LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy With or Without Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Protocol J2G-MC-JZJC(e) 
 
LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial 
Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy with or without 
Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small 
Cell Lung Cancer 
 
NCT04194944 
 
Approval Date: 15-Aug-2023 

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of selpercatinib (LY3527723), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial 
Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy with or without 
Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small 
Cell Lung Cancer 
Protocol Number: J2G-MC-JZJC 
Amendment: (e) 
Compound Number: LY3527723 
Study Phase: Phase 3 
Short Title: A Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed 
Therapy with or without Pembrolizumab (LIBRETTO-431) 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 144697 
EudraCT: 2019-001979-36 
EU trial number: 2023-506783-14-00 
Approval Date: Protocol Amendment (e) Electronically Signed and Approved By Lilly on date 
provided below. 
Document ID: VV-CLIN-063593 
Approved on 15 Aug 2023 GMT

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Protocol J2G-MC-JZJC(e) 
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Protocol Amendment Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment d 
18-Nov-2020
Amendment c 
26-Jun-2020
Amendment b 
10-Jun-2020
Amendment a 
07-Nov-2019
Original Protocol 
27-Jun-2019
Amendment (e) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update as per the latest Investigator Brochure (IB) 
and to align with EU Clinical Trial Regulation (EU-CTR) requirements. In addition, this 
amendment includes changes made to correct and clarify information for sites. This amendment 
also corrects typographical errors and inconsistencies that were noted in JZJC amendment(d). 
Protocol Amendment Summary of Changes Table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added 

Regulatory Agency Identifier
Number(s)

Study Population

Ethical Considerations of
Benefit/Risk
For EU-CTR compliance 
Updated the section to align with the 
changes in the main body of the protocol 
For consistency 
1.3. Schedule of Activities 
(SoA) 
Baseline, On-Study, and 
Poststudy Treatment Follow-
Up SoA for Patients on Arm 
A and Arm B 
Edited footnote “a” 

Footnote clarifying that V201 has no
maximum time duration

Clarification around window for
baseline crossover imaging
For clarification 
1.3. Schedule of Activities 
(SoA) 
Optional Crossover 
Treatment 
Clarification around window for the 
overall screening window 
For clarification 
5.1. Inclusion Criteria 
11. References
Fixed incorrect reference for AJCC 
Cancer Staging Manual. 8th edition 
Correction 
6. Study Intervention
Updated the definition of study 
intervention 
For EU-CTR compliance 
6.1. Study Intervention(s) 
Administered 
Added last row for “Authorized as defined 
by EU Clinical Trial Regulation” 
For EU-CTR compliance 
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Protocol J2G-MC-JZJC(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1.2. Packaging and 
Labeling 
Added new section 
For EU-CTR compliance 
6.6. Dose Modification 
Guidelines for Arm A and 
Arm B 

Statement about cycle durations was
located in section 6.6.1 but as it
applies to both arms, was moved to
6.6

Table was updated to clarify that 40
mg BID is an acceptable dose for
dose reduction

Footnote ‘a’ was updated
For clarification 
6.6.1. Dose Modifications and 
Toxicity Management 
Guidelines for Arm A 
Corrections made in hypersensitivity dose 
modification section 
Guidance for hypersensitivity 
recurrence was in the wrong section in 
previous amendment. Language was 
also clarified.  
Added updated dose modification 
guidance for interstitial lung 
disease/pneumonitis 
Updated as per Selpercatinib IB (Aug 
2023) 
7.1. Discontinuation of Study 
Intervention 
Note regarding approval for continuing 
study treatment beyond progression was 
clarified 
Clarified to align with Section 8.1.2 
8.1.1. Imaging 
Added “Section 8.2.2.2 and” to fourth 
paragraph 
For clarification 
8.1.2. BICR Assessment 
Added language for clarification 

Requirement for signing consent in
cases of treatment post-progression

Sponsor approval to continue
treatment not necessary if BICR does
not confirm progression

