A Phase III, Randomized, Open-Label Study of Pralsetinib Versus Standard of Care for First-Line Treatment of RET Fusion-Positive, Metastatic Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: RET-fusion Non Small Cell Lung Cancer, Lung Neoplasm, Carcinoma, Non-Small-Cell Lung, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Disease, Carcinoma, Bronchogenic, Bronchial Diseases, Head and Neck Neoplasms, Adenocarcinoma, Carcinoma, Neoplasms by Histologic Type, Neoplasms, Germ Cell and Embryonal, Neoplasms, Nerve Tissue
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase III, Randomized, Open-Label Study of Pralsetinib Versus 
Standard of Care for First-Line Treatment of RET Fusion-Positive, 
Metastatic Non-Small Cell Lung Cancer 
NCT Number: 
NCT04222972 
Document Date: 
Protocol Amendment Version 6: 23-Oct-2024 
 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
Pralsetinib—F. Hoffmann-La Roche Ltd 
Protocol BO42864, Version 6 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL STUDY 
OF PRALSETINIB VERSUS STANDARD OF CARE 
FOR FIRST-LINE TREATMENT OF 
RET FUSIONPOSITIVE, METASTATIC 
NONSMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO42864 
STUDY NAME 
AcceleRET-Lung 
VERSION NUMBER: 
6 
TEST PRODUCT: 
Pralsetinib (RO7499790) 
STUDY PHASE: 
Phase III 
REGULATORY AGENCY 
IDENTIFIERS: 
IND Number:  143094 
EudraCT Number:  2019-002463-10 
EU CT Number: 2023-505035-12-00   
NCT Number: NCT04222972 
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. 
 

Pralsetinib—F. Hoffmann-La Roche Ltd 
2/Protocol BO42864, Version 6 
PROTOCOL HISTORY 
Protocol 
Associated Country and/or Region-Specific Protocols 
Version 
Date Final 
Country and/or Region 
Version 
Date Final 
6 
See electronic date 
stamp on the final 
page of this document. 



5 
3 April 2024 
 
 
 
4 
28 April 2022 
 
 
 
3 
29 January 2021 
Ireland 
3 
27 July 2021 
2 
10 October 2019 
Ireland 
2 
15 December 2020 
1 
27 August 2019 
 
 
 
 
 
 

Pralsetinib—F. Hoffmann-La Roche Ltd 
3/Protocol BO42864, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
A review of fatal events in Study BO42864 for pralsetinib versus platinum-based 
standard of care identified an imbalance in fatal adverse events, in particular infectious 
fatal adverse events.  Following this review, severe infections, including opportunistic 
infections, are now an identified risk with pralsetinib.   
Protocol BO42864 has been amended to reflect changes in recommendations on 
monitoring participants for infection, pralsetinib dose interruption, reduction or permanent 
discontinuation, depending on severity of the adverse event.  Substantive changes to the 
protocol, along with a rationale for each change, are summarized below: 
 
Text has been updated to include review findings of infectious fatal adverse events 
and management guidelines for pralsetinib (Sections A5-1.1.1 [Table A5-1] and 
A5-1.1.2 [Table A5-3]). 
 
Additional minor changes have been made to improve clarity and consistency.  
New information appears in italics.  This amendment represents cumulative changes to 
the original protocol. 

Pralsetinib—F. Hoffmann-La Roche Ltd 
4/Protocol BO42864, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
1. 
PROTOCOL SUMMARY ............................................................... 11 
1.1 
Synopsis .................................................................................. 11 
1.2 
Study Schema ......................................................................... 15 
1.3 
Schedule of Activities and Sample Collection Schedules ........ 17 
2. 
INTRODUCTION ........................................................................... 26 
2.1 
Study Rationale ....................................................................... 26 
2.2 
Background.............................................................................. 27 
2.3 
Pralsetinib ................................................................................ 28 
2.3.1 
Nonclinical Activity ................................................................... 28 
2.3.2 
Clinical Experience .................................................................. 29 
2.4 
Benefit–Risk Assessment ........................................................ 32 
2.5 
COVID-19 Benefit-Risk Assessment ....................................... 33 
2.6 
COVID-19 Vaccines ................................................................. 33 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 34 
4. 
STUDY DESIGN ........................................................................... 35 
4.1 
Overall Design ......................................................................... 36 
4.1.1 
Main Treatment Period ............................................................ 36 
4.1.2 
Crossover Treatment Period .................................................... 37 
4.1.3 
End of Treatment Period and 30-Day Follow-Up Contact ........ 38 
4.1.4 
Follow-Up Period ..................................................................... 38 
4.1.5 
Independent Data Monitoring Committee ................................ 38 
4.2 
Rationale for Study Design ...................................................... 38 
4.2.1 
Rationale for Study Population ................................................ 38 
4.2.2 
Justification for Dose ............................................................... 40 
4.2.3 
Rationale for Control Group ..................................................... 40 
4.2.4 
Rationale for Biomarker Assessments ..................................... 42 
4.3 
End of Study Definition ............................................................ 43 
4.4 
Duration of Participation .......................................................... 43 
5. 
STUDY POPULATION .................................................................. 44 

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5/Protocol BO42864, Version 6 
5.1 
Inclusion Criteria For All Participants ....................................... 44 
5.2 
Exclusion Criteria For All Participants ...................................... 46 
5.3 
Crossover Eligibility Criteria ..................................................... 49 
5.4 
Lifestyle Considerations ........................................................... 49 
5.4.1 
Meals and Dietary Restrictions ................................................ 49 
5.4.2 
Caffeine, Alcohol, and Tobacco ............................................... 49 
5.4.3 
Activity ..................................................................................... 49 
5.4.4 
Contraception Requirements ................................................... 49 
5.5 
Screen Failures ........................................................................ 50 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY ........... 50 
6.1 
Study Treatments Administered ............................................... 50 
6.1.1 
Participants in Arm A and Participants Who Crossover 
from Arm B to Receive Pralsetinib ........................................... 53 
6.1.2 
Investigator’s Choice of SOC Platinum-Containing 
Anticancer Treatment Regimens:  For Participants in 
Arm B ....................................................................................... 53 
6.1.2.1 
Administration .......................................................................... 53 
6.1.3 
Timing of Dose Administration ................................................. 55 
6.2 
Preparation, Handling, Storage, and Accountability ................. 57 
6.3 
Treatment Assignment ............................................................. 58 
6.4 
Study Treatment Compliance .................................................. 59 
6.5 
Dose Modification .................................................................... 59 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 59 
6.7 
Treatment of Overdose ............................................................ 60 
6.8 
Concomitant Therapy .............................................................. 61 
6.8.1 
Permitted Therapies ................................................................ 61 
6.8.2 
Cautionary Therapy ................................................................. 62 
6.8.3 
Prohibited Therapy and Procedures ........................................ 63 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............ 64 
7.1 
Discontinuation of Study Treatment ......................................... 64 
7.1.1 
Liver Chemistry Stopping Criteria ............................................ 64 
7.2 
Participant Discontinuation or Withdrawal from the Study ....... 65 

Pralsetinib—F. Hoffmann-La Roche Ltd 
6/Protocol BO42864, Version 6 
7.3 
Participants Lost to Follow-Up ................................................. 65 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 66 
8.1 
Eligibility Review and Registration ........................................... 67 
8.2 
Demographic Information ........................................................ 68 
8.3 
Medical History ........................................................................ 68 
8.4 
Efficacy Assessments .............................................................. 68 
8.4.1 
Tumor and Response Evaluations ........................................... 68 
8.4.1.1 
Radiographic Assessments ..................................................... 69 
8.4.2 
Eastern Cooperative Oncology Group Performance Status .... 70 
8.5 
Safety Assessments ................................................................ 70 
8.5.1 
Physical Examinations ............................................................. 70 
8.5.2 
Vital Signs ................................................................................ 70 
8.5.3 
Electrocardiograms .................................................................. 71 
8.5.4 
Clinical Safety Laboratory Assessments .................................. 71 
8.5.5 
Pregnancy Testing ................................................................... 72 
8.6 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 72 
8.6.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 73 
8.6.2 
Follow-Up of Adverse Events and Serious Adverse Events .... 73 
8.6.3 
Adverse Events During Crossover ........................................... 73 
8.6.4 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................................... 74 
8.6.5 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................................... 74 
8.6.6 
Pregnancy................................................................................ 75 
8.6.7 
Death Events ........................................................................... 75 
8.6.8 
Adverse Events of Special Interest and Selected 
Adverse Events ........................................................................ 75 
8.6.8.1 
Adverse Events of Special Interest .......................................... 75 
8.6.8.2 
Selected Adverse Events ......................................................... 76 
8.6.9 
Medical Monitors and Emergency Medical Contacts ............... 76 
8.7 
Pharmacokinetics .................................................................... 76 
8.8 
Pharmacodynamics ................................................................. 76 

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8.9 
Genetics .................................................................................. 76 
8.10 
Biomarker Assessments .......................................................... 77 
8.11 
Immunogenicity Assessments ................................................. 77 
8.12 
Health Economics and Medical Resource Utilization ............... 77 
8.13 
Clinical Outcome Assessments ............................................... 77 
8.14 
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ........................................................ 77 
8.14.1 
Overview of the Research Biosample Repository .................... 77 
8.14.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 78 
8.14.3 
Sample Collection .................................................................... 78 
8.14.4 
Confidentiality .......................................................................... 78 
8.14.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 79 
8.14.6 
Withdrawal from the Research Biosample Repository ............. 79 
8.14.7 
Monitoring and Oversight ......................................................... 80 
9. 
STATISTICAL CONSIDERATIONS .............................................. 80 
9.1 
Statistical Hypotheses ............................................................. 80 
9.2 
Sample Size Determination ..................................................... 80 
9.2.1 
Analysis Sets ........................................................................... 81 
9.3 
Statistical Analyses .................................................................. 81 
9.3.1 
General Considerations ........................................................... 81 
9.3.2 
Primary Endpoint ..................................................................... 82 
9.3.2.1 
Sensitivity and Supplementary Analyses ................................. 84 
9.3.2.2 
Subgroup Analyses .................................................................. 85 
9.3.3 
Secondary Endpoints ............................................................... 85 
9.3.3.1 
Time-to-Event Endpoints (OS and DOR) ................................. 85 
9.3.3.2 
Binary Endpoints (ORR,  DCR, and CBR) ............................... 86 
9.3.3.3 
Participant-Reported Outcomes ............................................... 86 
9.3.3.4 
Safety Endpoints ...................................................................... 86 
9.3.4 
Other Analyses ........................................................................ 87 
9.3.4.1 
Summaries of Conduct of Study .............................................. 87 
9.3.4.2 
Summaries of Demographics and Baseline Characteristics .... 87 

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8/Protocol BO42864, Version 6 
9.3.4.3 
Pharmacokinetic Analyses ....................................................... 87 
9.4 
Interim Analyses ...................................................................... 87 
9.5 
Independent Data Monitoring Committee ................................ 87 
10. 
REFERENCES.............................................................................. 88 
 
 
LIST OF TABLES 
Table 1 
Schedule of Activities for Participants Randomized to Arm A 
and Participants Randomized to Arm B Who Did Not 
Crossover.................................................................................... 17 
Table 2 
Schedule of Activities for Participants Randomized to Arm B 
Who Crossed Over to Arm A ....................................................... 23 
Table 3 
Adverse Events and Treatment-Related Adverse Events 
Experienced by 15% of All Patients (n528) Treated at 
400 mg QD, in the ARROW (BLU-667-1101) Study ................... 30 
Table 4 
Objectives and Corresponding Endpoints ................................... 34 
Table 5 
Study Treatment Description ....................................................... 51 
Table 6 
Analysis Sets .............................................................................. 81 
Table 7 
Situations and Outcomes for the Primary Endpoint:  
Progression-Free Survival........................................................... 83 
Table 8 
Sensitivity and Supplementary Analyses of the Primary 
Endpoint:  Progression-Free Survival, as Assessed by the 
Investigator ................................................................................. 84 
Table 9 
Planned Statistical Analyses of the Secondary Endpoints .......... 85 
 
 
LIST OF FIGURES 
Figure 1 
Overall Study Design .................................................................. 15 
Figure 2 
Efficacy Summary (Blinded Independent Central Review) .......... 31 
Figure 3 
Tumor Shrinkage in Treatment-Naive Patients ........................... 32 
 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........... 92 
Appendix 2 
Clinical Safety Laboratory Tests ................................................. 99 
Appendix 3 
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ....................................... 100 
Appendix 4 
Contraceptive and Barrier Guidance ......................................... 119 
Appendix 5 
Safety Plan:  Management of Identified and Potential Risks ..... 122 
Appendix 6 
Anaphylaxis Precautions ........................................................... 130 
Appendix 7 
Eastern Cooperative Oncology Group Performance Status ...... 131 

Pralsetinib—F. Hoffmann-La Roche Ltd 
9/Protocol BO42864, Version 6 
Appendix 8 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) ........................................................................... 132 
Appendix 9 
Protocol Amendment History .................................................... 141 
Appendix 10 
List of Prohibited Medications and Foods ................................. 170 
Appendix 11 
Medications to Be Used with Caution ....................................... 172 
Appendix 12 
Examples of Standard Platinum-Based Chemotherapy 
Labeling Information ................................................................. 175 
Appendix 13 
Investigational Medicinal Product Designations (for Use in 
European Economic Area and United Kingdom) ....................... 177 
Appendix 14 
Abbreviations ............................................................................ 178 
 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
10/Protocol BO42864, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL STUDY 
OF PRALSETINIB VERSUS STANDARD OF CARE 
FOR FIRST-LINE TREATMENT OF 
RET FUSION-POSITIVE, METASTATIC 
NON-SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO42864 
STUDY NAME: 
AcceleRET-Lung 
VERSION NUMBER: 
6 
TEST COMPOUND: 
Pralsetinib (RO7499790) 
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 monitor. 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
11/Protocol BO42864, Version 6 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, OPEN-LABEL, STUDY OF 
PRALSETINIB VERSUS STANDARD OF CARE FOR FIRST-LINE 
TREATMENT OF RET FUSIONPOSITIVE, METASTATIC 
NONSMALL CELL LUNG CANCER 
REGULATORY 
AGENCY IDENTIFIERS: 
IND Number:  143094  
EudaCT Number:  2019-002463-10 
EU CT Number:  2023-505035-12-00  
NCT Number:  NCT04222972 
 
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of pralsetinib compared with 
standard-of-care (SOC) for the first-line treatment of patients with rearranged during transfection 
(RET) fusionpositive, metastatic nonsmall cell lung cancer (NSCLC).  SOC treatment will be 
investigator’s choice of SOC platinum-containing anticancer treatment regimens, as measured 
primarily by progression-free survival (PFS), for patients with RET fusionpositive metastatic 
NSCLC who have not previously received treatment with a multikinase inhibitor for metastatic 
disease. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Corresponding Endpoint 
 To assess whether pralsetinib 
improves PFS compared with 
investigator’s choice of SOC 
platinum-containing anticancer 
treatment regimens for 
participants with 
RET fusion-positive metastatic 
NSCLC 
 PFS, defined as the time from randomization date to 
the first documented PD, as assessed by investigator  
according to RECIST v1.1 or death due to any cause, 
whichever occurs first 
Key Secondary Objectives 
Key Corresponding Endpoints 
 To evaluate the efficacy of 
pralsetinib compared with 
investigator’s choice of SOC 
platinum-containing anticancer 
treatment regimens 
 ORR, defined as the proportion of participants with a 
CR or a PR on two consecutive occasions  4 weeks 
apart, as assessed by investigator according to 
RECIST v1.1 
 To evaluate OS 
 OS, defined as the time from randomization date to 
death due to any cause 
Additional Secondary Objectives 
Additional Corresponding Endpoints 
 To evaluate the safety and 
tolerability of pralsetinib 
compared with investigator’s 
choice of SOC 
platinum-containing anticancer 
treatment regimens 
 Incidence and severity of adverse events, with 
severity determined according to the NCI CTCAE v5.0 
 Change from baseline ECOG Performance Status 
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical laboratory 
test results 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
12/Protocol BO42864, Version 6 
 To compare additional measures 
of anticancer activity 
 DOR, defined as the time from the first occurrence of 
a documented objective response to disease 
progression or death from any cause (whichever 
occurs first), as assessed by investigator according to 
RECIST v1.1 
 CBR, defined as the proportion of participants who 
experience a best response of SD with a minimum 
duration of 6 months, a CR, or a PR, as assessed by 
investigator according to RECIST v1.1 
 DCR, defined as the proportion of participants who 
experience a best response of CR, or PR, or SD, as 
assessed by investigator according to RECIST v1.1 
CBR  clinical benefit rate; CR  complete response; CTCAE v5.0  Common Terminology 
Criteria for Adverse Events, Version 5.0; DCR  disease control rate; DOR  duration of 
response; ECOG  Eastern Cooperative Oncology Group; NCI  National Cancer Institute; 
NSCLC  non-small cell lung cancer; ORR  objective response rate; OS  overall survival; 
PD  progressive disease; PFS  progression-free survival;; PR  partial response; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; RET rearranged 
during transfection (oncogene); SD  stable disease; SOC  standard of care. 
 
OVERALL DESIGN AND STUDY POPULATION 
The Sponsor has decided to prematurely terminate the study due to Blueprint Medicines' 
decision to discontinue global marketing and development of pralsetinib in all territories 
(excluding US and Greater China).  The investigators were informed of premature study 
termination on 23 January 2024 by a study memo communicating this decision. 
This is a Phase III, randomized, open-label, two-arm, international study designed to evaluate 
the efficacy and safety of pralsetinib compared with platinum chemotherapy-based regimen 
chosen by the investigator from a list of SOC platinum-containing anticancer treatment 
regimens.   
Several key aspects of the study design and study population are summarized below. 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
13/Protocol BO42864, Version 6 
Phase: 
Phase III 
Population Type: 
Adult patients 
Control Method: 
Active comparator 
Population Diagnosis 
or Condition: 
Locally advanced 
unresectable or 
metastatic NSCLC with 
documented RET 
fusion 
Interventional 
Model: 
Parallel 
Population Age: 
 18 years 
Test Product: 
Pralsetinib 
(RO7499790) 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator:  Carboplatin/cisplatin 
and pemetrexed; 
 Pembrolizumab, 
carboplatin/cisplatin, 
and pemetrexed; 
 Carboplatin/cisplatin 
and gemcitabine; or 
 Pembrolizumab, 
carboplatin, and 
paclitaxel or 
nab-paclitaxel 
Study Treatment 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 226 
 
STUDY TREATMENT 
Pralsetinib 
Participants randomized to  pralsetinib (Arm A) or participants originally randomized to Arm B 
who cross over will receive 400 mg pralsetinib by mouth once a day.  Dosing will be continuous, 
with no inter-cycle rest periods.  The dose of pralsetinib can be reduced up to three times for 
management of drug-related toxicities. 
Standard of Care 
Participants randomized to the chemotherapy arm (Arm B) will receive one of six SOC 
platinum-containing anticancer treatment regimens at the study center as chosen by the treating 
investigator on the basis of NSCLC histology. 
 
For participants with NSCLC of non-squamous histology: 
– 
Carboplatin in combination with pemetrexed (with vitamin supplementation):  
Participants should receive pemetrexed 500mg/m2 followed by carboplatin to target 
area under the concentrationtime curve (AUC) of 5 mg  min/mL both on Day 1 every 
3 weeks (Q3W) for 4 or 6 cycles with an option to continue maintenance pemetrexed 
500 mg/m2 Q3W until progression or up to a maximum of 2 years. 
– 
Cisplatin in combination with pemetrexed (with vitamin supplementation):  Participants 
should receive pemetrexed 500 mg/m2 followed by cisplatin 75 mg/m2 both on Day 1 
Q3W for 4 or 6 cycles with an option to continue maintenance pemetrexed 500 mg/m2 
Q3W until progression or for up to a maximum of 2 years. 
– 
Pembrolizumab in combination with carboplatin and pemetrexed (with vitamin 
supplementation):  Participants should receive pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 (with vitamin supplementation) and carboplatin AUC of 
5 mg/mL/min all on Day 1 Q3W for four to six cycles followed by pembrolizumab 
200 mg together with pemetrexed 500 mg/m2 Q3W until progression or for up to a 
maximum of 2 years. 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
14/Protocol BO42864, Version 6 
– 
Pembrolizumab in combination with cisplatin and pemetrexed (with vitamin 
supplementation):  Participants should receive pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 (with vitamin supplementation) and cisplatin 75 mg/m2 all on 
Day 1 Q3W for 4 or 6 cycles followed by pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 Q3W until progression or for up to a maximum of 2 years. 
 
For participants with NSCLC of squamous histology, participants will receive one of 
following three SOC platinum-containing anticancer treatment regimens at the study center 
as chosen by the treating investigator: 
– 
Carboplatin in combination with gemcitabine:  Participants should receive carboplatin to 
target AUC of 5 mg  min/mL on Day 1 of each 3-week cycle and gemcitabine 
1250 mg/m2 on Days 1 and 8 of each 3-week cycle for 4 or 6 cycles. 
– 
Cisplatin in combination with gemcitabine:  Participants should receive cisplatin 
75 mg/m2 on Day 1 of every 3-week cycle and gemcitabine 1250 mg/m2 on Days 1 and 
8 of each 3-week cycle for 4 or 6 cycles. 
– 
Carboplatin in combination with paclitaxel/nab-paclitaxel and pembrolizumab:  
Participants should receive pembrolizumab 200 mg together with carboplatin to target 
AUC of 6 mg  min/mL and paclitaxel 200 mg/m2 on Day 1, or nab-paclitaxel 100 mg/m2 
on Days 1, 8, and 15 of each 3-week cycle for 4 or 6 cycles, followed by pembrolizumab 
200 mg Q3W until progression or for up to a maximum of 2 years. 
 
Each study site will administer chemotherapy for 4 or 6 cycles based on local guidelines.   
Doses of investigator’s choice of SOC platinum-containing anticancer therapy regimens may be 
modified or discontinued due to toxicity as described in the product labels and on institutional 
standards. 
DURATION OF PARTICIPATION 
The Sponsor has decided to prematurely terminate Study BO42864.  The duration of 
participation for each participant will depend on the treatment received: 
 
Participants receiving pralsetinib can remain on the study until disease progression as 
assessed by the investigator, until continued access solutions for pralsetinib are available, 
pralsetinib is no longer available, or precluded by toxicity, non-compliance, withdrawal of 
consent, death, or closure of the study by the Sponsor, whichever comes first.   
 
Participants receiving SOC platinum-containing anticancer treatment should be withdrawn 
from the study promptly.  In the event that the SOC treatment regimen used within the study 
is not available to the participant after withdrawal, the participant may remain in the study 
and continue to receive the SOC treatment but must discontinue, at the latest, by the time 
the last patient receiving pralsetinib has discontinued from the study.   Investigators will be 
given advanced notice of this timepoint.  Additional reasons for study discontinuation for 
participants that are eligible to remain in the study are toxicity, non-compliance, withdrawal 
of consent, death, or closure of the study by the Sponsor. 
 
COMMITTEES 
Independent Committees: independent Data Monitoring Committee 
Other Committees: 
Not applicable 
 
 

PralsetinibF. Hoffmann-La Roche Ltd
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1.2
STUDY SCHEMA
The overall study design is presented in Figure 1.
Figure 1
Overall Study Design
ECOG PSEastern Cooperative Oncology Group Performance Status; EOT  end of treatment; INV investigator; NSCLC non-small cell lung 
cancer; PD progressive disease; PTAPPost-Trial Access Program; Rrandomization; RETrearranged during transfection; SOC  standard of 
care; tx treatment.

 
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a For participants randomized to Arm A, study treatment will be discontinued either at the time of PD as assessed by the investigator or at the time 
continued access solutions (PTAP) for pralsetinib is available, or when pralsetinib is no longer available, whichever comes first. 
b For participants randomized to Arm B who crossed over to Arm A prior to protocol version 5, study treatment will be discontinued either at the 
time of PD as assessed by the investigator or at the time continued access solutions (PTAP) for pralsetinib is available, or when pralsetinib is no 
longer available, whichever comes first. 
c Participants in Arm B no longer have the option to cross over to Arm A as of protocol version 5. 
d Participants randomized to Arm B and still receiving SOC platinum-containing anticancer treatment at the time of protocol version 5 should be 
withdrawn from the study promptly.  In the event that the SOC treatment regimen used within the study is not available to the participant after 
withdrawal, the participant may remain in the study and continue to receive the SOC treatment but must discontinue, at the latest, by the time the 
last patient receiving pralsetinib has discontinued from the study. 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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1.3 
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION SCHEDULES 
Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover  
Assessment or 
Procedure a 
Screening 
Treatment Period (3-Week Cycles) 
EOT 
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 
Cycles 
717 
Cycles 18 
and Beyond c 
Discon. 
Visit  
(EOT) d 
Safety 
Follow-Up  
Days  28 
to  1 
Day 1 b 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Within 
14 Days 
after Final 
Dose 
Approx. 
30 Days after 
Final Dose 
Window (days) 
 
 
 1 
 4 
 4 
 4 
 4 
 4 
 4 
 
 
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
 
Review of inclusion 
and exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
 
 
 
Prior medications and 
antineoplastic 
therapies 
x 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications and 
procedures g 
 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x 
x 
Adverse events i 
x 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x 
x 
Physical examination j 
x 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x  
 
Vital signs 
x 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x  
 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover (cont.)  
Assessment or 
Procedure a 
Screening 
Treatment Period (3-Week Cycles) 
EOT 
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 
Cycles 
717 
Cycles 18 
and Beyond c 
Discon. 
Visit  
(EOT) d 
Safety 
Follow-Up  
Days  28 
to  1 
Day 1 b 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Within  
14 Days 
after Final 
Dose 
Approx. 
30 Days 
after Final 
Dose 
Window (days) 
 
 
 1 
 4 
 4 
 4 
 4 
 4 
 4 
 
 
ECOG Performance 
Status 
x 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x  
 
12-Lead ECG k 
x 
x 
 
 
 
x h 
 
x h, k 
x h, k 
x 
 
Tumor imaging a, e 
(including brain 
imaging) 
x 
As per local institutional standard of care. 
 
 
Serum or urine 
pregnancy test l 
x l 
x 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x 
 
Hematology m 
x 
x n 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x 
 
Coagulation:  PT, 
INR,  
and aPTT 
x 
  
 
 
  
 
  
  
 
x 
 
Serum chemistry 
panel m 
x 
x n 
x h 
x h 
x h 
x h 
x h 
x h 
x h 
x 
 
Serology:  HBV, HCV, 
and HIV o 
x 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
x o 
 
 
 
 
 
 
 
x 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
19/Protocol BO42864, Version 6 
Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover (cont.)  
Assessment or 
Procedure a 
Screening 
Treatment Period (3-Week Cycles) 
EOT 
Cycle 1 Cycle 2 Cycle 3 
Cycle4 
Cycle 5 Cycle 6 
Cycles 
717 
Cycles 18 
and Beyond c 
Discon. 
Visit  
(EOT) d 
Safety 
Follow-Up  
Days  28 
to  1 
Day 1 b 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Within  
14 Days 
after Final 
Dose 
Approx. 
30 Days 
after Final 
Dose 
Window (days) 
 
 
 1 
 4 
 4 
 4 
 4 
 4 
 4 
 
 
Tumor sample for 
central RET testing p 
x 
 
 
 
 
 
 
 
 
 
 
TSH, free T3, and free 
T4 q 
x 
 
 
x h 
 
x h 
 
x h 
x h, q 
x 
 
Pralsetinib r 
 
x (QD) 
 
 
Carboplatin or cisplatin s 
 
x 
x 
x 
x 
x u 
x u 
 
 
 
 
Gemcitabine r 
 
x 
x 
x 
x 
x u 
x u 
 
 
 
 
Pemetrexed r 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Pembrolizumab r 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Paclitaxel r 
 
x 
x 
x 
x 
x u 
x u 
 
 
 
 
Nab-paclitaxel t 
 
x 
x 
x 
x 
x u 
x u 
 
 
 
 
Survival and anti-cancer 
therapy follow-up 
 
 
 
 
 
 
 
