROTECTION 
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. 
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; the 
participant's name or any information that would make the participant identifiable will not 
be transferred. 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
118/Protocol GO43104, Version 8 
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the Informed Consent Form. 
Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A1–5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 150 sites globally will participate.  Approximately 690 participants are 
expected to be accrued in the induction phase to meet the goal of approximately 
 randomized participants total in the maintenance phase.  The number of participants 
in the induction phase of the study will be adjusted as necessary based on the actual 
screen failure rate for entering the maintenance phase to achieve the required number of 
approximately 
 participants in the maintenance phase of the study.  Enrollment will 
occur through an interactive voice or Web-based response system. 
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and pharmacokinetic analyses), as specified 
in Section 8 and Appendix 2.  Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. 
An independent Data Monitoring Committee (iDMC) will be employed to monitor and 
evaluate participant safety throughout the study.  An Independent Review Facility (IRF) 
will collect, store, and review imaging data. 
A1–6 
DISSEMINATION OF CLINICAL STUDY DATA 
Study data, which may include imaging data, may be submitted to government or other 
health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study.  These data may be 
combined with or linked to other data and used for research purposes, to advance 
science and public health, or for analysis, development, and commercialization of 
products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and/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 provided upon 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
119/Protocol GO43104, Version 8 
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/ 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Roche policy on study data publication. 
A1–7 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed CRF or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data).  
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided prior to study initiation 
in the various functional monitoring plans (including, but not limited to, Quality Tolerance 
Limit Management Plan and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the 
Trial Monitoring Plan to confirm that data entered into the CRF by authorized site 
personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, the 
ICH Guideline for Good Clinical Practice, and all applicable regulatory requirements. 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
120/Protocol GO43104, Version 8 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor 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. 
A1–8 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator's site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the 
Trial Monitoring Plan. 
A1–9 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 
 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study treatment development 
 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
121/Protocol GO43104, Version 8 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigator shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
A1–10 
PUBLICATION POLICY AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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 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. 
A1–11 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
122/Protocol GO43104, Version 8 
Appendix 2  
Clinical Laboratory Tests 
The tests detailed in Table A2-1 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Section 5. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 
Table A2-1 Protocol-Required Laboratory Assessments 
Local Laboratory Tests 
 Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and other cells)  
 Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide, sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, 
calcium, total bilirubin, ALP, ALT, AST, CPK and LDH 
 Coagulation:  INR and aPTT 
 Thyroid function testing:  TSH, free T3 (or total T3 for sites where free T3 is not performed), 
and free T4 
 HIV serology  
 HBV serology:  HBsAg, and total HBcAb for all individuals; HBV DNA for individuals with 
negative HBsAg test and a positive total HBcAb test 
 HCV serology:  HCV antibody for all individuals; HCV RNA for individuals with a positive HCV 
antibody test 
 C-reactive protein 
 Pregnancy test 
All female participants of childbearing potential will have a serum pregnancy test at 
screening (within 14 days prior to enrollment and randomization).  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.  
 Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and blood) 
HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B 
virus; HCV  hepatitis C virus. 
  
Investigators must document their review of each laboratory safety report. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
123/Protocol GO43104, Version 8 
Appendix 3  
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
TABLE OF CONTENTS 
A3–1 
Definition of Adverse Event.................................................... 125 
A3–2 
Definition of Serious Adverse Event ...................................... 126 
A3–3 
Recording and Follow-Up of Adverse Events and/or 
Serious Adverse Events ........................................................ 128 
A3–3.1 
Adverse Event and Serious Adverse Event Recording .......... 128 
A3–3.2 
Assessment of Severity ......................................................... 128 
A3–3.3 
Assessment of Causality ....................................................... 131 
A3–3.4 
Follow-up of Adverse Events and Serious Adverse Events ... 132 
A3–3.4.1 
Investigator Follow-Up ........................................................... 132 
A3–3.4.2 
Sponsor Follow-Up ................................................................ 132 
A3–4 
Reporting of Serious Adverse Events .................................... 133 
A3–4.1 
Serious Adverse Event Reporting to The Sponsor via an 
Electronic Collection Tool ...................................................... 133 
A3–4.2 
Serious Adverse Event Reporting to The Sponsor via 
Paper CRF ............................................................................. 133 
A3–5 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 133 
A3–5.1 
Events That Occur Prior to Study Treatment Initiation ........... 133 
A3–5.2 
Events That Occur After Study Treatment Initiation ............... 134 
A3–6 
Reporting Adverse Events That Occur after the Adverse 
Event Reporting Period .......................................................... 134 
A3–7 
Procedures for Recording Adverse Events ............................ 134 
A3–7.1 
Infusion-Related Reactions .................................................... 135 
A3–7.2 
Diagnosis Versus Signs And Symptoms ................................ 135 
A3–7.3 
Adverse Events that are Secondary to Other Events ............. 136 
A3–7.4 
Persistent or Recurrent Adverse Events ................................ 136 
A3–7.5 
Abnormal Laboratory Values ................................................. 137 
A3–7.6 
Abnormal Vital Sign Values ................................................... 138 
A3–7.7 
Abnormal Liver Function Tests .............................................. 138 
A3–7.8 
Deaths ................................................................................... 139 
A3–7.9 
Preexisting Medical Conditions .............................................. 140 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
124/Protocol GO43104, Version 8 
A3–7.10 
Lack of Efficacy or Worsening of SCLC ................................. 140 
A3–7.11 
Hospitalization or Prolonged Hospitalization .......................... 141 
A3–7.12 
Cases of Accidental Overdose or Medication Error ............... 141 
A3–7.13 
Participant-Reported Outcome Data ...................................... 143 
 
 ........................................................... 143 
 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
125/Protocol GO43104, Version 8 
A3–1 
DEFINITION OF ADVERSE EVENT 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
participant temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can; therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
the underlying disease) 
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
 
Signs, symptoms, or clinical sequelae of a suspected drugdrug interaction 
 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or 
self-harming intent.  Such overdoses should be reported regardless of 
sequelae. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as an adverse event 
or serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
126/Protocol GO43104, Version 8 
Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition 
 
The disease or disorder being studied or expected progression, signs, or symptoms 
of the disease or disorder being studied, unless more severe than expected for the 
participant's condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 
The condition that leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen 
 
A3–2 
DEFINITION OF SERIOUS ADVERSE EVENT 
If an event is not an adverse event per the definition in Section A3–1, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that: 
 
Results in death 
 
Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician's office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol GO43104, Version 8 
 
Results in persistent disability or incapacity 
The term "disability" means a substantial disruption of a person's ability to 
conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly or birth defect 
 
Is medically significant: 
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
 
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 National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section A33.2); 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 the investigator becomes aware of the 
event; see Section A35 for reporting instructions). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol GO43104, Version 8 
A3–3 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS 
AND/OR SERIOUS ADVERSE EVENTS 
A3–3.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, 
laboratory reports, and diagnostics reports) related to the event. 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 
It is not acceptable for the investigator to send photocopies of the participant's medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A3–3.2 
ASSESSMENT OF SEVERITY 
The investigator will assess the severity of each adverse event reported during the study 
through use of the NCI CTCAE v5.0 grading scale.  The investigator will use the grading 
scale in Table A3-1 for assessing the severity of adverse events that are not specifically 
listed in the NCI CTCAE.  In addition to the NCI CTCAE v5.0 grading scale, severity for 
cytokine release syndrome (CRS) will also be graded by the investigator according to 
the American Society of Transplantation and Cellular Therapy (ASTCT) consensus 
grading scale (Table A3-2; Lee et al. 2019). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol GO43104, Version 8 
Table A3-1 Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or limiting 
self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v 5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
a Examples of instrumental activities of daily living include 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 participants 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 A35 for reporting instructions), per the definition of serious 
adverse event in Section A32. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section A35 for 
reporting instructions), per the definition of serious adverse event in Section A32, with the 
exception of Grade 4 laboratory abnormalities for which the investigator should assess 
seriousness of the event on an individual basis. 
  

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol GO43104, Version 8 
Table A3-2 ASTCT Grading Scale for Cytokine Release Syndrome 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Fever a 
Temperature 
 38C 
Temperature 
 38C 
Temperature 
 38C 
Temperature 
 38C 
Death 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor 
with or without 
vasopressin 
Requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/or b 
Hypoxia 
None 
Requiring 
low-flow nasal 
cannula c or 
blow-by 
Requiring high-
flow nasal 
cannula c, 
facemask, 
nonrebreather 
mask, or 
Venturi mask 
Requiring 
positive 
pressure 
(e.g., CPAP, 
BiPAP, 
intubation and 
mechanical 
ventilation) 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine release 
syndrome. 
Note:  Organ toxicities associated with CRS may be graded according to NCI CTCAE v5.0 but 
they do not influence CRS grading. 
a 
Fever is defined as temperature  38°C not attributable to any other cause.  
In participants who have CRS and then receive antipyretic or anti-cytokine therapy such as 
tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.  In this 
case, CRS grading is driven by hypotension and/or hypoxia. 
b 
CRS grade is determined by the more severe event:  hypotension or hypoxia not 
attributable to any other cause.  For example, a patient with temperature of 39.5°C, 
hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified 
as Grade 3 CRS. 
c 
Low-flow nasal cannula is defined as oxygen delivered at  6 L/min.  Low flow also 
includes blow-by oxygen delivery, sometimes used in pediatrics.  High-flow nasal cannula is 
defined as oxygen delivered at  6 L/min. 
  

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol GO43104, Version 8 
A3–3.3 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
The investigator will also consult the Investigator's Brochures and/or prescribing 
information (for marketed products) in his or her assessment. 
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
For participants receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol GO43104, Version 8 
A3–3.4 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
A3–3.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor with a copy of any post-mortem findings, 
including histopathology. 
New or updated information should be recorded on the originally completed Adverse 
Event eCRF.  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 the investigator becomes 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 
 
During the adverse event reporting period (defined in Section 8.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the 
participant's medical record to facilitate source data verification. 
A3–3.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, e-mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol GO43104, Version 8 
A3–4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A3–4.1 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA AN ELECTRONIC COLLECTION TOOL 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A35. 
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations Form, as described in Section A35, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off line to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study participant or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken off line, the site can report this information 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A35. 
A3–4.2 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA PAPER CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations Form, as 
described in Section A35. 
A3–5 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A3–5.1 
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 (e.g., biopsy, 
discontinuation of medications) 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 
the investigator becomes aware of the event), either by faxing or by scanning and 
e-mailing the form, using the fax number or e-mail address provided to investigators. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol GO43104, Version 8 
A3–5.2 
EVENTS THAT OCCUR AFTER STUDY TREATMENT 
INITIATION 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until start 
of new systemic anti-cancer therapy; whichever occurs first.  Serious adverse events or 
adverse events of special interest believed to be related to prior exposure to study 
treatment will be reported indefinitely.  Investigators should record all case details that 
can be gathered immediately (i.e., within 24 hours after the investigator becomes aware 
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 
the investigator becomes aware of the event), either by faxing or by scanning and e-
mailing the form, using the fax number or e-mail address provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
Instructions for reporting serious adverse events that occur more than 90 days after the 
final dose of study treatment are provided in Section A36. 
A3–6 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (see Section 8.3.1), serious adverse 
events and adverse events of special interest that are believed to be related to prior 
exposure to study treatment 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 
e-mailing the paper Clinical Trial Adverse Event/Special Situations Form, using the fax 
number or e-mail address provided to investigators. 
A3–7 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the participant's medical records to the Medical Monitor in lieu of 
completion of the eCRF.  Investigators should use correct medical terminology and 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol GO43104, Version 8 
concepts when recording adverse events on the Adverse Event eCRF.  
Avoid colloquialisms and abbreviations.  Only 1 adverse event term should be recorded 
in the event field of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
A3–7.1 
INFUSION-RELATED REACTIONS 
Adverse events considered to be IRRs that occur during or within 24 hours after study 
treatment administration and are judged to be related to study treatment 
infusion/injection should be captured as a diagnosis (e.g., "infusion-related 
reaction"/"injection-site reaction"/"anaphylactic 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/Injection 
Reaction eCRF.  If a participant experiences both a local and systemic reaction to a 
single administration 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/Injection Reaction eCRF. 
A3–7.2 
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 1 adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol GO43104, Version 8 
A3–7.3 
ADVERSE EVENTS THAT ARE SECONDARY TO OTHER 
EVENTS 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
 