In crossover, BICR does not provide
confirmation of progression
For clarification 
8.2.1. Electrocardiograms 
Added guidance that if a potential 
alternative cause for QTcF prolongation is 
identified, sponsor should be consulted for 
dose reduction guidance. 
For closer sponsor oversight of QTcF 
prolongation management 
8.2.2.2. Chylothorax and 
Chylous Ascites Monitoring 
Added new section 
Updated as per Selpercatinib IB (Aug 
2023) 
8.2.2.3. Renal Safety 
Monitoring 
Added new section 
Updated as per Selpercatinib IB (Aug 
2023) 
8.2.2.4. Thyroid Function 
Monitoring 
Added new section for hypothyroidism to 
provide additional guidance 
Updated as per Selpercatinib IB (Aug 
2023) 
8.3. Adverse Events and 
Serious Adverse Events 
Added definition and details on adverse 
events 
For EU-CTR compliance 
8.3.3. Regulatory Reporting 
Requirements for SAEs 
Updated the section 
For EU-CTR compliance 
9.4.1. General Statistical 
Considerations 
Added a paragraph on handling of 
missing, unused, and spurious data 
For EU-CTR compliance 
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Protocol J2G-MC-JZJC(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.1. Regulatory and Ethical 
Considerations 
Added a bullet point regarding reporting 
of significant issues related to 
participant’s safety, rights, and data 
integrity 
For EU-CTR compliance 
10.1.3. Data Protection 
Updated the required language 
For EU-CTR compliance 
10.1.5. Dissemination of 
Clinical Study Data 
Added paragraph on “Reports” 
For EU-CTR compliance 
10.5. Appendix 5: Restricted 
and Prohibited Concomitant 
Medication 
Removed the web reference in footnote 
Editorial update 
Throughout the protocol 
Minor formatting and editorial changes 
Minor, therefore, not detailed 
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Protocol J2G-MC-JZJC(e) 
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Table of Contents 
Protocol Amendment Summary of Changes Table .........................................................................2
1.
Protocol Summary ..........................................................................................................8
1.1.
Synopsis ............................................................................................................................8
1.2.
Schema ............................................................................................................................12
1.3.
Schedule of Activities (SoA) ..........................................................................................13
2.
Introduction ...................................................................................................................32
2.1.
Study Rationale ...............................................................................................................32
2.2.
Background .....................................................................................................................32
2.3.
Benefit/Risk Assessment ................................................................................................34
3.
Objectives and Endpoints ............................................................................................36
4.
Study Design ..................................................................................................................38
4.1.
Overall Design ................................................................................................................38
4.2.
Scientific Rationale for Study Design ............................................................................39
4.3.
Justification for Dose ......................................................................................................39
4.4.
End of Study Definition ..................................................................................................40
5.
Study Population ...........................................................................................................41
5.1.
Inclusion Criteria ............................................................................................................41
5.2.
Exclusion Criteria ...........................................................................................................43
5.2.1.
Exclusion Criteria for Participants on Pembrolizumab ..................................................45
5.2.2.
Enrollment Criteria for Crossover Treatment .................................................................46
5.3.
Lifestyle Considerations .................................................................................................47
5.4.
Screen Failures ................................................................................................................47
6.
Study Intervention ........................................................................................................48
6.1.
Study Intervention(s) Administered................................................................................48
6.1.1.
Selection and Timing of Doses .......................................................................................48
6.1.2.
Packaging and Labeling ..................................................................................................50
6.2.
Preparation/Handling/Storage/Accountability ................................................................51
6.3.
Measures to Minimize Bias: Randomization and Blinding ............................................51
6.4.
Study Intervention Compliance ......................................................................................51
6.5.
Concomitant Therapy .....................................................................................................52
6.5.1.
Prohibited Concomitant Therapy ....................................................................................52
6.5.2.
Palliative Medicine and Supportive Care for Arm A and Arm B ...................................53
6.6.
Dose Modification Guidelines for Arm A and Arm B ...................................................54
6.6.1.
Dose Modifications and Toxicity Management Guidelines for 
Arm A .............................................................................................................................56
6.6.2.
Dose Modification and Toxicity Management Guidelines for 
Arm B..............................................................................................................................58
6.7.
Intervention after the End of the Study ...........................................................................61
6.7.1.
Treatment after Study Completion..................................................................................61
6.7.2.
Continued Access............................................................................................................61
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Protocol J2G-MC-JZJC(e) 
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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal........................................................................................63
7.1.
Discontinuation of Study Intervention ............................................................................63
7.2.
Participant Discontinuation/Withdrawal from the Study ................................................63
7.2.1.
Discontinuation of Inadvertently Enrolled Patients ........................................................64
7.3.
Lost to Follow up ............................................................................................................64
8.
Study Assessments and Procedures.............................................................................65
8.1.
Efficacy Assessments .....................................................................................................65
8.1.1.
Imaging ...........................................................................................................................65
8.1.2.
BICR Assessment ...........................................................................................................66
8.2.
Safety Assessments .........................................................................................................67
8.2.1.
Electrocardiograms .........................................................................................................67