 
 
x 
x 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover (cont.)  
CNS  central nervous system; Discon.  discontinuation; eCRF  electronic Case Report Form; ECOG  Eastern Cooperative Oncology Group; 
EOT  end of treatment; FT4  free thyroxin; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; 
HCV  hepatitis C virus; MN  mobile nursing; NA  not applicable; PET  positron emission tomography; PFS  progression-free survival;  
Q12W  every 12 weeks; QD  once a day; RET  rearranged during transfection; SOC  standard of care; T3  triiodothyronine; T4  thyroxine; 
TSH  thyroid-stimulating hormone. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
Every effort should be made to keep the scheduled assessments on time for each participant. 
a In general, assessments and procedures are to be performed on Day 1 and before the first dose of study drug for each cycle unless otherwise 
specified.  Treatment cycles are 3 weeks (21 days).  If treatment cycles are adjusted, all procedures except imaging will be completed 
according to the Cycle number and not weeks on treatment; imaging will be performed at the specified timepoints, regardless of treatment 
delays. 
b Participants should receive their first dose of study treatment no later than 7 calendar days after randomization.  After Day 1 of Cycle 1, each 
subsequent cycle may be delayed up to 28 days to allow for resolution of toxicities.  Additional safety tests (e.g., hematology, chemistry, ECG) 
may be performed whenever clinically indicated, at the Investigator’s discretion.  Unless otherwise indicated, all tests and procedures must be 
performed predose at each visit.  Whenever a test result is questionable, it should be repeated immediately. 
c After Cycle 19 is completed, study visits can occur every two cycles (i.e., Cycles 21, 23, 25, etc.) per the investigator’s discretion.  
Any additional monitoring necessary for chemotherapy management should be performed in accordance with SOC guidelines. 
d To be completed within 14 days after the permanent discontinuation of study treatment and before a participant starts another anticancer 
therapy.  EOT procedures do not need to be repeated if they were completed within 7 days.   
e Imaging will be performed as per local institutional standard of care.  
f Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 42 days 
(6 weeks) before randomization (refer to Section 8).  Any participant who will undergo RET testing outside of current SOC should sign the 
Prescreening Informed Consent Form prior to acquisition of tumor sample. 
g Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a participant in addition to protocol-mandated treatment.  Concomitant medications will be recorded on the 
Concomitant Medication eCRF from the time of signing informed consent to 30 days after the final dose.  Note:  Concomitant medications 
should also be recorded on Days 8 and 15 of Cycles 14 or 6 for participants receiving nab-paclitaxel and on Day 8 of Cycles 14 or 6 for 
participants receiving gemcitabine. 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover (cont.)  
h For participants at participating sites who have provided written informed consent to participate in MN visits, this assessment or procedure may 
be performed by a trained nursing professional at the participant's home or another suitable location in an appropriate setting.  For participants 
in Arm A receiving pralsetinib, MN visits may be performed, starting on Day 1 of Cycle 2.  For participants in Arm B, MN visits may be 
performed, starting on Day 1 of Cycle 4 or Cycle 6, or longer for participants receiving investigator’s SOC choice of pemetrexed and 
pembrolizumab. 
i After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported (see Section 8.6.1).  All adverse events will be reported from the start of treatment until 30 days after the 
final dose of study treatment.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be 
notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment 
(see Section 8.6.1 and Appendix 3).  Note:  Adverse events should also be reviewed on Days 8 and 15 of Cycles 14 or 6 for participants 
receiving nab-paclitaxel and on Day 8 of Cycles 14 or 6 for participants receiving gemcitabine. 
j A complete physical examination will be performed at the screening visit, including height.  Subsequent physical examinations will be disease 
and adverse events focused. 
k Twelve-lead ECGs will be performed at screening, on Day 1 of Cycle 1, every 12 weeks thereafter, and at the EOT.  QTc measurements will 
use the Fridericia’s correction method.  Other ECGs should be performed, if clinically indicated (for details, refer to Section 8.5.3). 
l For all female participants of childbearing potential:  A serum pregnancy test must be performed during screening within 7 days of starting 
Cycle 1.  At subsequent timepoints, serum testing is preferred, but urine testing is allowed if a blood draw for other assessments is not 
performed.  A serum or urine pregnancy test should be performed on Day 1 of each cycle after Day 1 of Cycle 1 and at the EOT.  When study 
visits are less frequent than every 4 weeks, a local serum or urine pregnancy test has to be performed as required by local regulations (at least 
monthly).  A positive urine test must be confirmed by a serum test. 
m All blood samples should be collected predose, unless otherwise specified.  Note:  Hematology and serum chemistry panel should be 
performed on Days 8 and 15 of Cycles 14 for participants receiving nab-paclitaxel and on Day 8 for participants receiving gemcitabine. 
n If the screening visit tests are performed within 7 days of Day 1 of Cycle 1, clinical laboratory tests do not need to be repeated on Day 1 of 
Cycle 1. 
o Viral serology includes HIV, HBsAg, total HBcAb, and HCV antibody.  HIV serology will be performed as per local standard after any applicable 
local consenting requirement is met.  HBV serology includes HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb test is 
positive) HBV DNA.  If a participant has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be 
performed to determine if the participant has an HBV infection, prior to randomization.  HCV serology includes HCV antibody and (if HCV 
antibody test is positive) HCV RNA.  If a participant has a positive HCV antibody test at screening, an HCV RNA test must also be performed 
to determine if the patient has an HCV infection. 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 1 
Schedule of Activities for Participants Randomized to Arm A and Participants Randomized to Arm B 
Who Did Not Crossover(cont.)  
p Tumor sample submitted for RET fusion status determination by central testing and assessment of other pathway biomarkers.  If archived 
tumor tissue is not available, participants are required to undergo a pretreatment biopsy. 
q Thyroid-stimulating hormone, free T3, and free T4 are to be checked every other cycle (i.e., every 6 weeks). 
r Treatment regimen will be based on the treatment arm to which the participant is randomly assigned.  If randomized to Arm B, specific SOC 
regimen will be based on investigator’s choice, including dosing on Day 8 of the first 4 or 6 cycles, if regimen contains gemcitabine and Days 8 
and 15 of Cycles 1-4 or 6 if the regimen contains nab-paclitaxel.  See Section 6.1 for treatment details.  Dispensing and accountability of study 
drug will also be performed at every visit for treatment regimen details. 
s Each study site will administer chemotherapy for 4 or 6 cycles according to institutional guidelines.  The selected chemotherapy agents should 
remain the same for all cycles (e.g., participants who start treatment with cisplatin should remain on cisplatin and not switch to carboplatin or 
vice versa and participants who start on paclitaxel should not switch to nab-paclitaxel).  However, for participants who experience 
unacceptable toxicity with the selected chemotherapy, a switch may be considered.  If a switch is considered due to toxicity, notify the Medical 
Monitor. 
t Nab-paclitaxel dosing will occur on Days 1, 8, and 15, and gemcitabine dosing will occur on Days 1 and 8 of each cycle for up to 4 or 6 cycles.  
Note:  Vital signs should be assessed on Days 8 and 15 of Cycles 14 or 6 for participants receiving nab-paclitaxel.  See Section 6.1 for 
treatment details. 
u SOC regimens can be administered up to 4 or 6 cycles based on local guidelines. 
 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 2 
Schedule of Activities for Participants Randomized to Arm B Who Crossed Over to Arm A  
Assessment or Procedure a  
Treatment Period (3-Week Cycles) 
EOT 
CC 1 
CC 2 
CC 3 
CC 4 
CC 5 
CC 6 
CCs 717 
CCs 18 and 
Beyond c 
Discon. Visit 
(EOT) d 
Safety 
Follow-up 
Day 1 b 
Day 1  
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Within  
14 Days after 
Final Dose 
Approx. 
30 Days after 
Final Dose 
Window (days) 
 
 1 
 4 
 4 
 4 
 4 
 4 
 4 
 
 
Informed consent 
x f 
 
 
 
 
 
 
 
 
 
Review of CC eligibility 
criteria g 
x 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and procedures h 
x 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
x 
Adverse events j 
x 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
x 
Physical examination k 
x 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
 
Vital signs 
x 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
 
ECOG Performance Status 
x 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
 
12-Lead ECG l 
x 
 
 
 
x h 
 
x h, l 
x h, l 
x 
 
Tumor imaging a, e 
(including brain imaging) 
As per local institutional standard of care. 
 
 
Serum or urine pregnancy 
test n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Hematology o 
x q 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
 
Coagulation o:  PT, INR, 
and aPTT 
x q 
 
 
 
 
 
 
 
x 
 
Serum chemistry panel o 
x q 
x i 
x i 
x i 
x i 
x i 
x i 
x i 
x 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 2 
Schedule of Activities for Participants Randomized to Arm B Who Crossed Over to Arm A (cont.) 
 
Assessment or Procedure a  
Treatment Period (3-Week Cycles) 
EOT 
CC 1 
CC 2 
CC 3 
CC 4 
CC 5 
CC 6 
CCs 717 
CCs 18 and 
Beyond c 
Discon. Visit 
(EOT) d 
Safety 
Follow-up 
Day 1 b 
Day 1  
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Within  
14 Days after 
Final Dose 
Approx. 
30 Days after 
Final Dose 
Window (days) 
 
 1 
 4 
 4 
 4 
 4 
 4 
 4 
 
 
Urinalysis 
x p 
 
 
 
 
 
 
 
x 
 
TSH, free T3, and T4 q 
 
 
x i 
 
x i 
 
x i, q 
x i, q 
x 
 
Pralsetinib r 
x (QD) 
 
 
Survival and anticancer 
therapy follow-up 
 
 
 
 
 
 
 
 
x 
x 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
Every effort should be made to keep the scheduled assessments on time for each participant. 
As of protocol version 5, participants are no longer eligible for crossover.  Participants randomized to Arm B who experience progressive 
disease, as assessed by the investigator according to RECIST v1.1 and confirmed by BICR in the main treatment period, may be offered the 
opportunity to cross over and receive treatment with pralsetinib following up to at a 28-day washout period after their last dose of investigator’s 
choice of SOC platinum-containing anticancer treatment regimen in Arm B.  Separate informed consent for participants will be required at the 
time of progression, as confirmed by the BICR, for the participant to be eligible for crossover. 
a In general, assessments and procedures are to be performed on Day 1 and prior to the first dose of study drug for each cycle unless otherwise 
specified and not weeks on treatment.  Imaging will be performed at the specified timepoints, regardless of treatment delays. 
b After Day 1 of CC 1, each subsequent cycle may be delayed up to 28 days to allow for resolution of toxicities.  Additional safety tests 
(e.g., hematology, chemistry, and ECG) may be performed whenever clinically indicated at the investigator’s discretion.  Unless otherwise 
indicated, all tests and procedures may be performed predose at each visit.  Whenever a test result is questionable, it should be repeated 
immediately. 
c After CC 19, study visits can occur every two cycles (i.e., CCs 21, 23, 25, etc.) per the investigator’s discretion. 
d If an alternate treatment is started within 14 days of the last dose of study drug, the EOT visit should be conducted before the first dose of 
alternate therapy.  EOT procedures do not need to be repeated if they are completed within 7 days (or within 28 days for disease response 
assessments). 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
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Table 2 
Schedule of Activities for Participants Randomized to Arm B Who Crossed Over to Arm A (cont.) 
 
e Imaging will be performed as per standard of care.  
f Participants must provide signed informed consent for crossover to praseltinib treatment prior to starting pralsetinib. 
g See Section 5.3 for a detailed explanation of the eligibility criteria and procedures for crossing over from Arm B to receive pralsetinib. 
h Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a participant in addition to protocol-mandated treatment.  Concomitant medications will be recorded on the 
Prior and Concomitant Medication and Therapies eCRF. 
i For participants at participating sites who have provided written informed consent to participate in MN visits, this assessment or procedure may 
be performed by a trained nursing professional at the participant's home or another suitable location in an appropriate.  Participants during the 
CC treatment period, MN visits may be performed, starting on Day 1 of CC 2. 
j After initiation of crossover study treatment, all adverse events will be reported until 30 days after the final dose of study treatment 
(see Section 8.6.1).  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Appendix 3).  
Any adverse events that were ongoing from Arm A and worsened in crossover should be recorded as a new adverse event in the Adverse 
Event eCRF with the onset date and severity reported from the onset of the worsening (see Section 8.6.3 and Appendix 3, Section A3–4.1). 
k A complete physical examination will be performed at the Day 1, CC 1 visit, including height.  Subsequent physical examinations will be 
disease and adverse event focused. 
l A single 12-lead ECG will be performed at screening, on Day 1 of CC 1, and every 12 weeks thereafter, and at the EOT.  Subsequently, ECG 
should be repeated if clinically indicated. 
n To be performed for female participants of childbearing potential.  At subsequent timepoints, serum testing is preferred, but urine testing is 
allowed if a blood draw for other assessments is not performed.  A serum pregnancy test should be performed on Day 1 CC 1 (within 7 days 
before Day 1 of CC 1).  A serum or urine pregnancy test should be performed starting on Day 1 of each cycle after Day 1 of CCs 1 and at the 
EOT.  When study visits are less frequent than every 3 weeks, a local serum or urine pregnancy test may be performed as required by local 
regulations (at least once every month).  A positive urine test must be confirmed by a serum test. 
o All blood samples should be collected predose unless otherwise specified. 
p If the clinical laboratory tests are performed within 7 days of Day 1 of CC 1, they do not need to be repeated on Day 1 of CC 1. 
q Thyroid-stimulating hormone, free T3, and T4 are to be checked every other cycle (i.e., every 6 weeks). 
r See Section 6.1 for treatment details.  Dispensing and accountability of pralsetinib will also be performed at every visit for treatment regimen 
details. 
 
 

 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
During the last two decades, the evolution of genetic testing has resulted in the 
identification of genetic alterations that play key roles as oncogenic drivers in lung 
cancer, leading to the development of targeted therapies and immunotherapies to treat 
patients in an individualized way (Rosell and Karachaliou 2016).  For patients with 
tumors harboring specific oncogenic drivers, such as EGFR, ALK, ROS1, and BRAF, 
targeted kinase inhibitor therapies have resulted in significantly higher overall survival 
(OS) compared with patients treated with conventional therapies (Barlesi et al. 2016; 
Rosell and Karachaliou 2016).  Oncogenic rearranged during transfection (RET) fusions 
have been identified in 1%2% of patients with non-small cell cancer (NSCLC).  
However, despite the clear role of RET as an oncogenic driver, owing to the lack of 
globally approved and available therapies targeting RET, diagnostic testing for RET is 
not standard of care (SOC), and patients with RET fusionpositive advanced NSCLC are 
treated per guidelines (National Institute for Health and Care Excellence [NICE] 2019; 
National Comprehensive Cancer Network [NCCN] 2020; Planchard et al. 2020) 
adenocarcinoma and squamous cell carcinoma that is negative for actionable molecular 
markers.  Standard treatment for patients with advanced, non-resectable NSCLC lacking 
a driver mutation is cytotoxic chemotherapy and immunotherapy with a checkpoint 
inhibitor.  Cytotoxic chemotherapy generally has a response rate of approximately 
30%40% in the first-line setting (using platinum-based combinations) and 
approximately 10% in the second-line setting (Ardizzoni et al. 2007; Herbst et al. 2018).  
Recent data indicate that patients with NSCLC carrying an oncogenic driver mutation are 
typically not responsive to checkpoint inhibitors (Mazieres et al. 2018; Sabari et al. 2018; 
Tufman et al. 2018).  This low immunotherapy response rate is seen despite expression 
of programmed deathligand 1 (PD-L1) in a substantial portion of the 
RET fusionpositive lung cancers and may be attributed to the overall lower tumor 
mutation burden in RET fusionpositive lung cancers compared with lung cancers that 
do not have activation of a dominant driver such as RET (Mazieres et al. 2018; 
Sabari et al. 2018; Tufman et al. 2018). 
Pralsetinib is a potent and selective inhibitor of oncogenic RET alterations.  Based on 
the promising results from the ARROW trial of pralsetinib in previously treated patients 
with advanced NSCLC, the potential for pralsetinib to offer a more effective treatment 
with improved tolerability than current SOC therapies in the RET-driven 
NSCLC population and the modest overall clinical benefit of standard first-line therapy 
for patients with RET-dependent NSCLC, novel approaches directly targeting RET are 
necessary for patients with advanced NSCLC in the first-line setting. 
The purpose of this study is to assess the efficacy and safety of pralsetinib compared 
with SOC for the first-line treatment of patients with RET fusionpositive, metastatic 
NSCLC.  SOC treatment will be investigator’s choice of SOC platinum-containing 
anticancer treatment regimens, as measured primarily by progression-free survival 

 
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(PFS), for patients with RET fusionpositive metastatic NSCLC who have not previously 
received treatment with a multikinase inhibitor (MKI) for metastatic disease. 
2.2 
BACKGROUND 
Pralsetinib (formerly known as BLU-667) is a potent and selective inhibitor of oncogenic 
RET alterations.  The RET receptor tyrosine kinase is expressed in several neural, 
neuroendocrine, and genitourinary tissue types that normally require ligand and 
co-receptor binding for activation.  Oncogenic RET rearrangements have been identified 
in 1%2% of NSCLC (Lin et al. 2015).  The rearrangements typically produce chimeric 
transcripts that encode a fusion protein consisting of the RET kinase domain coupled to 
a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4), resulting in a 
constitutively active kinase that promotes tumorigenesis. 
In the ongoing first-in-human study of pralsetinib (ARROW; BLU-667-1101), a 
preliminary response rate of 58% to pralsetinib monotherapy was observed in patients 
with advanced NSCLC bearing RET fusions as the sole oncogenic driver, and pralsetinib 
monotherapy has been generally well tolerated at doses up to 400 mg once a day (QD) 
(Gainor et al. 2019). 
Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 
2.1 million new cases and 1.8 million deaths in 2018 (WHO 2018).  Lung cancer has two 
main subtypes, small-cell lung cancer and NSCLC, with approximately 85% of patients 
falling into the histologic subtype of NSCLC.  NSCLCs are generally subcategorized into 
adenocarcinoma, squamous cell carcinoma, and large cell (undifferentiated) carcinoma. 
Oncogenic RET fusions have been identified in 1%2% of NSCLC (Lipson et al. 2012; 
Takeuchi et al. 2012; Stransky et al. 2014).  RET fusions are typically found in 
adenocarcinoma histology (although occasionally squamous) and tend to occur more 
frequently in young patients who are not smokers.  Owing to the lack of available 
therapies targeting RET, diagnostic testing for RET is not SOC, and patients with 
RET fusionpositive advanced NSCLC are treated per NCCN and European Society of 
Medical Oncology (ESMO) guidelines (NCCN 2020; Planchard et al. 2020) for actionable 
molecular marker–negative adenocarcinoma and squamous cell carcinoma.  Standard 
treatment for patients with advanced, non-resectable NSCLC lacking a driver mutation is 
cytotoxic chemotherapy and immunotherapy with checkpoint inhibitor.  Subsequent 
therapy for patients whose disease is refractory to treatment consists of best supportive 
care additional cytotoxic chemotherapy or enrollment in a clinical trial. 
Platinum-based chemotherapy regimens remain the mainstay of first-line therapy 
globally for patients with advanced NSCLC with no actionable oncogenic mutations.  
The addition of bevacizumab has also shown benefit for patients with adenocarcinoma, 
including patients with NSCLC, but is associated with a greater incidence of bleeding 
events and treatment-related deaths.  Immune checkpoint inhibition, either as 
monotherapy or in combination with platinum-based chemotherapy, with or without 

 
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bevacizumab, is also an option for patients lacking actionable oncogenic mutations.  
However, the presence of an oncogenic mutation is associated with low 
PD-L1 expression and is predictive of a lack of benefit of single-agent checkpoint 
inhibitor therapy (Mazieres et al. 2018).  
Detailed information on pralsetinib is provided in the Pralsetinib Investigator's Brochure. 
2.3 
PRALSETINIB 
Pralsetinib (formerly known as BLU-667) is a potent and selective inhibitor of RET fusion 
proteins and oncogenic RET mutants. 
2.3.1 
Nonclinical Activity 
Preclinical Pharmacology 
A summary of nonclinical information is provided in the Pralsetinib Investigator’s 
Brochure.  Key pharmacokinetic (PK) drugdrug interactions (DDIs) in the pralsetinib 
clinical program, based on recently completed studies, are presented below. 
In vitro studies demonstrated that the Phase I metabolism of pralsetinib is primarily 
mediated by CYP3A4, with minor contribution from CYP2D6 and CYP1A2, whereas 
glucuronidation is primarily catalyzed by UGT1A4.  Pralsetinib is also a P-glycoprotein 
(P-gp) substrate.  Therefore, strong CYP3A and/or P-gp inhibitors and inducers may 
affect circulating levels of pralsetinib. 
In vitro, pralsetinib is a reversible inhibitor of CYP2C8, CYP2C9, and CYP3A4 
(testosterone 6-hydroxylation) with Ki values of 9.6, 4.1, and 24 M, respectively.  
Pralsetinib also demonstrated time-dependent inhibition of CYP3A4 (testosterone 
6-hydroxylation) in vitro with a Kinact and KI of 0.24 min-1 and 154 M, respectively.  
The R1 values for CYP2C8, CYP2C9, and CYP3A4 inhibition, R1gut, and R2 value for 
CYP3A4 inhibition for pralsetinib are either at or above the threshold for a potential 
clinical DDI (i.e., R1  1.02, R1gut  11, and R2  1.25).  Therefore, clinical DDIs with 
concomitant medications for which CYP2C8-, CYP2C9-, or CYP3A-mediated 
metabolism constitute the primary mechanism of clearance are likely. 
In vitro in human hepatocytes, pralsetinib (0.03 to 10 M) was a weak inducer of 
CYP1A2 with a maximal induction of 2.0-fold ( 1% of positive control response), 2.7-fold 
(1% of positive control response), and 2.6-fold (2% of positive control response) in 
Lots 336, 348B, and 412, respectively.  Pralsetinib caused concentration-dependent 
induction of CYP2B6 mRNA expression in two lots with a maximal induction of 4.1-fold 
(35% of positive control response) and 3.5-fold (26% of positive control response) in 
Lots 336 and 412, respectively.  Pralsetinib 50% effective concentration (EC50) and 
maximum effective concentration (Emax) for CYP2B6 induction (based on 
mRNA expression) were estimated as 0.22 M and 3.6-fold, and 0.36 M and 3.7-fold in 
Lot 336 and Lot 412, respectively.  Pralsetinib caused concentration-dependent 
induction of CYP3A4 mRNA expression in all three lots tested with a maximal induction 

 
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of 9.6-fold (37% of positive control response), 3.7-fold (30% of positive control 
response), and 7.3-fold (74% of positive control response) in Lots 336, 348B, and 412, 
respectively.  Pralsetinib EC50 and Emax for CYP3A4 induction (based on mRNA 
expression) were estimated as 1.4 M and 8.7-fold, and 3.0 M and 3.7-fold in Lots 336 
and 348B, respectively.  Pralsetinib EC50 and Emax for CYP3A4 induction (based on 
enzyme activity levels) were estimated as 0.35 M and 3.2-fold in Lot 336.  
The estimated R3 value is  0.8, the threshold for a potential clinical DDI.  Given that 
activation of the pregnane X receptor results in co-induction of CYP3A and 
CYP2C enzymes, DDIs with comedications that are predominantly metabolized by these 
enzymes are likely. 
Pralsetinib is a dual P-gp/BCRP substrate but is not a substrate of OAT1, OAT3, 
OATP1B1, OATP1B3, OCT1, OCT2, BSEP, MATE1, or MATE2-K.  Results from in vitro 
studies indicate that at clinically relevant concentrations, pralsetinib is an inhibitor of 
P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K.  Therefore, 
pralsetinib may have the potential for PK drug interactions with substrates of these 
transporters.  Pralsetinib at clinically relevant concentrations did not significantly inhibit 
OAT3, OCT1, OCT2, or BSEP transport activity and the likelihood for a clinical DDI is 
low. 
2.3.2 
Clinical Experience 
The pralsetinib clinical development program was initiated in November 2016 and 
includes two ongoing clinical study in patients. 
 
Study BLU-667-1101 ("ARROW") is a Phase I/II study of the highly selective 
RET inhibitor, pralsetinib, in patients with medullary thyroid cancer (MTC), NSCLC, 
and other advanced solid tumors. 
 
Study BO41932 (Tapistry) is a Phase II tumor agnostic precision immune-oncology 
platform trial 
 
The Phase II portion of the ARROW study recruited patients at the recommended 
Phase II dose (RP2D) of 400 mg QD. 
Safety 
Overall, in the ARROW study, treatment at dose levels  400 mg, including the RP2D of 
400 mg orally (PO) QD, has demonstrated acceptable tolerability, with most adverse 
events being of low grade and reversible.  All adverse events that have occurred in 
 15% of all patients (n  528) treated at 400 mg QD dose level, as of the data cutoff date 
of 6 November 2020, including their severity and relatedness, are listed in Table 3. 
As of 6 November 2020, across the entire study, 6.3% of patients have discontinued 
treatment because of treatment-related toxicity.  Of the patients with NSCLC treated at a 
starting dose of 400 mg QD (n  281), a total of 7.5% of patients discontinued pralsetinib 
because of the following treatment-related toxicities, as follows:  pneumonitis (7 patients; 
2.5%):  pneumonia or thrombocytopenia (2 patients each;  1%); anemia, blood creatine 

 
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phosphokinase increased, chest pain, colitis, constipation, electrolyte imbalance, fatigue, 
gait disturbance, hyponatremia, hypoxia, lymphocyte count decreased, neutropenia, 
pancytopenia, respiratory distress, rhabdomyolysis, or stomatitis (1 patient each;  1%).  
Additional details are provided in Pralsetinib Investigator’s Brochure. 
Table 3 
Adverse Events and Treatment-Related Adverse Events 
Experienced by 15% of All Patients (n528) Treated at 400 mg 
QD, in the ARROW (BLU-667-1101) Study 
Adverse Event 
Adverse Events with 
Overall Rate  15% 
Treatment-Related Adverse Events 
Amongst Ones with 
Overall Rate  15% a 
All 
Grade  3 
All 
Grade 3 
Grade 4 
AST increased 
243 (46.0) 
30 (5.7) 
206 (39.0) 
12 (2.3) 
2 ( 1) 
Anemia 
241 (45.6) 
91 (17.2) 
179 (33.9) 
64 (12.1) 
0 
Constipation 
221 (41.9) 
3 ( 1) 
142 (26.9) 
3 ( 1) 
0 
ALT increased 
179 (33.9) 
22 (4.2) 
152 (28.8) 
10 (1.9) 
1 ( 1) 
Hypertension 
172 (32.6) 
85 (16.1) 
133 (25.2) 
64 (12.1) 
0 
Diarrhea 
155 (29.4) 
15 (2.8) 
79 (15.0) 
6 (1.1) 
0 
WBC count decreased 
142 (26.9) 
32 (6.1) 
133 (25.2) 
28 (5.3) 
1 ( 1) 
Pyrexia 
133 (25.2) 
6 (1.1) 
24 (4.5) 
0 
0 
Fatigue 
132 (25.0) 
12 (2.3) 
81 (15.3) 
8 (1.5) 
0 
Neutrophil count 
decreased 
128 (24.2) 
51 (9.7) 
120 (22.7) 
43 (8.1) 
5 ( 1) 
Blood creatinine 
increased 
118 (22.3) 
2 ( 1) 
76 (14.4) 
1 ( 1) 
0 
Neutropenia 
116 (22.0) 
59 (11.2) 
109 (20.6) 
46 (8.7) 
9 (1.7) 
Cough 
114 (21.6) 
3 ( 1) 
18 (3.4) 
2 ( 1) 
0 
Hypocalcemia 
109 (20.6) 
19 (3.6) 
49 (9.3) 
5 ( 1) 
2 ( 1) 
Hyperphosphatemia 
94 (17.8) 
1 ( 1) 
86 (16.3) 
0 
0 
Dyspnea 
89 (16.9) 
13 (2.5) 
10 (1.9) 
1 ( 1) 
0 
Blood CPK increased 
86 (16.3) 
34 (6.4) 
81 (15.3) 
24 (4.5) 
8 (1.5) 
Dry mouth 
84 (15.9) 
0 
63 (11.9) 
0 
0 
Nausea 
84 (15.9) 
1 ( 1) 
37 (7.0) 
0 
0 
Headache 
82 (15.5) 
2 ( 1) 
26 (4.9) 
1 ( 1) 
0 
Edema peripheral 
82 (15.5) 
1 ( 1) 
35 (6.6) 
0 
0 
Dysgeusia 
81 (15.3) 
0 
69 (13.1) 
0 
0 
Decreased appetite 
80 (15.2) 
5 ( 1) 
34 (6.4) 
1 ( 1) 
0 
CPK  creatine phosphokinase; QD  once a day. 
a No patient experienced a Grade 5 adverse reaction with an overall reporting rate  15%.  
Data cutoff date:  6 November 2019 

 
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Efficacy 
As presented at the American Society of Clinical Oncology (ASCO) in 2021 and shown 
in Figure 2, pralsetinib demonstrates broad and durable antitumor activity in patients with 
RET fusion-positive NSCLC, regardless of treatment history, RET fusion partner or 
mutation, or central nervous system (CNS) involvement.  The objective response rate 
(ORR) was 62% with 91% disease control rate (DCR) in patients with NSCLC previously 
treated with platinum chemotherapy.  In treatment-naive patients with 
RET fusionpositive NSCLC ORR was 79% (Curigliano et al. 2021). 
Figure 2 Efficacy Summary (Blinded Independent Central Review) 
 
CBR  clinical benefit rate; CR  complete response; DCR  disease control rate; 
ECOG PS  Eastern Cooperative Oncology Group performance status; mDOR  median duration 
of response; mPFS  median progression-free survival; NE  not evaluable; PD  progressive 
disease; ORR  overall response rate; PR  partial response; SD  stable disease. 
a Protocol amendment July 2019; this amendment expanded inclusion criteria to allow 
recruitment of treatment-naive patients eligible for standard platinum-based therapy who had 
previously not been permitted. 
b ECOG PS of 2 was permitted prior to protocol amendment in July 2018. 
c History of or current ECOG performance status. 
 

 
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Figure 3 Tumor Shrinkage in Treatment-Naive Patients 
 
a Protocol amendment July 2019; this amendment expanded inclusion criteria to allow 
recruitment of treatment-naive patients eligible for standard platinum-based therapy who had 
previously not been permitted. 
 
2.4 
BENEFIT–RISK ASSESSMENT 
To date, pralsetinib has demonstrated broad and durable anti-tumor activity in patients 
with RET fusionpositive NSCLC and RET-mutated MTC, regardless of treatment 
history, RET fusion partner or mutation, or CNS involvement.  The ORR of pralsetinib in 
these unmet need populations ranged from 58% up to 83% depending on the indication.  
The overall safety experience suggests that pralsetinib has a favorable tolerability profile 
in patients with advanced cancer and that most adverse events and serious adverse 
events are readily detected and managed with current safety monitoring procedures.  
Taken together, the available information indicates that the benefitrisk ratio for 
pralsetinib therapy is acceptable for further development and justifies studying 
pralsetinib in a randomized protocol setting to potentially replace the existing SOC. 
Refer to Appendix 5 for information on the anticipated risks during pralsetinib 
administration and risk mitigation measures, including guidelines for managing adverse 
events associated with pralsetinib. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of pralsetinib may be found in the Pralsetinib 
Investigator’s Brochure. 

 
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2.5 
COVID-19 BENEFIT-RISK ASSESSMENT 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are a more vulnerable population.  Infection 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses.  It is unclear whether or how cancer therapies, such as 
chemotherapy, targeted therapy, or immunotherapy, affect the incidence or severity of 
COVID-19.  It is not known whether any of the agents being investigated in this study will 
increase the risk of infection with SARS-CoV-2.  Participants with a serious infection 
requiring IV antibiotics within 7 days prior to initiation of study treatment or any active 
infection that, in the opinion of the investigator, could impact patient safety will be 
excluded from study participation, and participants will be carefully monitored for 
infections during the study. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with pralsetinib and clinical and radiologic features 
for SARSCoV-2 related interstitial pneumonia.  Thus, investigators should use their 
clinical judgment when evaluating and managing patients with pulmonary symptoms. 
2.6 
COVID-19 VACCINES 
Based on a specific benefit-risk assessment, taking into account the available relevant 
information, the approved non-live COVID-19 vaccines should be administered in 
patients who are in the study, as long as there is no other contraindication (e.g., known 
hypersensitivity to a vaccine component). 
Although there is no specific requirement regarding the timing of vaccine administration, 
the vaccination should ideally be at least commenced before study enrollment and 
initiation of study drug, whenever possible. 
Details of any COVID-19 vaccination received before study enrollment should be 
captured in the medical history section, at screening, whereas details regarding the 
COVID-19 vaccine received during the study should be recorded in the concomitant 
medication section. 
Investigators should share with patients' primary healthcare providers relevant 
information regarding any potential effect of respective study drugs on the response to 
COVID-19 vaccination, as applicable.  Also, patients should contact the investigators or 
site staff, when they are invited to receive a COVID-19 vaccine deployed in their region. 
The decision to vaccinate a patient should be based on a patient’s SARS-CoV-2 
infection/complication risk, general health condition, severity of underlying malignancy, 
and regional epidemiology of COVID-19.  COVID-19 vaccines should be administered in 
accordance with their respective prescribing information and applicable immunization 
guidelines. 