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
A3–7.4 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant 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 the investigator becomes aware 
that the event became serious; see Section A35 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 participant evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol GO43104, Version 8 
A3–7.5 
ABNORMAL LABORATORY VALUES 
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  
A laboratory value abnormality that is not associated with the underlying disease 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., dose 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 
 
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  upper limit of normal [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 A37.4 for 
details on recording persistent adverse events). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol GO43104, Version 8 
A3–7.6 
ABNORMAL VITAL SIGN VALUES 
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  
A vital sign abnormality that is not associated with the underlying disease 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., dose modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., 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 A37.4 for 
details on recording persistent adverse events). 
A3–7.7 
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 A37.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A35). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol GO43104, Version 8 
A3–7.8 
DEATHS 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 8.3.1) that are attributed by the 
investigator solely to progression of SCLC 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 A35).  
An independent monitoring committee will monitor the frequency of deaths from all 
causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only 1 such event should be reported.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
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 not related to progression of the underlying cancer and occurring within the 
adverse event reporting period, must be reported as serious adverse event, regardless 
of relationship to study treatment.  Deaths not related to progression of the underlying 
cancer and occurring outside the adverse event reporting period should only be reported 
as serious adverse event if considered related to prior exposure to study treatment.  
Deaths not related to progression of the underlying cancer and outside the adverse 
event reporting period and considered unrelated to prior exposure to study treatment 
should be reported through use of the Long-Term Follow-Up eCRF.  Deaths related to 
the progression of the underlying cancer occurring during the adverse event reporting 
period should be reported on the Death Attributed to Progressive Disease eCRF.  
Deaths related to the progression of the underlying cancer occurring outside the adverse 
event reporting period should be reported on the Long-Term Follow-Up eCRF (for an 
overview, see Table A3-3). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol GO43104, Version 8 
Table A3-3 Documentation Required for Reporting Deaths 
Cause of Death 
Timing 
During Adverse Event 
Reporting Period a 
After Adverse Event 
Reporting Period 
SCLC 
Death Attributed to Progressive 
Disease eCRF 
Long-Term Follow-Up eCRF 
Unrelated Grade 5 Adverse 
Event 
Adverse Event eCRF 
Long-Term Follow-Up eCRF b 
Related Grade 5 Adverse 
Event 
Adverse Event eCRF 
Adverse Event eCRF c 
eCRF  electronic Case Report Form; EDC  electronic data capture; SCLC  small-cell lung 
cancer. 
a Up to 90 days after final dose of study treatment or until start of new systemic anti-cancer 
therapy, whichever occurs first. 
b Record the primary cause of death as "other", for "other death cause" specify the Adverse 
Event term. 
c 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 e-mailing the paper Clinical Trial 
Adverse Event/Special Situations Form using the fax number or e-mail address provided to 
investigators. 
  
A3–7.9 
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"). 
A3–7.10 
LACK OF EFFICACY OR WORSENING OF SCLC 
Medical occurrences or symptoms of deterioration that are anticipated as part of SCLC 
should not be recorded as adverse events.  However, deterioration that is judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during the study should be recorded as an adverse event.  
When recording an unanticipated worsening of SCLC on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors (e.g., "accelerated worsening of small-cell carcinoma"). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol GO43104, Version 8 
A3–7.11 
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 A32), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of a tumor assessment for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The participant was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when treatment 
became necessary because of the expected normal progression of the 
condition 
– 
The participant 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 participant requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
A3–7.12 
CASES OF ACCIDENTAL OVERDOSE OR MEDICATION ERROR 
Accidental overdose and medication error (hereafter collectively referred to as 
"special situations") are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol GO43104, Version 8 
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 the investigator becomes aware 
of the event; see Section A35).  For lurbinectedin and atezolizumab, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
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. 
 
As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
All special situations associated with lurbinectedin and atezolizumab, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
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 name of the drug and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details. 
 
Intercepted medication error:  Enter the name of the drug and "intercepted 
medication error" as the event term.  Check the "Medication error" box.  Enter 
a description of the error in the additional case details. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
143/Protocol GO43104, Version 8 
A3–7.13 
PATIENT-REPORTED OUTCOME DATA 
Adverse event reports will not be derived from the Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) or other PRO data by 
the Sponsor.  In addition, the Sponsor will make no attempt to reconcile participant 
reports of treatment-related symptoms (via the PRO-CTCAE) with investigator reports of 
adverse events.  Sites are not expected to review the PRO-CTCAE or other PRO data 
for adverse events. 
 
 
 
 
 
 
REFERENCES 
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. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
144/Protocol GO43104, Version 8 
Appendix 4  
Contraceptive and Barrier Guidance 
TABLE OF CONTENTS 
A4–1 
Pregnancies in Female Participants ...................................... 145 
A4–2 
Pregnancies in Female Partners of Male Participants ........... 145 
A4–3 
Abortions................................................................................ 146 
A4–4 
Abnormal Pregnancy Outcomes ............................................ 146 
 
 
 

Appendix 4:  Contraceptive and Barrier Guidance 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
145/Protocol GO43104, Version 8 
A4–1 
PREGNANCIES IN FEMALE PARTICIPANTS 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during 
study treatment or within 5 months after the final dose of atezolizumab, 6 months after 
the final dose of carboplatin, or etoposide, or 7 months after the final dose of 
lurbinectedin, whichever occurs last.  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 the investigator becomes aware of the pregnancy), either by 
faxing or by scanning and e-mailing the form, using the fax number or e-mail address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study treatment and counsel the participant, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the participant should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly or 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. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A4–2 
PREGNANCIES IN FEMALE PARTNERS OF MALE 
PARTICIPANTS 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during study treatment or 
within 4 months after the final dose of lurbinectedin, or within 6 months after the final 
dose of carboplatin or etoposide, whichever occurs last.  The investigator should 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 e-mailing the form using 
the fax number or e-mail address provided to investigators.  Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male participant exposed to study treatment.  When permitted by the site, the pregnant 
partner would need to sign an Authorization for the Use and Disclosure of Pregnancy 

Appendix 4:  Contraceptive and Barrier Guidance 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
146/Protocol GO43104, Version 8 
Health Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male participant 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. 
A4–3 
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 the 
investigator becomes aware of the event; see Section A35). 
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 the investigator becomes aware of the event; 
see Section A35).  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. 
A4–4 
ABNORMAL PREGNANCY OUTCOMES 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment or the female partner of a male participant 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 the 
investigator becomes aware of the event; see Section A35). 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol GO43104, Version 8 
Appendix 5  
Genetics:  Use and Analysis of DNA 
Genetic variation may impact a participant's response to study treatment and 
susceptibility to, and severity and progression of, disease.  Variable response to study 
treatment may be due to genetic determinants that impact drug absorption, distribution, 
metabolism, and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated.  Therefore, where local regulations and 
the Institutional Review Board or Ethics Committee allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
DNA samples will be used for research related to lurbinectedin, atezolizumab, drug 
safety, small-cell lung cancer (SCLC) and related disease biology.  They may also be 
used to develop tests or assays, including diagnostic tests related to lurbinectedin, 
atezolizumab, SCLC and related diseases.  Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers throughout 
the genome. 
DNA samples will be analyzed for whole-genome sequencing (WGS) or 
 
 to identify variants that are predictive of response to study drug, are 
associated with progression to a more severe disease state, 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.  Additional analyses may be conducted if it is hypothesized that 
this may help further understand the clinical data.  The samples may be analyzed as part 
of a multistudy assessment of genetic factors involved in the response to lurbinectedin 
and atezolizumab and treatments of this drug class to understand the study disease or 
related conditions.  The results of genetic analyses may be reported in the Clinical Study 
Report or in a separate study summary. 
The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
lurbinectedin and atezolizumab and/or treatments of this drug class or SCLC disease 
continues but no longer than 15 years or other period as per local requirements. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
148/Protocol GO43104, Version 8 
Appendix 6  
Safety Plan:  Management of Identified and Potential Risks 
TABLE OF CONTENTS 
A6–1 
Risks Associated with Study Drugs ....................................... 150 
A6–1.1 
Lurbinectedin ......................................................................... 151 
A6–1.1.1 
Hematological Abnormalities ................................................. 151 
A6–1.1.2 
Liver Abnormalities ................................................................ 151 
A6–1.1.3 
Gastrointestinal Adverse Events ............................................ 152 
A6–1.1.4 
Renal Abnormalities ............................................................... 152 
A6–1.1.5 
Muscular Adverse Events ...................................................... 152 
A6–1.1.6 
Infusion Site Events ............................................................... 152 
A6–1.2 
Atezolizumab ......................................................................... 152 
A6–1.2.1 
Pulmonary Events .................................................................. 153 
A6–1.2.2 
Hepatic Events ....................................................................... 153 
A6–1.2.3 
Gastrointestinal Events .......................................................... 153 
A6–1.2.4 
Endocrine Events ................................................................... 154 
A6–1.2.5 
Ocular Events ........................................................................ 154 
A6–1.2.6 
Immune-Mediated Cardiac Events ......................................... 154 
A6–1.2.7 
Infusion-Related Reactions and Cytokine Release 
Syndrome .............................................................................. 155 
A6–1.2.8 
Pancreatic Events .................................................................. 156 
A6–1.2.9 
Dermatologic Events .............................................................. 156 
A6–1.2.10 
Neurologic Disorders ............................................................. 156 
A6–1.2.11 
Immune-Mediated Meningoencephalitis ................................ 157 
A6–1.2.12 
Renal Events ......................................................................... 157 
A6–1.2.13 
Immune-Mediated Myositis .................................................... 157 
A6–1.2.14 
Hemophagocytic Lymphohistiocytosis and Macrophage 
Activation Syndrome .............................................................. 158 
A6–1.3 
Risks Associated with Combination Use of Lurbinectedin 
and Atezolizumab .................................................................. 159 
A6–1.4 
Etoposide ............................................................................... 160 
A6–1.5 
Carboplatin ............................................................................ 160 
A6–2 
Management of Participants Who Experience Adverse 
Events .................................................................................... 160 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol GO43104, Version 8 
A6–2.1 
Dose Modifications ................................................................ 160 
A6–2.2 
Criteria for Treatment Continuation During Maintenance 
Phase .................................................................................... 162 
A6–2.3 
Treatment Interruption ........................................................... 164 
A6–2.3.1 
Lurbinectedin ......................................................................... 164 
A6–2.3.2 
Atezolizumab ......................................................................... 164 
A6–2.4 
Management Guidelines ........................................................ 165 
A6–2.4.1 
Guidelines for Management of Adverse Events Associated 
with Lurbinectedin .................................................................. 165 
A6–2.4.2 
Guidelines for Management of Adverse Events Associated 
with Atezolizumab .................................................................. 168 
 