8.2.2.
Clinical Safety Laboratory Assessments ........................................................................68
8.3.
Adverse Events and Serious Adverse Events .................................................................70
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................73
8.3.2.
Follow-up of AEs and SAEs ...........................................................................................74
8.3.3.
Regulatory Reporting Requirements for SAEs ...............................................................74
8.3.4.
Pregnancy ........................................................................................................................74
8.3.5.
Cardiovascular and Death Events ...................................................................................74
8.3.6.
Complaint Handling ........................................................................................................75
8.4.
Treatment of Overdose ...................................................................................................75
8.5.
Pharmacokinetics ............................................................................................................75
8.6.
Pharmacodynamics .........................................................................................................75
8.7.
Genetics ..........................................................................................................................75
8.7.1.
Whole Blood Sample for Pharmacogenetic Research ....................................................75
8.8.
Biomarkers ......................................................................................................................76
8.8.1.
Samples for Retrospective Evaluation of RET Status ....................................................76
8.8.2.
Biomarkers ......................................................................................................................77
8.9.
Medical Resource Utilization and Health Economics ....................................................77
8.9.1.
Patient-Reported Outcomes and Health Care Resource 
Utilization .......................................................................................................................77
9.
Statistical Considerations .............................................................................................80
9.1.
Statistical Hypotheses .....................................................................................................80
9.2.
Sample Size Determination ............................................................................................80
9.3.
Populations for Analyses ................................................................................................80
9.4.
Statistical Analyses .........................................................................................................81
9.4.1.
General Statistical Considerations ..................................................................................81
9.4.2.
Treatment Group Comparability .....................................................................................81
9.4.3.
Efficacy Analyses ...........................................................................................................82
9.4.4.
Safety Analyses ...............................................................................................................84
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................84
9.4.6.
Other Analyses ................................................................................................................85
9.5.
Interim Analyses .............................................................................................................86
10.
Supporting Documentation and Operational Considerations ..................................88
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Protocol J2G-MC-JZJC(e) 
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10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................88
10.1.1.
Regulatory and Ethical Considerations ...........................................................................88
10.1.2.
Informed Consent Process ..............................................................................................88
10.1.3.
Data Protection................................................................................................................89
10.1.4.
Committee Structure .......................................................................................................90
10.1.5.
Dissemination of Clinical Study Data.............................................................................90
10.1.6.
Data Quality Assurance ..................................................................................................90
10.1.7.
Source Documents ..........................................................................................................91
10.1.8.
Study and Site Closure ....................................................................................................91
10.1.9.
Provisions for Changes in Study Conduct During Emergencies ....................................91
10.2.
Appendix 2: Clinical Laboratory Tests ...........................................................................93
10.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................95
10.4.
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................98
10.5.
Appendix 5: Restricted and Prohibited Concomitant Medication ..................................99
10.6.
Appendix 6: Country-Specific Requirements ...............................................................102
10.7.
Appendix 7: Creatinine Clearance Formula .................................................................103
10.8.
Appendix 8: Abbreviations and Definitions .................................................................104
10.9.
Appendix 9: Protocol Amendment History ..................................................................110
11.
References ....................................................................................................................122
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Protocol J2G-MC-JZJC(e) 
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1.
Protocol Summary
1.1. 
Synopsis 
Protocol Title: 
LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing 
Selpercatinib to Platinum-Based and Pemetrexed Therapy with or without Pembrolizumab as 
Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer 
Short Title: A Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed 
Therapy with or without Pembrolizumab (LIBRETTO-431) 
Regulatory Agency Identifier Number(s) 
IND: 144697 
EudraCT: 2019-001979-36 
EU trial number: 2023-506783-14-00 
Rationale: 
Patients with RET fusion-positive non-small cell lung cancer (NSCLC) represent a population 
with high unmet need. Combination chemotherapy with or without immunotherapy has short-
term palliative potential in advanced NSCLC.  
The identification of activating genetic alterations in specific tyrosine kinases has led to a new 
classification of NSCLC based on molecular genotype rather than histology. Agents targeting 
specific alterations such as EGFR and BRAF activating mutations and ALK and ROS1 gene 
fusions have demonstrated compelling efficacy in patients with cancers that harbor the respective 
activating genetic alteration.  
Selpercatinib, a selective RET tyrosine kinase inhibitor, has demonstrated a favorable safety 
profile and evidence of durable antitumor activity in patients with advanced RET fusion-positive 
patients with NSCLC (both treatment-naïve and those previously treated with approved first-line 
chemotherapy with or without immunotherapy). As a result, selpercatinib may be of benefit as an 
initial treatment for advanced or metastatic RET fusion-positive NSCLC.  
The proposed Study J2G-MC-JZJC (hereafter referred to as JZJC) will evaluate selpercatinib in 
comparison to platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without 
pembrolizumab in patients with locally advanced or metastatic RET fusion-positive NSCLC. 
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Protocol J2G-MC-JZJC(e) 
9 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 