 
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After COVID-19 vaccination, one should continue to observe the applicable 
epidemiologic/public health and hygiene measures during the pandemic, along with per 
protocol safety measures and assessments in order to minimize the risk and to 
appropriately identify and assess potential adverse reactions (e.g., nausea, diarrhea, 
myalgia) possibly shared by vaccines and study drugs. 
Based on the published mechanism of action of the COVID-19 vaccines and the known 
mechanism of action of pralsetinib, there is no scientific rationale to expect that 
COVID-19 vaccines will affect the efficacy of pralsetinib. 
3. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of pralsetinib 
compared with investigator’s choice of SOC platinum-containing anticancer treatment 
regimens (for a description of the SOC anticancer treatment regimens, 
see Section 4.1.1) in participants with RET fusion-positive NSCLC who have not 
previously received treatment in the metastatic setting.  Specific objectives and 
corresponding endpoints for the study are presented in Table 4. 
Table 4 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
 To assess whether pralsetinib improves 
PFS compared with investigator’s choice 
of SOC platinum-containing anticancer 
treatment regimens for participants with 
RET fusionpositive metastatic NSCLC 
 PFS, defined as the time from randomization 
date to the first documented PD, as 
assessed by investigator according to 
RECIST v1.1 or death due to any cause, 
whichever occurs first 
Key Secondary Objectives 
Key Corresponding Endpoints 
 To evaluate the efficacy of pralsetinib 
compared with compared with 
investigator’s choice of SOC 
platinum-containing anticancer treatment 
regimens 
 ORR, defined as the proportion of 
participants with a CR or a PR on two 
consecutive occasions  4 weeks apart, as 
assessed by investigator according to 
RECIST v1.1 
 To evaluate OS 
 OS, defined as the time from randomization 
date to death due to any cause 
Additional Secondary Objectives 
Additional Corresponding Endpoints 
 To evaluate the safety and tolerability of 
pralsetinib compared with investigator’s 
choice of SOC platinum-containing 
anticancer treatment regimens 
 Incidence and severity of adverse events, 
with severity determined according to the 
NCI CTCAE v5.0 
 Change from baseline ECOG Performance 
Status 
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical 
laboratory test results 

 
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Table 4 
Objectives and Corresponding Endpoints (cont.)  
Additional 
Secondary Objectives (cont.) 
Additional 
Corresponding Endpoint(s) (cont.) 
 To compare additional measures of 
anticancer activity 
 DOR, defined as the time from the first 
occurrence of a documented objective 
response to disease progression or death 
from any cause (whichever occurs first), as 
assessed by investigator according to 
RECIST v1.1 
 CBR, defined as the proportion of 
participants who experience a best 
response of SD with a minimum duration of 
6 months, a CR, or a PR, as assessed by 
investigator according to RECIST v1.1 
 DCR, defined as the proportion of 
participants who experience a best 
response of CR, or PR, or SD, as assessed 
by investigator according to RECIST v1.1 
CBR  clinical benefit rate; CR  complete response; CTCAE v5.0  Common Terminology Criteria 
for Adverse Events, Version 5.0; DCR  disease control rate; DOR  duration of response; 
ECOG  Eastern Cooperative Oncology Group; NCI  National Cancer Institute; 
NSCLC  non-small cell lung cancer; ORR  objective response rate; OS  overall survival; 
PD  progressive disease; PFS  progression-free survival; PR  partial response; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; RET rearranged 
during transfection (oncogene); SD  stable disease; SOC  standard of care. 
  
4. 
STUDY DESIGN 
Following the Sponsor’s decision to prematurely terminate the study,  participants 
randomized to Arm A and participants in Arm B who crossed over to Arm A should 
continue to receive study treatment and undergo the revised study assessments as 
indicated in the schedule of activities (Section 1.3) and described in Section 8 until study 
discontinuation.   
Participants randomized to Arm B and still receiving SOC platinum-containing anticancer 
treatment at the time of protocol version 5 should be withdrawn from the study promptly.  
In the event that the SOC treatment regimen used within the study is not available to the 
participant after withdrawal, the participant may remain in the study and continue to 
receive the SOC treatment but must discontinue, at the latest, by the time the last patient 
receiving pralsetinib has discontinued from the study.  Investigators will be given 
advanced notice of this timepoint.  Crossover from Arm B (SOC) to Arm A will no longer 
be an option.  
The study will be closed once all patients receiving pralsetinib have left the study or 
pralsetinib is no longer available, whichever occurs first. 

 
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4.1 
OVERALL DESIGN 
This is a Phase III, randomized, open-label, two-arm, international study designed to 
evaluate the efficacy and safety of pralsetinib compared with platinum 
chemotherapy-based regimen chosen by the investigator from a list of 
SOC platinum-containing anticancer treatment regimens.  PFS, as assessed by 
investigator, is the primary endpoint for patients with RET fusionpositive metastatic 
NSCLC who have not previously received a systemic anticancer therapy for metastatic 
disease. 
The study is divided into two periods:  a screening period (of up to 28 days in length)and 
a treatment period of variable duration (as indicated by tolerance and disease status).  
Safety follow-up assessment will occur approximately 30 days after the final dose of 
study drug. 
All study visits are intended to be conducted on an outpatient basis but may be 
conducted on an inpatient basis, as needed.  Informed consent may be obtained up to 
42 days (6 weeks) before study drug administration on Day 1 of Cycle 1.  After informed 
consent, participants will be evaluated for study eligibility during the screening period, 
which is to be completed within 28 or fewer days before randomization.  For study 
eligibility, RET fusion status may be determined locally or centrally.  However, baseline 
tumor tissue samples for all participants must also be submitted for confirmation of 
RET fusion status by central testing. 
After the screening assessments are performed, participants will be randomly assigned 
in a 1:1 ratio to one of two treatment arms:  Arm A (pralsetinib) or Arm B (investigator’s 
choice of platinum-containing anticancer treatment regimen selected from a list of 
SOC regimens, with or without pembrolizumab; refer to Section 4.1.1 for description), 
stratified by history of brain metastasis (yes vs. no), Eastern Cooperative Oncology 
Group (ECOG) Performance Status (0 vs. 1), and intended use of pembrolizumab if 
randomized to the control arm (yes vs. no). 
4.1.1 
Main Treatment Period 
During the main treatment period, participants randomized to Arm A will receive 
pralsetinib at a dose of 400 mg QD PO in continuous 21-day treatment cycles.  
Participants may continue to receive pralsetinib until disease progression as assessed 
by the investigator, until continued access solutions for pralsetinib are available, when 
pralsetnib is no longer available, or precluded by toxicity, non-compliance, withdrawal of 
consent, death, or closure of the study by the Sponsor (see Section 7.2), whichever 
comes first. 

 
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Participants randomized to Arm B will receive one of the following 
SOC platinum-containing anticancer treatment regimens, as determined by the treating 
investigator: 
 
For participants with NSCLC of non-squamous histology 
– 
Carboplatin or cisplatin and pemetrexed (with vitamin supplementation); with 
optional pemetrexed (with vitamin supplementation) maintenance  
– 
Pembrolizumab in combination with carboplatin or cisplatin in combination 
pemetrexed (with vitamin supplementation), followed by pembrolizumab and 
optional pemetrexed (with vitamin supplementation) maintenance 
 
For participants with NSCLC of squamous histology 
– 
Carboplatin or cisplatin and gemcitabine 
– 
Pembrolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel 
 
Investigator’s choice of platinum-containing anticancer treatment regimen may continue 
in accordance with SOC (four or six 3-week treatment cycles according to institutional 
guidelines).  Participants with NSCLC of non-squamous histology receiving carboplatin- 
or cisplatin-containing regimens may optionally receive subsequent maintenance 
treatment with pemetrexed (and pembrolizumab, if selected).  Participants with NSCLC 
of squamous histology receiving carboplatin and paclitaxel-containing regimens may 
optionally receive maintenance treatment with pembrolizumab, if selected.  
Pembrolizumab and/or pemetrexed maintenance therapy can be continued for up to 
2 years unless stopped earlier owing to toxicity, confirmed disease progression, 
non-compliance, withdrawal of consent, death, or closure of the study by the Sponsor 
(see Section 7.2).  As of protocol version 5, participants receiving SOC 
platinum-containing anticancer treatment should be withdrawn from the study promptly.  
In the event that the SOC treatment regimen used within the study is not available to the 
participant after withdrawal, the participant may remain in the study and continue to 
receive the SOC treatment but must discontinue, at the latest, by the time the last patient 
receiving pralsetinib has discontinued from the study.  Investigators will be given 
advanced notice of this timepoint. 
All participants will present to the study center on Day 1 of Cycle 1 for the first dose of 
study drug, safety monitoring (including ECOG Performance Status assessment, 
physical examination, vital signs, ECG, safety laboratory tests, adverse event, and 
concomitant medication recording, etc.), quality-of-life (QoL) questionnaires, biomarker 
sample collection, and PK assessments.  Additional study visits for assessment of safety 
will be conducted periodically throughout study treatment in accordance with the 
schedule of activities (see Section 1.3, Table 1 and Table 2). 
4.1.2 
Crossover Treatment Period 
Following the Sponsor’s decision to prematurely terminate the study , the option for 
participants in Arm B (SOC) to crossover to Arm A (pralsetinib) was removed as of 

 
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protocol version 5.  Participants who have already crossed over will follow the 
assessments as indicated in the schedule of activities (Section 1.3, Table 2). 
4.1.3 
End of Treatment Period and 30-Day Follow-Up Contact 
All participants will attend an end of treatment (EOT) visit within 14 days after the final 
dose of study drug.  The EOT visit should be conducted before the participant starts an 
antineoplastic therapy.  The EOT procedures do not need to be repeated if they are 
completed within 7 days (or within 28 days for disease response assessments) prior to 
the final dose.  Safety follow-up assessment will occur approximately 30 days after the 
final dose of study drug or initiates an antineoplastic therapy.  
4.1.4 
Follow-Up Period 
Following the announcement of premature study termination, data on long-term PFS, 
OS, and new anti-cancer therapies will no longer be collected.  However, the safety 
follow-up assessment described in Section 4.1.3  is required.  
4.1.5 
Independent Data Monitoring Committee 
A formal independent Data Monitoring Committee (iDMC) will be formed for this study.  
The aim of the iDMC is to safeguard the interests of trial participants, monitor the main 
outcome measures, including safety and efficacy, and the overall conduct of the trial. 
The role of iDMC is to perform periodic review of the study’s progress, including 
adherence to protocol, follow-up assessments, and safety data.  The iDMC will receive 
information on the progress and data accumulation in this study and provide advice on 
the study conduct.  The iDMC will also make any necessary recommendations to the 
Sponsor relevant to the study design. 
The iDMC will perform reviews of unblinded safety data until the Sponsor is unblinded, 
after which the study team will be responsible for the ongoing monitoring of patient 
safety in the study.  
Further details, including membership and specific roles and responsibilities of the 
iDMC, will be described separately in the iDMC Charter. 
4.2 
RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population 
Targeted therapy has helped improve the care of patients with lung cancer with a 
specific molecular driver.  Novel targeted therapies have demonstrated robust response 
rates and PFS.  For example, in the case of EGFR-targeted therapy, an improvement in 
OS has recently been reported with a third generation TKI (Ramalingam et al. 2020).  
Similarly, for patients with ALK gene rearrangement, second-generation ALK inhibitors 
are associated with a median PFS of longer than 2 years (Peters et al. 2017).  

 
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Such agents are also associated with marked anticancer activity against brain 
metastasis, which is common in these molecular subsets of NSCLC. 
RET gene fusions are present in approximately 1%–2% of NSCLC.  RET is emerging as 
a new targetable driver for this population.  Despite sensitivity to platinum-based 
chemotherapy and conflicting small reports regarding the limited efficacy of immune 
checkpoint inhibitor (Mazieres et al. 2019), there have been limited treatment 
approaches for this subset of patients.  Multiple non-selective RET TKIs exhibited 
modest anti-RET activity with an increased off-target toxicity profile that often required 
dose interruption, reduction, or treatment cessation (Lee et al. 2017; Hida et al. 2019).  
The increased toxicity is because of stronger inhibition of other targets, such as VEGFR 
and EGFR inhibition, and an unfavorable PK profile for use in this setting. 
Platinum-based chemotherapy combinations are the current SOC for the first-line 
treatment of metastatic RET fusion–positive NSCLC; however, long-term responses are 
modest and therefore this is a population of high unmet need. 
Pralsetinib a selective RET inhibitor has demonstrated robust efficacy with a 
manageable side effect profile in the Phase I/II, single-arm ARROW study in both 
treatment-naive patients and platinum-exposed patients with RET fusion–positive 
NSCLC.  AcceleRET aims to investigate the safety and efficacy of pralsetinib in the 
first-line metastatic setting in the context of a randomized Phase III trial. 
This Phase III study is designed as a randomized, open-label, efficacy, and safety study.  
Participants who meet all study eligibility criteria will be randomly assigned in a 1:1 ratio 
to receive either pralsetinib or a platinum-containing regimen from an investigators’ 
choice list of SOC platinum-containing anticancer treatment regimens, with or without 
pembrolizumab (see Section 4.1.1).  Random assignment of participants minimizes bias 
and helps ensure that both known and unknown risk factors are distributed evenly 
between treatment arms. 
The study is not blinded because the distinct methods for study drug administration 
(capsules for pralsetinib compared with IV infusion of investigator’s choice of 
SOC platinum-containing anticancer treatment regimens) and the variable dosing 
durations make effective blinding challenging. 
An assessment of whether pralsetinib improves PFS relative to an investigator’s choice 
of SOC platinum-containing anticancer treatment regimens is the primary objective of 
the study.  Response assessments will be based on standard response criteria 
(RECIST v1.1; see Appendix 8). 
Key secondary endpoints include OS and ORR.  Additional secondary endpoints include 
duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), and 
safety and tolerability of pralsetinib. 

 
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4.2.2 
Justification for Dose 
In the dose-finding Phase I portion of the ARROW study, 52 patients received pralsetinib 
at doses ranging from 30 to 600 mg QD, with the maximum tolerated dose (MTD) 
determined to be 400 mg QD.  Of the 4 patients treated with 600 mg pralsetinib QD, 
2 patients experienced dose-limiting toxicities (DLTs), Grade 3 hyponatremia and 
Grade 3 hypertension.  Although both DLTs were reversible, per the protocol guidelines, 
600 mg QD exceeded the MTD, and the MTD of pralsetinib was determined to be 
400 mg QD.  The overall safety across doses ranging from 60 to 400 mg QD was 
favorable.  Most adverse events were Grade 1; the most commonly reported adverse 
events in Phase I portion of the study were constipation (reported in 24% of patients), 
increased ALT (22%), increased (AST 20%), and hypertension (16%).  Pralsetinib 
demonstrated rapid absorption, a long drug-elimination half-life, and a dose-dependent 
increase in exposure and pathway inhibition.  Exposure at the 400-mg MTD provided 
sustained coverage above the predicted tumor and brain RET IC90.  Based on these 
results, 400 mg QD will be the dose of pralsetinib patients will receive in this study. 
Participants will be treated with carboplatin, cisplatin, pemetrexed, gemcitabine, 
paclitaxel or nab-paclitaxel, and pembrolizumab according to approved dosage 
recommendations and SOC. 
4.2.3 
Rationale for Control Group 
The immunophenotype of RET-rearranged lung cancers is characterized by low levels of 
PD-L1 expression and low tumor mutational burden in the majority of patients.  Overall 
outcomes with single- and dual-agent immunotherapy are poor, and therefore these 
options were excluded as control group treatment regimens within the context of this 
study.  In a retrospective case study from Memorial Sloan Kettering Cancer Center, no 
responses to immune checkpoint inhibitors were observed in patients with metastatic 
RET-rearranged lung cancers and the best objective response to therapy in most 
patients was progressive disease (Offin et al. 2019).  Poor outcomes with immune 
checkpoint inhibitors were also noted in the international IMMUNOTARGET registry in 
the context of metastatic RET-rearranged NSCLC.  The ORR observed in patients with 
RET alterations was 6%, with a median PFS of 2.1 months (Mazieries et al. 2019). 
These findings are consistent with a growing body of evidence uncovering poor 
outcomes with immune checkpoint inhibition in selected oncogene-addicted lung 
cancers.  In EGFR-mutant and ALK-rearranged lung cancers, early data on the 
decreased activity (compared with unselected cancers) of immunotherapy resulted in the 
exclusion of patients with such tumors in registration-enabling studies. 
According to treatment guidelines, patients who have RET rearrangementpositive 
NSCLC should be treated with a RET inhibitor where available (NCCN 2020).  The lack 
of globally approved therapy targeting RET, coupled with low rates of testing for RET, 
leads to most patients with RET rearrangement being treated as no actionable 

 
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oncogenic mutation, that is, with platinum-based chemotherapy, with or without 
pembrolizumab. 
For patients with adenocarcinoma, pemetrexed is the preferred platinum partner shown 
in a Phase III non-inferiority randomized study comparing OS following treatment with 
pemetrexed with cisplatin compared with gemcitabine with cisplatin.  In the study, the 
treatment by histology analysis showed that in non-squamous NSCLC, OS was 
significantly improved in the cisplatin/pemetrexed arm compared with the 
cisplatin/gemcitabine arm (n  847; 12.6 vs. 10.9 months, respectively; hazard ratio 
[HR]:  0.84; 95% CI:  0.71 to 0.99; p  0.03) (Scagliotti et al. 2008). 
In a retrospective series, patients with advanced RET-rearranged lung cancers, systemic 
therapy with pemetrexed-based chemotherapy was shown to be active.  The ORR of 
45% and a median PFS of 19 months were observed relative to a historical response 
rate of 30% with platinum-doublet chemotherapy (Drillon et al. 2016). 
The benefit of platinum-based chemotherapy with pemetrexed and/or pembrolizumab 
has been demonstrated in KEYNOTE-189, a Phase III study of 616 patients with 
metastatic non-squamous NSCLC, regardless of PD-L1 status without prior systemic 
therapy.  Patients were randomized to receive platinum chemotherapy and pemetrexed 
plus pembrolizumab or placebo every 3 weeks for four cycles, followed by 
pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance 
therapy.  The OS at 12 months was 49.4% (95% CI:  42.1% to 56.2%) in the 
placebo-platinum therapy and pemetrexed arm (HR for death:  0.49; 95% CI:  0.38 to 
0.64; p  90.001), and 69.2% (95% CI:  64.1 to 73.8) in the pembrolizumab and 
chemotherapy arm (Gandhi et al. 2018). 
The benefit of platinum therapy with paclitaxel, nab-paclitaxel, and pembrolizumab was 
shown in KEYNOTE-407, a Phase III study of 559 patients with untreated metastatic 
squamous NSCLC.  Patients were randomized to receive either pembrolizumab in 
combination with chemotherapy or chemotherapy and placebo.  The combination of 
pembrolizumab and chemotherapy showed improved clinical benefit over chemotherapy 
plus placebo: OS (median OS: 17.1 months; 95% CI:  14.4 to 19.9 months vs. 
11.6 months; 95% CI:  10.1 to 13.7 months; HR:  0.71; 95% CI:  0.58 to 0.88 months) 
and PFS (median PFS:  8.0 months; 95% CI:  6.3 to 8.4 months vs. 5.1 months; 
95% CI:  4.3 to 6.0; HR: 0.57; 95% CI:  0.47 to 0.69) (Paz-Ares et al. 2020). 
Platinum therapy with gemcitabine is an accepted approved regimen for patients with 
squamous cell carcinoma.  Although comparable efficacy has been observed with 
several platinum-based regimens with third-generation cytotoxic agents (paclitaxel, 
gemcitabine, docetaxel, vinorelbine), gemcitabine-based platinum combinations have 
more favorable safety profiles.  The benefit of gemcitabine in combination with platinum 
therapy in metastatic squamous NSCLC has also been shown in a Phase III, 
non-inferiority, randomized study comparing OS following treatment with pemetrexed 

 
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with cisplatin versus gemcitabine with cisplatin.  OS for cisplatin/pemetrexed was 
non-inferior to cisplatin/gemcitabine (median OS:  10.3 vs. 10.3 months, respectively; 
HR:  0.94; 95% CI:  0.84 to 1.05) in the combined histology population.  However, in a 
treatment by histology analysis, the study found that for patients with squamous NSCLC, 
the OS gain was slightly higher with cisplatin and gemcitabine compared with cisplatin 
and pemetrexed (OS:  10.8 vs. 9.4 months, respectively; HR:  1.23; 95% CI:  1.00 to 
1.51; p  0.05) (Scagliotti et al. 2008). 
Second-line treatment options for patients with non-squamous and/or squamous NSCLC 
show limited clinical activity.  Single-agent checkpoint inhibition in this setting results in 
an ORR ranging from 14%20% and a PFS of 2.35.2 months (Borghaei et al. 2015; 
Brahmer et al. 2015; Herbst et al. 2016; Fehrenbacher et al. 2018). 
In this study, investigators will have the option to select from a choice of 
SOC platinum-containing anticancer treatment regimens aligned with local regulations 
and institutional guidance. 
4.2.4 
Rationale for Biomarker Assessments 
RET fusions are oncogenic drivers in 1%2% of NSCLCs.  The most common 
RET fusion in NSCLC is KIF5B-RET, but many other RET fusion partners have been 
reported (Ou et al. 2020).  KIF5B-RET fusion can occur in different variants depending 
on the point of fusion (Kohno et al. 2012).  Different RET fusion variants or RET fusion 
partners as well as genomic alterations in tumor-related genes that exist prior to 
RET inhibitor treatment may influence the efficacy of pralsetinib treatment.  Several 
molecular mechanisms of resistance to tyrosine kinase inhibitors (TKIs) have been 
implicated in drug resistance, including target modification (e.g., acquired mutations 
within the kinase domain), gene amplification or overexpression, or activation of bypass 
signaling pathways (Chen and Fu 2011; Lovly 2015).  RET mutations and mutations in 
cancer-related genes may appear as a result of biologic selection pressure on tumor 
cells induced by RET TKI treatment.  RET mutation-mediated resistance in single 
patients has been reported for MKIs (Wirth et al. 2019).  Mechanisms of acquired 
resistance to selective RET TKIs, such as selpercatinib and pralsetinib, remain mainly 
unknown.  However, the emergence of a RET solvent front mutation (G810) together 
with the re-emergence of the RET gatekeeper mutation (V804M) during selpercatinib 
treatment has been reported (Solomon et al. 2020). 
Understanding different RET-driver mutations influence on treatment efficacy and 
underlying resistance mechanisms to pralsetinib is critical to develop strategies to 
optimize treatment benefit and to overcome resistance. 
Genomic alterations and copy number variations that may lead to drug resistance can be 
detected in nucleic acids from tissue and in circulating nucleic acids from plasma.  
Tumor nucleic acids (e.g., circulating tumor DNA [ctDNA]) are shed into the circulation 
and can be analyzed by next-generation sequencing (NGS).  Circulating tumor nucleic 

 
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acids may be used to help to elucidate the molecular profile of RET fusion-positive 
NSCLC and to detect changes in the molecular profile during RET TKI treatment and at 
progression. 
Comprehensive diagnostic tests are required to test patients with NSCLC for rare 
targetable oncogenic driver alterations to select the best treatment option for their 
disease.  Comprehensive tissue and blood-based companion diagnostic (CDx) tests for 
pralsetinib are essential to identify patients with RET fusion-positive NSCLC who can 
benefit from this targeted treatment.  Blood-based assays to detect RET and other 
oncogenic driver alterations will provide a diagnostic testing option for patients who do 
not have sufficient or no tumor tissue available for biomarker testing.  Additionally, 
blood-based testing of changes in RET or cancer-related genes from circulating tumor 
nucleic acids will provide a less-invasive option for participants to be tested for their 
tumor mutational status during treatment and at tumor progression.  Data generated may 
support registration of tissue and plasma NGS assays as a CDx for pralsetinib in 
RET fusionpositive NSCLC. 
Data may 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. 
4.3 
END OF STUDY DEFINITION 
The Sponsor has decided to prematurely terminate Study BO42864.  The end of this 
study is defined as the date when the last participant, last visit occurs. 
4.4 
DURATION OF PARTICIPATION 
The Sponsor has decided to prematurely terminate Study BO42864.  The duration of 
participation for each participant will depend on the treatment received: 
 
Participants receiving pralsetinib can remain on the study until disease progression 
as assessed by the investigator, until continued access solutions for pralsetinib are 
available, pralsetinib is no longer available, or for reasons as described in 
Section 7.2, whichever comes first.   
 
Participants receiving SOC platinum-containing anticancer treatment should be 
withdrawn from the study promptly.  In the event that the SOC treatment regimen 
used within the study is not available to the participant after withdrawal, the 
participant may remain in the study and continue to receive the SOC treatment but 
must discontinue, at the latest, by the time the last patient receiving pralsetinib has 
discontinued from the study.   Investigators will be given advanced notice of this 
timepoint.  Additional reasons for study discontinuation for participants that are 
eligible to remain in the study are described in Section 7.2. 
  

 
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5. 
STUDY POPULATION 
Approximately 226 participants are planned to be enrolled and randomized in a 1:1 ratio 
to one of the following two arms: 
 
Arm A:  approximately 113 participants randomized to receive pralsetinib 
 
Arm B:  approximately 113 participants randomized to receive a platinum-containing 
chemotherapy regimen from an investigator’s choice list of SOC regimens 
 
Prospective approval of protocol deviations to recruitment and eligibility criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA FOR ALL PARTICIPANTS 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
 
Participant provides signed informed consent (as described in Appendix 1) to 
participate in this study, which includes compliance with the requirements and 
restrictions listed in the Informed Consent Form and in this protocol. 
 
Participant must be age  18 years at the time of signing Informed Consent Form. 
 
Participant has pathologically or cytologically confirmed, definitively diagnosed, 
locally advanced unresectable NSCLC (i.e., Stage IIIB not eligible for definitive 
chemoradiotherapy) or metastatic NSCLC (i.e., Stage IV), per the Union 
Internationale Contre le Cancer/American Joint Committee on Cancer staging 
system (Amin et al. 2017) of either squamous or non-squamous histology based on 
the major histologic component that has not been treated with systemic anticancer 
therapy for metastatic disease.  For further details on testing methods, refer to 
Section 8.10. 
 
Participant has documented RET fusion that meets one of the following two criteria: 
– 
Documented RET fusion using either tissue or plasma, as determined by an 
appropriate validated local test performed by a Clinical Laboratory Improvement 
Amendments (CLIA)-certified or equivalent accredited diagnostic laboratory.  
For details of acceptable testing methods, see Section 8.10. 
– 
Documented RET fusion by a positive result from tumor tissue testing performed 
centrally by Foundation Medicine (FMI) clinical trial assay or an alternate, 
approved central laboratory for that region. 
 
The participant agrees to provide preferably adequate tumor tissue (archived, 
if available, or a fresh biopsy) or if tumor tissue cannot be obtained, a fixed and 
embedded cell pellet from pleural effusion would be acceptable for central 
confirmation of RET fusion status using an NGS-based assay.  If no adequate tumor 
material is available and a new biopsy is not feasible, the participant will not be 
eligible for enrollment.  This specimen must be accompanied by the full laboratory 
report of the RET fusion local test and must also be submitted within 2 weeks of 
enrollment for confirmation of RET status by central testing. 

 
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 
A representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a 
paraffin block (preferred) or a target of 1520 slides containing unstained, freshly 
cut, serial sections  is required for participation in this study. 
– 
A minimum of 1014 slides is acceptable if the slides meet the tissue 
requirements in Section 8.10.  Notify the Medical Monitor if less than 15 slides 
are available. 
– 
Note:  If only a fixed and embedded cell pellet from pleural effusion is available 
it is highly recommended to submit the entire FFPE block for processing at the 
central lab as this sample type is more challenging to process with NGS. 
 
Participant has an ECOG Performance Status 0 or 1 (see Appendix 7). 
 
Participants who have a negative HIV test at screening, with the following exception:  
Individuals 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. 
 
Participant has measurable disease, as determined by the local site investigator or 
radiologic assessment according to RECIST v1.1 (see Appendix 8). 
– 
Lesions located in a previously irradiated area are considered measurable 
if progression has been demonstrated after irradiation. 
 
Participant cannot have received any prior anticancer therapy for metastatic 
disease. 
– 
Participants can have received previous anticancer therapy (except a selective 
RET inhibitor) in the neoadjuvant or adjuvant setting but must have experienced 
an interval of at least  6 months from completion of therapy to recurrence. 
– 
Participants who have received previous immune checkpoint inhibitors in the 
adjuvant setting or consolidation therapy following chemoradiation are not 
allowed to receive pembrolizumab if randomized to Arm B. 
 
Participant is an appropriate candidate for and agrees to receive one of the 
investigator choice platinum-based anticancer regimens if randomized to Arm B. 
 
For women of childbearing potential:  participants who agree to remain abstinent 
(refrain from heterosexual intercourse) or use contraception, as defined below: 
– 
Women must remain abstinent or use a highly effective method of 
non-hormonal contraception with a failure rate of  1% per year during the 
treatment period and for a period of a minimum of 14 days after the final dose 
of pralsetinib.  The duration of contraceptive methods for participants receiving 
SOC platinum-containing anticancer treatment regimens is as indicated in the 
respective applicable labeling documents (refer to Appendix 4, Section A4–1). 
– 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (i.e.,  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 

 
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(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
– 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male partner sterilization, 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. 
 
For men:  participants who agree 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, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of  1% per 
year, during the treatment period and for 7 days after the final dose of 
pralsetinib to avoid exposing the embryo.  With pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 7 days after the final dose of pralsetinib to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period.  The duration of 
contraceptive methods for participants receiving investigator’s choice of SOC 
platinum-containing anticancer treatment is as indicated in the respective 
applicable labeling documents (refer to Appendix 4, Section A4–2). 
– 
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 and withdrawal are not adequate methods of preventing 
drug exposure.  If required per local guidelines or regulations, information about 
the reliability of abstinence will be described in the local Informed Consent 
Form. 
 
5.2 
EXCLUSION CRITERIA FOR ALL PARTICIPANTS 
Participants are excluded from the study if any of the following criteria apply: 
 
Participant’s tumor has any additional known primary driver alterations other than 
RET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF.  
Investigators should inform the Medical Monitor about the enrollment of participants 
with tumors having comutations. 
 
Participant previously received treatment with a selective RET inhibitor. 
 
Participant received radiotherapy or radiosurgery to any site within 14 days before 
randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before 
randomization. 

 
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 
Participants with a history of pneumonitis of non-infectious etiology within the last 
12 months. 
 
Participants with autoimmune disease that requires systemic therapy (excluding 
thyroid, vitiligo). 
 
Participants with autoimmune disease within 2 years of study enrollment are not 
eligible for the pembrolizumab-containing regimen. 
 
Participants with a medical condition that requires immunosuppression. 
 
Participant has either CNS metastases or a primary CNS tumor that is associated 
with progressive neurological symptoms or requires increasing doses of 
corticosteroids to control the CNS disease. 
– 
If a participant requires corticosteroids for management of CNS disease, the 
dose must be stable for the 2 weeks prior to Day 1 of Cycle 1. 
 
Participant has significant cardiovascular disease, as evidenced by any of the 
following conditions: 
– 
Participant has a QT interval corrected through the use of Fridericia’s formula 
(QTcF)  480 ms. 
– 
Participant has a history of prolonged QT syndrome or torsades de pointes. 
– 
Participant has a familial history of prolonged QT syndrome. 
– 
Participant has clinically significant, uncontrolled, cardiovascular disease, 
including Grade III or IV congestive heart failure according to the New York 
Heart Association (NYHA) classification; myocardial infarction or unstable 
angina within the previous 6 months, uncontrolled hypertension, or clinically 
significant, uncontrolled arrhythmias, including bradyarrhythmias that may 
cause QT prolongation (e.g., Type II second-degree or third-degree heart 
block). 
 