 
 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol GO43104, Version 8 
The anticipated important safety risks for lurbinectedin and atezolizumab are outlined 
below.  Please refer to the lurbinectedin and atezolizumab Investigator's Brochures for a 
complete summary of safety information. 
Several measures will be taken to ensure the safety of study participants.  
Eligibility criteria have been designed to exclude individuals at higher risk for toxicities.  
Participants will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for treatment interruption or discontinuation, are 
provided below. 
A6–1 
RISKS ASSOCIATED WITH STUDY DRUGS 
The safety plan for participants in this study is based on clinical experience with 
lurbinectedin and atezolizumab in completed and/or ongoing studies and the most recent 
prescribing information for etoposide and carboplatin.  The anticipated important safety 
risks are outlined below.  Refer to the current lurbinectedin and atezolizumab 
Investigator's Brochures for a complete summary of safety information for each 
respective study drug. 
Measures will be taken to ensure the safety of participants in this study, including the 
use of stringent inclusion and exclusion criteria (see Section 5.1 and Section 5.2, 
respectively) and close monitoring of participants during the study as indicated below.  
An independent Data Monitoring Committee (iDMC) will periodically review safety data 
as outlined in Section 9.6 with more detail provided in the iDMC Charter.  Administration 
of study treatment will be performed in a monitored setting in which there is immediate 
access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  Guidelines for reporting adverse events and for managing 
participants who experience anticipated adverse events, including criteria for treatment 
interruption or discontinuation, are provided in Section 8.3.1, Section 8.3.5, Appendix 3, 
and Appendix 6. 
Participants 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 COVID-19 appears to be associated with a cytokine release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- 
(Merad and Martin 2020).  If a participant develops suspected CRS during the study, 
a differential diagnosis should include COVID-19, which should be confirmed or refuted 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol GO43104, Version 8 
through assessment of exposure history, appropriate laboratory testing, and clinical 
or radiologic evaluations per investigator judgment.  If a diagnosis of COVID-19 is 
confirmed, the disease should be managed as per local or institutional guidelines. 
A6–1.1 
LURBINECTEDIN 
Lurbinectedin has been associated with risks such as the following:  
reversible myelosuppression (including neutropenia, lymphopenia, anemia, and 
thrombocytopenia), increased liver transaminases, nausea, vomiting, constipation, 
increased serum creatinine, and increased creatine phosphokinase.  See Sections A6
1.1.1 (Hematological Abnormalities), A61.1.2 (Liver Abnormalities), A61.1.3 
(Gastrointestinal Adverse Events), A61.1.4 (Renal Abnormalities), A61.1.5 (Muscular 
Adverse Events), and A6–1.1.6 (Infusion Site Events) of the protocol and Section 5 
(summary of the data and guidance for the investigator) of the Lurbinectedin 
Investigator's Brochure for a detailed description of anticipated safety risks for 
lurbinectedin. 
See Section A6–2.4.1 for details on the management guidelines for risks associated with 
lurbinectedin. 
A6–1.1.1 
Hematological Abnormalities 
Reversible myelosuppression is the most frequent abnormality related to single-agent 
lurbinectedin at a dose level of 3.2 mg/m2.  Regardless of relationship to lurbinectedin, 
Grade 3/4 neutropenia was observed in 40.8% of participants treated at this dose level 
in Phase II and III studies, and it reached Grade 4 in 21.9% of participants.  
Other Grade 3/4 hematological abnormalities were less common, including lymphopenia 
(33.4% of participants), leukopenia (29.4% of participants), anemia (17.4% of 
participants) and thrombocytopenia (9.7% of participants).  Treatment-related febrile 
neutropenia was observed in 6.5% of participants. 
A6–1.1.2 
Liver Abnormalities 
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with lurbinectedin.  Most transaminase increases observed in Phase II and III 
studies with single-agent lurbinectedin at 3.2 mg/m2 every 3 weeks (Q3W) were mild or 
moderate, transient and asymptomatic.  Regardless of relationship to lurbinectedin, 
Grade 3/4 ALT increases occurred in 6.4% of participants (Grade 4 in 2 participants 
[0.4%]) and Grade 3/4 AST increase occurred in 3.2% of participants (Grade 4 in 
3 participants [0.5%]).  In addition, Grade 3/4 bilirubin increases occurred in 2.4% of 
participants (Grade 4 in 1 participant [0.2%]).  No Hy's Law cases, as defined in the 
U.S. Food and Drug Administration (FDA) guidelines, were observed in these studies. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol GO43104, Version 8 
A6–1.1.3 
Gastrointestinal Adverse Events 
Despite standard anti-emetic prophylaxis, mild to moderate gastrointestinal toxicity 
occurred frequently with single-agent lurbinectedin at 3.2 mg/m2.  The most common 
gastrointestinal adverse events were nausea, vomiting, and constipation. 
A6–1.1.4 
Renal Abnormalities 
In Phase II and III trials with single-agent lurbinectedin administered at 3.2 mg/m2 Q3W, 
84.3% of participants had creatinine increases of any Grade, including 9 participants 
(1.6%) with Grade 3 events. 
Lurbinectedin is not significantly eliminated through the urine, thus participants with 
limited renal function are not expected to be impacted differently than participants with 
normal renal function.  Nevertheless, no participants with less than 30 mL/min of 
calculated creatinine clearance have been included in clinical trials with lurbinectedin to 
date. 
A6–1.1.5 
Muscular Adverse Events 
Regardless of relationship to lurbinectedin, creatine phosphokinase (CPK) increases 
were reported in 9.4% of participants treated with single-agent lurbinectedin at 
3.2 mg/m2 Q3W in Phase II and III studies.  Of these, only 2 participants (0.4%) 
experienced a Grade 3 CPK increase.  Episodes of rhabdomyolysis were reported in 
2 clinical trial participants treated with single-agent lurbinectedin at a dose that was 
higher than 3.2 mg/m2 Q3W. 
A6–1.1.6 
Infusion Site Events 
Extravasation of lurbinectedin may result in skin and soft tissue injury.  This includes rare 
reports from post-marketing use of lurbinectedin of necrosis requiring debridement. 
A6–1.2 
ATEZOLIZUMAB 
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs), 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).  
See Section A6–2.4.2 of the protocol and Section 6 of the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
A6–1.2.1 
Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Participants 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 (COPD), or 
pulmonary hypertension.  COVID-19 evaluation should be performed per institutional 
guidelines where relevant. 
Management guidelines for pulmonary events are described in Section A6−2.4.2. 
A6–1.2.2 
Hepatic Events 
Eligible participants 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 A6-5. 
Participants 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 participants with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
A6–1.2.3 
Gastrointestinal Events 
Management guidelines for diarrhea or colitis are provided in Table A6-5. 
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 3−5 specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol GO43104, Version 8 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol GO43104, Version 8 
A6–1.2.4 
Endocrine Events 
Management guidelines for endocrine events are provided in Table A6-5. 
Participants 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 participant should be 
referred to an endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating 
hormone and free T3 and T4 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. 
A6–1.2.5 
Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table A6-5. 
A6–1.2.6 
Immune-Mediated Cardiac Events 
Management guidelines for cardiac events are provided in Section A6–2.4.2. 
Immune-Mediated Myocarditis 
Immune-mediated myocarditis should be suspected in any participant 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 participant who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac 
conditions, or progression of malignancy. 
All participants 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. 
Participants with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-5. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol GO43104, Version 8 
Immune-Mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability. 
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer-related (metastatic disease or chest radiotherapy), cardiac 
injury related (post-myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table A6-5.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
A6–1.2.7 
Infusion-Related Reactions and Cytokine Release Syndrome 
No premedication is indicated for the administration of Cycle 1 (induction phase) of 
atezolizumab.  However, participants who experience an IRR or CRS with atezolizumab 
may receive premedication with antihistamines, 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. 
Infusion-related reactions are known to occur with the administration of monoclonal 
antibodies and have been reported with atezolizumab.  These reactions, which are 
thought to be due to release of cytokines and/or other chemical mediators, occur within 
24 hours of atezolizumab administration and are generally mild to moderate in severity. 
Cytokine release syndrome is defined as a supraphysiologic response following 
administration of any immune therapy that results in activation or engagement of 
endogenous or infused T cells and/or other immune effector cells.  Symptoms can be 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol GO43104, Version 8 
progressive, always include fever at the onset, and may include hypotension, capillary 
leak (hypoxia), and end-organ dysfunction (Lee et al. 2019).  Cytokine release syndrome 
has been well-documented with chimeric antigen receptor T-cell therapies and bispecific 
T-cell engager antibody therapies but has also been reported with immunotherapies that 
target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and Feldman 2019), including 
atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs during Cycle 1 are provided in Table A6-
5.  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- (Merad and Martin 2020).  
If a participant 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. 
A6–1.2.8 
Pancreatic Events 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table A6-5. 
A6–1.2.9 
Dermatologic Events 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson Syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table A6-5. 
A6–1.2.10 
Neurologic Disorders 
Participants 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 A6-5. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol GO43104, Version 8 
A6–1.2.11 
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis should be suspected in any participant 
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 participants 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. 
Participants with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table A6-5. 
A6–1.2.12 
Renal Events 
Eligible participants must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Participants 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 participant to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Participants with signs and symptoms of nephritis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-5. 
A6–1.2.13 
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. 
Participants with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table A6-5. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol GO43104, Version 8 
A6–1.2.14 
Hemophagocytic Lymphohistiocytosis 
Immune-mediated reactions may involve any organ system and may lead to 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. 
Participants with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A participant should be classified as having HLH if 5 of 
the following 8 criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least 2 of the following: 
− Hemoglobin  90 g/L (9 g/dL) 
− Platelet count  100  109/L (100,000/L) 
− ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Participants with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile participant should 
be classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least 2 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) 
 
Participants with suspected HLH or MAS should be treated according to the guidelines in 
Table A6-5. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol GO43104, Version 8 
A6–1.3 
RISKS ASSOCIATED WITH COMBINATION USE OF 
LURBINECTEDIN AND ATEZOLIZUMAB 
Lurbinectedin and atezolizumab have anticipated molecule-specific safety profiles based 
on their mechanism of action and adverse events that may overlap. 
 
The most frequent adverse events specific to each drug include hematological 
toxicities for lurbinectedin and immune-mediated adverse events for atezolizumab. 
 
Atezolizumab treatment is not predicted to further impact hematological 
abnormalities commonly observed with lurbinectedin treatment in the proposed 
Phase III Study GO43104.  However, given the risk factors of this participant 
population, primary G-CSF prophylaxis and monitoring via hematological tests have 
been implemented as risk mitigation measures (see Section 6.1.3 for more 
information). 
 
Immune-mediated adverse events observed with atezolizumab treatment are 
well-known, manageable and/or reversible.  The Sponsor does not predict 
lurbinectedin treatment to impact immune-mediated adverse events. 
 
Overlapping adverse events may include hepatotoxic, gastrointestinal, muscular and 
renal events, as well as signs and symptoms such as fatigue and decreased appetite 
that may be related to multiple system organ class events.  For the management of such 
potentially overlapping adverse events in participants treated with lurbinectedin in 
combination with atezolizumab, adverse events should be managed according to the 
recommendations in Section A62.3.1 (lurbinectedin) and Section A62.3.2 
(atezolizumab), applied to the component of the study treatment judged to be the 
primary cause. 
The attribution of causality for certain adverse events may be uncertain when the drugs 
are administrated as a combination treatment and warrants diagnostic investigation.  
If causality for an adverse event with study treatment cannot be adequately determined, 
conservative management recommendations should be followed to include dose 
modification/interruption of both agents. 
At present, considering the different mechanisms of action of lurbinectedin and 
atezolizumab, the initial safety profile from Study ML40908 
(lurbinectedin  atezolizumab), and data from molecules with similar mechanisms of 
action (Chawla et al. 2018; Gordon et al. 2018), overlapping toxicities are expected to be 
limited and no exacerbations are anticipated. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol GO43104, Version 8 
A6–1.4 
ETOPOSIDE 
The risk of overlapping toxicities between atezolizumab, carboplatin, and etoposide is 
thought to be minimal.  Etoposide is known to cause bone marrow suppression including 
myelosuppression, anemia, thrombocytopenia, gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea), hepatotoxicity, and alopecia.  Etoposide-based chemotherapy is 
considered to be moderately emetogenic.  Etoposide carries a risk of secondary 
hematologic malignancy.  Participants will be monitored for etoposide-related adverse 
events. 
For more details regarding the safety profile of etoposide, refer to the etoposide 
prescribing information. 
A6–1.5 
CARBOPLATIN 
The risk of overlapping toxicities between atezolizumab, carboplatin, and etoposide is 
thought to be minimal.  Carboplatin is known to cause bone marrow suppression 
including myelosuppression, anemia, and thrombocytopenia.  Carboplatin-based 
chemotherapy is considered to be moderately emetogenic.  Participants will be 
monitored for carboplatin-related adverse events. 
For more details regarding the safety profile of carboplatin, refer to the carboplatin 
prescribing information. 
A6–2 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS 
A6–2.1 
DOSE MODIFICATIONS 
Lurbinectedin 
Dose modifications for lurbinectedin are as follows: 
 