To compare PFS of selpercatinib with the
combination of platinum-based (carboplatin or
cisplatin) therapy, pemetrexed, and
pembrolizumab in patients with advanced or
metastatic RET fusion-positive NSCLC

To compare PFS of selpercatinib with the
combination of platinum-based (carboplatin or
cisplatin) and pemetrexed therapy, with or
without pembrolizumab, in patients with
advanced or metastatic RET fusion-positive
NSCLC

PFS per RECIST 1.1 by BICR
Secondary 

To compare the efficacy of selpercatinib with
the combination of platinum-based
(carboplatin or cisplatin) therapy, pemetrexed,
and pembrolizumab in patients with advanced
or metastatic RET fusion-positive NSCLC

To compare the efficacy of selpercatinib with
the combination of platinum-based
(carboplatin or cisplatin) and pemetrexed
therapy, with or without pembrolizumab, in
patients with advanced or metastatic RET
fusion-positive NSCLC

PFS per RECIST 1.1 by investigator

ORR/DOR/DCR per RECIST 1.1 by BICR

ORR/DOR/DCR per RECIST 1.1 by
investigator

Intracranial ORR/DOR per RECIST 1.1 by
BICR

Time to CNS progression per RECIST 1.1. by
BICR

Intracranial ORR/DOR per RANO-BM by
BICR

OS

PFS2

Time to deterioration in pulmonary
symptoms: cough, chest pain, and dyspnea as
measured by the NSCLC-SAQ

To assess safety and tolerability of
selpercatinib compared to platinum-based and
pemetrexed therapy with pembrolizumab

To assess safety and tolerability of
selpercatinib compared to platinum-based and
pemetrexed therapy with or without
pembrolizumab

Including but not limited to SAEs, AEs,
deaths, and clinical laboratory abnormalities
per CTCAE v5.0

To assess/evaluate performance of RET local
laboratory tests compared to a single, central
test

RET fusion status
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Protocol J2G-MC-JZJC(e) 
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Abbreviations: AE = adverse event; BICR = blinded independent central review; CNS = central nervous system; 
CTCAE = Common Terminology Criteria in Adverse Events; DCR = disease control rate; DOR = duration of 
response; NSCLC = non-small cell lung cancer; NSCLC-SAQ = Non-Small Cell Lung Cancer Symptom 
Assessment Questionnaire; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; 
RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases; RECIST 1.1= Response Evaluation 
Criteria in Solid Tumors, version 1.1; SAE = serious adverse event.  
Overall Design: 
Study JZJC is a global, multicenter, randomized, open-label, controlled Phase 3 study of 
selpercatinib (Arm A) compared to platinum-based and pemetrexed therapy with or without 
pembrolizumab (Arm B) in patients with locally advanced or metastatic, RET fusion-positive 
nonsquamous NSCLC. Enrolled patients will be stratified based on geography (East Asia vs. 
non-East Asia), brain metastases per investigator assessment (presence vs. absence or unknown), 
and investigator’s choice of treatment if randomized to Arm B (with or without pembrolizumab 
and cisplatin vs. carboplatin – choice/intent of treatment regimen must be declared prior to 
randomization). Patients will be randomized in a ratio of 2:1, Arm A to Arm B. Patients will be 
allowed cross over from the comparator Arm B to Arm A upon confirmation of disease 
progression by a blinded independent central review if they meet the eligibility criteria for 
crossover. The primary endpoint being evaluated is PFS per RECIST 1.1 by BICR. 
Study Population 

Stage IIIB-IIIC or Stage IV NSCLC that is predominantly nonsquamous in histology.