Participant requires treatment with a prohibited medication or herbal remedy 
(as specified in Section 6.8.3) that cannot be discontinued at least 2 weeks prior to 
the start of study drug administration. 
– 
Pralsetinib may be started within 14 days of stopping a prohibited medication if 
considered by the investigator to be safe and in the best interest of the 
participant.  Inform the medical monitor if you are considering administering 
pralsetinib within 14 days of stopping a prohibited medication. 
 
Participant received treatment with hematopoietic growth factor support within 
14 days of the first dose of study drug. 
 
Participant has had a major surgical procedure within 14 days of the first dose of 
study drug or is planned to have such procedure during the study period. 
– 
Procedures, such as central venous catheter placement, tumor needle biopsy, 
and feeding tube placement, are not considered major surgical procedures. 
 
Participant has had a history of another primary malignancy that has been 
diagnosed or required therapy within the past 3 years prior to randomization. 

 
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– 
The following prior malignancies are not exclusionary:  completely resected 
basal cell and squamous cell skin cancer, curatively treated localized prostate 
cancer, curatively treated localized thyroid cancer, and completely resected 
carcinoma in situ of any site. 
 
Participant has any of the following within 14 days prior to the first dose of study 
drug: 
– 
Platelet count  75  109/L 
– 
ANC  1.0  109/L 
– 
Hemoglobin  9.0 g/dL 
RBC transfusion and erythropoietin may be used to reach at least 9.0 g/dL but must 
have been administered at least 2 weeks before the first dose of study drug. 
– 
AST or ALT  3  the upper limit of normal (ULN) if no hepatic metastases are 
present;  5  ULN if hepatic metastases are present 
– 
Total bilirubin  1.5  ULN;  3  ULN in presence of Gilbert disease 
– 
Estimated (according to the Cockcroft-Gault formula) or measured creatinine 
clearance  45 mL/min 
– 
Total serum phosphorous  5.5 mg/dL 
 
Participant has a known hypersensitivity to cisplatin, carboplatin, pemetrexed, or 
pembrolizumab (for participants with NSCLC of non-squamous histology only), or 
carboplatin, gemcitabine, pembrolizumab, paclitaxel, or nab-paclitaxel (for 
participants with NSCLC of squamous histology only). 
 
Participant with a serious infection requiring systemic antibiotics within 7 days prior 
to initiation of study treatment, or any active infection that, in the opinion of the 
investigator, could impact patient's safety. 
– 
In the setting of a pandemic or epidemic, screening for active infections should 
be considered according to local or institutional guidelines or guidelines of 
applicable professional societies (e.g., ASCO or ESMO). 
 
Participant has an active, uncontrolled infection (viral, bacterial, or fungal). 
– 
Participants with controlled infections who are stable on treatment may be 
eligible if the benefitrisk assessment is justified, and permission is granted 
from the Sponsor. 
 
Participant has positive hepatitis C virus (HCV) antibody test at screening. 
– 
Participants positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA. 
 
Participant has positive hepatitis B surface antigen (HBsAg) test at screening. 
– 
Participants with a previous hepatitis B virus (HBV) infection or resolved HBV 
infection (hepatitis B core antibody [HBcAb] positive, but negative HBsAg) are 
eligible only if the HBV DNA test is negative. 

 
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 
Participant is unwilling or unable to comply with scheduled visits, study drug 
administration plan (including the inability or unwillingness to swallow capsules), 
laboratory tests, or other study procedures and study restrictions. 
 
Participant is pregnant, as documented by a serum -human chorionic gonadotropin 
(hCG) pregnancy test consistent with pregnancy obtained within 7 days before the 
first dose of study drug. 
– 
Participants with -hCG values that are within the range for pregnancy but are 
not pregnant (falsepositives) may be enrolled with written consent of the 
Sponsor after pregnancy has been ruled out.  Women of non-childbearing 
potential (postmenopausal for more than 1 year, documented bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy) do not require a serum 
-hCG test. 
 
Participant is breastfeeding. 
 
Participant with concurrent enrollment in another clinical study, unless it is an 
observational (noninterventional) clinical study, or during the follow-up period of an 
interventional study  
 
Participant has had a prior or has an ongoing clinically significant illness, medical 
condition, surgical history, physical finding, or laboratory abnormality that, in the 
investigator’s opinion, could affect the safety of the participant, alter the absorption, 
distribution, metabolism, or excretion of the study drug, or impair the assessment of 
study results. 
 
5.3 
CROSSOVER ELIGIBILITY CRITERIA 
Following the sponsor’s decision to prematurely terminate the study, the option for 
participants in Arm B (SOC) to crossover to Arm A (pralsetinib) has been removed as of 
protocol version 5. 
5.4 
LIFESTYLE CONSIDERATIONS 
5.4.1 
Meals and Dietary Restrictions 
This study has the following meal and dietary restrictions: 
Participants in Arm A treated with pralsetinib should refrain from consumption of 
grapefruit or grapefruit juice, during treatment. 
 
5.4.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.4.3 
Activity 
This study has no activity restrictions. 
5.4.4 
Contraception Requirements 
During the study, participants must use contraception or take other precautions as 
described in Section 5.1. 

 
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5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomly assigned to study drug.  A minimum set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from health authorities.  Minimum information 
includes demographics, screen failure details, eligibility criteria, and any pretreatment 
serious adverse event. 
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 two screenings per individual) at 
the investigator's discretion.  Rescreened participants will be assigned the same patient 
number as for the initial screening. 
Individuals are not required to re-sign the consent form if they are re-screened within 
30 days after previously signing the consent form.  The investigator will record reasons 
for screen failure in the screening log (see Section 8). 
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. 
In this study, pralsetinib, and the comparators carboplatin, cisplatin, gemcitabine, 
pemetrexed, paclitaxel, nab-paclitaxel, and pembrolizumab are considered 
investigational medicinal products (IMPs).  Appendix 13 identifies all IMPs for this study. 
6.1 
STUDY TREATMENTS ADMINISTERED 
A description of assigned study treatments for this study is presented in Table 5. 

 
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Table 5 
Study Treatment Description 
 
Pralsetinib 
Carboplatin a 
Cisplatin a 
Pemetrexed a Pembrolizumab a 
Gemcitabine a 
Paclitaxel a 
Nab-Paclitaxel a 
Use 
Experimental 
Comparator 
Comparator Comparator 
Comparator 
Comparator 
Comparator 
Comparator 
Type of 
medicinal 
product 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Formulation 
Capsule 
Concentrate for 
solution for 
infusion 
Concentrate 
for solution 
for infusion 
Powder for 
concentrate 
for solution 
for infusion 
Concentrate 
for solution for 
infusion 
Powder 
for solution 
for infusion 
Concentrate 
for solution 
for infusion 
Powder for 
suspension for 
infusion 
Unit dose 
strength 
100 mg 
450 mg 
50 mg 
500 mg 
100 mg 
1000 mg 
150 mg 
100 mg 
Dosage 
level(s) 
400 mg QD 
Target AUC of 
5 mg  min/mL 
Q3W b 
75 mg/m2 
Q3W 
500 mg/m2 
Q3W 
200 mg Q3W 
1250 mg/m2 
Days 1 and 8 of 
each cycle 
200 mg/m2 
Q3W c 
100 mg/m 2 on 
Day 1, 8, and 15 
of each cycle 
Labeling 
Per local requirements 
Route of 
administration 
Oral 
IV injection or 
infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
Packaging 
HDPE bottles 
containing a 
desiccant 
and a 
child-resistant 
closure 
Vials:  Each vial 
will be labeled 
as required per 
country 
requirement. 
Vials:  Each 
vial will be 
labeled as 
required per 
country 
requirement. 
Vials:  Each 
vial will be 
labeled as 
required per 
country 
requirement. 
Vials:  Each vial 
will be labeled as 
required per 
country 
requirement. 
Vials:  Each vial 
will be labeled as 
required per 
country 
requirement. 
Vials:  Each 
vial will be 
labeled as 
required per 
country 
requirement. 
Vials:  Each vial 
will be labeled as 
required per 
country 
requirement. 
Source 
Sponsor 
Sponsor or locally by the trial site, subsidiary, or designee 
Storage 
conditions 
Refer to the pharmacy manual. 
 

 
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Table 5 
Study Treatment Description (cont.) 
 
AUC  area under the concentrationtime curve; HDPE  high-density polyethylene; IMP  investigational medicinal product; Q3W  every 3 weeks; 
QD  once a day; SOC  standard of care. 
a Dosing information and handling procedures for the investigator’s choice SOC anticancer treatment regimens should follow the guidance 
provided in the product label and institutional SOC (see Appendix 1). 
b For participants with squamous NSCLC using the pembrolizumab  carboplatin  paclitaxel or nab-paclitaxel regimen, the dose of carboplatin is 
target AUC of 6 mg  min/mL (see Section 6.1.2.1). 
c For participants of Asian race/ethnicity:  175 mg/m2 administered by IV infusion. 
 
 

 
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Guidelines for dose modification and treatment interruption or discontinuation 
for participants who experience adverse events are provided in Appendix 5. 
6.1.1 
Participants in Arm A and Participants Who Crossover from 
Arm B to Receive Pralsetinib 
Participants randomized to the pralsetinib (Arm A) or participants originally randomized 
to Arm B who cross over will receive 400 mg pralsetinib PO QD.  Dosing will be 
continuous, with no inter-cycle rest periods. 
Doses of pralsetinib may be modified or discontinued for toxicity as described in 
Section 6.5 and Appendix 1, Section A5–1.1.1. 
Pralsetinib doses should be administered with a glass of water in a fasted state, with no 
food intake from 2 hours before until 1 hour after study drug administration.  Participants 
should be instructed to swallow study drug whole and to not chew the study drug. 
Each dose should be administered in the morning, at approximately the same time each 
day.  If a planned dose of pralsetinib is missed, participants can make up that dose 
unless the next dose is due within 12 hours.  Resume the regular daily dose schedule for 
pralsetinib the next day.  If a participant vomits during or after taking pralsetinib, 
re-dosing is not permitted until the next scheduled dose. 
Participants will be dispensed the appropriate number of packaged and labeled 
pralsetinib bottles on Day 1 to allow dosing for 21-day treatment cycles; alternatively, 
participants may be dispensed the appropriate bottle(s) until the next scheduled visit.  
Participants must return all unused capsules (or the empty bottles) at each scheduled 
visit. 
All participants should complete the drug (pralsetinib) self-administration diary and bring 
it to each site visit. 
6.1.2 
Investigator’s Choice of SOC Platinum-Containing Anticancer 
Treatment Regimens:  For Participants in Arm B 
6.1.2.1 
Administration 
Participants randomized to the chemotherapy arm (Arm B) will receive one of six 
SOC platinum-containing anticancer treatment regimens at the study center as chosen 
by the treating investigator on the basis of NSCLC histology. 
For participants with NSCLC of non-squamous histology: 
 
Carboplatin in combination with pemetrexed (with vitamin supplementation):  
Participants should receive pemetrexed 500 mg/m2 followed by carboplatin to target 
area under the concentrationtime curve (AUC) of 5 mg  min/mL both on Day 1 
every 3 weeks (Q3W) for 4 or 6 cycles with an option to continue maintenance 
pemetrexed 500 mg/m2 Q3W until progression or up to a maximum of 2 years. 

 
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 
Cisplatin in combination with pemetrexed (with vitamin supplementation):  
Participants should receive pemetrexed 500 mg/m2 followed by cisplatin 75 mg/m2 
both on Day 1 Q3W for 4 or 6 cycles with an option to continue maintenance 
pemetrexed 500 mg/m2 Q3W until progression or for up to a maximum of 2 years. 
 
Pembrolizumab in combination with carboplatin and pemetrexed (with vitamin 
supplementation):  Participants should receive pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 (with vitamin supplementation) and carboplatin AUC of 
5 mg  min/mL all on Day 1 Q3W for 4 or 6cycles followed by pembrolizumab 
200 mg together with pemetrexed 500 mg/m2 Q3W until progression or for up to a 
maximum of 2 years. 
 
Pembrolizumab in combination with cisplatin and pemetrexed (with vitamin 
supplementation):  Participants should receive pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 (with vitamin supplementation) and cisplatin 75 mg/m2 all on 
Day 1 Q3W for 4 or 6 cycles followed by pembrolizumab 200 mg together with 
pemetrexed 500 mg/m2 Q3W until progression or for up to a maximum of 2 years. 
 
For participants with NSCLC of squamous histology, participants will receive one of 
following three SOC platinum-containing anticancer treatment regimens at the study 
center as chosen by the treating investigator: 
 
Carboplatin in combination with gemcitabine:  Participants should receive 
carboplatin to target AUC of 5 mg  min/mL on Day 1 of each 3-week cycle and 
gemcitabine 1250 mg/m2 on Days 1 and 8 of each 3-week cycle for 4 or 6 cycles. 
 
Cisplatin in combination with gemcitabine:  Participants should receive cisplatin 
75 mg/m2 on Day 1 of every 3-week cycle and gemcitabine 1250 mg/m2 on Days 1 
and 8 of each 3-week cycle for 4 or 6 cycles. 
 
Carboplatin in combination with paclitaxel/nab-paclitaxel and pembrolizumab:  
Participants should receive pembrolizumab 200 mg together with carboplatin to 
target AUC of 6 mg  min/mL and paclitaxel 200 mg/m2 on Day 1, or nabpaclitaxel 
100 mg/m2 on Days 1, 8, and 15 of each 3-week cycle for 4 or 6 cycles, followed by 
pembrolizumab 200 mg Q3W until progression or for up to a maximum of 2 years. 
 
Each study site will administer chemotherapy for 4 or 6 cycles based on local guidelines.  
The selected chemotherapy agent should remain the same for all cycles 
(e.g., participants who start treatment with cisplatin should remain on cisplatin and not 
switch to carboplatin or vice versa and participants that start treatment with 
nab-paclitaxel should not switch to paclitaxel).  However, for participants who experience 
unacceptable toxicity with the selected platinum chemotherapy, a switch may be 
considered.  If a chemotherapy switch is considered, notify the Medical Monitor. 
Doses of investigator’s choice of SOC platinum-containing anticancer therapy regimens 
may be modified or discontinued due to toxicity as described in the product labels and 
on institutional standards. 

 
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Participants should receive appropriate hydration, premedication, and supportive care 
measures as deemed necessary by the treating Investigator and consistent with the 
SOC for their institution.  
Administration of SOC anticancer therapy will be performed in a monitored setting where 
there is immediate access to trained personnel and adequate equipment and medicine 
to manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 6. 
6.1.3 
Timing of Dose Administration 
Study treatment should be administered on Day 1 of each cycle after all procedures and 
assessments have been completed.  Study treatment can be administered within 
 4 days of the targeted Day 1 for each cycle, except Cycle 2 (when study treatment can 
be administered  1 day of the targeted Day 1).  For Cycle 1, study treatment should be 
started within 7 days of randomization (see the schedule of activities in Table 1). 
Cisplatin 
Cisplatin 75 mg/m2 should be infused approximately 30 minutes after the pemetrexed 
infusion Q3W for the first 4 or 6 cycles and should be immediately preceded and 
followed by hydration procedures and administered according to local prescribing 
information and institutional standards. 
Carboplatin 
Carboplatin AUC 5 mg  min/mL (or 6 mg.ml/min for participants with squamous NSCLC 
using the Carboplatin in combination with paclitaxel/nab-paclitaxel and pembrolizumab 
regimen) will be administered as an IV infusion over 1560 minutes Q3W for 4 or 
6 cycles immediately after pemetrexed as per local prescribing information and 
institutional standards. 
Pemetrexed 
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W as 
per prescribing information and institutional standards for up to 2 years unless stopped 
earlier due to centrally confirmed disease progression, unacceptable toxicity, withdrawal 
of consent, or discontinuation for other reasons. 
All participants taking pemetrexed should receive the appropriate supplementation of 
vitamin B12 and folic acid and corticosteroid prophylaxis as listed below: 
 
Folic acid 3501000 g PO:  At least five doses of folic acid must be taken during 
the 7 days preceding the first dose of pemetrexed, and folic acid dosing must 
continue during the full course of therapy and for 21 days after the final dose of 
pemetrexed. 
 
Vitamin B12 1000 g intramuscular (IM) injection:  in the week preceding the first 
dose of pemetrexed and once every three cycles thereafter. 
– 
Subsequent vitamin B12 injections may be given the same day as pemetrexed 
administration. 

 
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 
Dexamethasone prophylaxis 4 mg (or equivalent) PO twice per day:  the day before, 
day of, and day after pemetrexed administration. 
– 
Higher or additional doses are permitted for anti-emetic prophylaxis during 
Cycles 14. 
 
Pemetrexed supplementation may be adjusted as deemed necessary by the treating 
Investigator and consistent with the local prescribing information and/or the institutional 
standards. 
Pembrolizumab 
Pembrolizumab should be administered as a 200 mg IV infusion over 30 minutes Q3W 
as per local prescribing information and institutional standards, for up to 2 years unless 
stopped earlier owing to centrally confirmed disease progression, unacceptable toxicity, 
withdrawal of consent, or discontinuation for other reasons. 
When administering pembrolizumab in combination with chemotherapy, administer 
pembrolizumab before chemotherapy when given on the same day. 
Paclitaxel 
In general, paclitaxel will be administered intravenously at a dose of 200 mg/m2 over 
3 hours Q3W as per local prescribing information and institutional standards, for up to 
4 or 6 cycles, followed by carboplatin.  Participants of Asian race/ethnicity will receive a 
lower starting dose of paclitaxel at 175 mg/m2 by IV infusion over 3 hours.  The term 
“Asian race/ethnicity” refers to a pan-ethnic/racial group that includes diverse 
populations who either live or have ancestral origins in East Asia, Southeast Asia, or 
South Asia.  The applicability of such term in a particular participant will be at the 
discretion of the treating investigator and should be based on the participant’s clinical 
characteristics and country of origin. 
When administering paclitaxel in combination with pembrolizumab and chemotherapy, 
administer pembrolizumab before paclitaxel followed by carboplatin. 
Sites should follow their institutional standard of care for dose adjustments in the event 
of participant weight changes.  For paclitaxel infusion, exceptions to the infusion time of 
3 hours will be allowed for sites that have an institutional policy of infusing paclitaxel 
more quickly (over 90 minutes) or more slowly (up to 4 hours for the first infusion). 
All participants taking paclitaxel should receive the appropriate corticosteroid prophylaxis 
as listed below: 
 
Dexamethasone 20 mg (or equivalent) PO approximately 12 and 6 hours before 
paclitaxel administration 
– 
Participants may be treated with dexamethasone 1020 mg IV within 1 hour 
prior to paclitaxel infusion if the participant did not take the oral dexamethasone 

 
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 
Diphenhydramine 50 mg (or equivalent) administered by IV infusion 3060 minutes 
prior to paclitaxel administration 
 
Cimetidine 300 mg or ranitidine 50 mg (or equivalent) administered by IV infusion 
3060 minutes prior to paclitaxel administration 
 
Paclitaxel supplementation may be adjusted to as deemed necessary by the treating 
Investigator and consistent with the local prescribing information and/or the institutional 
standards. 
Nab-Paclitaxel 
Nab-paclitaxel will be administered intravenously at a dose of 100 mg/m2 over 
30 minutes on Days 1, 8, and 15 of each 21-day cycle, as per local prescribing 
information and institutional standards for up to 4 or 6 cycles.  Nab-paclitaxel should be 
completely administered before initiating carboplatin dose. 
Sites should follow their institutional standard of care for determining the nab-paclitaxel 
dose for participants who are obese and for dose adjustments in the event of participant 
weight changes.  The infusion site should be closely monitored for possible infiltration 
during drug administration. 
Gemcitabine 
Gemcitabine 1250 mg/m2 will be administered intravenously over 30 minutes on Days 1 
and 8 of each 21-day cycle for the first 4 or 6 cycles according to the prescribing 
information and institutional standards. 
Guidelines for medical management of infusion-related reactions and injection-site 
reactions are provided in Appendix 3, Section A3–6.7. 
Additional Medication for Participants in Arm B Who Receive Pemetrexed 
and Nab-Paclitaxel 
Participants in Arm B who receive pemetrexed and nab-paclitaxel should receive the 
appropriate supplementation as described in Section 6.1.3 or per institutional guidance. 
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, using an 
interactive web-based response system (IwRS) by returning the appropriate 

 
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documentation form 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. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the Pralsetinib Investigator's Brochure or local 
prescribing information for information on IMP preparation, storage, handling, and 
accountability. 
6.3 
TREATMENT ASSIGNMENT 
This study is open-label; potential bias will be reduced by the central randomization. 
Participants who meet all study eligibility criteria will be randomly assigned in a 1:1 ratio 
to receive pralsetinib PO QD or an SOC platinum-containing anticancer treatment 
regimen from an investigator’s choice from a list of SOC regimens. 
The randomization assignment will be implemented by an IwRS.  Before the study is 
initiated, the log in information and directions for the IwRS will be provided to each site. 
Randomization will be stratified by the following: 
 
History of brain metastasis (yes vs. no) 
 
ECOG Performance Status (0 vs. 1) 
 
Intended use of pembrolizumab if randomized to the control arm (yes vs. no) 
  

 
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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 date and time of each 
dose administered in the clinic will be recorded in the source documents and recorded 
on the electronic Case Report Form (eCRF).  The dose of study treatment and study 
participant 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. 
When participants self-administer pralsetinib at home, compliance with study treatment 
will be assessed.  Participant compliance with study drug administration will be assessed 
at each visit.  Compliance with pralsetinib dosing will be assessed by review of dosing 
diary and counting returned capsules.  Deviation(s) from the prescribed dosage regimen 
should be recorded on the eCRF. 
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated adverse events, should be reported as described in Appendix 3. 
Participants randomized to the investigator’s choice of SOC platinum-containing 
anticancer regimen arm will receive IV treatment at the study center. 
6.5 
DOSE MODIFICATION 
The dose of pralsetinib can be reduced up to three times for management of 
drug-related toxicities, as described in Appendix 5, Section A5–1.1.1. 
6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
The Sponsor will offer continued access to Roche IMP (pralsetinib) free of charge to 
eligible participants in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A participant will be eligible to receive Roche IMP (pralsetinib) after completing the study 
if all of the following conditions are met: 
 
The participant received Roche IMP during study conduct. 
 
The participant has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment 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. 
 
Eligible participants may be provided access to Roche IMP after completing the study 
until Roche IMP is no longer available. 

 
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A participant will not be eligible to receive Roche IMP (pralsetinib) after completing the 
study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the participant's country and is 
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). 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for NSCLC with RET fusionpositive tumors. 
 
The Sponsor has reasonable safety concerns regarding the IMP as a treatment for 
NSCLC with RET fusionpositive tumors. 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
participant's country. 
 
The Roche IMP is no longer manufactured. 
 
In these situations, the investigator and primary care physician will transition the study 
participant to an alternative therapy in accordance with institutional or local guidelines.  
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
https://assets.cwp.roche.com/f/176343/x/92d6b13ee6/policy_continued_access_to_inve
stigational_medicines.pdf 
6.7 
TREATMENT OF OVERDOSE 
Participants should be informed to contact their doctor immediately if they have taken 
more than the prescribed dose of medication and should hold off taking additional 
investigational drug until instructed to do so by their study investigator.  Clinic staff 
should be notified immediately, and supportive care should be given if needed and as 
indicated. 
For this study, overdose is defined as the administration of either IMP in a quantity that 
is higher than the prescribed dose.  There is no known antidote for treating an overdose 
of pralsetinib or any of the comparator drugs.  Overdoses will not be considered serious 
adverse events unless the outcome of the overdose meets the seriousness criteria as 
defined in Appendix 3.  Overdoses should be reported as special situation 
(see Appendix 3, Section A3–6.11).  In the event of an overdose that causes a serious 
adverse event, the Sponsor should be notified within 24 hours of the investigator’s 
knowledge of the event.  The participant should be carefully monitored for potential 
adverse reactions and symptomatic treatment instituted as per institutional SOC.  
The investigator will determine if and when dosing should resume. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
on the basis of clinical evaluation of the participant.  The Medical Monitor is available to 
provide advice on trial-related medical questions regarding dose interruption and 
modifications. 

 
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6.8 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a participant in addition to protocol-mandated treatment.  
Concomitant medications will be recorded on the Prior and Concomitant Medication and 
Therapy eCRF from the time of signing informed consent to 30 days after the final dose. 
6.8.1 
Permitted Therapies 
Medications and treatments, including palliative and supportive care for disease-related 
symptoms, are permitted during the study. 
Participants should be closely monitored, and treatment is to be instituted for 
disease-related symptoms, as appropriate.  Supportive care measures for treating 
adverse events should be instituted as soon as they are recognized. 
In general, investigators may manage a participant's care (including preexisting 
conditions) through use of supportive therapies, as clinically indicated and per local 
standard practice, with the exception of prohibited therapies defined in Section 6.8.3 and 
taking into account cautionary therapies defined in Section 6.8.2.  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, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen, 
2-adrenergic agonists). 
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered at the discretion of the investigator. 
For Participants Treated with Pemetrexed 
All participants taking pemetrexed should receive the appropriate supplementation of 
vitamin B12 and folic acid and corticosteroid prophylaxis as listed below or per 
institutional standards: 
 
Folic acid 3501000 g PO:  at least five doses of folic acid must be taken during 
the 7 days preceding the first dose of pemetrexed, and folic acid dosing must 
continue during the full course of therapy and for 21 days after the final dose of 
pemetrexed 
 
Vitamin B12 1000 g intramuscular injection:  in the week preceding the first dose of 
pemetrexed and once every three cycles thereafter 
– 
Subsequent vitamin B12 injections may be given the same day as pemetrexed 
administration. 

 
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 
Dexamethasone prophylaxis 4 mg (or equivalent) PO twice per day:  the day before, 
day of, and day after pemetrexed administration 
– 
Higher or additional doses are permitted for anti-emetic prophylaxis during 
Cycles 14. 
 
For Participants Treated with Paclitaxel 
All participants taking paclitaxel should receive the appropriate corticosteroid prophylaxis 
as listed below or per institutional standards: 
 
Dexamethasone prophylaxis 20 mg (or equivalent) PO approximately 12 and 
6 hours before paclitaxel administration 
– 
Participants may be treated with dexamethasone 1020 mg IV within 1 hour 
prior to paclitaxel infusion if the participant did not take the oral dexamethasone 
 
Diphenhydramine 50 mg (or equivalent) administered by IV infusion 3060 minutes 
prior to paclitaxel administration 
 
Cimetidine 300 mg or ranitidine 50 mg (or equivalent) administered by IV infusion 
3060 minutes prior to paclitaxel administration 
 
For Participants Treated with Nab-Paclitaxel 
Anti-emetic medications, anti-allergic measures, and other treatments for concomitant 
nab-paclitaxel toxicities may be used at the discretion of the investigator, taking into 
account precautions in the Summary of Product Characteristics. 
Refer to the Summary of Product Characteristics (Package Insert) for nab-paclitaxel for 
all boxed warnings and contraindications. 
For Participants Treated with Carboplatin and Cisplatin 
Carboplatin and cisplatin are considered to be highly emetogenic.  Anti-emetic 
treatments for nausea and vomiting associated with carboplatin and cisplatin are to be 
administered in accordance with each product’s prescribing information and institutional 
standards.  Anti-emetic treatments for all other chemotherapy regimens may be used at 
the investigator’s discretion and in accordance with local guidelines or equivalent after 
documented nausea or vomiting has occurred without medications having been used.  
The choice of anti-emetic treatment, if required, will be made at the investigator’s 
discretion.  Antidiarrheal medications may also be used after documented diarrhea has 
occurred, at the investigator’s discretion. 
6.8.2 
Cautionary Therapy 
The following medications are to be used with caution only for participants treated with 
pralsetinib during the study: 
 
In vitro metabolism studies in human liver microsomes have demonstrated that 
pralsetinib is a direct moderate inhibitor and inducer of multiple P450 enzymes 
(CYP2C8, CYP3A4, and CYP2C9).  Pralsetinib is also a time-dependent inhibitor of 
CYP3A4/5. 

 
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 
Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and 
MATE2-K at clinically relevant concentrations.  In participants pralsetinib may alter 
or increase the plasma concentration of co-administered sensitive CYP2C8, 
CYP3A4, CYP2C9, Pgp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and 
MATE2-K substrates. 
– 
Hence, medications that are sensitive CYP2C8, CYP3A4, CYP2C9, P-gp, 
BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K substrates with 
known DDI potential should be used with caution. 
 
Drugs and foods to be used with caution for participants treated with pralsetinib are 
provided in Appendix 10.  The above list of medications is not necessarily 
comprehensive.  The investigator should consult the local prescribing information when 
determining whether a concomitant medication can be safely administered with study 
treatment.  For cautionary medications related to carboplatin, cisplatin, gemcitabine, 
pemetrexed, paclitaxel, nab-paclitaxel, and pembrolizumab, refer to the local prescribing 
information or Summary of Product Characteristics. 
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above. 
6.8.3 
Prohibited Therapy and Procedures 
The following medications and procedures are prohibited during study treatment: 
 
For participants treated with pralsetinib:  In vitro metabolism studies indicate that 
pralsetinib oxidation is primarily mediated by CYP3A4 and to a minor extent by 
CYP1A2 and CYP2D6 and glucuronidation by UGT1A4.  As a precaution, strong 
inhibitors as well as inducers of CYP3A4 are prohibited.  Drug transporter studies in 
cells overexpressing Pgp indicate that pralsetinib is likely also a Pgp substrate.  
Medications that are strong dual inhibitors of Pgp and CYP3A4 are prohibited. 
Refer to Appendix 10 for a list of prohibited medications and foods. 
 
Any investigational agent or device other than pralsetinib, including commercially 
available agents that are investigational for the treatment of the participant’s 
underlying malignancy 
 
Any antineoplastic treatment other than study drugs 
 
Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to randomization 
and during treatment (for participants receiving pembrolizumab) 
 
If radiation or surgical excision of a target lesion is determined to be in the best 
clinical interest of the participant and cannot be avoided, the Medical Monitor should 
be informed, as radiation or surgical excision of target lesions may render 
participants unevaluable for further response assessments. 
 
For prohibited medications related to carboplatin, cisplatin, gemcitabine, pemetrexed, 
paclitaxel, nab-paclitaxel, and pembrolizumab, refer to the local prescribing information 
and Summary of Product Characteristics (Package Insert). 

 
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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
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 for additional safety assessments.  Refer to the 
schedules of activities (see Section 1.3, Table 1 and 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 they experience any of the 
following: 
 
Any medical condition that the investigator determines may jeopardize the 
participant's safety if he or she continues to receive study treatment 
 
Investigator determination that treatment discontinuation is in the best interest of the 
participant 
 
Pregnancy 
 
Use of an anticancer therapy not required per protocol 
 
Confirmed progression per the investigator according to RECIST v1.1 
 
Any event that meets stopping criteria 
 
Other reasons, including major protocol violation or non-compliance 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Participants will return to the clinic for an EOT discontinuation visit within 14 days after 
the final dose of study drug, and for a safety follow-up assessment  approximately 
30 days after the final dose of study drug or initiates an antineoplastic therapy. 
If a participant requests to be withdrawn from treatment or follow-up assessments, this 
request must be documented in the source documents and signed by the investigator. 
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 Appendix 3, Section A3–6.6, or if the 
investigator believes that it is in best interest of the participant when abnormal liver 
function results not meeting protocol-specified stopping rules. 