Up to 2 individual lurbinectedin dose reductions are allowed (Table A6-1).  Once the 
dose has been reduced for an individual participant, it must not be re-escalated 
again under any circumstances.  Participants who continue to experience 
treatment-related toxicity and/or frequent dose delays after permitted dose 
reductions must discontinue treatment with lurbinectedin.  They can continue 
receiving the study medication if objective clinical benefit is adequately documented 
by the investigator, and upon agreement with the Sponsor.  If the participant 
receives a lurbinectedin dose of 2 mg/m2 and experiences a toxicity that would 
warrant a lurbinectedin dose reduction, treatment with lurbinectedin must be 
permanently discontinued. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol GO43104, Version 8 
 
Participants may continue lurbinectedin at a reduced dose after they have 
adequately recovered from any of the following: 
– 
Grade  3 treatment-related non-hematological toxicity 
– 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia concomitantly with 
Grade  3 bleeding 
– 
Grade 4 neutropenia, any Grade febrile neutropenia or neutropenia 
associated with infection/sepsis 
– 
Frequent or prolonged ( 1 week) dose delay due to treatment-related 
adverse events 
 
Refer to Table A6-2 for a list of criteria for treatment continuation. 
Exceptions: patients experiencing treatment-related Grade  3 nausea and/or vomiting 
not optimally treated, Grade 3 asthenia lasting  3 days, Grade 3 diarrhea lasting 
 2 days or not optimally treated, Grade 3 transient ALT/AST elevations which are rapidly 
reversible and not leading to subsequent delays, and non-clinically relevant biochemical 
abnormalities, may continue treatment at the same prior dose without any dose 
reduction being applied, provided optimal concomitant treatment is given for the 
applicable toxicity. 
Participants who experience Grade 3 or Grade 4 hypersensitivity reactions or Grade 3 or 
Grade 4 rhabdomyolysis will be discontinued from lurbinectedin. 
Table A6-1 Lurbinectedin Dose Reduction Levels 
Dose Reduction Schedule Lurbinectedin Dose (mg/m2) a 
Starting dose 
3.2 
First reduction 
2.6 
Second reduction 
2.0 
a Dose rounded to the first decimal. 
  
In case atezolizumab is discontinued due to immune-related severe adverse events, 
treatment with lurbinectedin may continue as a single agent.  If immune toxicity 
re-occurs despite discontinuation of atezolizumab, the participant will also discontinue 
lurbinectedin. 
Participants may continue with atezolizumab as a single agent in case of lurbinectedin 
discontinuation. 
Atezolizumab 
There will be no dose modifications for atezolizumab in this study. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol GO43104, Version 8 
Carboplatin and Etoposide 
Dose modifications for carboplatin and etoposide are permitted for toxicity according to 
the prescribing information and local standard of care. 
A6–2.2 
CRITERIA FOR TREATMENT CONTINUATION DURING 
MAINTENANCE PHASE 
If a participant experiences adverse events during the maintenance treatment phase, the 
criteria outlined in Table A6-2 must be met in order to continue study treatment. 
Table A6-2 Criteria for Treatment Continuation in Arm A During the 
Maintenance Phase 
 
Lurbinectedin 
Atezolizumab 
Day 1 
Day 1 
ANC 
 1.5  109/L for participants 
of non-African descent or 
 1.3  109/L for participants 
of African descent 
No defined requirements 
Platelets 
 100  109/L 
No defined requirements 
Hemoglobin a 
 9 g/dL 
Total bilirubin (or direct bilirubin) 
 1.5  ULN 
For participants with known Gilbert disease: 
total bilirubin  3  ULN 
AST/ALT 
 2.5  ULN 
For participants with documented metastatic liver disease, 
AST and ALT levels  5  ULN 
Serum creatinine 
 1.5  ULN or creatinine clearance  30 mL/min 
TSH b 
No defined requirements 
Within normal range 
If TSH is above ULN, T4 must 
be within normal range 
Muscular toxicity 
(myalgia, muscular weakness, 
CPK increase, rhabdomyolysis) 
Grade 1 or better 
Immune-related toxicities 
(colitis, pneumonitis, 
endocrinopathies c and others) 
No defined requirements 
Grade 1 or better 
Other non-hematological 
drug-related adverse events 
(except increased GGT, 
amylase/lipase, nausea and 
vomiting, alopecia, asthenia, 
dermatologic events, and/or 
neuropathy d) 
Grade 1 or better 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol GO43104, Version 8 
Table A6-2 Criteria for Treatment Continuation in Arm A During the 
Maintenance Phase 
 
Lurbinectedin 
Atezolizumab 
Day 1 
Day 1 
Active infection (including sepsis) 
and/or bleeding (any grade) 
Absence 
CPK  creatine phosphokinase; GGT  gamma-glutamyl transferase; ULN  upper limit of normal. 
a Participants may receive packed red blood cells transfusion and/or erythropoietin treatment, if 
clinically indicated, to increase or maintain adequate hemoglobin levels. 
b See Section A6–2.4.2 for more information on management guidelines of endocrine event. 
c For Grade 2 endocrinopathies, please see Table A6-5 for more details. 
d Any grade is accepted for increased GGT.  Amylase and/or lipase increases of up to 2.0  ULN 
are allowed.  Up to Grade 2 is allowed for alopecia, neuropathy, asthenia, dermatologic 
events, and nausea or vomiting. 
  
If a participant does not meet the requirements for re-treatment on Day 1 of Cycle 2 or 
any subsequent cycles, reassessments will be performed at least every 4872 hours.  
Treatment with lurbinectedin can be withheld up to a maximum of 3 weeks.  
Participants not meeting re-treatment criteria after withholding lurbinectedin for a 
maximum of a 3-week delay should discontinue lurbinectedin treatment.  In case of 
objective clinical benefit, the participant could continue to receive lurbinectedin treatment 
upon the Sponsor's agreement. 
Participants may continue with atezolizumab as a single agent in case lurbinectedin is 
discontinued. 
In case atezolizumab is discontinued due to an immune-related severe adverse event, 
treatment with lurbinectedin may continue as a single agent.  If immune toxicity 
re-occurs despite discontinuation of atezolizumab, the participant will also discontinue 
lurbinectedin.  Up to 2 dose reductions of lurbinectedin are allowed. 
Chemotherapy 
Dose modifications for carboplatin and etoposide are permitted for toxicity according to 
the prescribing information and local standard of care. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol GO43104, Version 8 
A6–2.3 
TREATMENT INTERRUPTION 
Dose interruptions of study treatment may occur at any time and independently from 
each other at the discretion of the investigator for management of adverse events. 
A6–2.3.1 
Lurbinectedin 
Lurbinectedin treatment may be temporarily suspended in participants experiencing 
toxicity considered to be related to lurbinectedin. 
The administration of a new cycle of lurbinectedin should be delayed if the re-treatment 
criteria for adequate organ function are not met on Day 1 of the next scheduled cycle.  
Parameters will be periodically reevaluated until appropriate recovery.  A maximum 
delay of 21 days will be allowed for recovery from treatment-related adverse events.  If 
recovery has not occurred after a 21-day delay, the participant should discontinue 
lurbinectedin, except in case of clear evidence of objective benefit per investigator's 
judgment.  The Medical Monitor is available to advise as needed.  Participants who 
remain on lurbinectedin treatment after a 21-day delay because of the reasons 
described above, will do so after appropriate dose reduction of lurbinectedin. 
A6–2.3.2 
Atezolizumab 
Atezolizumab treatment may be temporarily suspended in participants experiencing 
toxicity considered to be related to atezolizumab.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over 1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.  Treatment with 
atezolizumab may be resumed if the event improves to Grade 1 or better within 
12 weeks and if corticosteroids have been reduced to  10 mg/day oral prednisone or 
equivalent within 12 weeks.  If atezolizumab is withheld for  12 weeks (or 4 cycles) of 
initiating steroids, the participant will be discontinued from atezolizumab. 
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) at the investigator's discretion.  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 lurbinectedin, see Section A62.4.1 for lurbinectedin and 
Section A62.4.2 for atezolizumab. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol GO43104, Version 8 
A6–2.4 
MANAGEMENT GUIDELINES 
A6–2.4.1 
Guidelines for Management of Adverse Events Associated with 
Lurbinectedin 
A6–2.4.1.1 Management of Hematological Abnormalities 
Regular monitoring of hematological tests, including differential WBC counts will be 
performed prior to each dose administration and in addition, on Day 10 of Cycle 1 and 
Cycle 2 (see the schedule of activities in Section 1.3, Table 2) in order to allow 
re-treatment of participants with lurbinectedin. 
Participants with hematologic toxicities may require additional or more frequent 
laboratory tests according to institutional guidelines.  The administration of a new cycle 
of lurbinectedin should be delayed until the participant's blood counts have reached 
adequate levels.  Table A6-3 provides treatment guidelines for severe cases of 
neutropenia and thrombocytopenia deemed related to lurbinectedin. 
Dose adjustment, if applicable, should always be considered in participants who 
experience febrile neutropenia, neutropenic infection, sepsis or Grade 4 neutropenia or 
thrombocytopenia in prior cycles.  Supportive care for thrombocytopenia or anemia, such 
as transfusions, may be managed according to institutional guidelines. 
Extensive early antibiotic coverage and all available supportive measures as indicated 
should be applied during a febrile neutropenia episode or Grade 4 neutropenia with 
clinical or epidemiological signs of infection after lurbinectedin treatment.  
Conversely, the presence of fever or signs of infection during the second week after 
lurbinectedin treatment start (usually from Days 818) must always motivate a thorough 
clinical examination and complete blood counts, including differential WBC counts. 
No increase in opportunistic infections associated with lymphopenia or prolonged 
Grade 4 neutropenia (more than 2 weeks) has been described in trial participants with 
solid tumors, although no specific conclusions may be drawn due to the lack of 
randomized data.  Nevertheless, no prophylactic antibiotic coverage is indicated at 
current available clinical guidelines/recommendations. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol GO43104, Version 8 
Table A6-3 Lurbinectedin Management Guidelines for Hematological 
Abnormalities 
  
A6–2.4.1.2 Management of Liver Abnormalities 
If Grade 3/4 increases in liver function tests (LFTs) are found, dose reduction and/or 
delays until resolution to at least Grade 1 are indicated.  Re-evaluation before 
re-treatment is mandatory. 
It is recommended that participants 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 participants 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 lurbinectedin treatment are provided 
in Table A6-4. 
Event 
Management 
Grade 1, 2 or 3 
neutropenia or 
Grade 1, 2 or 3 
thrombocytopenia 
without bleeding 
 Manage according to institutional practice. 
 Continue lurbinectedin when ANC is  1.5  109/L for participants 
of non-African descent or  1.3  109/L for participants of African 
descent and when platelets are  100  109/L. 
Neutropenia 
Grade 4 or any grade 
of febrile neutropenia 
 Interrupt lurbinectedin. 
 Restart lurbinectedin, at reduced dose, when ANC  1.5  109/L for 
non-African descent or ANC  1.3  109/L for African descent and 
resolution of any infections. 
Thrombocytopenia 
Grade 3 with bleeding 
or Grade 4 
 Interrupt lurbinectedin until platelet count  100  109/L 
(100,000/L) and resolution of any bleeding. 
 Restart lurbinectedin at reduced dose. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol GO43104, Version 8 
Table A6-4 Lurbinectedin Management Guidelines for Liver Abnormalities 
Severity of Transaminase 
(ALT or AST) Elevations by 
NCI CTCAE 
Management 
Grade 1 or 2 
 Dose reduction is usually not required. 
 Consider discontinuing concomitant hepatotoxic medications 
and adding supportive care as indicated. 
Grade  3 
 Interrupt lurbinectedin and consider more frequent 
monitoring of ALT and/or AST. 
 Restart lurbinectedin at a reduced dose when AST and ALT 
 2.5  ULN (or for participants with documented metastatic 
liver disease, AST and ALT levels  5  ULN). 
 Discontinue if laboratory abnormalities cannot be reversed 
despite interruption of lurbinectedin. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events; 
ULN  upper limit of normal. 
  