Must have a RET gene fusion in tumor using polymerase chain reaction (PCR) or next
generation sequencing (NGS). Results in blood using NGS are also acceptable.

Must have measurable disease per RECIST 1.1.

Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0
to 2.

Must not have received prior systemic therapy for metastatic disease

Must not have additional validated oncogenic drivers in NSCLC, if known

Must not have symptomatic central nervous system (CNS) metastases
Disclosure Statement: This is a randomized, active treatment study with 2 arms where the 
participant and investigator will not be blinded, but the aggregate data in the clinical research 
database will be blinded to sponsor personnel.
Number of Participants: 
Approximately 250 participants will be randomly assigned to study intervention (approximately 
167 patients in the experimental arm vs. approximately 83 patients in the control arm).  
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Protocol J2G-MC-JZJC(e) 
11 
Intervention Groups and Duration: 
Arm A 
(Selpercatinib) 
Arm B 
(Investigator’s discretion of carboplatin or cisplatin + pemetrexed ± 
pembrolizumab) 
Intervention 
Selpercatinib 
Carboplatin 
Cisplatin 
Pemetrexed 
Pembrolizumab 
(investigator’s 
choice) 
Dose 
160 mg 
AUC 5 
(maximum dose 
750 mg) 
75 mg/m2
500 mg/m2
(with vitamin 
supplementation) 
200 mg 
Schedule 
BID in 21-day 
continuous 
cycles 
Day 1 Q3W for 
4 cycles 
Day 1 Q3W 
for 4 cycles 
Day 1 Q3W 
Day 1 Q3W  
up to 35 cycles 
Route 
Oral 
IV 
IV 
IV 
IV 
Authorized 
as defined by 
EU Clinical 
Trial 
Regulation 
Authorized 
and used 
according to 
EU 
authorization 
Authorized and 
used according 
to EU 
authorization 
Authorized and 
used according to 
EU authorization 
Authorized and 
used according 
to EU 
authorization 
Authorized and used 
according to EU 
authorization 
Abbreviations: AUC = area under the concentration versus time curve; BID = twice a day; IV = intravenous; m = 
meter; mg = milligrams; Q3W = every 3 weeks. 
Ethical Considerations of Benefit/Risk: 
The need for targeted therapies to treat RET fusion-positive NSCLC and the clinical safety and 
efficacy profile of selpercatinib in patients with RET-altered solid tumors (including NSCLC) in 
the ongoing Phase 1/2 trial (LIBRETTO-001), the risk/benefit assessment supports evaluation of 
selpercatinib in the proposed patient population. 
Data Monitoring Committee: Yes
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Protocol J2G-MC-JZJC(e) 
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1.2. 
Schema 
Abbreviations: AUC = area under the concentration versus time curve; BICR = blinded independent central review; 
BID = twice a day; m = meter; mg = milligrams; n = number of participants; NSCLC = non-small cell lung 
cancer; PFS = progression-free survival; Q3W = every 3 weeks; R = randomization; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors, version 1.1. 
a Stratification factors: geography (East Asia vs. non-East Asia), brain metastases per investigator assessment 
(presence vs. absence or unknown), and investigator’s choice of treatment if randomized to Arm B (with or 
without pembrolizumab– choice/intent of treatment regimen must be declared prior to randomization).  
b To Arm A (selpercatinib) allowed at radiographic disease progression confirmed by BICR. 
c Patients with the intent by the investigator to be treated without pembrolizumab will be restricted to 20%. 
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Protocol J2G-MC-JZJC(e) 
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1.3. 
Schedule of Activities (SoA) 
This section includes the following SoAs: 

Prescreening

Baseline, On-Study, and Poststudy Treatment Follow-Up SoA for Patients on Arm A and
Arm B

Optional Crossover Treatment (for patients crossing over from Arm B to Arm A)