 
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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. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the schedule of activities (see Section 1.3, Table 1 
and Table 2).  Refer to the schedule of activities for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
The participant will be permanently discontinued both from the study treatment and from 
the study at that time. 
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 not otherwise 
restricted by local law. 
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. 
The Sponsor informed all investigators of the decision of premature study termination on 
23 January 2024. 
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 

 
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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, three 
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 and will be withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole are handled as presented in 
Appendix 1, Section A1–9.
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.  Any participant who consents to
RET testing outside of current SOC should sign the Prescreening Informed Consent 
Form prior to acquisition of tumor sample.  Prescreening may occur any time prior to 
screening.  Participants should wait until the RET results are known before signing the 
main study Informed Consent Form.
The schedules of activities are provided in Section 1.3, Table 1 for the main treatment 
period and Table 2 for the crossover treatment period.  All clinical and laboratory safety 
assessments will be assessed by the investigator for clinical significance, and clinically 
significant findings will be reported as adverse events.  Additional safety assessments 
may be performed when clinically indicated at the investigator’s discretion.
Unless otherwise indicated, all assessments must be performed predose at each visit. 
Whenever a result is questionable, it should be repeated immediately.
 
Study procedures and their timing are summarized in the schedules of activities
(see Section 1.3, Table 1 and Table 2).
 
Immediate safety concerns should be discussed with the Sponsor immediately upon
occurrence or awareness to determine if the participant should continue or 
discontinue study drug.
 
Adherence to the study protocol requirements, including those specified in the 
schedule of activities, is essential and required for study conduct.  Protocol waivers
or exemptions are not allowed.
 
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria.  The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

 
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 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood tests, radiologic tumor assessments, bone marrow aspirates and 
biopsies) and obtained before signing of the Informed Consent Form may be utilized 
for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the screening window defined 
in the schedule of activities. 
 
Participants will be closely monitored for safety throughout the study.  Participants 
should be assessed for presence of 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. 
At applicable sites, following Day 1 of Cycle 2 or Day 1 of crossover Cycle 2 certain 
study assessments may be performed by a MN (mobile nursing) professional at the 
participant's home or another suitable location to improve access and convenience for 
participants participating in the study.  The Sponsor will select a health-care company 
that will be responsible for providing MN services for participating sites (the MN vendor).  
The MN vendor is responsible for ensuring that all MN professionals are licensed, 
qualified, and in good standing, as per applicable regulations, and that appropriate 
background checks 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 network 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 schedules of activities (see Section 1.3, Table 1 and Table 2) specify the 
assessments that may be performed by an MN professional. 
8.1 
ELIGIBILITY REVIEW AND REGISTRATION 
Participants who are candidates for enrollment into the study will be evaluated for 
eligibility by the investigator to ensure that the inclusion and exclusion criteria 
(see Sections 5.1 and 5.2, respectively) have been satisfied.  The timeframe for 
obtaining informed consent is provided in the schedule of activities.  The investigator will 
confirm eligibility for all participants before receipt of the first dose of study treatment.  
For study eligibility, RET fusion status may be determined locally.  However, baseline 
tumor tissue samples for all participants must also be submitted within 2 weeks of 
enrollment for confirmation of RET status by central testing. 
Pretreatment tumor tissue will be analyzed centrally for analysis of RET fusion status 
retrospectively and for biomarkers that may correlate with anti-neoplastic activity and 
resistance.  This tissue may be from an archived sample or from a fresh biopsy. 

 
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If no local test is available to determine RET eligibility, if approved by the Sponsor, the 
participant may submit adequate tumor tissue for central testing by a FMI clinical trial 
assay or an alternate, approved central laboratory for that region. 
If a participant is enrolled using local RET testing methods, the following are required: 
 
Adequate tumor tissue, accompanied by the full laboratory report of the RET fusion 
local test, must be submitted within 2 weeks of enrollment for central confirmation of 
RET fusion status.  If RET fusion status for enrollment is determined on the basis of 
tissue determined through the use of F1CDx test or the alternative, approved central 
laboratory for that region, tissue sample will still be required for other biomarker 
analysis, but a repeated central F1CDx test (or the alternative, approved central 
laboratory for that region) will not be required. 
 
If archived tumor tissue is not available, participants are required to undergo a 
pretreatment biopsy.  If performed after the baseline radiographic imaging, 
pretreatment biopsies must be taken from a non-target lesion. 
 
Details regarding where the local assay was performed, the method used, the tissue 
and specimen type tested, RET fusion details, and local assay name, are to be 
entered on the corresponding eCRF. 
 
Additional exploratory biomarker research may be performed using residual tumor tissue 
samples and material derived from these samples in view of developing new genetic and 
mechanistic biomarkers with documented participant consent. 
8.2 
DEMOGRAPHIC INFORMATION 
The following demographic information will be collected at screening (if allowed per local 
regulations):  year of birth, sex, ethnicity, and race. 
8.3 
MEDICAL HISTORY 
A participant’s medical history should be reviewed during screening.  This includes, but 
is not limited to, documentation of diagnosis, including history of disease and other 
malignancies, responses to prior anti-neoplastic treatments (if available), prior and 
concomitant medications, and prior and concurrent medical conditions and surgeries.  
Relevant historical and ongoing medical events should be recorded on the appropriate 
eCRF.  Confirmation that a female participant is of non-childbearing potential is 
considered relevant medical history. 
8.4 
EFFICACY ASSESSMENTS 
8.4.1 
Tumor and Response Evaluations 
As of protocol version 5, the tumor assessment schedule will be conducted as per 
local institutional standard of care and recorded in the eCRF until radiographic 
disease progression per RECIST v1.1 as assessed by the investigator or 
discontinuation from the study.  

 
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All measurable and/or evaluable lesions should be assessed and documented at 
screening.  Tumor assessments performed as SOC prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening, as long as they meet criteria outlined below. 
8.4.1.1 
Radiographic Assessments 
Due to the Sponsor’s decision to prematurely terminate the study and as of 
protocol version 5, tumor scans will no longer be collected prospectively by the 
Sponsor or submitted to a BICR facility as BICR will not be utilized.  
Screening assessments must include computed tomography (CT) scans with contrast 
(per institutional standard operating procedures) of the chest, abdomen, and pelvis.  If a 
CT scan with contrast is contraindicated (e.g., in participants with contrast allergy or 
impaired renal clearance), a non-contrast CT scan of the chest may be performed and 
MRI scans (with contrast, if feasible) of the abdomen and pelvis should be performed.  
CT or MRI scans of other disease sites should be performed as clinically indicated. 
All participants must undergo an MRI (preferred) or CT scan (with contrast) of the brain 
at screening and all subsequent tumor visits regardless of the presence or absence of 
metastases at baseline.  In the event of an equivocal CT scan at screening, an MRI scan 
of the brain is required to confirm or refute the diagnosis of CNS metastases.  Brain 
scans should be performed for all participants until disease progression per the schedule 
of activities. 
Participants with known or suspected bone metastases should undergo bone scans or 
other institutional standard bone imaging at screening and at subsequent tumor 
assessments as clinically indicated. 
At the investigator's discretion, other methods of assessment of disease as per 
RECIST v1.1 may be used.  If a CT scan for tumor assessment is performed in a 
PET/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
Details regarding imaging procedures will be provided in an imaging manual. 
Radiographic images collected prior to protocol version 5 will be submitted to a BICR 
facility for a quality and completeness check, for central review, and for temporary 
storage prior to transferring images to the Sponsor. 
Assessment of response and progression status will be evaluated at each scheduled 
disease response assessment locally by the investigator using RECIST v1.1 
(see Appendix 8), as outlined in the schedule of activities (see Section 1.3, Table 1 and 
Table 2).  Assessments should be performed by the same individual, if possible, to 
ensure internal consistency across visits.  CT or MRI of chest, abdomen, pelvis, and any 

 
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other known sites of metastatic disease may be used; however, the same method of 
assessment used at screening should be utilized throughout the study for each location.  
CT with IV contrast is the preferred imaging modality, unless a site of disease is better 
evaluated by MRI.  If a participant is not tolerant of IV contrast, non-contrast scans may 
be performed. 
Endpoints (e.g., ORR, PFS, CBR), will be calculated programmatically by the Sponsor 
on the basis of investigator assessments of response at each specified timepoint. 
8.4.2 
Eastern Cooperative Oncology Group Performance Status 
Determination of ECOG Performance Status will be performed at the visits outlined in 
the schedule of activities in Section 1.3, Table 1 and Table 2.  Refer to Appendix 7 for 
the ECOG Performance Status Scale. 
8.5 
SAFETY ASSESSMENTS 
8.5.1 
Physical Examinations 
A complete physical examination will be performed at the screening visit.  A complete 
physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems.  Height will also be measured 
and recorded at least once during screening and does not need to be repeated with 
each physical examination.  Weight should be recorded at each physical examination. 
Subsequent physical examinations will be performed as outlined in the schedule of 
activities and will be disease and adverse event focused.  Investigators should pay 
special attention to clinical signs related to previous serious illnesses. 
8.5.2 
Vital Signs 
Vital sign measurement will include the following: 
 
Temperature 
 
Pulse rate 
 
Respiratory rate 
 
Systolic and diastolic blood pressure 
 
Systolic and diastolic blood pressure and pulse measurements will be assessed while 
the participant is seated or supine.  Blood pressure and pulse measurements should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions (e.g., television, cell phones). 
Vital signs should be to be collected before blood collection for laboratory tests and 
before dosing with study drug.  
Vital sign measurements may be performed by an MN professional. 

 
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8.5.3 
Electrocardiograms 
Several 12-lead ECGs will be obtained as outlined in the schedules of activities 
(see Section 1.3, Table 1 and Table 2) using an ECG machine that automatically 
calculates the following heart rate and measures:  PR, QRS, QT, and QTcF.  
The QTc measurements will use QTcF.  ECG should be repeated if clinically indicated. 
When the timing of a blood sample coincides with the timing of a 12-lead 
ECG measurement, the ECG will be completed within 1 hour before or after the 
collection of the blood sample. 
8.5.4 
Clinical Safety Laboratory Assessments 
Clinical laboratory evaluations for safety will be performed by the local laboratory.  
Before starting the study and throughout its duration, the investigator will provide the 
Sponsor (or its designee) copies of all laboratory certifications and normal ranges for all 
laboratory assessments to be performed by that laboratory. 
Clinical laboratory evaluations will be conducted at the timepoints outlined in the 
schedules of activities (refer to Section 1.3, Table 1 and Table 2).  In addition, all 
clinically significant laboratory abnormalities noted on testing will be followed by repeat 
testing and further investigated according to the judgment of the investigator. 
If the screening visit tests are performed within 7 days prior to Day 1 of Cycle 1, clinical 
laboratory tests do not need to be repeated on Day 1 of Cycle 1. 
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 dose modification), the results must be recorded on the eCRF. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the schedule of activities. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study on the Adverse Event CRF.  
The laboratory reports must be filed with the source documents.  Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  A laboratory test result must be reported as an adverse event if it 
meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 

 
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 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the final dose of study treatment should 
be repeated until the values return to normal or baseline or are 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. 
Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final Clinical Study Report. 
8.5.5 
Pregnancy Testing 
The schedule for pregnancy testing for enrolled female participants is specified in the 
schedules of activities (refer to Section 1.3, Table 1 and Table 2). 
8.6 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
Each participant must be carefully monitored for the development of any adverse events 
throughout the study from signing of the Informed Consent Form to 30 days after the 
final dose.  See Section 8.6.1 and Appendix 3 for details on how these events should be 
recorded and reported.  In addition, serious adverse events that are assessed as related 
to study drug that occur  30 days after the final dose also are to be reported. 
Complete details on adverse event and serious adverse event monitoring are provided in 
Section 8.6.1. 
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 or the study (see Section 7.2). 

 
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8.6.1 
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 (e.g., biopsy) 
should be recorded in the Adverse Event eCRF and reported.  The paper Clinical Trial 
Adverse Event/Special Situations Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  All other medical 
occurrences that begin before the start of study treatment but after obtaining informed 
consent 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 at the timepoints specified in the schedules of activities 
(see Section 1.3, Table 1 and Table 2). 
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 them 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. 
8.6.2 
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 severity 
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. 
8.6.3 
Adverse Events During Crossover 
Ongoing Grade 1 adverse events from previous therapy that worsen after crossover 
should be recorded and reported as a new adverse event.  Further information on 
recording of crossover adverse events is provided in Appendix 3, Section A3–3.4. 

 
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8.6.4 
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 will 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. 
8.6.5 
Regulatory Reporting Requirements for 
Serious Adverse Events 
Prompt notification 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 regulatory authority (which includes 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 
Pralsetinib 
Pralsetinib Investigator's Brochure  
Carboplatin 
UK Summary of Product Characteristics 
Cisplatin 
UK Summary of Product Characteristics 
Pemetrexed 
EU Summary of Product Characteristics 
Pembrolizumab 
EU Summary of Product Characteristics 
Gemcitabine 
UK Summary of Product Characteristics 
Paclitaxel 
UK Summary of Product Characteristics 
Nab-paclitaxel 
EU Summary of Product Characteristics 
 

 
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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 Pralsetinib 
Investigator’s Brochure and will notify the IRB/EC, if appropriate according to local 
requirements. 
8.6.6 
Pregnancy 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within treatment 14 days after the final dose of pralsetinib or according to the 
contraceptive requirements in the respective local labels for standard of care therapies. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
7 days after the final dose of pralsetinib or according to the contraceptive requirements 
in the respective local labels for standard of care therapies. 
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 2. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
The Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring 
visit to obtain additional case details and outcome information (e.g., from hospital 
discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
8.6.7 
Death Events 
Information on reporting of deaths is provided in Section A3–6.7. 
8.6.8 
Adverse Events of Special Interest and Selected 
Adverse Events 
8.6.8.1 
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 

 
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of the event; see Section A3–4 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  Appendix 3, Section A3–6.6) 
 
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. 
 
8.6.8.2 
Selected Adverse Events 
Additional data will be collected for the following selected adverse events: 
 
Pneumonitis 
 
Pneumonia 
 
Hepatotoxicity 
 
Hypertension 
 
Hemorrhagic events 
 
Tumor lysis syndrome 
 
8.6.9 
Medical Monitors and Emergency Medical Contacts 
Investigators will be provided with contact information for the Medical Monitor.  
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.  
8.7 
PHARMACOKINETICS 
As of protocol version 5, no new PK samples will be collected due to the Sponsor’s 
decision to prematurely terminate the study.  However, samples already collected may 
be analyzed.  
8.8 
PHARMACODYNAMICS 
Pharmacodynamic biomarker assessments will not be performed in this study. 
8.9 
GENETICS 
Genetic biomarker assessments will not be performed in this study. 

 
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8.10 
BIOMARKER ASSESSMENTS 
As of protocol version 5, no new biomarker blood or tissue samples will be collected due 
to the Sponsor’s decision to prematurely terminate the study.  However, biomarker 
samples already collected may be analyzed. 
8.11 
IMMUNOGENICITY ASSESSMENTS 
Immunogenicity assessments will not be performed in this study. 
8.12 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economics and medical resource utilization assessments will not be performed in 
this study. 
8.13 
CLINICAL OUTCOME ASSESSMENTS 
As of protocol version 5, participant-reported outcome data will no longer be collected 
due to the Sponsor’s decision to prematurely terminate the study. 
8.14 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
There are no additional assessments and procedures requiring separate consent or 
performed only at participating sites. 
8.14.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  
The collection, storage, and analysis of RBR samples will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from 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 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 

 
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8.14.2 
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 8.14.2) 
will not be applicable at that site. 
8.14.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to pralsetinib, lung diseases, 
or drug safety: 
 
Leftover plasma and tumor tissue samples (with the exception of remaining archival 
tissue blocks, which will be returned to sites) and any derivatives thereof (e.g., DNA, 
RNA, proteins, and peptides), including leftover tissue samples from medically 
indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion during the study. 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
8.14.4 
Confidentiality 
The RBR samples and associated data will be labeled with a unique participant 
identification number. 

 
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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. 
8.14.5 
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(s) 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. 
8.14.6 
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 

 
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wishes to withdraw consent to the testing of his or her RBR samples after closure of the 
site, the investigator must inform the Sponsor by emailing the study number and 
participant number to the following email 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. 
8.14.7 
Monitoring and Oversight 
RBR 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 primary objective of the study is to assess whether pralsetinib improves PFS 
compared with investigator’s choice platinum-containing chemotherapy regimens for 
patients with RET fusionpositive metastatic NSCLC. 
Following the Sponsor’s decision to prematurely terminate the study, the analysis of the 
primary efficacy endpoint of PFS will no longer be conducted as per the original study 
protocol.  Considering the expected lack of maturity of the data, the analysis of PFS will 
only be reported in a descriptive manner.  No formal testing will be performed.  
Consequently, p-values will not be able to be claimed as statistically significant and 
therefore will be reported as descriptive in nature. 
9.2 
SAMPLE SIZE DETERMINATION 
Originally, the sample size of this study was determined by the primary endpoint; 
therefore, the study was event driven. 
Following the Sponsor’s decision to prematurely terminate the study and considering the 
expected lack of maturity of the data, the analysis of the primary efficacy endpoint of 
PFS will only be reported in a descriptive manner.  Consequently, the study analysis will 
no longer be triggered by reaching a given number of events of interest.  No formal 
testing will be performed for neither the primary nor for the key secondary efficacy 
endpoints.  Accordingly, a control for the overall type I error () applying a gate-keeping 

 
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hierarchical sequential testing method will no longer be implemented.  As a result, 
p-values will not be able to be claimed as statistically significant and therefore will be 
reported as descriptive in nature. 
9.2.1 
Analysis Sets 
The analysis sets are defined in Table 6.  For all efficacy analyses, participants will be 
grouped according to the treatment assigned at randomization.  For safety analyses for 
the main treatment period, patients will be grouped according to whether any amount of 
experimental treatment is received, including cases in which experimental treatment was 
received in error.  The safety analyses for the crossover treatment period will be 
reported separately. 
Table 6 
Analysis Sets 
Analysis Set 
Description 
ITT 
All randomized patients whether or not the assigned study 
treatment is received 
Safety 
All patients who receive any amount of any study drug 
ITT  intent to treat;  
  
9.3 
STATISTICAL ANALYSES 
This section is a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints. 
9.3.1 
General Considerations 
In addition to specific analyses and presentations that are detailed in the following 
sections, study results will be presented by treatment arm (with total when appropriate) 
and summarized according to the nature of the variables: 
 
For continuous variables, using descriptive statistics, including the number of 
patients contributing to summary statistics, mean, standard deviation, median, and 
range as appropriate.  
 
For categorical variables, using the frequency and proportion of patients falling into 
each category, grouped by treatment arm (and total).  The percentages given in 
these tables will be rounded and therefore may not always sum to 100%.  If a 
missing category is not presented in the data display, only patients with non-missing 
values for the parameter being assessed will be included in the percentage 
calculation. 
 
Time-to-event endpoints (i.e., PFS, OS, and DOR) will be estimated using Kaplan-Meier 
techniques.  The median along with 95% CI will be provided using Brookmeyer and 
Crowley methodology (Brookmeyer and Crowley 1982) with a log-log transformation for 
constructing the confidence intervals.  Rates at fixed timepoints will be derived from the 
Kaplan-Meier estimate and corresponding CI will be derived based on Greenwood 
formula (Greenwood 1926) for variance derivation and on log-log transformation applied 

 
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on the survivor function S(t) (Kalbfleisch and Prentice 1980).  Unless otherwise 
specified, the stratified log-rank test will be performed to test the comparison between 
time-to-event endpoints.  Stratification factors will be history of brain metastasis 
(yes vs. no), ECOG Performance Status (0 vs. 1), and intended use of pembrolizumab if 
randomized to the control arm (yes vs. no).  Unless otherwise specified, the stratified HR 
between treatment groups along with its 95% CI will be obtained by fitting a stratified 
Cox model (Cox 1972), with treatment arm as a unique covariate.  Stratification factors 
will be similar to the ones used in the stratified log-rank test as entered into the IwRS. 
Categorical endpoints will be summarized by category for each treatment arm.  
The proportion will be computed in each treatment group along with the exact 95% CI 
using Clopper-Pearson method (Clopper and Pearson 1934).  An estimate of the 
absolute difference in proportions and corresponding 95% CI using the normal 
approximation to the binomial distribution will be calculated and tested through the use 
of the stratified Cochran-Mantel-Haenszel test (Cochran 1954; Mantel and 
Haenszel 1959).  In addition, the stratified odds ratios (Mantel-Haenszel estimator) 
between the treatments will be provided along with the 95% CI.  The number and 
percentage of patients assigned to each response category (i.e., CR, PR, stable 
disease, progressive disease, not evaluable, and unknown) will be summarized by 
treatment arm along with the Clopper and Pearson two-sided 95% confidence limits. 
9.3.2 
Primary Endpoint 
The primary objective of the study is to assess whether pralsetinib improves PFS, as 
assessed by investigator compared with investigator’s choice of SOC 
platinum-containing anticancer treatment regimens for patients with RET fusionpositive 
metastatic NSCLC. 
The population targeted is defined in the inclusion and exclusion criteria as part of the 
study protocol.  Patients may be male or female and have pathologically confirmed, 
definitively diagnosed, locally advanced unresectable or metastatic NSCLC.  Patients 
cannot have received any prior anticancer therapy for metastatic disease. 
The primary endpoint, PFS, is defined as the time from randomization to the first 
occurrence of progression according to RECIST v1.1, as assessed by investigator, or 
death from any cause, whatever occurs first.  Patients without disease progression or 
who have not died will be censored at the time of the last tumor assessment or, if no 
tumor assessments are performed after the baseline visit, on the date of randomization.  
The primary analysis of PFS will be analyzed in the intent-treat (ITT) population. 
The treatment condition of interest to compare is the experimental treatment (pralsetinib) 
and any subsequent therapies vs. control treatment (investigator’s choice platinum 
containing chemotherapy regimens) and any subsequent therapies, including 
experimental treatment.  Indeed, the primary comparison of PFS will be made 
irrespective of premature discontinuation of randomized treatment or use of alternative 

 
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medications not permitted by the trial protocol before the occurrence of progressive 
disease. 
Table 7 specifies assignment of event and censoring dates for the 
investigator-assessed-PFS analysis (i.e., specifies how dates of progression events and 
dates for censoring will be assigned in the primary analysis of PFS). 
Table 7 
Situations and Outcomes for the Primary Endpoint:  
Progression-Free Survival 
Situation 
Strategy to Handle 
Situation 
Outcome (Date of 
Progression or Censoring) 
Patients with no tumor assessments 
performed after the baseline visit 
As missing data 
Censored on the date of 
randomization 
Patients without disease progression 
who have not died 
As missing data 
Censored at the time of the 
last tumor assessment 
Progressive disease as assessed by 
investigator 
As event of interest 
Event at the date of tumor 
assessment at which 
progression was 
documented  
Death before progressive disease 
As event of interest 
Event at the date of death 
Start of subsequent anticancer therapy 
before disease progression as 
assessed by investigator or death  
To be evaluated for 
progressive disease and 
survival.  
Event or censored (i.e., the 
value for the variable PFS is 
used regardless of whether 
the situation occurs) 
Premature discontinuation of 
randomized treatment before disease 
progression as assessed by 
investigator 
To be evaluated for 
progressive disease and 
survival. 
Event or censored (i.e., the 
value for the variable PFS is 
used regardless of whether 
the situation occurs) 
Discontinuation or withdrawal from the 
study and lost to follow-up before 
disease progression as assessed by 
investigator 
As missing data 
Censored at the time of the 
last tumor assessment 
PFS  progression-free survival. 
  
The primary analysis of the study will compare the PFS distributions in the experimental 
(pralsetinib) and control (investigator’s choice SOC platinum-containing anticancer 
regimens) arms, as described in Section 9.1.  The treatment comparison will be 
performed using a one-sided, log-rank test (overall level of significance, 0.025) stratified 
by history of brain metastasis (present vs. absent), ECOG Performance Status (0 vs. 1) 
and intended use of pembrolizumab if randomized to the control arm (yes vs. no) as 
entered into the IwRS. 
The survival distribution of -PFS will be estimated using the Kaplan-Meier method.  PFS 
curves will be estimated for each group, considered separately, and compared 

 
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statistically using the stratified log-rank test.  The Kaplan-Meier plots will display the 
number of patients at risk at equidistant timepoints. 
Kaplan-Meier (i.e., product-limit) estimates of median PFS time will be presented by 
treatment arm together with two-sided 95% CIs calculated according to Brookmeyer and 
Crowley (Brookmeyer and Crowley 1982).  Kaplan-Meier estimates of PFS probability at 
12, 18, and 24 months will be estimated with corresponding two-sided 95% CIs derived 
using the log-log transformation according to Kalbfleisch and Prentice (1980).  
The estimate of the standard error will be computed using Greenwood’s formula. 
The validity of the log-rank test relies on the same assumptions for censoring as validity 
of the Kaplan-Meier estimator of the survival curve (Bland and Altman 1998) namely, 
that censoring is unrelated to prognosis, the survival probabilities are the same for 
participants who are recruited early and late in the study, and the events that occur at 
the times specified. 
The primary comparison of interest is the HR for PFS (i.e., estimates of the treatment 
effect in terms of PFS will be expressed as an HR).  The HR will be estimated using a 
stratified Cox’s proportional hazard model using the same stratification factors as the 
log-rank test.  Each stratum will define a separate baseline hazard function, i.e., for the 
ith stratum the hazard function is expressed as follows: 
hi(t)  hi0(t) exp(x), 
for which hi0(t) defines the baseline hazard function for the ith stratum, x defines the 
treatment arm (0  investigator’s choice, 1  pralsetinib), and  is the unknown regression 
parameter. 
The HR for PFS will be calculated along with its 95% CI.  The purpose of the two-sided 
95% CI is to give an estimate of the respective treatment effect together with a 
comparable measure of reliability. 
9.3.2.1 
Sensitivity and Supplementary Analyses 
Following the Sponsor’s decision to prematurely terminate the study, only minimal 
sensitivity or supplementary analyses will be performed as listed in Table 8.   
Table 8 
Sensitivity and Supplementary Analyses of the Primary Endpoint:  
Progression-Free Survival, as Assessed by the Investigator 
Analysis 
Analysis Set 
Variable 
Definition 
Comment 
Sensitivity to assess 
the impact of 
stratification 
ITT 
PFS 
As primary analysis 
Unstratified log-rank 
and Cox model 
ITT  intent to treat; PFS  progression-free survival. 
  

 
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9.3.2.2 
Subgroup Analyses 
Following the Sponsor’s decision to prematurely terminate the study, subgroup analyses 
will not be performed. 
9.3.3 
Secondary Endpoints 
The secondary endpoints are defined in Section 3 (see Table 4), and will be analyzed 
according to their type as described in Table 9. 
Table 9 
Planned Statistical Analyses of the Secondary Endpoints 
Endpoint(s) 
Type of 
Endpoint 
Analysis Set 
Summary of Measure 
Supportive Analysis 
ORR 
Binary 
ITT 
 Stratified CMH test 
 
 Absolute difference 
(see Section 9.3.3) 
 
OS 
Time to 
event 
ITT 
As primary 
Analysis censoring 
patients at crossover 
 DOR 
Binary 
ITT (restricted to 
responders only) 
As primary 
 
DCR 
Binary 
ITT  
As ORR 
 
 CBR  clinical benefit rate; CMH  Cochran-Mantel-Haenszel; DCR  disease control rate; 
DOR  duration of response; ITT  intent to treat;  ORR  objective response rate; OS  overall 
survival; PFS  progression-free survival;  
  
Safety analyses are described in Section 9.3.3.4. 
9.3.3.1 
Time-to-Event Endpoints (OS and DOR) 
Time-to-event endpoints will be analyzed in the ITT population for OS and  DOR 
(see Section 9.2.1). 
Analyses of treatment differences of time-to-event endpoints will use the same methods 
as the primary endpoint PFS.   
As described in Section 9.3.2, unless otherwise specified, the stratified log-rank test will 
be performed to test the comparison between time-to-event distributions.  The stratified 
hazard ratio between the experimental and control groups along with its 95% confidence 
interval will be obtained by fitting a stratified Cox model with the treatment group variable 
as a unique covariate.  The p-values for time-to-event endpoints are for descriptive 
purposes only, and there will be no multiplicity adjustment for these analyses. 
The definition of OS, as specified in Table 4, is evaluating the OS benefit assuming 
subsequent anticancer therapies represent clinical practice, including the experimental 
treatment.   

 
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9.3.3.2 
Binary Endpoints (ORR,  DCR, and CBR) 
Binary endpoints will be analyzed in the ITT-population (see Section 9.2.1). 
As described in Section 9.3.1, the number and proportion of responders in each 
treatment arm, together with the two-sided 95% CIs with use of the Clopper-Pearson 
method will be produced.  Treatment comparison of response will be made using 
stratified Cochran-Mantel-Haenszel test.  The absolute difference and its CI between the 
treatment arms will be determined using the normal approximation to the binomial 
distribution. 
Patients not meeting response criterion, including patients without any postbaseline 
tumor assessment, will be considered as non-responders. 
9.3.3.3 
Participant-Reported Outcomes 
Following the Sponsor’s decision to prematurely terminate the study, the analysis of 
PRO data will no longer be performed. 
9.3.3.4 
Safety Endpoints 
Safety analyses will be performed on the safety population.  Safety will be assessed 
through summaries of exposure to study treatment, adverse events, changes in 
laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.  
The main treatment period and the crossover treatment period will be summarized 
separately.  Adverse events with onset dates prior to the date at which the patient 
receives the first dose of crossover treatment will be reported in the main treatment 
period and adverse events occurring on or after that date will be reported in the 
crossover treatment period.  Additionally, if there is an ongoing adverse event that has 
not resolved before crossover and worsens during the crossover treatment period, it will 
be reported in the crossover treatment period summary. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to NCI 
CTCAE v5.0.  All adverse events, serious adverse events, adverse events leading to 
death, adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur after the first dose of study drug (i.e., treatment-emergent 
adverse events) will be summarized by mapped term, appropriate thesaurus level, and 
severity grade.  For events of varying severity, the highest grade will be used in the 
summaries.  Deaths and cause of death will be summarized. 

 
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Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
9.3.4 
Other Analyses 
9.3.4.1 
Summaries of Conduct of Study 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study treatment discontinuation will also 
be tabulated.  The number of patients who cross over from investigator’s choice of 
SOC platinum-containing anticancer treatment regimens to receive pralsetinib will also 
be summarized.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm. 
9.3.4.2 
Summaries of Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment arm.  
The baseline value will be defined as the last available value recorded prior to the 
initiation of study treatment.  Descriptive statistics (mean, standard deviation, median, 
and range) will be presented for continuous variables and frequencies with percentages 
will be presented for categorical variables. 
9.3.4.3 
Pharmacokinetic Analyses 
Following the Sponsor’s decision to prematurely terminate the study, no PK analysis will 
be conducted.   
9.4 
INTERIM ANALYSES 
Following the Sponsor’s decision to prematurely terminate the study, no interim analyses 
will be conducted.  No formal testing will be performed for neither the primary nor for the 
key secondary efficacy endpoints.  Accordingly, a control for the overall type I error () 
applying a gate-keeping hierarchical sequential testing method will no longer be 
implemented.  
9.5 
INDEPENDENT DATA MONITORING COMMITTEE 
Refer to Section 4.1.5 for details regarding the iDMC for this study. 