A6–2.4.1.3 Management of Gastrointestinal Adverse Events 
Premedication with IV serotonin (5-HT3) antagonists (ondansetron or equivalent) plus a 
steroid (dexamethasone or equivalent) will be provided before the first lurbinectedin 
administration (Cycle 1, Day 1; see Section 6.1.3 for more details on prophylactic 
medications).  The requirement for premedication for anti-emetic prophylaxis for the 
subsequent cycles (i.e., Day 1, Cycle 2 and subsequent cycles) should be evaluated on 
an individual basis, and its administration left to investigator judgment.  In addition, 
extended 5-HT3 antagonists and/or steroids can be administered orally for 35 days after 
drug infusion, if necessary.  Prokinetics and additional anti-emetic treatment should be 
evaluated on an individual basis; however, aprepitant or any other neurokinin-1 (NK-1) 
antagonist or related Substance P-antagonists (except rolapitant) must NOT be 
administered with lurbinectedin due to the risk of lurbinectedin overexposure and the 
resulting severe and prolonged myelosuppression. 
A6–2.4.1.4 Management of Renal Abnormalities 
Lurbinectedin may cause dehydration due to nausea/vomiting, as well as other toxicities 
such as diarrhea, or even sepsis, which may lead to secondary renal impairment 
(pre-renal causes).  Hence, a normal blood pressure and adequate participant hydration 
are required before treatment with lurbinectedin. 
Regular monitoring of plasma creatinine levels before each new cycle, as well as 
electrolytes will be performed. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol GO43104, Version 8 
A renal function with creatinine clearance of at least 30 mL/min is required at baseline, 
as well as re-treatment criterion.  Assessment of creatinine clearance before the 
administration of each new cycle will be performed. 
A6–2.4.1.5 Management of Muscular Adverse Events 
Level of CPK enzyme will be monitored before each new cycle as specified in the 
schedule of activities in Section 1.3 (Table 2).  Participants are required to have 
≤Grade 1 elevations at baseline or before re-treatment in order to be eligible to receive 
lurbinectedin infusions.  Grade 3 or higher CPK levels will require lurbinectedin dose 
interruption followed by dose reduction once the adverse event resolves to Grade 1 or 
better. 
Permanently discontinue lurbinectedin treatment if the participant experiences Grade 3 
or 4 rhabdomyolysis. 
A6–2.4.1.6 Management of Infusion Site Reactions 
Careful handling of lurbinectedin is advised.  Although short infusion times (one hour) 
make extravasation unlikely, episodes of extravasation were reported in three 
participants (0.5%) treated with single-agent lurbinectedin at 3.2 mg/m2 in Phase II and 
III studies. 
Extravasation of lurbinectedin may result in skin and soft tissue injury, including necrosis 
requiring debridement.  Use of a central venous catheter is suggested to reduce the risk 
of extravasation, particularly in participants with limited venous access.  Participants 
must be monitored for signs and symptoms of extravasation during lurbinectedin 
infusions.  In the event of extravasation, the infusion must be discontinued immediately, 
the infusion catheter must be removed, and the participant must be monitored for signs 
and symptoms of tissue necrosis.  The time to onset of necrosis after extravasation may 
vary. 
A6–2.4.2 
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, 
when clinically indicated. 
Although toxicities observed with atezolizumab have been mild and self-limiting, they 
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. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol GO43104, Version 8 
Management guidelines for patients who experience adverse events associated with 
atezolizumab are provided in Table A6-5. 
 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol GO43104, Version 8 
Table A6-5 Dose Modification and Management Guidelines for Patients Who Experience Adverse Events 
Associated with Atezolizumab 
GENERAL GUIDANCE 
Early Recognition and Close Monitoring: 
Timely and up-to-date information about the risks associated with atezolizumab should be shared with patients and family caregivers prior to 
initiating atezolizumab and throughout treatment and survival follow-up.  Patients and caregivers should be instructed to have a high level of 
suspicion that new symptoms are treatment-related.  Patients should be assessed for signs and symptoms of organ dysfunctions throughout the 
study, including monitoring of results of thyroid function, liver function, and oth er laboratory tests as appropriate (e.g., blood glucose, 
creatinine, amylase, lipase, urine protein).  Patients presenting with adverse events of any severity grade should be monitored closely and 
referred promptly to specialists for evaluation.  Treatment and supportive care measures should be initiated as per institutional guidelines. 
Monitoring of high-risk cardiac patients: 
In high-risk cardiac patients (including those with abnormal baseline cardiac troponin levels, when available), TTE monitoring should be performed 
on a regular basis, if clinically indicated and considered appropriate per institutional practice. 
Monitoring for Myocarditis, Myositis, and Myasthenia Gravis: 
Myocarditis symptoms are nonspecific and may occur as early as days or weeks after the first or second dose of atezolizumab.  Although 
myocarditis events are rare, myocarditis is often severe and associated with myositis or myasthenia gravis.  All patients with possible 
myocarditis should be urgently evaluated by performing a cardiac enzyme assessment, an ECG, a chest X-ray, a TTE for evaluation of left 
ventricular ejection fraction and global longitudinal strain, and a cardiac MRI as appropriate per institutional practice.  A cardiologist should be 
consulted.  An endomyocardial biopsy may be performed to enable a definitive diagnosis and appropriate treatment, if clinically indicated.  For 
suspicion of myositis, myocarditis, and/or myasthenia gravis, there is a possibility of overlapping symptoms, and patients should therefore be  
evaluated with a shared set of diagnostics, including erythrocyte sedimentation rate, C-reactive protein, creatine kinase, antibody tests 
(acetylcholine, muscle-specific kinase, striational), aldolase, troponin, ECG, nerve conduction, and electromyography).  Such patients should 
undergo frequent pulmonary evaluations. 
Use of Corticosteroids and Immunosuppressants for Managing Adverse Events: 
In the guidance for specific events below, treatment with high-dose corticosteroids refers to 12 mg/kg/day oral prednisone (or equivalent) or IV 
methylprednisolone (or equivalent), and an additional immunosuppressive agent can be added if symptoms do not improve within 48 hours after 
initiating high-dose corticosteroids.  If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day of 
oral prednisone before atezolizumab can be resumed. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol GO43104, Version 8 
Action to be Taken with Atezolizumab: 
Treatment with atezolizumab may be withheld or permanently discontinued because of toxicities, as specified below.  If atezolizumab is withheld, 
treatment can be resumed if the event resolves to Grade 1 or better, or when symptoms improve as specified below.  As a general rule, 
atezolizumab can be withheld for up to 12 weeks after event onset.  Treatment with atezolizumab may be resumed if the event improves to 
Grade  1 within 12 weeks and if corticosteroids have been reduced to   10 mg/day oral prednisone or equivalent within 12 weeks.  If 
atezolizumab is withheld for   12 weeks (or 4 cycles) of initiating steroids, the participant will be discontinued from atezolizumab. 
If an event does not resolve to Grade 1 or better while withholding atezolizumab, permanently discontinue atezolizumab and contact the Medical 
Monitor.  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from an immune-mediated 
event, except when resumption of atezolizumab is expressly prohibited as described below.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator's benefit-risk assessment and should be documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
Event 
Symptoms or CTCAE 
Severity Grade 
Action to be Taken with 
Atezolizumab 
Adverse Event Management [To Be Implemented in 
Combination with Above General Guidance] 
Pulmonary event 
Grade 1 
 Continue with one exception:  
For pneumonitis, consider 
withholding and resuming on 
radiographic evidence of 
improvement. 
 Re-evaluate on serial imaging. 
 Closely monitor patients, including asymptomatic 
patients. 
Grade 2 
 Withhold. 
 Consider bronchoscopy or BAL with or without 
transbronchial biopsy. 
 Initiate treatment with high-dose oral corticosteroids. 
Recurrent Grade 2 
or 
Grade 2 event not 
improving after 4872 
hours of corticosteroids 
or 
Grade 3 or 4 
 Permanently discontinue. 
 In case of pneumonitis, 
atezolizumab should not be 
resumed under any 
circumstances. 
 Bronchoscopy or BAL with or without transbronchial biopsy 
is recommended. 
 Initiate treatment with oral or IV broad-spectrum antibiotics 
and high-dose IV corticosteroids. 
 If event does not improve, consider adding an 
immunosuppressive agent. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol GO43104, Version 8 
AST or ALT increases to 
 10  ULN or total 
bilirubin increases to 
 3  ULN 
 Permanently discontinue. 
 Consider liver biopsy to establish etiology of hepatic injury. 
 Initiate treatment with high-dose oral corticosteroids. 
 If event does not improve, consider adding an 
immunosuppressive agent. 
Diarrhea or colitis 
Grade 1 
 Continue. 
 Closely monitor patient. 
 For events of  7 days' duration, endoscopy is 
recommended. 
Grade 2 
 Withhold. 
 Endoscopy is recommended. 
 If strong clinical suspicion for immune-mediated colitis, 
initiate empiric IV corticosteroids while waiting for definitive 
diagnosis. 
 For recurrent events or events that persist  5 days, initiate 
treatment with high-dose oral corticosteroids. 
 If event does not improve, consider adding an 
immunosuppressive agent. 
Grade 3 
 Withhold. 
 Order confirmatory biopsy. 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement. 
 If event does not improve or patient is unable to transition 
to oral corticosteroids, consider adding an 
immunosuppressive agent. 
Grade 4 
 Permanently discontinue. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol GO43104, Version 8 
Hypothyroidism 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 
 Consider withholding. 
 If withheld, resume when 
symptoms are controlled and 
thyroid function is improving. 
 Initiate treatment with thyroid replacement hormone. 
Grade 3 or 4 
 Withhold. 
 Resume when symptoms are 
controlled and thyroid 
function is improving. 
 Permanently discontinue and 
contact the Medical Monitor 
for life-threatening 
immune-mediated 
hypothyroidism. 
 Initiate treatment with thyroid replacement hormone. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
Hyperthyroidism 
Grade 1, TSH  0.1 
mU/L and  0.5 mU/L 
 Continue. 
 Monitor TSH every 4 weeks. 
Grade 1, TSH 
 0.1 mU/L 
or 
Grade 2 
 Consider withholding. 
 Resume when symptoms are 
controlled and thyroid 
function is improving. 
 Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
Grade 3 or 4 
 Withhold. 
 Resume when symptoms are 
controlled and thyroid 
function is improving. 
 Permanently discontinue for 
life-threatening 
immune-mediated 
hyperthyroidism. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol GO43104, Version 8 
Symptomatic adrenal 
insufficiency 
Grade 2, 3, or 4 
 Withhold. 
 If event resolves to Grade 1 
or better and patient is stable 
on replacement therapy, 
resume. 
 If event does not resolve to 
Grade 1 or better or patient is 
not stable on replacement 
therapy while withholding, 
permanently discontinue. 
 Perform appropriate imaging. 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement, followed 
by taper. 
 Monitor for signs of adrenal crisis, such as hemodynamic 
instability. 
Hyperglycemia 
Grade 1 or 2 without 
Type I diabetes 
 Continue. 
 Closely monitor patient. 
Grade 3 or 4 
or 
Type 1 diabetes 
 Withhold. 
 Resume when symptoms 
resolve and glucose levels 
are stable. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis. 
Hypophysitis 
(pan-hypopituitarism) 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 or 3 
 Withhold. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement, followed 
by taper. 
 Initiate other hormone replacement if clinically indicated, 
only after corticosteroid replacement to avoid adrenal 
crisis. 
Recurrent hypophysitis 
Grade 2 or 3 
or 
Grade 4 
 Permanently discontinue. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol GO43104, Version 8 
Ocular event 
Grade 1 
 Continue. 
 Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
Persistent Grade 1 
despite treatment 
or 
Grade 2 
 Withhold. 
Grade 3 or 4 
 Permanently discontinue. 
 Initiate treatment with high-dose oral corticosteroids. 
Myocarditis or 
pericardial disorders 
Grade 1 
 Withhold 
 Conduct a detailed cardiac evaluation to determine the 
etiology and manage accordingly. 
Grade 2, 3, or 4 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
 Consider anti-arrhythmic drugs, temporary pacemaker, 
ECMO, VAD, or pericardiocentesis as appropriate. 
 Initiate treatment with higher-dose IV corticosteroids 
equivalent to 1 g/day IV methylprednisolone for 35 days 
and convert to high-dose oral corticosteroids upon 
improvement. 
 If event does not improve within 24 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
Amylase and/or lipase 
elevation 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2, amylase and/or 
lipase  1.52.0  ULN 
 Continue. 
 For prolonged elevation (e.g.,  3 weeks), consider 
treatment with oral corticosteroids equivalent to 10 mg/day 