Continued Access SoA for All Patients
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Protocol J2G-MC-JZJC(e) 
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Prescreening 
Abbreviation: FNA = fine needle aspiration; ICF = informed consent form. 
Visit 
Prescreening 
Instructions 
Prescreening ICF 
X 
In geographies or sites where RET testing is not standard of care and/or an acceptable local test (as defined by Lilly) is not 
available, a prescreening consent may be used to provide information to the patient regarding testing to determine tumor 
RET status. The results may also include other genes (e.g. EGFR, ALK, ROS1, KRAS, BRAF, HER2, MET, NTRK1, 
NTRK2, or NTRK3).  
If it is considered safe to perform, patients who do not have sufficient available tumor tissue may undergo a fresh tumor 
biopsy/FNA to determine initial eligibility. 
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Protocol J2G-MC-JZJC(e) 
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Baseline, On-Study, and Poststudy Treatment Follow-Up SoA for Patients on Arm A and Arm B 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
Informed consent 
X 
ICF must be signed before 
any protocol-specific 
procedures are performed. See 
Appendix 1. 
Inclusion/exclusion 
criteria 
X 
See Section 5. 
Medical history 
X 
Including assessment of pre-
existing conditions, historical 
illnesses, prior anticancer 
therapy, and habits (e.g., 
smoking status). 
Confirm 
acceptability of 
local RET 
assessment  
X 
The test may have occurred 
prior to consent. Lilly must 
confirm acceptability of 
results, preferably and if 
feasible, prior to conducting 
other screening procedures. 
Molecular report(s) describing 
RET and other alterations 
must be submitted for review 
(see Section 8.8). 
Local PD-L1 
assessment 
X 
Submit if PD-L1 status is 
known, preferably prior to 
enrollment. The test may have 
occurred prior to consent. 
Archived tumor 
tissue or fresh 
biopsy 
See 
Instructions 
If available, this sample 
should be submitted as 
described in Section 8.8.1, 
preferably within 30 days of 
C1D1. A single sample 
submitted outside of the 
30-day window will not be 
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CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
16 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
considered a protocol 
deviation. Please submit 
sample from the most recent 
biopsy with adequate tissue.  
Optional 
postprogression 
tumor biopsy 
X 
See 
Instructions 
Can be obtained any time 
prior to the start of next 
therapy  
Concomitant 
medication 
X 
X 
X 
X 
Record prior and concurrent 
medications at baseline. 
Record all premedication, 
supportive care, and 
concomitant medication 
throughout the study. 
Physical 
examination 
X 
X 
X 
X 
X 
Physical examination and 
review of relevant systems at 
Screening. Symptom-directed 
physical examinations may be 
performed at other time 
points. 
Height, weight, 
and vital signs 
X 
X 
X 
X 
X 
Includes height (only at 
baseline), weight, blood 
pressure, pulse rate, pulse 
oximetry, and temperature. 
All patients should have their 
blood pressure optimized (if 
necessary) prior to initiation 
of study drug to a reading of 
≤140/90 mmHg. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
17 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
ECG 
X 
X 
X 
See 
Instructions 
Obtain triplicate local ECGs 
at Screening, C1D1, C1D8, 
and C2-6D1. For Arm A 
patients, it is preferable to 
obtain approximately 2 hours 
after the morning dose. For 
Arm B patients, obtain 
following the last infusion. 
See Section 8.2.1 for 
additional information, 
including requirements for 
potential adjudication. 
ECOG 
performance status 
X 
X 
X 
X 
X 
Karnofsky 
performance scale  
X 
X 
X 
X 
X 
For RANO-BM assessment. 
AE collection 
X 
X 
X 
X 
Collect throughout the study. 
Use CTCAE Version 5.0. All 
SAEs (regardless of causality) 
should be reported for 90 days 
from the last dose of study 
drug (or until a new therapy 
starts). After 90 days, only 
SAEs related to study 
treatment or protocol 
procedures are reported in 
long-term follow-up. 
Radiologic 
imaging and 
measurement of 
palpable or visible 
lesions (X-ray, CT 
scan with bone 
X 
See 
Instructions 
X 
X 
Perform assessments at 6 
weeks (±7 days) and 12 weeks 
(±7 days) and then every 9 
weeks (±7 days) for the first 
48 weeks following C1D1 and 
then every 12 weeks (±7 days) 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
18 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
windows, MRI, 
bone scintigraphy, 
PET scan or PET 
component of 
PET/CT scan) 
thereafter until progression, 
the start of a new anticancer 
therapy, death, or study 
completion. For patients with 
nonmeasurable bone disease 
bone scintigraphy (preferred) 
or PET scan or PET 
component of PET/CT scan 
may be obtained every 24 
weeks (±7 days) or more often 
if clinically indicated. The 
scanning interval should be 
maintained even if cycles are 
delayed. As a result, the scans 
may not always occur at the 
end of a cycle. See Section 
8.1. 
Intracranial 
evaluation with CT 
or MRI 
X 
See 
Instructions 
X 
X 
Required for all patients. 
Should be obtained at baseline 
and then at the same 
frequency as other radiologic 
imaging and as clinically 
indicated. See Section 8.1. 
Submit scans 
X 
See 
Instructions 
X 
X 
All scans taken for tumor 
assessment (e.g., 
radiographic, bone, and 
intracranial) should be 
submitted to Lilly’s designee 
within 5 business days of 
collection for central review 
by the BICR. A single scan 
sent outside the assessment 
windows will not be 
considered a protocol 
deviation, but repeated 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
19 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
excursions may be, unless 
approval has been obtained 
from the Sponsor. 
Pregnancy test 
X 
See Instructions 
X 
X 
See 
Instructions  
Applies only to women of 
childbearing potential. 
Perform within 24 hours prior 
to the first dose of study drug. 
Notes: 