 
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10. 
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Mazieres J, Drilon AE, Mhanna L, et al. Efficacy of immune-checkpoint inhibitors (ICI) in 
non-small cell lung cancer (NSCLC) patients harboring activating molecular 
alterations (ImmunoTarget). J Clin Oncol 2018;36 (15 Suppl):90109010. 
[NCCN®] National Comprehensive Cancer Network. NCCN Guidelines®. 2020. 
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management [resource available on the internet]. Published date: 28 March 2019. 
Available from: https://www.nice.org.uk/guidance/ng122. Accessed on: 
7 December 2020. 
Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of 
RET-rearranged lung cancers. J Precis Oncol 2019;3:PO.18. 00386. Epub ahead 
of print: 16 May 2019. 
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Cooperative Oncology Group. Am J Clin Oncol 1982;5:64955. 
Ou S-H I, Zhu VW, Nagaaska M. Catalog of 5’ fusion partners in ALK NSCLC circa 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
TABLE OF CONTENTS 
A1–1 
Regulatory and Ethical Considerations .................................... 93 
A1–2 
Financial Disclosure ................................................................. 93 
A1–3 
Informed Consent Process ...................................................... 94 
A1–4 
Data Protection ........................................................................ 94 
A1–5 
Administrative Structure ........................................................... 95 
A1–6 
Dissemination of Clinical Study Data ....................................... 95 
A1–7 
Data Quality Assurance ........................................................... 96 
A1–8 
Source Documents .................................................................. 97 
A1–9 
Study and Site Closure ............................................................ 97 
A1–10 
Publication Policy ..................................................................... 98 
A1–11 
Protocol Deviations .................................................................. 98 
 

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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 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 4.3). 

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A1–3 
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study 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 30 days from the previous Informed Consent Form 
signature date. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each participant the objectives of the exploratory 
research.  Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period.  
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research.  Participants who decline to 
participate in this optional research will not provide this separate signature. 
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.  

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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. 
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 140 sites globally will participate to enroll approximately 226 participants.  
Enrollment will occur through an interactive web-based response system (IwRS). 
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and pharmacokinetic [PK] 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 (for details, refer to Section 4.1.5).  
A BICR facility will collect, store, and review imaging data. 
A1–6 
DISSEMINATION OF CLINICAL STUDY DATA 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and/or other summaries of clinical study results 
may be available in health authority databases for public access, as required by local 

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regulation, and will be provided upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
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 or electronic Case 
Report Forms (CRFs) 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 (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. 

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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. 
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 on the electronic Case Report Form (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 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 
 
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 

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inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
A1–10 
PUBLICATION POLICY 
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. 
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. 
 

 
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Appendix 2  
Clinical Safety Laboratory Tests 
The tests detailed in Table A2-1 will be performed by the local laboratory except for 
carcinoembryonic antigen (CEA), pharmacokinetic and biomarker assessments which 
will be performed at a central laboratory. 
Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively. 
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 
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 (if considered 
standard of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, 
AST, urate, and lactate dehydrogenase  
 Coagulation:  INR, aPTT, and PT 
 Thyroid-function testing:  thyroid-stimulating hormone, free T3, and free T4  
 HIV serology 
 HBV serology:  HBsAg, HBsAb, and total HBcAb for all individuals; HBV DNA for individuals 
with negative HBsAg and HBsAb tests and a positive total HBcAb test 
 HCV serology:  HCV antibody for all individuals; HCV RNA for individuals with a positive 
HCV antibody test 
 Pregnancy test 
 
All women of childbearing potential will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, and 
bacteria) 
 
CEA 
 
Tissue, blood, PK plasma, and biomarker sample collection 
CEA  carcinoembryonic antigen; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B 
surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; PK pharmacokinetic; 
T3  triiodothyronine; T4  thyroxine. 
 
Investigators must document their review of each laboratory safety report. 

 
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Appendix 3  
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
TABLE OF CONTENTS 
A3–1 
Definition of Adverse Event.................................................... 102 
A3–2 
Definition of Serious Adverse Event ...................................... 103 
A3–3 
Recording and Follow-Up of Adverse Events and/or 
Serious Adverse Events ........................................................ 104 
A3–3.1 
Adverse Event and Serious Adverse Event Recording .......... 104 
A3–3.2 
assessment of Severity .......................................................... 105 
A3–3.3 
Assessment of Causality ....................................................... 106 
A3–3.4 
Adverse Event and Serious Adverse Event Recording 
during crossover .................................................................... 107 
A3–3.5 
Follow-up of Adverse Events and Serious Adverse Events ... 108 
A3–3.5.1 
Investigator Follow-Up ........................................................... 108 
A3–3.5.2 
Sponsor Follow-Up ................................................................ 108 
A3–4 
Reporting of Serious Adverse Events and adverse events 
of special interest ................................................................... 109 
A3–4.1 
Events That Occur Prior to Study Treatment Initiation ........... 109 
A3–4.2 
Events That Occur After Study Treatment Initiation ............... 110 
A3–5 
Reporting Adverse Events That Occur after the Adverse 
Event Reporting Period .......................................................... 110 
A3–6 
Procedures for Recording Adverse Events ............................ 110 
A3–6.1 
Diagnosis Versus Signs And Symptoms ................................ 111 
A3–6.2 
Adverse Events that are Secondary to Other Events ............. 111 
A3–6.3 
Persistent of Recurrent Adverse Events ................................ 111 
A3–6.4 
Abnormal Laboratory Values ................................................. 112 
A3–6.5 
Abnormal Vital Sign Values ................................................... 113 
A3–6.6 
Abnormal Liver Function Tests .............................................. 113 
A3–6.7 
Deaths ................................................................................... 114 
A3–6.8 
Preexisting Medical Conditions .............................................. 114 
A3–6.9 
Lack of Efficacy or Worsening of NSCLC .............................. 115 
A3–6.10 
Hospitalization or Prolonged Hospitalization .......................... 115 

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A3–6.11 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 116 
A3–6.12 
Participant-Reported Outcome Data ...................................... 118 
A3–6.13 
Safety Biomarker Data ........................................................... 118 
 

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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, or are considered clinically significant in 
the medical and scientific judgment of the investigator (i.e., not related to 
progression of 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 
 
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) 

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– 
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, at any 
dose: 
 
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. 
 
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 

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 
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 [NCI] Common Terminology Criteria for Adverse Events [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 electronic Case Report Form (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 A3–4 for reporting instructions). 
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.  In addition, serious adverse events and non-serious adverse 
events of special interest are required to be reported immediately (i.e., no more than 
24 hours after learning of the event) using the paper Clinical Trial Adverse Event/Special 
Situations Form (see Section A3–4 for details). 
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. 

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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 on the basis of 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. 

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Follow-Up, and Reporting 
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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
CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a 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 A3–4 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 A3–4 for
reporting instructions), per the definition of serious adverse event in Section A3–2.
 
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. 

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The investigator will also consult the Investigator’s Brochure 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. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A3–3.4 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING DURING CROSSOVER 
At the time of crossover, an ongoing Grade 1 adverse event, whose onset was during 
the therapy with the standard-of-care study drugs, that eventually worsens after 
crossover, should be recorded as a new adverse event in the Adverse Event eCRF. 
The onset date of the new adverse event should be recorded as the date of the 
worsening.  Its initial severity should be the one assessed at the date of worsening.  
The new adverse event's causality should also be re-assessed in relationship to both 
therapies (i.e., standard of-care study drugs and pralsetinib) received during the study. 
The initial adverse event, which was ongoing at crossover time, should first be updated 
with an outcome of "Not recovered/Not resolved" (if the adverse event had been of a 
Grade 1 severity since its onset) or "Recovering/Resolving" (if its severity had decreased 
to Grade 1, before the crossover).  When the worsened adverse event eventually 
resolves or reaches a definitive outcome (e.g., resolved with sequelae), both adverse 
events (i.e., the one that started during the therapy with standard-of-care study drugs, as 
well as the one that worsened after crossover) will be updated with that same definitive 
outcome. 

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Follow-Up, and Reporting 
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If the event worsens to a serious adverse event or an adverse event of special interest, 
the event should also be reported to the Sponsor using the paper Clinical Trial Adverse 
Event/Special Situations Form within 24 hours of awareness (see Section A3–4). 
A3–3.5 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
A3–3.5.1 
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. 
New or updated information will be recorded in the originally completed CRF and for 
serious adverse events and non-serious adverse events of special interest is require 
to be immediately (i.e., no more than 24 hours after learning of the event) reported 
as well using the paper Clinical Trial Adverse Event/Special Situations Form  
(see Section A3–4 for details). 
The investigator will submit any updated serious adverse event data to the Sponsor 
within 24 hours of receipt of the information.  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 8.6.1), 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. 
A3–3.5.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 

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summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
A3–4 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE 
EVENTS OF SPECIAL INTEREST 
The primary mechanism for reporting serious adverse events and adverse events of 
special interest to the Sponsor will be the paper Clinical Trial Adverse Event/Special 
Situations Form provided to investigators.  This 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 event), either by faxing or by scanning and emailing 
the form, using the fax number or email address provided to investigators.  In addition, 
the 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 as described in Section A3–4. 
The investigator should report any new significant follow-up information as detailed in 
Section A3–4.1, to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the information). 
After the study is completed at a given site, the clinical database will be taken offline to 
prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event during this period from a study 
participant or receives updated data on a previously reported serious adverse event 
after the clinical database has been taken off line, the site should report this information 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A3–4. 
A3–4.1 
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 
emailing the form, using the fax number or email address provided to investigators. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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110/Protocol BO42864, Version 6 
A3–4.2 
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 approximately 30 days after the final dose of study 
treatment.  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 paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators 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 emailing the form, using the fax number or 
email address provided to investigators.  
Instructions for reporting serious adverse events that occur more than 30 days after the 
final dose of study treatment are provided in Section A3–5. 
A3–5 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 30 days after the final 
dose of study treatment), all deaths, regardless of cause, should be reported through 
use of the Death eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported by either 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form, using the fax number or email address provided to investigators.  
In addition, the event should be recorded in the eCRF, if it is still available to the site. 
A3–6 
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 
concepts when recording adverse events on the Adverse Event eCRF.  Avoid 
colloquialisms and abbreviations.  Only one adverse event term should be recorded in 
the event field 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 

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Follow-Up, and Reporting 
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participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
A3–6.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
A3–6.2 
ADVERSE EVENTS THAT ARE SECONDARY TO 
OTHER EVENTS 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
A3–6.3 
PERSISTENT OF 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 

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Follow-Up, and Reporting 
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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 A3–4 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. 
A3–6.4 
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." 

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Follow-Up, and Reporting 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A3–6.4 for 
details on recording persistent adverse events). 
A3–6.5 
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 A3–6.4 for 
details on recording persistent adverse events). 
A3–6.6 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 

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Follow-Up, and Reporting 
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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 A3–6.2) 
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 A3–4). 
A3–6.7 
DEATHS 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 8.6.1) that are attributed 
by the investigator solely to progression of non–small cell cancer (NSCLC) should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, regardless of relationship to study 
treatment, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section A3–4).  An independent Data Monitoring Committee will 
monitor the frequency of deaths from all causes (see Section 4.1.4). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section A3–3.5. 
A3–6.8 
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"). 

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Follow-Up, and Reporting 
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A3–6.9 
LACK OF EFFICACY OR WORSENING OF NSCLC 
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event.  When recording an unanticipated worsening of non-small cell lung cancer 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 non-small 
cell lung cancer”).  Events that are clearly consistent with the expected pattern of 
progression of the underlying disease should not be recorded as adverse events.  
These data will be captured as efficacy assessment data only.  In most cases, the 
expected pattern of progression will be based on Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1).  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
A3–6.10 
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 
 
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 
 

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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 
 
A3–6.11  
CASES OF OVERDOSE, MEDICATION ERROR, DRUG ABUSE,
  
 
OR DRUG MISUSE
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations") are defined as follows:
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher
than the assigned dose
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher
than the assigned dose
 
Medication error:  accidental deviation in the administration of a drug
– 
In some cases, a medication error may be intercepted prior to administration of
the drug.
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or
dependence, physical harm, and/or psychological harm
 
Drug misuse:  intentional deviation in the administration of a drug that does not
qualify as drug abuse
– 
In cases where drug is to be self-administered by the participant, drug misuse
could involve the drug being administered to someone other than the 
participant.
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, both the special 
situation and 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 A3–4).  
For pralsetinib, adverse events associated with special situations should be recorded as 
described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 

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Follow-Up, and Reporting 
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 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  
Check the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with pralsetinib, regardless of whether they 
result in an adverse event, or they result in a non-serious adverse event, which is not an 
adverse events of special interest, should be recorded on the Adverse Event eCRF 
and reported via the paper Clinical Trial Adverse Event/Special Situations Form within 
30 calendar days of awareness, as described below: 
 
Accidental overdose:  Enter pralsetinib and "accidental overdose" as the event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter Pralsetinib and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter pralsetinib 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 pralsetinib and "intercepted medication error" as 
the event term.  Check the "Medication error" box.  Enter a description of the error in 
the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter Pralsetinib and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter Pralsetinib and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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 
Drug misuse that does not qualify as an overdose:  Enter Pralsetinib and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter Pralsetinib and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
 Drug administered to someone other than the participant:  Enter Pralsetinib and 
"participant supplied drug to third party" as the event term.  Check the "Drug 
misuse" box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
A3–6.12 
PARTICIPANT-REPORTED OUTCOME DATA 
Adverse event reports will not be derived from participant-reported outcome (PRO) data 
by the Sponsor.  Sites are not expected to review the PRO data for adverse events. 
A3–6.13 
SAFETY BIOMARKER DATA 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
 

 
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Appendix 4  
Contraceptive and Barrier Guidance 
TABLE OF CONTENTS 
A4–1 
Pregnancies in Female Participants ...................................... 120 
A4–2 
Pregnancies in Female Partners of Male Participants ........... 120 
A4–3 
Abortions................................................................................ 121 
A4–4 
Abnormal Pregnancy Outcomes ............................................ 121 
 
 

Appendix 4:  Contraceptive and Barrier Guidance 
Pralsetinib—F. Hoffmann-La Roche Ltd 
120/Protocol BO42864, Version 6 
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 the 
study or within 2 weeks after the final dose of pralsetinib, and according to the 
contraceptive requirements in the respective local labels for standard of care therapies. 
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 
emailing the form, using the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event electronic Case Report Form 
(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. 
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 the study or within 
1 week after the final dose of pralsetinib, and according contraceptive requirements in 
the respective local labels for standard of care therapies. 
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 emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male participant exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available.  An investigator who is contacted by the male participant or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 

Appendix 4:  Contraceptive and Barrier Guidance 
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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 A3–4). 
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 A3–4).  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 A3–4). 
 

 
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Appendix 5  
Safety Plan:  Management of Identified and Potential Risks 
Pralsetinib has been recently approved in the United States for the treatment of 
non-small lung cancer (NSCLC), and clinical development is ongoing.  The safety plan 
for participants in this study is based on clinical experience with pralsetinib in completed 
and ongoing studies.  The anticipated important safety risks for pralsetinib are outlined 
below.  Refer to the Pralsetinib Investigator's Brochure 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 dose modification and treatment interruption or 
discontinuation, are provided below. 
A5–1 
DOSE MODIFICATIONS AND INTERRUPTIONS 
A5–1.1 
GENERAL GUIDANCE FOR DOSE MODIFICATIONS, 
INTERRUPTIONS, AND RE-ESCALATION 
General dose modification guidelines for pralsetinib are summarized in  
Section A5–1.1.1.  For details related to dose modification and management of specific 
pralsetinib-related adverse events, refer to Section A5–1.1.2.  Guidance for pralsetinib 
dose interruptions is provided in Section A5–1.1.3.  These guidelines should be followed 
by clinical Investigators; however, for an individual participant, dose interruptions, 
reductions, and treatment discontinuation should also be based on the clinical 
circumstance.  Guidance for re-escalation after resolution of adverse drug reactions is 
provided in Section A5–1.1.4.  Deviation from these guidelines must be documented and 
communicated to the Sponsor. 
Dose modification or interruption guidelines for carboplatin, cisplatin, pemetrexed, 
gemcitabine, paclitaxel, and nab-paclitaxel are provided in Section A5–1.1.5 and for 
pembrolizumab in Section A5–1.1.5. 
Comprehensive assessments of any study drug-related adverse events (adverse drug 
reactions) experienced by the participant will be performed throughout the study.  
The severity of the event, as well as clinical judgment will be utilized to determine 
appropriate management of the participant for any adverse event experienced while 
participating in this study.  Adverse events are to be graded according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 
(CTCAE v5.0). 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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Any medication, including those administered for therapy of symptoms considered to be 
associated with study drug administration, should be reported on the appropriate 
Concomitant Medication page of the participant’s electronic Case Report Form (eCRF).  
The symptoms should be reported on the Adverse Event page. 
A5–1.1.1 
Guidance for Pralsetinib Dose Modifications 
Pralsetinib dose reductions to below 100 mg once a day (QD) are not permitted 
(see Table A5-1).  If a participant requires dose reduction below these dose levels, study 
drug should be discontinued. 
Table A5-1 Dose Modification Guidelines for Pralsetinib-Related Toxicity 
Toxicity 
Modification 
Non-hematologic toxicity (for pneumonitis, infections, tumor lysis syndrome, hemorrhagic 
events and hypertension, refer to Section A5–1.1.2 further below) 
Grade 1 
 No dose interruption or modification required. 
Grade 2 
 No dose interruption or modification required.  If dose interruption is 
necessary, on improvement resume dosing without dose reduction. 
Grade 3 
 Occurrence:  Hold until event is Grade  2 or has returned to baseline and 
then resume by reducing the dose by 100 mg less than the current dose. 
 Occurrence at 100 mg:  Discontinue pralsetinib. 
Grade 4 
 Occurrence:  Hold until event is Grade  2 or has returned to baseline, and 
then resume by reducing the dose by 100 mg less than the current dose. 
 If same adverse events recurs at Grade 3 or higher, discontinue pralsetinib. 
Hematologic toxicity:  anemia, neutropenia, and thrombocytopenia 
Grade 1 or 
Grade 2 
 No dose interruption or modification required. 
Grade 3 or 4 
 Occurrence:  Hold until event is Grade  2 or has returned to baseline, and 
then resume by reducing the dose by 100 mg less than the current dose. 
 Occurrence at 100 mg:  Discontinue pralsetinib. 
Hematologic toxicity:  lymphopenia 
Grade 1 or 2 
 No dose interruption or modification required. 
Grade 3 
 Occurrence:  Reduce the dose by 100 mg less than the current dose.  
Interruption of dosing can be done based on clinical circumstances but is not 
required. 
 Occurrence at 100 mg:  Discontinue pralsetinib. 
Grade 4 
 Occurrence:  Hold until event is Grade  3 or has returned to baseline, and 
then resume by reducing the dose by 100 mg less than the current dose. 
 Occurrence at 100 mg:  Discontinue pralsetinib. 
 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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A5–1.1.2 
Dose Modification and Management of Specific 
Pralsetinib-Related Adverse Events 
Pneumonitis 
Pneumonitis, including interstitial lung disease, is a known side effect of tyrosine kinase 
inhibitors (TKIs), particularly TKIs used in the treatment of NSCLC and has also been 
observed with pralsetinib.  Drug-related pneumonitis may be associated with signs and 
symptoms such as dyspnea, hypoxia, cough, hemoptysis, and fever as well as radiologic 
evidence of parenchymal or interstitial changes. 
The diagnosis of pneumonitis and determination of causal relationship to the drug is 
often confounded by the underlying disease (especially lymphangitic carcinomatosis) 
and other factors, such as lung infection and radiation effect due to non-specific signs 
and symptoms as well as similar radiological appearance.  Pneumonitis should be 
suspected when such signs and symptoms develop or in asymptomatic participants 
when a new ground glass opacity or interstitial infiltration is noted in imaging studies.  
If a participant is considered to have the potential diagnosis of drug-related pneumonitis, 
physical examination, assessment of oxygen saturation, and evaluation for infectious 
etiologies, and thoracentesis, bronchoscopy, or open lung biopsy should be considered 
to reach a diagnosis.  If the causality is at least possibly related to the study drug, 
management of pneumonitis, including dose interruption and potentially discontinuation 
is required, as presented in Table A5-2. 
Table A5-2 Pralsetinib Dose Modification Recommendations for 
Treatment-Related Pneumonitis 
Toxicity Grade 
Dose Modification 
Grade 1 
 Interrupt dosing for a minimum of 7 days. 
 Resume dosing without dose reduction when the pneumonitis has 
improved to Grade 1 or less. 
 If pneumonitis recurs, interrupt dosing until improves to Grade 1 or less, 
then resume dosing with a dose reduction of 100 mg. 
 If pneumonitis recurs, consider permanently discontinuing pralsetinib.  
Dosing interruption and dose reduction may be repeated; however, 
repeated dosing interruption and dose reduction are at the discretion of 
the Investigator and should be balanced with the need to treat the 
underlying disease. 
Grade 2 
 Interrupt dosing for a minimum of 7 days. 
 Resume dosing with a dose reduction of 100 mg when the pneumonitis 
has improved to Grade 1 or less. 
 If pneumonitis recurs, consider permanently discontinuing pralsetinib.  
Dosing interruption and dose reduction may be repeated; however, 
repeated dosing interruption and dose reduction are at the discretion of 
the Investigator and should be balanced with the need to treat the 
underlying disease. 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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Table A5-2 Pralsetinib Dose Modification Recommendations for 
Treatment-Related Pneumonitis (cont.) 
Toxicity Grade 
Dose Modification 
Grade 3 
 Permanently discontinue treatment, unless the investigator discusses with 
the Sponsor and believes the benefit–risk assessment justifies 
retreatment, and even then, the pneumonitis must be completely resolved, 
and the dose must be reduced by 100 mg less than the current dose. 
 If pneumonitis recurs, permanently discontinue treatment. 
Grade 4 
 Permanently discontinue treatment. 
 
Infections 
Infections (including opportunistic infections), some of which have been fatal, have been 
reported with participants treated with pralsetinib.  Some severe and fatal infections have 
not been preceded by neutropenia or lymphopenia.  Any significant infection should be 
managed with systemic antibiotics (if appropriate) and other supportive management.  
Monitor closely for signs and symptoms of infection and treat appropriately. 
A causal relationship between pralsetinib and severe infection, including opportunistic 
infection, has now been established. 
Regardless of investigator causality assessment, dose interruption and dose reduction 
and/or discontinuation should follow the guidelines in Table A5-3. 
Table A5-3 Pralsetinib Dose Modification Recommendations for 
Infection 
Toxicity Grade 
Dose Modification 
Grade 23 
 
Interrupt dosing for a minimum of 7 days. 
 
Resume dosing with dose reduction by 100 mg less than the 
previous dose prior to dose interruption, when the infection has 
improved to Grade  1 (infection completely cleared). 
Grade 4 
 
Permanently discontinue pralsetinib. 
 
Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) has been observed following pralsetinib treatment.  
Investigators should monitor electrolyte status and renal function by means of laboratory 
testing.  Participants with TLS may require supportive care with IV fluids and correction 
of electrolyte imbalances. 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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Participants that are at risk for TLS at study entry, such as those with high tumor burden, 
should be well hydrated before initiation of pralsetinib and avoid dehydration during the 
first cycle.  If TLS is suspected, investigators should manage the adverse event(s) 
according to standard institutional practices or accepted oncology management 
guidelines (Coiffier et al. 2008; Klastersky et al. 2016). 
Hemorrhagic Events 
In the ARROW study, hemorrhagic adverse events have very commonly been observed.  
Severe, including fatal, hemorrhagic adverse events, can occur in participants receiving 
pralsetinib. 
A hemorrhagic adverse event considered possibly related to pralsetinib should be 
managed according to applicable standard-of-care guidelines.  Pralsetinib dose 
interruption, reduction and/or discontinuation due to a severe related hemorrhagic 
adverse event will observe the following guidelines: 
 
Interrupt pralsetinib administration until resolution or improvement of hemorrhage 
to Grade 1; resume pralsetinib at a reduced dose. 
 
Permanently discontinue pralsetinib in the event of a life-threatening or recurrent 
severe hemorrhagic adverse event related to pralsetinib. 
 
Hypertension 
Treat with standard of care antihypertension therapy.  Dose modifications not required if 
hypertension is able to be managed with standard of care antihypertensive therapy.  
If dose modification is necessary, use dose medication for non-hematologic toxicity, as 
described in Table A5-1. 
A5–1.1.3 
Dose Interruptions for Pralsetinib 
Pralsetinib doses may be interrupted for study drugrelated toxicities for up to 56 days 
(8 weeks).  In general, if a study drugrelated toxicity does not resolve to Grade  2 or 
has not returned to baseline after dose interruption for more than 56 days, the participant 
must be discontinued from study drug unless after discussion with the Medical Monitor, 
resumption of treatment is considered to be in the best medical interest of the participant 
and this is documented in writing. 
Additionally, the Sponsor’s Medical Monitor must be contacted if an adverse event 
deemed unrelated to treatment requires a dose interruption for more than 56 days; a 
longer recovery period may be considered in discussion with the medical monitor.  If a 
participant resumes treatment after a dose hold of  28 days, an unscheduled disease 
assessment should occur before restarting pralsetinib to assess status of disease after 
the dose hold. 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
Pralsetinib—F. Hoffmann-La Roche Ltd 
127/Protocol BO42864, Version 6 
For participants who require an interruption due to surgery or another procedure, study 
drugs should be discontinued 48 hours before the procedure and resumed 48 hours 
after the procedure is completed.
During dose interruptions, study sites should continue to observe the study schedule as 
planned.
A5–1.1.4 
Dose Re-Escalation after Resolution of Pralsetinib
 
          Adverse Drug Reactions
Re-escalation of pralsetinib after dose modification for adverse events is discouraged. 
However, if in the opinion of the treating investigator re-escalation is warranted, this 
must be undertaken after consultation with the Sponsor.  To be a candidate for 
re-escalation, the adverse event that led to dose modification must not have recurred 
and no other Grade 3 or 4 adverse events must have been observed during the 
preceding 28 days.
Participants may receive step-wise pralsetinib dose re-escalations up to 400 mg QD 
(e.g., 100 mg QD to 200 mg QD to 300 mg QD to 400 mg QD) if the above criteria 
continue to be met.  A participant should be treated and tolerate therapy well for at least 
one cycle at each higher dose level before the dose is escalated again.  In no 
circumstances should a participant receive a pralsetinib dose higher than 400 mg QD.
A5–1.1.5 
Guidance for Cisplatin, Carboplatin, Pemetrexed, Paclitaxel,
 
          Nab-paclitaxel and Gemcitabine Dose Modifications
Guidance for dose modifications for adverse events thought to be related to cisplatin,
carboplatin, pemetrexed, paclitaxel, nab-paclitaxel and gemcitabine should follow the 
guidance provided in the product label and on institutional standard of care.
A5–1.1.6 
Guidance for Pembrolizumab Dose Modifications
Dose modifications for adverse events thought to be related to pembrolizumab should 
follow the guidance provided in the product label and institutional standard of care.
A brief (but not all inclusive) guidance for dose modifications due to immune-related 
adverse reactions related to pembrolizumab is provided in Table A5-4.

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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Table A5-4 Recommended Treatment Modifications for Pembrolizumab 
Immune-Related 
Adverse 
Reactions 
Severity 
Treatment Modification 
Pneumonitis 
Grade 2 
 Withhold until adverse reactions 
recover to Grade 1 a or better. 
Grade 3 or 4, or recurrent 
Grade 2 
 Permanently discontinue. 
Colitis 
Grade 2 or 3 
 Withhold until adverse reactions 
recover to Grade 1 a or better. 
Grade 4 or recurrent Grade 3 
 Permanently discontinue. 
Nephritis 
Grade 2 with creatinine   1.5 
to  3  ULN 
 Withhold until adverse reactions 
recover to Grade 1 a or better. 
Grade  3 with creatinine 
 3  ULN 
 Permanently discontinue. 
Endocrinopathies 
Symptomatic hypophysitis 
 Withhold until adverse reactions 
recover to Grade 1 a or better. 
Type 1 diabetes associated 
with  3  ULN hyperglycemia 
(glucose  250 mg/dL or 
 13.9 mmol/L) or associated 
with ketoacidosis 
 For participants with Grade 3 or 4 
endocrinopathy that improves to 
Grade 2 or less and is controlled with 
hormone replacement, if indicated, 
continuation of pembrolizumab may 
be considered after corticosteroid 
taper, if needed.  Otherwise, 
treatment should be discontinued. 
Hyperthyroidism Grade  3 
 Hypothyroidism may be managed 
with replacement therapy without 
treatment interruption. 
Hepatitis 
Grade 2 with AST or  
ALT  3 to 5 ULN or  
total bilirubin  1.5 to 3  ULN 
 Withhold until adverse reactions 
recover to Grade 1 a or better. 
Grade ≥ 3 with AST or ALT 
 5 times ULN or  
total bilirubin  3 ULN 
 Permanently discontinue. 
In case of liver metastasis with 
baseline Grade 2 elevation of 
AST or ALT, hepatitis with 
AST, or ALT increases  50% 
that lasts 1 or more weeks 
 Permanently discontinue. 

Appendix 5:  Safety Plan:  Management of Identified and Potential Risks 
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Table A5-4 Recommended Treatment Modifications for Pembrolizumab 
(cont.) 
Immune-Related 
Adverse 
Reactions 
Severity 
Treatment Modification 
Skin reactions 
Grade 3 or suspected 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
 Withhold until adverse reactions recover 
to Grade 1a or better. 
Grade 4 or confirmed 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
 Permanently discontinue. 
Other 
immune-related 
adverse 
reactions 
Based on severity and type 
of reaction (Grade 2 or 3) 
 Withhold until adverse reactions recover 
to Grade 1a or better. 
Grade 3 or 4 myocarditis 
Grade 3 or 4 encephalitis 
 Permanently discontinue. 
Grade 3 or 4 Guillain-Barré 
syndrome 
 Permanently discontinue. 
Infusion-related 
reactions 
Grade 3 or 4 
 Permanently discontinue. 
ULN  upper limit of normal. 
Note:  Toxicity grades are in accordance with National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v.5). 
a If treatment-related toxicity does not resolve to Grade 1 or better within 12 weeks after last 
dose of pembrolizumab, or if corticosteroid dosing cannot be reduced to  10 mg/day 
prednisone or equivalent within 12 weeks, pembrolizumab should be permanently 
discontinued. 
  
Pembrolizumab should be permanently discontinued for Grade 4 or recurrent Grade 3 
adverse reactions, unless otherwise specified in Table A5-4. 
REFERENCES 
Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: 
ESMO Clinical Practice Guidelines. Ann Oncol 2016;27(Suppl 5):v1118. 