prednisone. 
Grade 2, asymptomatic 
with amylase and/or 
lipase  2.05.0  ULN 
or 
Grade 3 or 4 
 Withhold. 
 For recurrent events, 
permanently discontinue. 
 Consider treatment with high-dose oral corticosteroids. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol GO43104, Version 8 
Pancreatitis 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 or 3 
 Withhold. 
 For recurrent events, 
permanently discontinue. 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement. 
Grade 4 
 Permanently discontinue. 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement. 
 If event does not improve, consider adding an 
immunosuppressive agent. 
Dermatologic event 
Grade 1 
 Continue. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Grade 2 
 Continue. 
 Consider biopsy, if indicated. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical 
corticosteroids if the event does not improve. 
 If unresponsive to topical corticosteroids, consider oral 
corticosteroids equivalent to 0.5 mg/kg/day prednisone. 
Grade 3 
 Withhold. 
 Order a biopsy, if indicated. 
 Initiate treatment with oral corticosteroids equivalent to 
10 mg/day prednisone, increasing to high-dose oral 
corticosteroids if event does not improve within 
4872 hours. 
Grade 4 
 Permanently discontinue. 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Suspected event, any 
grade 
 Withhold. 
 Order a biopsy, if indicated. 
 Follow the applicable treatment/management guidelines for 
dermatologic events above. 
Confirmed event, any 
grade 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
178/Protocol GO43104, Version 8 
Myasthenia gravis and 
Guillain-Barré 
syndrome 
Any grade 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed after permanent 
discontinuation. 
 Consider initiation of high-dose oral or IV corticosteroids. 
 Consider IVIG or plasmapheresis in patients with rapid 
progression with development of bulbar and/or respiratory 
symptoms. 
 In life-threatening cases, consider higher-dose IV 
methylprednisolone 1 g/day for 35 days and other 
immunosuppressive agents. 
Facial paresis 
Grade 1 or 2 
 Withhold. 
 If event resolves fully, 
resume. 
 If event does not resolve fully 
while withholding, 
permanently discontinue. 
 Investigate etiology. 
 Closely monitor patient or initiate high-dose oral 
corticosteroids (if progressing from mild). 
 Initiate non-opioid treatment (e.g., gabapentin, pregabalin, 
duloxetine) for pain. 
Grade 3 or 4 
 Permanently discontinue. 
 Follow guidelines for management of myasthenia gravis 
and Guillain-Barré syndrome. 
Other cranial nerve 
disorder (excluding 
facial paresis) 
Grade 1 or 2 
 Withhold. 
 Investigate etiology. 
Grade 3 or 4 
 Permanently discontinue. 
 Follow guidelines for management of myasthenia gravis 
and Guillain-Barré syndrome. 
Other neuropathy 
(excluding myasthenia 
gravis, Guillain-Barré 
syndrome, facial 
paresis, and other 
cranial nerve 
disorders) 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 
 Withhold. 
 Investigate etiology. 
Grade 3 or 4 
 Permanently discontinue. 
 Follow guidelines for management of myasthenia gravis 
and Guillain-Barré syndrome. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol GO43104, Version 8 
Myelitis 
Grade 1 
 Continue unless symptoms 
worsen or do not improve. 
 Investigate etiology. 
Grade 2 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
 Investigate etiology and rule out infection. 
 Initiate treatment with high-dose oral corticosteroids. 
Grade 3 or 4 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
 Initiate non-opioid treatment (e.g., gabapentin, pregabalin, 
duloxetine) for pain. 
 Hospitalize patient. 
 Initiate treatment with IV corticosteroids equivalent to 
1 g/day methylprednisolone. 
 If event does not improve or there is worsening of 
symptoms within 48 hours, consider IVIG or 
plasmapheresis and manage as per institutional practice. 
Meningoencephalitis 
Any grade 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
 Initiate treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement. 
 If event does not improve, consider adding an 
immunosuppressive agent. 
Renal event 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 
 Withhold. 
 Initiate treatment with high-dose oral corticosteroids. 
Grade 3 or 4 
 Permanently discontinue. 
 Consider renal biopsy. 
 Initiate treatment with high-dose oral corticosteroids. 
 If event does not improve, consider adding an 
immunosuppressive agent. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol GO43104, Version 8 
Myositis 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 
 Withhold. 
 Consider treatment with high-dose IV corticosteroids and 
convert to oral corticosteroids upon improvement. 
 If the event does not improve, consider adding an 
immunosuppressive agent. 
Grade 3 
 Withhold. 
 If event does not resolve to 
Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumab and 
atezolizumab should not be 
resumed under any 
circumstances. 
 Initiate treatment with high-dose IV corticosteroids, or 
higher-dose bolus if patient is severely compromised 
(e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to oral 
corticosteroids upon improvement. 
 If event does not improve within 2448 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 Consider IVIG or plasmapheresis. 
Recurrent Grade 3 
or 
Grade 4 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
Suspected HLH a 
Any grade 
 Permanently discontinue. 
 Atezolizumab should not be 
resumed under any 
circumstances. 
 Consider initiation of IV corticosteroids, an 
immunosuppressive agent, and/or anti-cytokine therapy. 
 If the event does not respond to treatment within 24 hours, 
contact the Medical Monitor and initiate treatment as 
appropriate according to published guidelines. b 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol GO43104, Version 8 
IRR and CRS 
Grade 1 c: 
Fever d 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. 
 In case of rapid decline or prolonged CRS ( 2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, 
and/or analgesics, and monitor closely for IRRs and/or 
CRS. 
Grade 2 c:  
Fever d with hypotension 
not requiring 
vasopressors 
and/or 
hypoxia requiring low-
flow oxygen e by nasal 
cannula or blow-by 
 If event occurs during 
infusion, immediately 
discontinue.  Do not restart 
infusion. 
 If symptoms resolve to Grade 
1 or better for 3 consecutive 
days, the next dose of 
atezolizumab may be 
administered. 
 Permanently discontinue 
atezolizumab for patients 
with Grade  3 wheezing, 
bronchospasm, or urticaria. 
 If event occurs during or 
within 24 hours after 
infusion, administer next 
 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. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy if the patient is not 
responding as expected after initiating corticosteroids. 
 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 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
182/Protocol GO43104, Version 8 
dose at  50% of initial 
infusion rate. 
ICU is recommended), permanently discontinue 
atezolizumab, and contact the Medical Monitor. 
 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. 
Grade 3 c: 
Fever d with hypotension 
requiring a vasopressor 
(with or without 
vasopressin) 
and/or 
hypoxia requiring 
high-flow oxygen e by 
nasal cannula, face 
mask, non-rebreather 
mask, or Venturi mask 
 Permanently discontinue f. 
 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. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Administer an 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. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol GO43104, Version 8 
Grade 4 c 
Fever d 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 f. 
 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. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Administer an anti-cytokine therapy.  For patients who are 
refractory to anti-cytokine therapy, experimental 
treatments g may be considered at the discretion of the 
investigator and in consultation with the Medical Monitor. 
 Hospitalize patient until complete resolution of symptoms. 
Atezolizumab-related 
event not described 
above 
Grade 1 
 Continue. 
 Closely monitor patient. 
Grade 2 
 Consider withholding and 
resuming when event 
resolves to Grade 1 or better. 
 Refer to current standard guidelines for management of 
immune checkpoint inhibitor-related toxicities, such as 
those provided by a professional society (e.g., NCCN, 
ESMO, SITC, ASCO). 
Grade 3 
 Withold. 
Grade 4 
 Permanently discontinue. 
ASCO  American Society of Clinical Oncology; ASTCT  American Society for Transplantation and Cellular Therapy; BAL  bronchoscopic 
alveolar lavage; BiPAP  bi-level positive airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine release syndrome; 
CTCAE  Common Terminology Criteria for Adverse Events; ECMO  extracorporeal membrane oxygenation; eCRF  electronic Case Report 
Form; ESMO  European Society for Medical Oncology; HLH  hemophagocytic lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-
related reaction; IVIG  intravenous immunoglobulin; MRI  magnetic resonance imaging; NCCN  National Comprehensive Cancer Network; 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
184/Protocol GO43104, Version 8 
NCI  National Cancer Institute; SITC  Society for Immunotherapy of Cancer; TTE  transthoracic echocardiogram; VAD = ventricular assist 
device; ULN = upper limit of normal. 
a Patients with suspected HLH should be diagnosed according to published criteria by McClain and Eckstein (2014). 
b Refer to La Rosée (2015); Schram and Berliner (2015); La Rosée et al. (2019). 
c Grading system for these management guidelines is based on ASTCT Consensus Grading Scale 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. 
d Fever is defined as temperature  38C not attributable to any other cause.  In patients who develop CRS and then receive antipyretic, 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. 
e Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen delivered at  6 L/min. 
f For subsequent infusions, administer oral premedication with antihistamines, antipyretic medications, and/or analgesics, and monitor closely for 
IRRs and/or CRS.  Premedication with corticosteroids and extending the infusion time may also be considered after assessing the benefit-risk 
ratio. 
g Refer to Riegler et al. (2019). 
 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
185/Protocol GO43104, Version 8 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
Chawla SP, Sankhala KK, Ravicz JR, et al. Clinical experience with combination 
chemo-/immunotherapy using trabectedin and nivolumab for advanced soft tissue 
sarcoma. 2018;36(Suppl 15). 
Gordon EM, Sankhala KK, Stumpf N, et al. Cancer immunotherapy using trabectedin 
and nivolumab in advanced soft tissue sarcoma: a retrospective analysis. J Clin 
Oncol 2018;36(Suppl 5):40. 
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. 
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. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
186/Protocol GO43104, Version 8 
Appendix 7  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment administration in a clinical setting: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for intramuscular (preferred route), SC, IV, or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
IV infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment administration, 
the following procedures should be performed: 
1. 
Stop the study treatment administration, if possible. 
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 participant status and as directed by the physician in charge. 
6. 
Continue to observe the participant and document observations. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol GO43104, Version 8 
Appendix 8  
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 
Note:  This study requires a tumor assessment at induction screening with the 
assignment of target and non-target lesions per RECIST v1.1.  This is required so that 
investigators can assess tumor response at the time of maintenance screening given 
that only participants with partial response (PR), complete response (CR), or stable 
disease (SD) are eligible for the maintenance phase of the study.  However, in order to 
assess the treatment effect of the experimental treatment in this study, lurbinectedin, all 
subsequent tumor assessments performed during the maintenance phase (and follow-up 
phase if applicable) must be compared against the scans done at maintenance 
screening (or nadir achieved at or after maintenance screening) and NOT against the 
scan performed at induction screening. 
The potential need for palliative radiotherapy should be considered, if possible, during 
the selection of target lesions as an irradiated target lesion renders the patient non-
evaluable for RECIST v1.1 tumor response with the exception of the assessment of 
disease progression. 
For participants who achieve a CR in target lesions following the completion of induction 
therapy, but with residual disease in other lesions, new target and non-target lesions 
must be assigned at maintenance screening.  For other participants, the investigator 
should carefully assess the maintenance screening scans and consider whether a 
reassignment of target and non-target lesions is warranted.  For participants with an 
overall response of CR after the completion of induction therapy (i.e., participants with 
no radiographic evidence of disease at maintenance baseline), the guidance in 
Table A8-1 should be followed for the assessment of overall response at a single 
timepoint post-maintenance baseline.  In those participants, the recurrence of disease 
(to be reported as new lesion[s]) or the appearance of a new lesion results in an overall 
response assessment of progressive disease (PD). 
 