During study treatment,
perform at least monthly 
or as required per local 
regulations and/or 
institutional guidelines.
See Appendix 2. 

Only patients on 
pembrolizumab require 
a pregnancy test
approximately 120 days
poststudy treatment
discontinuation.
Hematology 
X 
See 
Instructions 
X 
X 
X 
X 
X 
If screening testing is 
performed ≤7 days prior to 
C1D1, repeat testing does not 
need to occur on C1D1. 
Additional assessments may 
be obtained at the discretion 
of the investigator. See 
Appendix 2. 
Coagulation 
X 
X 
If baseline testing is 
performed ≤7 days prior to 
C1D1, repeat testing does not 
need to occur on C1D1. 
Additional assessments may 
be obtained at the discretion 
of the investigator. See 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
20 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
Appendix 2.  
Urinalysis 
X 
X  
See 
Instructions 
X 
X 
If baseline testing is 
performed ≤7 days prior to 
C1D1, repeat testing does not 
need to occur on C1D1. For 
Cycles 2-n, as clinically 
indicated. See Appendix 2. 
Clinical chemistry 
X 
See 
Instructions 
X 
X 
X 
X 
If baseline testing is 
performed ≤7 days prior to 
C1D1, repeat testing does not 
need to occur on C1D1. 
Should be performed on D1 of 
every subsequent cycle (e.g., 
C2D1, C3D1). Additional 
assessments may be obtained 
at the discretion of the 
investigator. See Appendix 2. 
Routine hepatic 
safety monitoring 
X 
See 
Instructions  
Including AST, ALT, 
total/direct bilirubin, and 
ALP. Should be performed on 
C1D15, C2D15, and C3D15. 
Additional assessments may 
be obtained at the discretion 
of the investigator 
Thyroid function 
X 
See 
Instructions 
X 
X 
Starting in Cycle 2 and every 
other cycle for the first 8 
cycles (e.g., Cycles 2, 4, 6, 8). 
Thereafter should be collected 
at the investigator’s 
discretion. Patients receiving 
pembrolizumab should 
continue to be monitored 
every other cycle. See 
Appendix 2. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
21 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
Plasma for cfDNA 
analysis and 
exploratory 
biomarkers 
X 
(Predose) 
X 
X 
X 
X 
Whole blood for 
genomic DNA 
X 
Sample can be collected at 
any time if not collected on 
C1D1. 
Blood sample for 
pharmacokinetics  
X 
X 
Arm A only: Samples to be 
drawn prior to the morning 
dose (-2 to 0 hr) in Cycles 1 to 
6. See Section 8.5.
Survival and PFS2 
information 
X 
Survival information may be 
collected by contacting the 
patient or family directly (e.g., 
via telephone) if no 
procedures are required. This 
information should be 
collected approximately every 
90 days from the end of short-
term follow up. See Section 
8.1. 
Collection of 
poststudy 
treatment 
anticancer therapy 
information 
X 
Perform every 90 days from 
the end of short-term follow 
up for the first 2 years after 
discontinuation from study 
treatment and approximately 
every 6 months thereafter 
until death or study 
completion. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
22 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
EORTC QLQ-C30 
X 
X 
X 
X 
The patient will complete 
electronically at the clinic site. 
Please collect at C1-n, D1 prior 
to study intervention. If the 
patient completed their 30-day 
assessments (V201) and 
discontinue prior to crossing 
over, they will not need to 
complete the Visit 801 
assessments. For the long-term 