 
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Appendix 6  
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), subcutaneous, intravenous, or 
endotracheal administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment administration, 
the following procedures should be performed: 
 
Stop study treatment administration, if possible. 
 
Call for additional medical assistance. 
 
Maintain an adequate airway. 
 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by participant status and as directed by the physician in charge. 
 
Continue to observe the participant and document observations. 
 

 
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Appendix 7  
Eastern Cooperative Oncology Group Performance Status 
Grade 
Symptomatology 
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, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
 

 
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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 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
 
 
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, Version 1.1 (RECIST v1.1) 
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mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
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. 

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134/Protocol BO42864, Version 6 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a participant is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
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 patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 

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

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on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 

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lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
– 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 

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 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table A8-1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at baseline. 

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Table A8-1 Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  
The objective response status of such patients is to be determined by evaluation of 
target and non-target lesions as shown in Table A8-1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 

Appendix 8:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
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REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 

 
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Appendix 9  
Protocol Amendment History 
A rationale for the current amendment precedes the Table of Contents. 
PROTOCOL AMENDMENT, VERSION 5 (3 APRIL 2024): 
As communicated to sites and Investigators in the memo sent on 23 January 2024, the 
Sponsor has decided to terminate the BO42864 study (AcceleRET-Lung) due to 
Blueprint Medicines' decision to discontinue global marketing and development of 
pralsetinib in all territories with the exclusion of  the US and Greater China.  Screening 
was closed on 26 January 2024 and the last patient was enrolled on 6 February 2024.   
Investigators may continue to maintain patients on pralsetinib until continued access 
solutions are available.  Participants randomized to Arm B and still receiving the 
standard-of-care (SOC) platinum-containing anticancer treatment regimen at the time of 
protocol version 5 should be withdrawn from the study promptly and treated according to 
the discretion of the investigator.  In the event that the SOC treatment regimen used 
within the study is not available to the participant after withdrawal, the participant may 
remain in the study and continue to receive SOC treatment but must discontinue, at the 
latest, by the time the last patient receiving pralsetinib has discontinued from the study.  
Investigators will be given advanced notice of this timepoint.  Crossover from standard of 
care (Arm B) to pralsetinib will no longer be an option.   
Protocol BO42864 has been primarily amended to reflect changes to the study design, 
assessments, objectives and endpoints following the termination of the study.  
Substantive changes to the protocol, along with a rationale for each change, are 
summarized below. 
The following changes, aimed at reducing burden to patients and sites, have been made 
as a result of the Sponsor’s decision to prematurely terminate the study:  
 
The study schema has been updated to reflect changes to the study design 
(Section 1.2).  
 
The study period of long-term follow-up (i.e., progression-free survival [PFS] 
follow-up and survival follow-up) has been removed (Sections 1.3, 4.1, 4.1.4, 7.1). 
 
The timepoints for tumor imaging assessments have been updated to be performed 
as per the standard of care at the study site (Sections 1.3 and 8.4).   
 
Assessments that do not directly impact patient care and investigator's decision for 
participant to remain on treatment (i.e., patient-reported outcome [PRO] 
assessments, blood sample collection for pharmacokinetics, carcinoembryonic 
antigen, and biomarkers and tumor tissue collection at disease progression) have 
been removed (Sections 1.3 [Tables 1 and 2], 4.1.1, 8.1, 8.7, 8.10, and 8.13; 
Tables 3 and 4, Sections 8.13.1, 8.13.2, 8.13.2.1, and 8.13.2.2, and 

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Appendices 911 have been deleted and subsequent tables/sections/appendices 
have been renumbered). 
 
Secondary and exploratory objectives and endpoints and statistical analysis related 
to PRO, pharmacokinetics, and biomarkers have been removed because the 
corresponding assessments will no longer be performed (Sections 3, 4.2.1, 4.2.4, 
9.3.3.3, and 9.3.4.3).   
 
The exploratory objective to assess CNS activity has been removed (Section 3). 
 
Instructions for participants to take pralsetinib after sample collection and 
completion of pretreatment assessments have been removed as it is no longer 
applicable (Section 6.1.1). 
 
As blinded independent central review (BICR) will no longer be used in this study to 
confirm disease progression, all requirements for BICR confirmation of disease 
progression have been removed (Section 4.1.3 and 7.1) and the following changes 
have also been introduced: 
– 
The primary endpoint of PFS and secondary endpoints of overall response rate, 
duration of response, clinical benefit rate, and disease control rate have been 
revised to be assessed by the investigator instead of BICR (Sections 3, 4.1, 
4.1.1, 9.1, 9.2, 9.2.1, 9.3.2, 9.3.2.1, 9.3.3, 9.3.3.1, 9.3.3.2). 
– 
Text has been added to specify that tumor assessment scans will no longer be 
collected prospectively by the Sponsor or submitted to BICR facility 
(Section 8.4.1.1).  
– 
Text related to imaging review by BICR has been removed (Section 8.4.1.1) 
 
Text describing the  premature termination of this study and next steps for the 
participants has been added to inform and provide guidance to investigators 
(Sections 4 and 4.1.1). 
 
Text has been added to inform investigators that the option for participants in Arm B 
to crossover to Arm A has been removed (Sections 4.1.2 and 5.3).  As a result, text 
related to the crossover process and eligibility criteria has been removed 
(Sections 4.1.2, 5.3, and 8.6.3). 
 
Text has been added to state that the independent Data Monitoring Committee will 
review unblinded safety data until the Sponsor is unblinded, after which the study 
team will be responsible for monitoring patient safety in the study (Section 4.1.5).  
 
The end of study definition has been updated to reflect the premature termination of 
the study (Section 4.3). 
 
The duration of participation has been updated to reflect the premature termination 
of the study (Section 4.4). 
 
A statement has been added to specify that all investigators were informed of the 
premature study termination on 23 January 2024 (Section 7.2). 

Appendix 9:  Protocol Amendment History 
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 
The planned statistical analyses have been updated to reflect that the primary 
endpoint will only be reported descriptively and there will be no formal testing of the 
primary and secondary efficacy endpoints (Sections 9.1, 9.2, 9.2.2, 9.3.3.1). 
 
Text has been added to specify that control of the overall type I error (α) applying a 
gate-keeping hierarchical sequential testing method will no longer be implemented 
and text related to type I error has been removed (Sections 9.2, 9.2.2, and 9.4). 
 
The modified intent-to-treat (mITT) BICR, mITT investigator, and pharmacokinetic 
analysis sets have been removed as these analysis sets are no longer applicable 
(Section 9.2.3). 
 
The text describing the Statistical Analysis Plan (SAP) has been removed because 
a SAP will no longer be written for the study, as there is no intention to submit the 
statistical methods for review to Regulatory Authorities or external scientific advisors 
(Section 9.3). 
 
All planned supplementary and sensitivity analyses related to the primary endpoint, 
with the exception of "sensitivity to assess the impact of stratification", have been 
removed because the primary endpoint will only be reported descriptively and there 
will be no formal testing (Section 9.3.2.1). 
 
The description for subgroup analyses have been removed as these subgroup  
analyses will no longer be performed (Section 9.3.2.2). 
 
Duplication of the safety analyses description has been removed (Section 9.3.3).  
 
Text has been added to specify that an interim analysis is no longer planned given 
that the study is being prematurely terminated; as a result text related to the planned 
interim analysis and the hierarchical testing method has been removed (Section 9.4; 
Sections 9.4.1, 9.4.1.1, 9.4.1.2, and 9.4.2 have been deleted). 
 
The following changes have been made to align with Clinical Trials Regulation (CTR) 
requirements: 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (front matter and Section 8.6.9).  
Medical Monitor contact information in Section 8.6.9 has been replaced with a 
sentence indicating that this information will be provided separately to sites. 
 
The synopsis has been simplified to align with CTR and other guidelines 
(Section 1.1). 
 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products has been added to align with CTR requirements (Section 6 and 
Appendix 13). 
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 8.6.5). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section A1-4). 

Appendix 9:  Protocol Amendment History 
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 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section A1-6). 
 
Additional changes have been made as follows: 
 
Text has been modified to align with updates to the Roche Global Policy on 
Continued Access to Investigational Medicinal Products (Section 6.6). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 8.14.6). 
 
Text has been clarified to indicate that 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 
(Section A1-1). 
  
PROTOCOL AMENDMENT, VERSION 4 (28 APRIL 2022): 
Protocol BO42864 has been amended to merge all the changes from the five protocol 
clarification letters issued to sites, merge changes from the local Irish amendment into 
the global amendment, align the protocol with the current version of the investigator’s 
brochure (version 6) and clarify the study requirements for adverse event reporting and 
tumor assessments for participants in the crossover portion of the study.  While none of 
the individual changes are considered substantial, the cumulative sum of changes is 
considered substantial.  Changes to the protocol, along with a rationale for each change, 
are summarized below. 
 
Table 1 was revised as follows: 
– 
Changed the Survival follow up period to “every 3 months” from every 12 weeks 
to better reflect the annual frequency of the follow up visits. 
– 
Clarified tumor imaging requirements to align with the protocol requirement for 
brain imaging at every imaging visit. 
– 
Added assessment time points for Carboplatin or Cisplatin, Gemcitabine, 
Paclitaxel, and Nab-paclitaxel for alignment with the rest of the protocol. 
– 
Clarified that participants should receive their first dose of study treatment no 
later than 7 calendar days after randomization to allow for vitamin 
supplementation that is required for some of the standard of care (SOC) 
therapies. 
– 
Clarified that participants should continue with the same tumor assessment 
schedule in follow up until confirmation of progression by BICR in alignment 
with the rest of the protocol. 

Appendix 9:  Protocol Amendment History 
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145/Protocol BO42864, Version 6 
– 
Clarified the recording period for concomitant medications and the review 
period for adverse events for participants receiving gemcitabine and 
participants receiving nab-paclitaxel to align with the dosing schedule of these 
SOC treatment options. 
– 
Clarified the order in which PROs should be completed by participants and that 
PRO assessments are only required at Month 3 And Month 6 posttreatment 
discontinuation in order to assess long term outcomes of participants following 
treatment. 
– 
Added a request to maintain hard copy originals of the PRO questionnaires as 
part of the participant’s medical record at the site for source data verification. 
– 
Clarified that SOC regimens can be administered up to 4 or 6 cycles based on 
local guidelines to align with the language in the rest of the protocol. 
– 
Clarified that in exceptional cases where not safe or medically feasible in the 
investigator’s opinion, carcinoembryonic (CEA) samples may be omitted to 
allow for flexibility in the collection of this non-safety related assessment in 
exceptional circumstances. 
– 
Amended the requirement for biomarker collection from Cycle 24 to Cycle 25, to 
align with the schedule of events allowance for participants to transition to every 
other cycle visits after Cycle 19. 
 
Table 2 was revised as follows: 
– 
Changed the Survival follow up period to “every 3 months” from every 12 weeks 
to better reflect the annual frequency of the follow up visits. 
– 
Clarified tumor imaging requirements to align with the protocol requirement for 
brain imaging at every imaging visit. 
– 
Amended the reporting requirements for adverse events in crossover to align 
with the updated protocol requirement for ongoing adverse events during 
crossover. 
– 
Clarified the order in which PROs should be completed by participants and that 
PRO assessments are only required at Month 3 and 6 posttreatment 
discontinuation in order to assess long term outcomes of participants following 
treatment. 
– 
Added a request to maintain hard copy originals of the PRO questionnaires as 
part of the participant’s medical record at the site for source data verification. 
– 
Aligned the pregnancy testing footnote regarding sample requirements for 
pregnancy testing with the main schedule of assessments. 
– 
Amended the requirement for biomarker sample collection from Cycle 24 to 
Cycle 25 to align with the schedule of events allowance for participants to 
transition to every other cycle visits after Cycle 19. 

Appendix 9:  Protocol Amendment History 
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146/Protocol BO42864, Version 6 
 
Amended the biomarker sample collection for cross-cover participants (Table 4) to 
align with the language in the schedule of events and amend the biomarker sample 
collection from Cycle 24 to Cycle 25. 
 
Added Study BO41932 to Section 2.3.1.2 to reflect the current clinical development 
of pralsetinib. 
 
Amended the efficacy and safety background information in Section 2.3.1.2 to 
reflect updated pralsetinib data from the ARROW study. 
 
Updated Section 2.5 to address the overlap in clinical and radiological features for 
pulmonary toxicity with pralsetinib and SARS-Cov-2 related interstitial pneumonia 
and advise investigators to use their clinical judgement when evaluating and 
managing participants with pulmonary symptoms. 
 
Added Section 2.6 to provide the COVID-19 vaccine benefit-risk assessment in line 
with the requirement from the Medicines and Healthcare Products Regulatory 
Agency (MHRA). 
 
Amended Section 4.1.2 to clarify that participants who consider participating in the 
crossover part of the study, if assessed by local assessment to have disease 
progression, should not discontinue treatment until progression (per RECIST v1.1) 
has been confirmed by BICR unless: 
 
The participant experiences an adverse event that requires drug discontinuation. 
 
The investigator believes that the treatment is no longer effective for the 
participant due to symptomatic deterioration or locally confirmed progression. 
 
Updated Section 4.1.2 to align with the updated protocol requirement for ongoing 
adverse events during crossover in Section 8.6.3 and Appendix 3.  Additionally, this 
section was also amended to allow participants in the crossover portion of the study 
to discontinue disease assessments after progressive disease has been confirmed 
by the investigator without BICR confirmation.  This update was implemented to 
allow investigators to discontinue participants from the crossover when the 
participant is not benefiting from therapy given that crossover progression is not tied 
to an endpoint necessitating central review. 
 
Revised Section 4.1.4 to require participants in follow-up to continue with the same 
tumor assessment schedule after study treatment discontinuation until confirmation 
of progression in alignment with other sections of the protocol. 
 
Amended Section 5, in addition to the rest of the protocol, to remove any reference 
to Medical Monitor approval of protocol-specific eligibility criteria from the protocol.  
The Principal Investigator (PI) may consult with the Medical Monitor/Sponsor for 
advice or clarification of any eligibility criteria and may share risk factor information 
pertinent to the participant, but the decision of whether a participant meets the 
eligibility criteria to enroll to the protocol is the responsibility of the PI.  This is a 
clarification of the responsibilities of the Principal Investigator and the role of the 
Medical Monitor during eligibility to ensure optimal execution of the study. 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
147/Protocol BO42864, Version 6 
 
Amended Section 5.1 to allow for the submission of fixed and embedded cell pellets 
from pleural effusion for central confirmation of RET fusion if a tumor issue cannot 
be obtained given that RET fusion testing can be performed on this type of sample.  
This section was also amended to omit the requirement for the submission of a 
pathology report with the tumor sample for RET confirmatory testing as all of the 
required information is already captured in the clinical database. 
 
Revised the eligibility criteria in Section 5.1 to align the contraceptive methods for 
men with the investigator’s brochure, that is, men who are not sterile, must use a 
condom plus an additional highly effective contraceptive method with a female 
partner of childbearing potential. 
 
Revised Table 7 to correct a misalignment with the study treatment formulations, 
unit dose strengths, and storage conditions and to clarify the carboplatin dose for 
participants with squamous NSCLC when used in combination with pembrolizumab 
and paclitaxel/nab-paclitaxel. 
 
Revised Section 6.1.1 to clarify the pralsetinib administration instructions in case of 
missed dose. 
 
Revised Section 6.1.3 to include the 7day window between randomization and 
timing of dose administration for Cycle 1 Day 1.  The requirements for pemetrexed 
and paclitaxel supplementation were also updated to accommodate for the variance 
in SOC supplementation globally. 
 
Amended Section 7.1 to align with the rest of the protocol in requiring participants in 
follow-up to continue tumor assessments per the on-treatment tumor assessment 
schedule of events. 
 
Revised the acceptable imaging techniques in Section 8.4.1.1 to simplify the bone 
scan requirement at subsequent tumor assessments when clinically indicated. 
 
Updated section 8.10 to omit the requirement for the submission of a pathology 
report with the submission of a tumor sample for central confirmation as all of the 
required information is captured in the clinical database. 
 
Added Section 8.6.3 to describe adverse event criteria during crossover to allow the 
investigator to adequately capture and ascribe causality to ongoing adverse events 
that worsen in crossover after administration of pralsetinib. 
 
Clarified the pregnancy reporting period in section 8.6.6 to align with Appendix 4 
and require study participants to inform the investigator of any pregnancy during the 
study and after the final dose of the study treatment based on the contraceptive 
periods in the respective local labels for standard of care therapies. 
 
Updated Section 9.3.2.1, Table 13 to included additional supplementary analysis to 
assess the impact of the start of new anti-cancer treatment before disease 
progression. 
 
Updated Section 9.3.3.4 to reflect the amended reporting of ongoing adverse events 
in crossover. 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
148/Protocol BO42864, Version 6 
 
Updated secondary Medical Monitor/Emergency Medical contact (Section 8.6.9). 
 
Updated data collection instructions for PRO assessments (Section 8.13.1) to reflect 
the update from electronic PRO collection to paper PRO collection. 
 
Updated Appendix 2, Table 1 to correctly reflect that all safety evaluations will be 
performed by the local laboratory.  Only specific assessments such as 
pharmacokinetic and biomarker assessments require central 
laboratory assessments. 
 
Added Section A33.4 (Appendix 3) to describe criteria for adverse events during 
crossover to allow the investigator to adequately capture and ascribe causality to 
ongoing adverse events that worsen following crossover during administration of 
pralsetinib. 
 
Revised multiple sections in Appendix 3 to describe the mechanism for reporting 
serious adverse events and adverse events of special interest to the Sponsor from 
electronic reporting system, to align with the current mechanism for reporting of 
adverse events and adverse events of special interest, which is the paper Clinical 
Trial Adverse Event/Special Situations Form. 
 
Added a requirement for sites to report special situations related to pralsetinib 
whether they do not result in an adverse event or that result in a non-serious 
adverse event which is not an adverse event of special interest, to be reported to 
the sponsor within 30 days of awareness using the paper reporting form.  
This change was made to align with internal guidance 
 
Updated Section A41 and Section A42 (Appendix 4) to align with Section 8.6.6 to 
require study participants to inform the investigator of any pregnancy during the 
study and after the final dose of the study treatment based on the contraceptive 
periods in the respective local labels for standard of care therapies.  This change 
was implemented to account for the variance in the contraceptive periods for the 
SOC drugs based on the regional labels. 
 
Amended Appendix 5 to include pralsetinib dose modification recommendations for 
hemorrhagic adverse events to address a request from Ireland’s Health Regulatory 
Products Authority (HPRA). 
  
PROTOCOL AMENDMENT, VERSION 3 (29 JANUARY 2021) 
Protocol BO42864 has been amended to reflect the change to F. Hoffmann-La Roche 
Ltd (hereafter referred to as Roche) as the Sponsor of this study.  Roche, in 
collaboration with Blueprint Medicine, will be responsible for the global co-development 
of pralsetinib.  In addition, the protocol has been revised according to the Transcelerate 
Common Protocol Template (CPT) format and structure.  Owing to the change in 
protocol template wording and to align with the CPT format, some sections that were 
previously part of the main protocol have been moved to appendices.  In addition, the 
study design has been modified to incorporate additional approved treatment regimens 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
149/Protocol BO42864, Version 6 
combining immunotherapy with chemotherapy for patients with squamous cell 
carcinoma.  Such regimens have been shown to have superior overall survival outcomes 
compared with the chemotherapy-alone option currently permitted in the control arm for 
participants with rearranged during transfection (RET) fusion–positive non–small lung 
cancer (NSCLC) of squamous histology (Arm B). 
The sample size and statistical analysis of data for this study have been modified based 
on results from the Phase I/II ARROW study. 
The schedules of activities have been amended, including additional assessment and 
change in frequency of assessments.  Details are referenced in summary of changes 
table below. 
Changes that were previously made in response to feedback from Ireland’s Health 
Regulatory Products Authority in the Ireland-specific version (Protocol BO42864, 
Version 2, Ireland; date final: 15 December 2020) included the following: 
 
The inclusion of patients with squamous NSCLC and treatment options owing to 
exclusion of patients with squamous NSCLC from enrollment in the study were 
deleted.  The removal of patients with NSCLC of squamous cell histology as a 
treatment option in Arm B was due to differences in standard-of-care (SOC) options 
in Ireland, which had to include paclitaxel or nab-paclitaxel as part of the regimen. 
 
Note:  In this amendment, the protocol was revised to include enrollment of 
participants with either squamous or non-squamous NSCLC.  Additionally, the 
choice of SOC therapies, including paclitaxel and nab-paclitaxel, has been updated 
to align with currently approved therapies for squamous NSCLC. 
 
Required female participants to be tested for pregnancy at least once a month.  
The requirement for monthly pregnancy testing has been implemented in this 
amendment. 
 
Updated drug–drug interactions (DDIs) with concomitant drugs with pralsetinib to 
align with the Pralsetinib Investigator’s Brochure, Version 4 
 
DDIs have been updated in this amendment based on Pralsetinib Investigator’s 
Brochure, Version 5. 
 
The Summary of Changes for the Ireland-specific amendment is presented in 
Appendix 13. 
Changes that have not previously implemented at any site are presented in the following 
table. 
This amendment is considered to be substantial. 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
150/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Title page and footers  
 
The protocol number has been changed from 
Blueprint Medicine Protocol BLU-667-230 to 
Roche Protocol BO42864. 
 
The Sponsor of the study has been changed 
from Blueprint Medicine to Roche, including the 
Sponsor’s legal registered address. 
 
The NCT number has been added. 
 
Reference to Blueprint Medicine’s BLU-667 has 
been deleted and replaced with Roche 
RO7499790. 
 
The Medical Monitor’s name for the study has 
been added. 
 
Electronic date stamp of protocol approval has 
been added. 
Changes have been made to reflect the change in 
Sponsor from Blueprint Medicine to Roche and CPT 
format 
Approval page 
The approval page has been deleted. 
Approval page deleted in lieu of electronic date stamp 
on the  title page per Roche’s standard operating 
procedures. 
Protocol Amendment 
Acceptance Form 
The form has been added. 
Per Roche’s standard operating procedures 
Global changes 
 
Reference to “investigator’s choice, platinum-
based chemotherapy regimens” has been 
changed to “investigator’s choice of SOC 
platinum-containing anticancer treatment 
regimens throughout the document where 
instituted. 
 
The term investigator’s choice of SOC 
platinum-containing anticancer treatment 
regimens more accurately reflects the 
comparator therapy that might comprise both 
chemotherapy and immunotherapy 
depending on investigator’s choice. 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
151/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
 
Reference to patient has been changed to 
participant. 
 
Reference to schedule of assessments has been 
changed to schedule of activities. 
 
Per harmonized CPT content 
Synopsis 
The Synopsis has been revised to reflect changes made 
to the protocol. 
Changes made for consistency with the body of the 
protocol 
Section 1.2, Study Schema, 
and Figure 1, Overall Study 
Design 
Section 1.2 and Figure 1 have been retitled (previously, 
Study Diagrams and Study Design).  Figure 1 was 
revised to reflect the following changes in study design: 
 
Updated to reflect the reduction in overall 
sample size from 250 to 226 participants 
 
Added another investigator’s choice of SOC 
platinum-containing anticancer treatment for 
patients with squamous histology 
(pembrolizumab in combination with carboplatin, 
paclitaxel, or nab-paclitaxel).  
 
Clarified to indicate that participants in Arm B 
may elect to cross over to receive pralsetinib 
treatment only after confirmation of progressive 
disease by BICR 
 
Added ECOG Performance Status of 0 or 1 
 
Revised the sample size based on updated 
assumptions for accrual and dropout rates 
used in the determination of sample size 
 
The addition of pembrolizumab plus paclitaxel 
or nab-paclitaxel was based on the Phase III 
KEYNOTE-407 study results, which showed 
the addition of pembrolizumab to standard 
chemotherapy of paclitaxel or nab-paclitaxel 
and a platinum agent resulted in significantly 
longer overall survival and progression-free 
survival than chemotherapy alone. 
 
To accurately reflect changes to the study 
design 
 
ECOG Performance Status added for 
completeness 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
152/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 1.3, Schedule of 
Activities, Table 1 and Table 
2, Table 3 (Pralsetinib PK 
Sample Collection), and 
Table 4 (Biomarker Sample 
Collection) 
 
Section 1.3 has been retitled (previously, 
Schedule of Assessments).   
 
Addition of inclusion and exclusion criteria 
review on Day 1 of Cycle 1 (Table 1) 
 
Optional mobile nursing (MN) visits have been 
added for participants and footnote h who 
provide consent to Table 1 for the main 
treatment period and Table 2 for the crossover 
treatment period.  MN assessments include vital 
signs, adverse event reporting, concomitant 
medications, hematologic, physical examination, 
coagulation, and chemistry profile, urinalysis, 
CEA, thyroid-stimulating hormone, free T4 and 
free T3, and PK and plasma biomarker 
assessments. 
 
Assessment of CEA (Table 1 only), thyroid-
stimulating hormone, free T4 and free T3, 
hepatitis B and C virus and HIV serology added 
in Tables 1 and 2 and footnotes 
 
The frequency of pregnancy testing has been 
updated to reflect that female participants are 
required to have a local serum or urine 
pregnancy test has to be performed as required 
by local regulations (at least monthly).   
 
Per Roche’s model document structure 
 
Clarification that inclusion and exclusion 
review should occur before the administration 
of the first dose of study treatment to avoid 
enrolling ineligible participants 
 
Optional MN added to reduce participant 
burden 
 
Carcinoembryonic antigen (CEA) samples 
added to monitor cancer treatment, including 
response to therapy and recurrence, and for 
correlation of CEA with cell free DNA and 
circulating tumor DNA, as an early measure 
of tumor progression 
 
Change implemented based on health 
authority feedback 
 
Clarification of coagulation parameters 
 
TSH, free T3, and free T4 added for 
monitoring of thyroid function, which is 
particularly important in participants receiving 
pembrolizumab 
 
HBV, HCV and HIV serology at screening 
was added to align with Roche standard 
inclusion criteria in oncology studies 
 
The frequency of ECG measurements 
updated to add ECG measurements every 12 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
153/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
 
Coagulation has been clarified to include PT, 
INR, and aPTT (Tables 1 and 2) 
 
HBV, HCV, and HIV serology assessment has 
been added at screening visit to support the 
additional inclusion criteria in Section 5.1. 
 
The frequency of 12-lead ECG measurements 
has been updated to include measurements 
every 12 weeks during the treatment period.  
 
Multiple footnotes have been updated to provide 
additional details regarding assessments 
and procedures. 
weeks while the participants are receiving 
treatment to better characterize the effect of 
pralsetinib on QTc prolongation. 
 
Clarification of assessments and procedures 
Section 1.3, Schedule of 
Activities, Table 1 and Table 
2, Table 3 (Pralsetinib PK 
Sample Collection), and 
Table 4 (Biomarker Sample 
Collection) (cont.) 
 
The participant-reported outcome (PRO) 
schedule has been revised to include additional 
collection times at safety follow-up as well as 
during progression-free survival follow-up 
(Tables 1 and 2). 
 
Addition of two study drugs, paclitaxel and 
nab-paclitaxel in the schedule of administration 
to align with the options in the investigator's 
choice of SOC platinum-containing anticancer 
treatment regimens for patients with squamous 
NSCLC. 
 
All biomarkers have been consolidated into one 
row to clarify that plasma samples for 
 
Inclusion of additional PRO assessment 
timepoints will allow for more complete PRO 
collection 
 
On-treatment plasma biomarker samples will 
be used to explore response, early 
progressors by analyzing changes in ctDNA 
(kinetics, alterations) and may help to identify 
high-risk participants who may need 
additional treatment.  In addition, samples 
may be used to inform future combination 
treatments with pralsetinib. 
 
Moved PK collection schedule from Appendix 
9 to Table 3 per CPT format and clarified 
predose sampling requirements  

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
154/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
biomarkers which also include assessment of 
circulating tumor DNA (Tables 1 and 2).   
 
Table 3, Pralsetinib Pharmacokinetic Collection 
Schedule:  Footnote b has been added 
specifying that predose samples are to be 
collected within 2 hours prior to receiving study 
treatment.   
 
Details of the biomarker schedule and samples 
are presented in Table 4.   
 
Added Table 4, Biomarker Sample Collection 
Section 1.3, Schedule of 
Activities and Sample 
Collection 
Moved the PK sampling collection table from Appendix 9 
to Table 3, Pralsetinib Pharmacokinetic Sample 
Collection, and added Table 4, Biomarker Sample 
Collection 
Per CPT structure and format 
Section 2.4, Benefit–Risk 
Assessment 
Section title revised and section updated to include 
impact of COVID-19 on the benefit–risk profile 
Per Roche’s Drug Safety’s guidance 
Section 3, Objectives and 
Endpoints, and Table 6, 
Objectives and 
Corresponding Endpoints 
 
Introduction describing overall aim of study 
added. 
 
Section 3.2, Secondary Objectives and 
Endpoints, and Section 3.3, Exploratory 
Objectives and Endpoints, consolidated in 
Section 3, Table 6, Objectives and 
Corresponding Endpoints. 
 
The primary, key secondary, additional 
secondary and exploratory objectives and 
corresponding endpoints definitions have been 
The endpoints have been updated to reflect Roche 
model document wording and the addition and 
reprioritization of objectives and endpoints. 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
155/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
revised and updated to reflect Roche standard 
language. 
– 
The objective to assess the central nervous 
system activity of pralsetinib has been moved 
from an additional secondary objective to an 
exploratory objective, reflecting reprioritization of 
endpoints. 
– 
The objectives to assess patient health-related 
quality of life, lung cancer symptoms and health 
status moved from additional secondary 
objectives to exploratory objectives, reflecting 
reprioritization of endpoints. 
– 
The objectives to correlate steady-state systemic 
exposure of pralsetinib with safety endpoints and 
anti-tumor activity moved from additional 
secondary objectives to exploratory objectives, 
reflecting reprioritization of endpoints 
– 
An exploratory objective added to characterize 
the pharmacokinetics of pralsetinib in a subset of 
participants to obtain more complete PK data. 
– 
An exploratory objective added to identify and/or 
evaluate predictive biomarkers, prognostic 
biomarkers, and pharmacodynamic biomarkers 
to increase the knowledge and understanding of 
disease biology of RET fusion–positive NSCLC. 
Section 4.1, Overall Study 
Design, Section 6.3, 
Treatment Assignment, and 
Section 9.4.1, General 
Considerations 
 
The definition of the brain metastasis 
stratification factor has been changed to now 
read:  history of brain metastasis (yes vs. no).  
Reference to “at baseline” has been deleted. 
 
Participants with previously treated brain 
metastasis that are surgically excised will be 
included with participants with brain 
metastasis identified at baseline in the same 
stratification group, owing to prognostic 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
156/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
differences in participants with no history of 
intracranial disease. 
Section 4.1.1, Main 
Treatment Period 
 
Revised descriptions of Arms A and B to specify 
enrollment of participants with non-squamous 
and squamous NSCLC  
 
Added a second investigator’s SOC choice of 
platinum-containing anticancer regimens to 
include pembrolizumab with carboplatin and 
paclitaxel or nab-paclitaxel for participants with 
squamous NSCLC. 
 