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 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
188/Protocol GO43104, Version 8 
Table A8-1 Participants with No Radiographic Evidence of Disease at 
Maintenance Baseline:  Criteria for Overall Response at a Single 
Timepoint 
Target Lesions 
Non-Target Lesions 
New Lesion 
Overall Timepoint 
Response 
NA 
NA 
No 
NED 
NA 
NA 
Yes 
PD 
NA   not applicable; NED   no evidence of disease; PD   progressive disease. 
  
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"). 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol GO43104, Version 8 
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 participant, these are 
preferred for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
190/Protocol GO43104, Version 8 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed with use of calipers (e.g., skin nodules).  For the case 
of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
Computed tomography is the best currently available and reproducible method to 
measure lesions selected for response assessment.  In this guideline, the definition of 
measurability of lesions on CT scan is based on the assumption that CT slice thickness 
is  5 mm.  When CT scans have slice thickness of  5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  Magnetic resonance imaging is 
also acceptable. 
If prior to enrollment it is known that a participant is unable to undergo CT scans with 
IV contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (without IV contrast) will be used to evaluate the participant at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For participants who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the participant should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
191/Protocol GO43104, Version 8 
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 participants have only 
one or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be considered non-target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol GO43104, Version 8 
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 completely disappeared, 
the measurement should be recorded as 0 mm 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
193/Protocol GO43104, Version 8 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size 
(short axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
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 
 
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. 
 
SD:  Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to 
qualify for PD 
 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
194/Protocol GO43104, Version 8 
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 
NO RADIOGRAPHIC EVIDENCE OF DISEASE AT MAINTENANCE BASELINE 
Participants with no radiographic evidence of disease at maintenance baseline will be 
assigned the response below at subsequent overall response timepoint(s): 
 
NED:  Absence of new lesions or recurrence 
 
PD:  Recurrence of disease or the appearance of a new lesion 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Participants with Measurable and Non-Measurable Disease 
For participants 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 participant's baseline lesions show PR 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol GO43104, Version 8 
or CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan showing the new lesion. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table A8-2 provides a summary of the overall response status calculation at each 
response assessment timepoint for participants who have measurable disease at 
baseline. 
Table A8-2 Criteria for Overall Response at a Single Timepoint:  
Participants 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. 
  
In order to meet eligibility for enrollment in the induction phase, participants are required 
to present with measurable disease as defined per RECIST v1.1 at induction screening.  
Due to response to induction treatment, participants may no longer present with 
measurable disease at the time of maintenance screening.  They may have an overall 
response of "complete response," that is, no evidence of disease (refer to Table A8-1, 
which provides a summary of the overall timepoint response assessment for participants 
with no evidence of disease at maintenance screening) or they may present with 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
196/Protocol GO43104, Version 8 
non-measurable disease only at the time of maintenance screening.  Table A8-3 
provides a summary of the overall response status calculation at each response 
assessment timepoint during the maintenance phase for participants who have only non-
measurable disease at maintenance screening. 
Table A8-3 Timepoint Response:  Participants with Non-Target Disease 
Only at Maintenance Screening 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
  
MISSING ASSESSMENTS AND NOT EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the participant 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 participant had 
a baseline sum of 50 mm with three measured lesions and during the study only 
two lesions were assessed, but those gave a sum of 80 mm, the participant will have 
achieved PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Participants 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 continue 
radiographic tumor response assessments 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 participants is to be 
determined by evaluation of target and non-target lesions as shown in Table A8-2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
197/Protocol GO43104, Version 8 
POTENTIAL LYMPHADENOPATHY AFTER COVID-19 VACCINATION 
Vaccination is an established but uncommon cause of ipsilateral transient 
lymphadenopathy.  Lymphadenopathy has been described as an uncommon adverse 
reaction with COVID-19 vaccines with a reported incidence of 0.3% for Pfizer/BioNTech, 
which generally resolved within 10 days, and as 'uncommon' (i.e., less than 1%) for 
AstraZeneca as per respective product information (Polack et al. 2020; 
PfizerBioNTech 2021; AstraZeneca 2021).  Axillary swelling or tenderness has been 
reported with an overall incidence of 8.5% with the COVID-19 vaccine from 
Moderna (Baden et al. 2021; Moderna 2021), with an incidence of 16% in the younger 
age group (1864 years; Centers for Disease Control 2020). 
Lymphadenopathy, particularly in the ipsilateral axilla, in people who have received a 
COVID-19 vaccination may appear similar to malignant nodal involvement and; hence, 
could impact image interpretation.  This is of particular importance for clinical studies 
with tumor response as primary or secondary endpoint and with progressive disease 
triggering study treatment discontinuation.  We would therefore like to draw your 
attention to the potential lymphadenopathy as a consequence of a COVID-19 
vaccination and recommend the following: 
 
Participants on clinical trials should receive their COVID-19 vaccine based on an 
individual benefit–risk assessment and local availability.  The schedule of tumor 
response assessments should not be a consideration when scheduling the 
vaccination. 
 
The per protocol schedule for tumor response assessments must continue to be 
followed, regardless of when the COVID-19 vaccine was administered.  
When interpreting tumor response on imaging, take the timing of the vaccination 
and the side of the vaccination into consideration.  Consider performing follow-up 
assessments as per your clinical judgment and published guidance to discern 
lymphadenopathy resulting from malignancy from swollen lymph nodes related to 
the vaccine (Edmonds et al. 2021; Lehman et al. 2021; McIntosh et al. 2021; 
Tu et al. 2021). 
 
Please note that vaccines are considered concomitant medication and must be 
reported on the Concomitant Medication eCRF according to the protocol instructions 
for concomitant medications. 
 
Should you have any questions or require additional information, please do not hesitate 
to contact your study Monitor. 

Appendix 8:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
198/Protocol GO43104, Version 8 
REFERENCES 
AstraZeneca. COVID-19 Vaccine Summary of Product Characteristics [resource on the 
Internet] 2021. Available from: 
https://www.ema.europa.eu/en/documents/product-information/covid-19-vaccine-
astrazeneca-product-information-approved-chmp-29-january-2021-pending-
endorsement_en.pdf. 
Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA1273 
SARSCoV-2 vaccine. N Engl J Med 2021;384:40316. 
Centers for Disease Control. Local reactions, systemic reactions, adverse events, and 
serious adverse events: Moderna COVID-19 vaccine [resource on the Internet] 
2020. Available from: 
https://www.cdc.gov/vaccines/covid-19/info-by-
product/moderna/reactogenicity.html. 
Edmonds CE, Zuckerman SP, Conant EF. Management of unilateral axillary 
lymphadenopathy detected on breast MRI in the era of coronavirus disease 
(COVID-19) vaccination. AJR Am J Roentgenol 2021. Online ahead of print. 
doi: 10.2214/AJR.21.25604. 
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. 
Lehman CD, Lamb LR, D'Alessandro HA. Mitigating the impact of coronavirus disease 
(COVID-19) vaccinations on patients undergoing breast imaging examinations: 
a pragmatic approach. AJR Am J Roentgenol 2021. Online ahead of print. 
doi: 10.2214/AJR.21.25688. 
McIntosh LJ, Bankier AA, Vijayaraghavan GR, et al. COVID-19 vaccination-related 
uptake on FDG PET/CT: an emerging dilemma and suggestions for management. 
AJR Am J Roentgenol 2021. Online ahead of print. doi: 10.2214/AJR.25728. 
Moderna COVID-19 Vaccine Emergency Use Authorization Fact Sheet [resource on the 
Internet] Revised 2021. Available from: 
https://www.fda.gov/media/144637/download. 
Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162B2 mRNA 
COVID-19 vaccine. N Engl J Med 2020;383:260315. 
PfizerBioNTech COVID-19 Vaccine Emergency Use Authorization Fact Sheet 
[resource on the Internet] Revised 2021. Available from: 
https://www.fda.gov/media/144413/download. 
Tu W, Gierada DS, Joe BN. COVID-19 vaccination-related lymphadenopathy: what to be 
aware of. Radiol Imaging Cancer 2021;3:e210038. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
199/Protocol GO43104, Version 8 
Appendix 9  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about  50% of waking hours 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol GO43104, Version 8 
Appendix 10  
EuroQol EQ-5D-5L 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
Under each heading, please check the ONE box that best describes your health 
TODAY. 
MOBILITY 
 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
SELF-CARE 
 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
209/Protocol GO43104, Version 8 
Appendix 15  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Participants should be carefully questioned regarding their history of acquired or 
congenital immune deficiencies or autoimmune disease.  Participants 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 participants with a medical history of such entities as atopic disease or childhood 
arthralgias where the clinical suspicion of autoimmune disease is low.  Participants 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 participants 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. 
 
Acute disseminated 
encephalomyelitis 
 
Addison disease 
 
Ankylosing spondylitis 
 
Anti-phospholipid 
antibody syndrome 
 
Aplastic anemia 
 
Autoimmune hemolytic 
anemia 
 
Autoimmune hepatitis 
 
Autoimmune 
hypoparathyroidism 
 
Autoimmune hypophysitis 
 
Autoimmune myocarditis 
 
Autoimmune myelitis 
 
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 
 
Granulomatosis with 
polyangiitis 
 
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 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
210/Protocol GO43104, Version 8 
Appendix 16  
Cytochrome P450 3A Inhibitors and Inducers 
Table A16-1 
Examples of Clinical Inhibitors for CYP450-Mediated 
Metabolism (for Concomitant Use Clinical DDI Studies and/or 
Drug Labeling; 6 March 2020) 
 
Strongest Inhibitors 
( 10-Fold Increase) 
Strong Inhibitors 
(105-Fold 
Increase) 
Moderate 
Inhibitors 
(25-Fold 
Increase) 
Weak Inhibitors 
(1.252-Fold 
Increase) 
Inhibitors 
CYP3A4 
boceprevir, cobicistat1, 
danoprevir and 
ritonavir2, elvitegravir 
and ritonavir2, 
grapefruit juice3, 
indinavir and ritonavir2, 
itraconazole1, 
ketoconazole, lopinavir 
and ritonavir1,2, 
paritaprevir and 
ritonavir and 
(ombitasvir and/or 
dasabuvir)2, 
posaconazole, 
ritonavir1,2, saquinavir 
and ritonavir1,2, 
telaprevir1, tipranavir 
and ritonavir(1,2, 
telithromycin, 
troleandomycin, 
voriconazole 
Clarithromycin2, 
idelalisib, 
nefazodone, 
nelfinavir1 
aprepitant, 
ciprofloxacin, 
conivaptan4, 
crizotinib, 
cyclosporine, 
diltiazem5, 
dronedarone1, 
erythromycin, 
fluconazole, 
fluvoxamine, 
imatinib, 
tofisopam, 
verapamil1, 
Seville orange 
chlorzoxazone, 
cilostazol, 
cimetidine, 
clotrimazole, 
fosaprepitant, 
istradefylline, 
ivacaftor1, 
lomitapide, 
ranitidine, 
ranolazine1, 
ticagrelor1 
Inducers 
CYP3A 
apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John's 
wort6 
bosentan, 
efavirenz, 
etravirine, 
phenobarbital, 
primidone 
armodafinil, 
modafinil7, 
rufinamide 
Source:  FDA Drug Development and Drug Interactions:  Table of Substrates Inhibitors and 
Inducers 2020. 
AUC  area under the concentrationtime curve; DDI  drug-drug interaction; FDA  U.S. Food and 
Drug Administration; HCV  hepatitis C virus; P-gp  P-glycoprotein. 
This table is prepared to provide examples of clinical inhibitors and inducers and is not intended 
to be an exhaustive list.  DDI data were collected based on a search of the University of 
Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), 
Hum Genomics, 5(1):61]. 

Appendix 16:  Cytochrome P450 3A Inhibitors and Inducers 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
211/Protocol GO43104, Version 8 
1 Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥ 1.25-fold). 
2 Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical 
practice. Caution should be used when extrapolating the observed effect of ritonavir alone to 
the effect of combination regimens on CYP3A activities. 
3 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent. Studies have shown that it can be classified as a "strong CYP3A 
inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a 
"moderate CYP3A inhibitor" when another preparation was used (e.g., low-dose, single 
strength). 
4 The classification is based on studies conducted with intravenously administered conivaptan. 
5 Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 
5-fold. 
6 The effect of St. John's wort varies widely and is preparation-dependent. 
7 Based on effect of 200 mg/day modafinil.  A higher-dose (400 mg/day) modafinil had larger 
induction effect on CYP3A. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
212/Protocol GO43104, Version 8 
Appendix 17  
Veterans Administration Lung Study Group Staging System for 
Small-cell Lung Cancer 
Stage 
Characteristics 
Limited SCLC 
 Disease confined to one hemithorax, although local extensions 
may be present 
 No extrathoracic metastases except for possible ipsilateral, 
supraclavicular nodes if they can be included in the same 
portal as the primary tumor; and 
 Primary tumor and regional nodes that can be adequately 
treated and totally encompassed in every portal  
Extensive SCLC 
 Inoperable patients who cannot be classified as having limited 
disease 
SCLC  small-cell lung cancer. 
Note:  Adapted from Micke et al. (2002). 
  
REFERENCES 
Micke P, Faldum A, Metz T, et al. Staging small cell lung cancer: veterans administration lung 
study group versus international association for the study of lung cancer—what limits 
limited disease? Lung Cancer 2002;37:2716. 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
213/Protocol GO43104, Version 8 
Appendix 18  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European Economic 
Area and United Kingdom) 
Table A18-1 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP/AxMP 
Designation 
Marketing 
Authorization Status 
in EEA  
Used within 
Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product) a 
Authorized 
No b 
Lurbinectedin 
(PM01183/JZP712) 
IMP (test product) 
Unauthorized 
Not applicable 
Carboplatin 
AxMP (background 
treatment) 
Authorized 
Yes 
Etoposide 
AxMP (background 
treatment) 
Authorized 
Yes 
Ondansetron 
(or equivalent) 
AxMP (rescue 
medication) 
Authorized 
Yes 
Metoclopramide 
(or equivalent) 
AxMP (rescue 
medication) 
Authorized 
Yes 
Dexamethasone 
(or equivalent) 
AxMP (rescue 
medication) 
Authorized 
Yes 
Pegylated G-CSF 
AxMP (rescue 
medication) 
Not applicable c 
Not applicable c 
Prednisone 
AxMP (rescue 
medication) 
Authorized 
Yes 
Methylprednisolone 
AxMP (rescue 
medication) 
Authorized 
Yes 
Thyroid replacement 
hormone 
AxMP (rescue 
medicine) 
Authorized 
Yes 
Methimazole/ 
Carbimazole 
AxMP (rescue 
medicine) 
Authorized 
Yes 
AxMP  auxiliary medicinal product; EEA  European Economic Area; ES-SCLC  extensive-
stage small-cell lung cancer; G-CSF  granulocyte colony-stimulating factor; 
IMP  investigational medicinal product. 
a Atezolizumab is considered to be an IMP test product as well as an IMP comparator. 
b Atezolizumab, in combination with carboplatin and etoposide, is approved for the first-line 
treatment of adult patients with ES-SCLC, but not in combination with lurbinectedin. 
c G-CSF is a class of medicine and not an individual product.  Therefore, this field is not 
applicable.  The Sponsor expects that appropriate G-CSF is given as standard treatment per 
local practice. 
  

Appendix 18:  Investigational Medicinal Product and Non-Investigational Medicinal 
Product Designations (for Use in European Economic Area and United 
Kingdom) 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
214/Protocol GO43104, Version 8 
Table A18-2 
Investigational and Non-Investigational Medicinal Product 
Designations for the United Kingdom 
Product Name 
IMP/NIMP 
Designation 
Marketing 
Authorization Status 
in UK  
Used within 
Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product) a 
Authorized 
No b 
Lurbinectedin 
(PM01183/JZP712) 
IMP (test product) 
Unauthorized 
Not applicable 
Carboplatin 
NIMP (background 
treatment) 
Authorized 
Yes 
Etoposide 
NIMP (background 
treatment) 
Authorized 
Yes 
Ondansetron 
(or equivalent) 
NIMP (rescue 
medication) 
Authorized 
Yes 
Metoclopramide 
(or equivalent) 
NIMP (rescue 
medication) 
Authorized 
Yes 
Dexamethasone 
(or equivalent) 
NIMP (rescue 
medication) 
Authorized 
Yes 
Pegylated G-CSF 
NIMP (rescue 
medication) 
Not applicable c 
Not applicable c 
Prednisone 
NIMP (rescue 
medication) 
Authorized 
Yes 
Methylprednisolone 
NIMP (rescue 
medication) 
Authorized 
Yes 
Thyroid replacement 
hormone 
NIMP (rescue 
medicine) 
Authorized 
Yes 
Methimazole/ 
Carbimazole 
NIMP (rescue 
medicine) 
Authorized 
Yes 
ES-SCLC  extensive-stage small-cell lung cancer; G-CSF  granulocyte colony-stimulating 
factor; IMP  investigational medicinal product; NIMP  non-investigational medicinal product; 
UK  United Kingdom. 
a Atezolizumab is considered to be an IMP test product as well as an IMP comparator. 
b Atezolizumab, in combination with carboplatin and etoposide, is approved for the first-line 
treatment of adult patients with ES-SCLC, but not in combination with lurbinectedin. 
c G-CSF is a class of medicine and not an individual product.  Therefore, this field is not 
applicable. The Sponsor expects that appropriate G-CSF is given as standard treatment per 
local practice. 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
215/Protocol GO43104, Version 8 
Appendix 19  
Protocol Amendment History 
A rationale for the current amendment precedes the Table of Contents. 
PROTOCOL AMENDMENT, VERSION 7: 27 NOVEMBER 2023 
Protocol GO43104 has been amended to align the risks and management guidelines 
with Atezolizumab Investigator's Brochure Version 20.  In addition, the alpha spending 
function for the primary endpoint of overall survival was changed from O'Brien-Fleming 
to Hwang-Shih-DeCani with the gamma parameter of 1.5.  Further, the protocol has 
been updated to express the primary study objectives and the analyses sets using the 
estimand framework in accordance with the ICH E9(R1) statistical principles for clinical 
trials (ICH 2020). 
Substantive changes to the protocol, along with a rationale for each change, are 
summarized below. 
 
 
 
 
 
 
 
 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Section 2.2.4). 
 
The primary objectives are expressed using the estimand framework.  Applicable 
changes have been made to Table 4 in Section 3 and duplicative language has 
been removed from Section 9.4.2.1.  In addition, the description of the analysis sets 
has been amended in accordance with the estimand framework (Section 9.3). 
 
The definition of the analysis populations was removed from Table 5 for consistency 
as the analysis sets per estimand framework are defined in Section 9. 
 
The EQ-5D-5L analysis was removed as an endpoint because only summaries of 
responses are needed.  Additional minor changes to the PRO endpoints were made 
in Section 9.4.5.5 to improve clarity. 
 
Based on the observed participant recruitment, the length of the study has been 
updated in Section 4.4 from approximately 52 months to approximately 60 months 
 
 

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
216/Protocol GO43104, Version 8 
 
 
 
, the contraception period for 
women has been extended to 7 months after the last dose of lurbinectedin 
(Section 5.1.1, Section 5.2.1, Section 5.2.2 and Appendix 4 A4-1). 
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 8.3.4). 
 
 
 the statistical testing boundary 
has been changed from O'Brien-Fleming to Hwang-Shih-DeCani with the gamma 
parameter of 1.5 (Section 9). 
 
 
 
 
 
 
 
 
 
 
Previous sections under statistical considerations on sensitivity analyses, 
supplementary analyses and subgroup analyses have been removed from the study 
protocol because details of these exploratory analyses will be outlined in the 
Statistical Analysis Plan. 
 
A footnote has been added to Table A6-2 to align the treatment continuation 
guidance for atezolizumab for endocrinopathies with that in Table A6-8 
(Section A6-2.2). 
 
Lurbinectedin management guidelines for hematological abnormalities have been 
updated to allow management according to institutional practice of Grade 3 
thrombocytopenia without bleeding (Table A6-2.4.1.1, Appendix 6). 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure Version 20 (Section A6-2.4.2). 
 
 
 
  

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
218/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
219/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
220/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
 
 

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
221/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

Appendix 19:  Protocol Amendment History 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
222/Protocol GO43104, Version 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
223/Protocol GO43104, Version 8 
Appendix 20  
Abbreviations 
Abbreviation or Term 
Definition 
1L 
first-line 
5-HT3 
serotonin 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
AGP 
-1-acid glycoprotein 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUC 
area under the concentration–time curve 
AxMP 
auxiliary medicinal product 
BSA 
body surface area 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRF 
Case Report Form 
CRS 
cytokine release syndrome 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTFI 
chemotherapy-free interval 
CTR 
Clinical Trial Regulation 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECIS 
European Cancer Information System 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEA 
European Economic Area 
EORTC 
European Organisation for Research and Treatment of Cancer 
ES-SCLC 
extensive-stage small-cell lung cancer 
FA 
final analysis 
FAS 
full analysis set  
Fc 
fragment crystallizable 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FPI 
first participant in the maintenance phase 
G-CSF 
granulocyte colony-stimulating factor 

Appendix 20:  Abbreviations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
224/Protocol GO43104, Version 8 
Abbreviation or Term 
Definition 
GHS 
global health status 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health related quality of life 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IL 
interleukin 
IL46 
Item List 46 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRF 
Independent Review Facility 
IRR 
infusion-related reaction 
ITT 
intent-to-treat 
IxRS 
interactive voice or Web-based response system 
LDH 
lactate dehydrogenase 
LPLV 
last participant last visit 
MAS 
macrophage activation syndrome 
MN 
mobile nurse 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
next-generation sequencing 
NIMP 
non-investigational medicinal product 
NK-1 
neurokinin-1 receptor 
NSCLC 
nonsmall-cell lung cancer 
ORR 
objective response rate 

Appendix 20:  Abbreviations 
Lurbinectedin and Atezolizumab—F. Hoffmann-La Roche Ltd 
225/Protocol GO43104, Version 8 
Abbreviation or Term 
Definition 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCI 
prophylactic cranial irradiation 
PD 
progressive disease 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
P-gp  
P-glycoprotein 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events 
PS 
performance status 
Q3W 
every 3 weeks 
QLQ-C30 
Quality of Life QuestionnaireCore 30 
QLQ-LC13 
Quality of Life QuestionnaireLung Cancer Module 
QoL 
quality of life 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SITC 
Society for Immunotherapy of Cancer 
TAM 
tumor-associated macrophage 
TTCD 
time to confirmed deterioration 
TTE 
transthoracic echocardiogram 
ULN 
upper limit of normal 
USPI 
United States Prescribing Information 
VALG 
Veterans Administration Lung Study Group 
 
 
WGS 
whole-genome sequencing 
 

Signature Page for Protocol - GO43104 - TECENTRIQ - v8 - Global/Core - Published
System identifier: RIM-CLIN-989061
Approval Task
Company Signatory
05-Mar-2025 15:16:48 GMT+0000