The addition of pembrolizumab plus paclitaxel 
or nab-paclitaxel as a treatment option for 
participants with squamous NSCLC was 
based on the Phase III KEYNOTE-407 study 
results, which showed the addition of 
pembrolizumab to standard chemotherapy of 
paclitaxel or nab-paclitaxel and a 
platinum-based drug resulted in significantly 
longer OS and PFS than chemotherapy 
alone. 
Section 4.1.2, Crossover 
Treatment Period 
 
Clarified that participants randomized to Arm B 
who experience disease progression:  
Confirmation has been changed from radiology 
review to blinded independent central review 
(BICR) during investigator’s choice of SOC 
platinum-containing anticancer treatment 
regimen for eligible participants to cross over to 
receive pralsetinib after confirmation of their 
disease progression by BICR.  Participants with 
locally determined progressive disease not 
confirmed by BICR will be ineligible for 
crossover and will continue to survival follow-up. 
 
Added description of optional mobile nursing 
visits during which certain assessments may be 
 
Administrative clarifications 
 
To reduce patient burden 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
157/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
performed for consented participants at 
applicable sites, following Day 1 of Cycle 2 or 
Day 1 of crossover Cycle 1. 
Section 4.1.3, End of 
Treatment Period and 30 
Day Follow-Up Contact 
Section has been revised to reflect that a tumor biopsy 
with central submission of tissue is encouraged at the 
time of disease progression, if safe and medically 
feasible.  The word optional has been deleted.  
Administrative clarification 
Section 4.1.4, Follow-Up 
Period 
Section has been updated to require participants without 
confirmed progressive disease by BICR to continue PFS 
follow-up even after initiation of a new anticancer 
therapy. 
To allow complete collection of PFS events  
Section 4.1.5, Independent 
Data Monitoring Committee 
Previously in Section 7, the description of the 
independent Data Monitoring Committee (iDMC) has 
been moved to the study design section of the protocol 
and updated, shortening the section and referring the 
reader to the iDMC Charter for further details.  
For consistency with Roche model document wording 
Section 4.2.1 Rationale for 
Study Population  
Section added to include rationale for the target study 
population with RET fusion–positive NSCLC  
Per CPT structure and format 
Section 4.2.3, Rationale for 
Control Group 
Section added to include rationale for addition of 
pembrolizumab in combination with carboplatin and 
paclitaxel as an SOC comparator for participants with 
squamous NSCLC based on previous study results. 
Per CPT structure and format 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
158/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 4.2.4, Rationale for 
Biomarker Assessments 
Section added. 
New section has been added to align with Roche 
model document wording and CPT template 
Section 4.4, Duration of 
Participation 
 The section has been updated to reflect a longer 
study duration based on updated enrollment 
projections extending the time of accrual. 
 The long-term follow-up duration has been updated 
and the total number of OS events expected at the 
end of the study has been added. 
 
Section 5, Study Population 
Section revised incorporating the change in participant 
enrollment in Arms A and B from 125 participants in 
each arm to 113 participants in each arm. 
For consistency with change in sample size 
Section 5.1, Inclusion 
Criteria for All Participants 
 
Clarified language to specify the NSCLC staging 
as unresectable NSCLC (Stage IIIB) or 
metastatic NSCLC (Stage IV) per Union 
Internationale Contre le Cancer/American Joint 
Committee on Cancer staging system 
 
Updated details regarding RET testing for 
central confirmation of RET fusion positivity 
 
Inclusion criterion requiring that all participants 
either have an HIV negative test at screening or 
are on stable antiretroviral therapy with a CD4 
count  200/L and an undetectable viral load 
added 
 
Clarified contraceptive requirements for male 
and female contraception 
 
To define the enrollment criteria based on 
updated staging definitions for NSCLC 
 
Added for completeness 
 
To further clarify the inclusion criteria for 
patients with HIV on the study 
 
Amended to align with labeling information 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
159/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 5.2, Exclusion 
Criteria for All Participants 
 
Criterion regarding the presence of lung disease 
revised to exclude participants with a history of 
pneumonitis within the previous 12 months  
 
Combined two exclusion criteria for participants 
with significant cardiovascular disease into one 
 
The criterion regarding study drug 
hypersensitivity was revised to include 
pembrolizumab, paclitaxel, and nab-paclitaxel. 
 
The exclusion criteria clarified regarding the 
eligibility of patients with infections, including the 
addition of criteria for patients with viral, bacterial 
or fungal infections, and participants with 
hepatitis B and C virus 
 
An exclusion criterion was added to clarify that 
patients are not eligible for the study if they are 
concurrently enrolled in another clinical study 
 
To align with Roche standard exclusion 
criteria language 
 
To align with the updated safety profile of 
pralsetinib  
 
Clarification 
 
To reflect all SOC therapy options included in 
the study 
 
Added additional exclusion criteria to ensure 
participant safety 
 
Per Roche’s standard procedures 
Section 5.3, Crossover 
Eligibility Criteria 
Added wording to clarify that participants with locally 
determined progressive disease not confirmed by BICR 
will be ineligible for crossover 
Clarification 
Section 5.4, Lifestyle 
Considerations 
Added subsections describing meals and dietary 
restrictions, caffeine, alcohol, and tobacco, activity, and 
contraception requirements 
Per CPT structure 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
160/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 5.5, Screen Failures 
Section updated to further clarify that participants may 
qualify for one additional re-screening opportunity (for 
two screenings total) and to clarify that participants do 
not need to be re-consented if re-screened within 30 
days after previously signing the consent form. 
Clarification 
Section 5.5.1, Contraceptive 
Requirements, and 
Appendix 4, Contraceptive 
and Barrier Guidance 
Wording outlining acceptable contraceptive methods 
deleted and moved to Section 5.4.4, Contraception 
Requirements, and cross reference to Section 5.1 
added. 
Per CPT structure and format and Roche model 
document wording 
Section 6.1, Study 
Treatments Administered 
 
Table 7 has been amended to include paclitaxel 
and nab-paclitaxel comparators 
 
Footnote b has been added to indicate the 
dosing regimen of paclitaxel for participants of 
Asian race/ethnicity. 
To reflect the addition of pembrolizumab in 
combination with carboplatin and paclitaxel/nab-
paclitaxel as a second option of investigator’s choice 
of platinum-containing anticancer treatment regimen 
for patients with NSCLC of squamous histology 
Section 6.1.1, Participants in 
Arm A and Participants Who 
Cross Over from Arm B to 
Receive Pralsetinib 
Section updated to clarify that all participants should 
complete a pralsetinib self-administration diary 
throughout their treatment period 
To ensure patient compliance and for 
pharmacokinetic sampling 
Section 6.1.2, Investigator’s 
Choice of SOC Platinum-
Containing Anticancer 
Treatment Regimens:  For 
Participants in Arm B 
 
Amended to include the administration details for 
the new comparator choices for squamous 
NSCLC, paclitaxel and nab-paclitaxel 
 
Clarification added to define that platinum-based 
chemotherapy will be administered for four or six 
cycles based on local guidelines, and guidelines 
have been added regarding switching of 
platinum therapy during a patient’s participation 
in the study.  In addition, instructions have been 
added that dose modification and 
For completeness 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
161/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
discontinuation of investigator’s choice of SOC 
platinum-containing anticancer therapy regimens 
should follow product labels and institutional 
standards. 
Section 6.1.3, Timing of 
Dose Administration 
Revised to include timing of dose administration details 
for paclitaxel and nab-paclitaxel as well as prophylaxis 
guidelines 
For completeness 
Section 6.4, Study 
Treatment Compliance, 
Section 6.5, Dose 
Modification, and 
Section 6.6, Continued 
Access to Study Treatment 
after the End of the Study 
Sections added. 
Per CPT structure and Roche model document 
wording 
Section 6.8.1, Permitted 
Therapies 
Section updated to include permitted therapies for 
paclitaxel and nab-paclitaxel 
For completeness 
Section 6.8.2, Cautionary 
Therapy 
 
Section updated for cautionary medication for 
participants receiving pralsetinib.  
 
Section updated to include a statement that 
investigators should consult the local prescribing 
information when determining whether a 
concomitant medication can be safely 
administered with study treatment, and for 
cautionary medications related to carboplatin, 
cisplatin, gemcitabine, pemetrexed, paclitaxel, 
nab-paclitaxel, and pembrolizumab, the 
investigator should refer to the local prescribing 
 
To reflect updates in the Pralsetinib 
Investigator’s Brochure, Version 5 
 
For completeness 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
162/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
information and Summary of Product 
Characteristics (Package Insert). 
Section 6.8.3, Prohibited 
Therapy and Procedures 
 
Section updated for prohibited therapies for 
participants receiving pralsetinib.  
 
Section updated to clarify that for participants 
receiving pembrolizumab any live, attenuated 
vaccine (e.g., FluMist®) within 4 weeks prior to 
randomization, and during treatment are 
prohibited. 
 
Section updated to include a statement that 
investigators should refer to the local prescribing 
information and Summary of Product 
Characteristics (Package Insert) for prohibited 
therapy related to carboplatin, cisplatin, 
gemcitabine, pemetrexed, paclitaxel, nab-
paclitaxel, and pembrolizumab.  
 
To reflect updates in the Pralsetinib 
Investigator’s Brochure, Version 5 
 
To ensure participant safety 
 
For completeness 
Section 6.10, Overdose 
Section deleted and replaced with Appendix 3, 
Section A3-7.11 (Cases of Overdose, Medication Error, 
Drug Abuse, or Drug Misuse) 
Per CPT structure and revised text to align with 
Roche model document wording 
Section 7, Discontinuation of 
Study Treatment and 
Participant Discontinuation 
or Withdrawal 
Dose modifications, interruptions and re-escalation 
guidelines moved to Appendix 5 and updated with 
information on discontinuation of study treatment, liver 
chemistry stopping criteria, participant discontinuation or 
withdrawal from the study, and participants lost to 
following 
Per CPT structure and format and Roche model 
document wording 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
163/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 8, Study 
Assessments and 
Procedures 
 
Sections re-organized to align with the Roche 
CPT template 
 
Wording added to reflect that at participating 
sites, certain assessments might be performed 
by mobile nursing (MN). 
 
Per CPT structure and format and Roche 
model document wording 
 
Optional mobile nursing added to reduce 
participant burden 
Section 8.11, Eligibility 
Review and Registration 
Wording added to provide more detail on the timing of 
the submission of tumor tissue samples to the central 
testing site, as well as the quality and quantity of tumor 
tissue required for central testing. 
Added for completeness 
Section 8.2, Demographic 
Information 
Wording included clarifying that demographic information 
such as ethnicity and race will be collected only if 
permissible per local regulations 
Change implemented based on health authority 
feedback 
Section 8.4, Efficacy 
Assessments 
 Timepoints for the collection of tumor tissue samples 
updated to include windows of  7 days 
 Clarified requirement for routine brain scans per the 
schedule of activities for all study participants 
 Clarified requirement for bone scans for all patients 
with known or suspected bone metastases 
 Wording added to include the provision of an 
imaging manual 
 The section has been updated to clarify that central 
imaging will be assessed by a blinded independent 
central review (BICR). 
 Added for completeness 
 Brain scans required for all patients to help 
assess the impact of study treatment on brain 
metastases 
 Bone scans required to better assess disease 
burden of disease for both response and 
assessment 
 Imaging manual added for completeness  
 The section has been updated to clarify that 
crossover is allowable only if progression is 
determined by blinded independent central review 
Section, 8.5, Safety 
Assessments 
 
Section, 8.5, Safety Assessments 
 
Section, 8.5, Safety Assessments 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
164/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 8.6, Adverse 
Events, Serious Adverse 
Events, and Other Safety 
Reporting 
 
Section 8.6, Adverse Events, Serious Adverse 
Events, and Other Safety Reporting 
 
Section 8.6, Adverse Events, Serious 
Adverse Events, and Other Safety Reporting 
Section 8.6.8, Medical 
Monitors and Emergency 
Medical Contacts 
Section added with the Medical Monitors’ emergency 
contact information. 
Per CPT structure and format 
Section 8.7, 
Pharmacokinetics 
 
Additional blood sample collection from 
approximately 25 patients in Arm A added  
 
The timeline for the storage of pharmacokinetic 
samples updated to no later than 5 years after 
the final Clinical Study Report 
 
Included to characterize the 
pharmacokinetics of pralsetinib 
 
Updated to align with Roche requirements 
and CPT structure and format 
Section 8.10, Biomarker 
Assessments 
A new template section added to further clarify details on 
biomarker sample collection 
Updated to align with Roche requirements and CPT 
structure and format 
Section 8.13, Clinical 
Outcome Assessments 
Language added to allow for the collection of 
participant-reported outcome assessments by telephone 
call in exceptional circumstances if the patient cannot get 
to the site. 
To reduce participant burden 
Section 8.14, Additional 
Assessments and 
Procedures Requiring 
Separate Consent or 
Performed Only at 
Participating Sites 
New section added to clarify details regarding Research 
Biosample Repository (RBR) and details on the 
approval, sample collection confidentiality, consent and 
withdrawal  
Updated to align with Roche RBR model document 
wording and CPT structure and format 
Section 9, Statistical 
Considerations 
The description and section headers of the statistical 
methods sections were deleted and renamed from 
previous Section 10 and moved to Section 9. 
Per CPT structure and format and revised to align 
with Roche model document wording 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
165/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 9.1, Statistical 
Hypotheses 
A description of the statistical hypothesis assuming 
proportional hazards model for the primary endpoint and 
hypothesis testing were added. 
Per Roche statistical requirements 
Section 9.2, Sample Size 
Determination 
 
The description of sample size determination 
has been clarified and reorganized into sections 
by the primary endpoint (Section 9.2.1) and 
secondary endpoints (Section 9.2.2). 
 
Sample size, timing of analyses, and power 
estimates have been updated for the primary 
and key secondary endpoints (Sections 9.2.1 
and 9.2.2). 
 
Assumptions for median overall survival in Arm 
B and the hazard ratio for overall survival have 
been updated (Section 9.2.2). 
 
Table 8, Clinical Trial Simulations, Table 9, 
Operating Characteristics, and Table 10, Timing 
of Analyses, have been added. 
 
For clarity 
 
Sample size, the timing of analyses and 
power estimates have been updated to reflect 
updated assumptions for accrual and drop-
out rates 
 
Assumptions for median overall survival in 
Arm B and the corresponding hazard ratio for 
overall survival have been updated to reflect 
the impact of crossover. 
 
For completeness 
Section 9.3, Analysis Sets 
 
Previously described in Section 10.2, the table 
has been moved and revised to specify an 
intent-to-treat population for the primary analysis 
of progression-free survival as well as for overall 
survival and PRO analyses. 
 
The mITT-BICR and mITT-INV analysis sets 
have been added and the response-evaluable 
population has been deleted. 
 
For consistency with the intent-to-treat (ITT) 
principle and to allow the broader inclusion of 
patients, the ITT population as well as 
modified ITT-BICR and mITT-INV populations 
have been added and the modified-ITT and 
response-evaluable populations have been 
removed.  The primary analysis of 
progression-free survival, as well as the 
analysis of overall survival and PRO 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
166/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
endpoints, will be conducted in the ITT 
population and will include all randomized 
patients, regardless of whether they receive 
treatment or their RET fusion status was 
confirmed by central testing. A supplementary 
A supplementary analysis, excluding 
participants who do not have centrally 
confirmed RET fusions, may be conducted 
and is described in Table 13. 
 
The analysis of BICR-ORR and INV-ORR will 
be conducted in the mITT-BICR and mITT-
INV. 
Section 9.4.1, General 
Considerations 
 
Previously described in Section 10.2, the 
description has been moved and expanded with 
additional details on analyses of the time-to-
event timepoints, the primary endpoints. 
 
Table 12, Situations and Outcomes for the 
Primary Endpoint:  Progression-Free Survival, 
as Assessed by Blinded Independent Central 
Review, has been added. 
 
Subsections added describing sensitivity and 
supplementary analyses, subgroup analyses, 
and analyses of secondary endpoints have been 
added, including supportive Table 13 and Table 
14. 
For completeness 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
167/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Section 9.4.3.2, Binary 
Endpoints (BIRC-ORR, 
BICR-DCR, and  
Section added and the analysis population specified. 
For completeness 
BICR-CBR)  
Previously in Section 10.5.3.2, the description of the 
analyses of PRO endpoints has been revised. 
Wording added for completeness  
Section 9.4.3.3, Participant 
Reported Outcomes 
Previously in Section 10.5.5, the description of the safety 
analyses has been updated. 
Per CPT structure and format and Roche model 
document. Additional details added for completeness 
Section 9.4.3.4, Safety 
Endpoints 
Previously in Section 10.5, the subsections have been 
reorganized to include information on summaries of 
conduct of study, summaries of demographics and 
baseline characteristics, and PK analyses. 
Per CPT structure and format and Roche model 
document 
Section 9.5.1, Planned 
Interim Analyses 
Previously in Section 10.5.7, the section has been 
moved and revised to include descriptions of the planned 
interim analysis and stopping boundaries and 
probabilities to stop for efficacy at the interim or final 
analysis in text and 
Per CPT structure and format and Roche model 
document 
Section 9.5.2, Optional 
Interim Analysis 
newly added Table 15. 
Wording added to adapt to information that may 
emerge during the course of the study. 
Section 12, Protocol 
Amendment History, and 
Section 12.1, Amendment 1 
Section added.  
Per CPT structure and format 
Appendix 1, Regulatory, 
Ethical, and Study Oversight 
Considerations 
Sections have been moved to Appendix 12. 
Per CPT structure and format and Roche model 
document wording 
Appendix 2, Clinical Safety 
Laboratory Tests 
Appendix added with details (e.g., final disclosure, 
informed consent process, data protection, 
administrative structure, Sponsor’s publication policy). 
Per CPT structure and format 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
168/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Appendix 3, Adverse 
Events:  Definitions and 
Procedures for Recording, 
Evaluating, Follow-Up, and 
Reporting 
Appendix added 
Per CPT structure and format and Roche model 
document wording 
Appendix 4, Contraceptive 
and Barrier Guidance 
 
Appendix added 
 
Requirements for SOC therapies aligned with 
labelling language detailed in this appendix.  
 
Per CPT structure and format and Roche 
model document wording 
 
Implemented per health authority feedback 
Appendix 5, Safety Plan:  
Management of Identified 
and Potential Risks 
Text removed from body of protocol to appendix and 
updated to include the risks of paclitaxel and 
nab-paclitaxel 
Per CPT structure and format and Roche model 
document wording 
Appendix 6, Anaphylaxis 
Precautions 
Appendix added 
Added as a reference document for investigators and 
sites 
Appendix 8, Response 
Evaluation Criteria in Solid 
Tumors, Version 1.1 
(RECIST v1.1) 
Appendix added 
Added as a reference document for response 
assessments to be performed by investigators 
Appendix 9, Timepoints for 
Pharmacokinetic Blood 
Sampling 
Timepoints for Pharmacokinetic Blood Sampling table 
deleted (now in Section 1.3, Table 3) and replaced with 
the European Organisation for the Research and 
Treatment of Cancer Quality-of-Life Questionnaire  
Core 30 
Per CPT structure and format 
Appendix 10, Confidentiality 
and Investigator Statement 
Appendix has been deleted, and the participant-reported 
outcome assessments reordered accordingly. 
Per CPT structure and format 
Appendix 12, Protocol 
Amendment History 
Appendix added 
Per CPT structure and format 

Appendix 9:  Protocol Amendment History 
Pralsetinib—F. Hoffmann-La Roche Ltd 
169/Protocol BO42864, Version 6 
Protocol Location(s) 
Description of Change(s) 
Rationale for Change(s) 
Appendix 13, Country-
Specific Requirements 
The Summary of Changes has been added for the 
Ireland-specific protocol amendment, Version 2 
Per CPT structure and format 
Appendix 14, List of 
Prohibited Medications and 
Foods, and Appendix 15, 
Medications to Be Used with 
Caution 
Appendices have been moved to Appendices 13 and 14 
from Appendices 3 and 4, respectively, and updated. 
Updated lists of prohibited medications and foods and 
medications with potential drug-drug interactions for 
alignment with Pralsetinib Investigator’s Brochure,  
Version 5. 
Appendix 16, Examples of 
Standard Platinum-Based 
Chemotherapy Labeling 
Information 
Appendix revised to include paclitaxel and nab-paclitaxel 
labeling information 
For completeness 
Appendix 17, Abbreviations 
Previously in Section 13, the table has been moved to a 
separate appendix. 
Per CPT structure and format and revisions based on 
changes made to the protocol 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
170/Protocol BO42864, Version 6 
Appendix 10 List of Prohibited Medications and Foods 
Medications and food to be avoided out of concern for interaction with the study drugs: 
Strong Inhibitors of CYP3A4 
Strong Inducers of CYP3A4 
Boceprevir 
Apalutamide 
Conivaptan 
Carbamazepine 
Danoprevir and ritonavir 
Enzalutamide 
Elvitegravir and ritonavir 
Mitotane 
Grapefruit and grapefruit juice 
Phenytoin 
Idelalisib 
Rifampin 
Indinavir and ritonavir 
St. John’s wort 
Ketoconazole 
 
Nefazodone 
 
Ombitasvir and/or dasabuvir 
 
Posaconazole 
 
Paritaprevir and ritonavir 
 
Ribociclib 
 
Telithromycin 
 
Troleandomycin 
 
Voriconazole 
 
Combined P-gp and Strong CYP3A4 Inhibitors 
 
Clarithromycin 
 
Cobicistat 
 
Itraconazole 
 
Lopinavir and ritonavir 
 
Mifebradil 
 
Nelfinavir 
 
Ritonavir 
 
Saquinavir and ritonavir 
 
Telaprevir 
 
Tipranavir and ritonavir 
 
P-gp  P-glycoprotein. 
  
The above list of medications is not necessarily comprehensive.  Thus, the investigator 
should consult the prescribing information for any concomitant medication as well as the 
internet references provided below when determining whether a certain medication 
strongly inhibits or induces CYP3A4 or inhibits P-glycoprotein.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding any 
medications not listed above. 

Appendix 10:  List of Prohibited Medications and Foods 
Pralsetinib—F. Hoffmann-La Roche Ltd 
171/Protocol BO42864, Version 6 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table3-2 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
172/Protocol BO42864, Version 6 
Appendix 11  
Medications to Be Used with Caution 
Medications to be used with caution for participants treated with pralsetinib out of 
concern for interaction with pralsetinib are listed in the following table. 
Note:  The list of medications above is not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the internet references provided below when determining whether a certain 
medication is a substrate of CYPs or transporters.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding any medications not listed in the 
following table. 

Appendix 11:  Medications to Be Used with Caution 
Pralsetinib—F. Hoffmann-La Roche Ltd 
173/Protocol BO42864, Version 6 
Sensitive 
CYP3A4 
Substrates 
Sensitive 
CYP2C9 
Substrates 
Sensitive  
CYP2C8 
Substrates 
P-gp 
Substrates 
BCRP 
Substrates 
OATP1B1 and 
OATP1B3 
Substrates 
Sensitive OAT1 
Substrates 
Sensitive 
MATE1 and 
MATE2-K 
Substrates 
Alfentanil 
Avanafil 
Buspirone 
Conivaptan 
Darifenacin 
darunavir 
Ebastine 
Everolimus 
Ibrutinib 
Lomitapide 
Lovastatin 
midazolam 
Naloxegol 
Nisoldipine 
Saquinavir 
Simvastatin 
Sirolimus 
Tacrolimus 
Tipranavir 
Triazolam 
vardenafil 
Budesonide 
dasatinib 
Dronedarone 
Eletriptan 
Eplerenone 
felodipine 
Celecoxib 
Repaglinide 
Dabigatran 
etexilate 
Digoxin 
fexofenadine 
Rosuvastatin 
Sulfasalazine 
Asunaprevir 
Atorvastatin 
Bosentan 
Danoprevir 
Docetaxel 
Fexofenadine 
Glyburide 
Nateglinide 
Paclitaxel 
Pitavastatin 
Pravastatin 
Repaglinide 
Rosuvastatin 
Simvastatin acid 
Adefovir cefaclor 
Ceftizoxime 
Famotidine 
Furosemide 
Ganciclovir 
Methotrexate 
Oseltamivir 
Carboxylate 
Penicillin G 
Metformin 

Appendix 11:  Medications to Be Used with Caution 
Pralsetinib—F. Hoffmann-La Roche Ltd 
174/Protocol BO42864, Version 6 
Sensitive 
CYP3A4 
Substrates 
Sensitive 
CYP2C9 
Substrates 
Sensitive  
CYP2C8 
Substrates 
P-gp 
Substrates 
BCRP 
Substrates 
OATP1B1 and 
OATP1B3 
Substrates 
Sensitive OAT1 
Substrates 
Sensitive 
MATE1 and 
MATE2-K 
Substrates 
Indinavir 
Lurasidone 
Maraviroc 
Quetiapine 
Sildenafil 
Ticagrelor 
Tolvaptan 
 
 
 
 
 
 
 
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
175/Protocol BO42864, Version 6 
Appendix 12  
Examples of Standard Platinum-Based Chemotherapy 
Labeling Information 
Carboplatin 
U.S. prescribing information for carboplatin is available at:  
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=carboplatin 
The Summary of Product Characteristics for carboplatin is available at:  
https://www.medicines.org.uk/emc/product/6005/smpc 
The Canadian product monograph for carboplatin is available at: 
https://www.pfizer.ca/sites/g/files/g10050796/f/201901/Carboplatin_PM_E_2018-12-
31.pdf 
Cisplatin 
U.S. prescribing information for cisplatin is available at:  
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=cisplatin 
The Summary of Product Characteristics for cisplatin is available at:  
https://www.medicines.org.uk/emc/product/6111/smpc 
The Canadian product monograph for cisplatin is available at:  https://health-
products.canada.ca/dpd-bdpp/dispatch-
repartition.do;jsessionid=18CB926B1CCBEB101ED1B22741A1C981#results 
Pemetrexed 
U.S. prescribing information for pemetrexed is available at:  
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=pemetrexed 
The Summary of Product Characteristics for pemetrexed is available at:  
https://www.ema.europa.eu/en/documents/product-information/alimta-epar-product-
information_en.pdf 
The Canadian product monograph for pemetrexed is available at:  
http://pi.lilly.com/ca/alimta-ca-pm.pdf 
Gemcitabine 
U.S. prescribing information for gemcitabine is available at: 
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=gemcitabine 
The Summary of Product Characteristics for gemcitabine is available at:  
https://www.medicines.org.uk/emc/product/2490/smpc 
The Canadian product monograph for gemcitabine is available at: 
https://www.sandoz.ca/sites/www.sandoz.ca/files/Gemcitabine_Inj_PMe_20140814.pdf 

Appendix 12:  Examples of Standard Platinum-Based Chemotherapy Labeling Information 
Pralsetinib—F. Hoffmann-La Roche Ltd 
176/Protocol BO42864, Version 6 
Pembrolizumab 
U.S. prescribing information for pembrolizumab is available at:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-
71b91a02b287 
The Summary of Product Characteristics for pembrolizumab is available at:  
https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-
information_en.pdf 
The Canadian product monograph for pembrolizumab is available at:  
https://pdf.hres.ca/dpd_pm/00049463.PDF 
Paclitaxel 
U.S. prescribing information for paclitaxel is available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf 
The Summary of Product Characteristics for paclitaxel is available at:  
https://www.medicines.org.uk/emc/product/3891/smpc 
The Canadian product monograph for paclitaxel is available at:   https://health-
products.canada.ca/dpd-bdpp/dispatch-
repartition.do;jsessionid=18CB926B1CCBEB101ED1B22741A1C981 
Nab-Paclitaxel 
U.S. prescribing information for nab-paclitaxel is available at:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf 
The Summary of Product Characteristics for nab-paclitaxel is available at:  
https://www.ema.europa.eu/en/documents/product-information/abraxane-epar-product-
information_en.pdf 
The Canadian product monograph for nab-paclitaxel is available at:  
https://media2.celgene.com/content/uploads/sites/23/Abraxane_Product_Monograph_En
glish_Version.pdf

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
177/Protocol BO42864, Version 6 
Appendix 13  
Investigational Medicinal Product Designations (for Use in 
European Economic Area and United Kingdom) 
Table A13-1 Investigational Medicinal Product Designations for the 
European Economic Area and the United Kingdom 
Product Name 
IMP Designation 
Marketing Authorization 
Status in EEA/UK  
Used within Marketing 
Authorization 
Pralsetinib 
(RO7499790) 
IMP (test product)  
Authorized 
Yes 
Carboplatin 
IMP (comparator) 
Authorized 
Yes 
Cisplatin 
IMP (comparator) 
Authorized 
Yes 
Pemetrexed 
IMP (comparator) 
Authorized 
Yes 
Pembrolizumab 
IMP (comparator) 
Authorized 
Yes 
Gemcitabine 
IMP (comparator) 
Authorized 
Yes 
Paclitaxel 
IMP (comparator) 
Authorized 
Yes 
Nab-paclitaxel 
IMP (comparator) 
Authorized 
Yes 
EEA  European Economic Area; IMP  investigational medicinal product; UK  United Kingdom.  
 

 
Pralsetinib—F. Hoffmann-La Roche Ltd 
178/Protocol BO42864, Version 6 
Appendix 14  
Abbreviations 
Abbreviation or Term 
Definition 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration–time curve 
-hCG 
human chorionic gonadotropin 
BICR 
blinded independent central review 
CBR 
clinical benefit rate 
CDx 
companion diagnostic 
CEA 
carcinoembryonic antigen 
CR 
complete response 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DCR 
disease control rate 
DDI 
drugdrug interaction 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESMO 
European Society for Medical Oncology 
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-level version 
FDA 
(U.S.) Food and Drug Administration 
F1CDx 
FoundationOne companion diagnostic 
FFPE 
formalin-fixed, paraffin-embedded 
FMI 
Foundation Medicine 
GHS 
global health status 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 

Appendix 14:  Abbreviations 
Pralsetinib—F. Hoffmann-La Roche Ltd 
179/Protocol BO42864, Version 6 
Abbreviation or Term 
Definition 
IPCW 
inverse probability of censoring weighting 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IwRS 
interactive web-based response system 
mITT 
modified intent to treat 
MKI 
multikinase inhibitor 
MN 
mobile nursing 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 
NGS 
next-generation sequencing 
NICE 
National Institute for Health and Care Excellence 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD-L1 
programmed deathligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PO 
orally (by mouth) 
PR 
partial response 
PRO 
participant-reported outcome 
Q3W 
every 3 weeks 
QD 
once a day 
QoL 
quality of life 
QTcF 
QT interval corrected through use of Fridericia's formula 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
RET 
rearranged during transfection (oncogene) 
SAP 
Statistical Analysis Plan 

Appendix 14:  Abbreviations 
Pralsetinib—F. Hoffmann-La Roche Ltd 
180/Protocol BO42864, Version 6 
Abbreviation or Term 
Definition 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOC 
standard of care 
TBD 
to be determined 
T3 
triiodothyronine 
T4 
thyroxine 
TKI 
tyrosine kinase inhibitor 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 

Signature Page for Protocol - BO42864 - GAVRETO - v6 - Global/Core - Published
System identifier: RIM-CLIN-675282
Approval Task
Company Signatory
23-Oct-2024 15:32:42 GMT+0000