follow-up collection, please 
collect until disease 
progression. See Section 8.9.  
EORTC IL19 
X 
X 
X 
X 
X 
X 
The patient will complete 
electronically on the provided 
electronic device at home (not 
at the site). Items 1 to 5 of the 
EORTC IL19 will be 
collected. See Section 8.9. 
NSCLC-SAQ 
X 
X 
X 
X 
X 
X 
The patient will complete 
electronically on the provided 
electronic device at home (not 
at the clinic site, except 
C1D1). Please collect at 
C1D1 prior to study 
intervention. See Section 8.9. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
23 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
PRO-CTCAE 
X 
X 
X 
X 
X 
X 
The patient will complete 
electronically on the provided 
electronic device at home (not 
at the clinic site, except 
C1D1). Selected items will be 
collected. Please collect at 
C1D1 prior to study 
intervention. See Section 8.9. 
FACT-GP5 
X 
X 
X 
X 
X 
X 
The patient will complete 
electronically on the provided 
electronic device (not at the 
clinic site, except C1D1). 
Please collect at C1D1 prior 
to study intervention. See 
Section 8.9. 
EQ-5D-5L 
X 
X 
X 
X 
X 
The patient will complete 
electronically at the clinic site. 
Please collect at C1-n, D1 
prior to study intervention. If 
the patient completed their 30 
day assessments (V201) and 
discontinued prior to crossing 
over, they will not need to 
complete the Visit 801 
assessment. For the long-term 
follow-up collection, please 
collect until disease 
progression. In Long-term 
follow-up completion is only 
required if the patient is 
physically in clinic (e.g. for 
radiographic assessment). See 
Section 8.9. 
Patient dosing 
diary 
X 
For Patients on Arm A: 
Provide patient diary Day 1. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
24 
Study Period 
Baseline 
Study Treatment (Cycle = 21 days) 
Safety assessments prior 
to crossover  
(only for patients on Arm 
B) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening 
Cycle 1 
Cycle 2-n 
V201a 
V801: 
Short-
Term 
Follow-upa 
V802-X: 
Long-
Term 
Follow-upb 
Visit 
Duration/Window 
Up to 
28 days 
-3 days
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 days 
1-30 (±7
days) 
1-x days
30±7 days 
90±7 days 
Relative Day 
within Dosing 
Cycle 
≤28 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
N/A 
N/A 
N/A 
N/A 
Procedure 
Completed daily by patient. 
Review at each study visit. 
Dispense 
selpercatinib 
X 
For Patients on Arm A. See 
Section 6.1. 
Premedication 
X 
X 
X 
As appropriate for the therapy 
(e.g., folic acid, B12, 
dexamethasone prior to 
pemetrexed therapy) and 
following local practice and 
labels. See Section 6.1. 
Administer 
cisplatin or 
carboplatin 
X 
X 
See Section 6.1. 
Administer 
pemetrexed 
X 
X 
See Section 6.1. 
Administer 
pembrolizumab 
X 
X 
See Section 6.1. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
25 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BICR = blinded independent central review; C = cycle; 
cfDNA = circulating cell-free DNA; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; 
EORTC IL19 = European Organisation for Research and Treatment of Cancer Item library 19; EQ-5D-5L = EuroQol Five Dimension Five Level; FACT-GP5 = Functional Assessment of Cancer 
Therapy-Side Effects; hr = hour; ICF = informed consent form; MRI = magnetic resonance imaging; N/A = not applicable; NSCLC-SAQ = Non-Small Cell Lung Cancer-Symptom Assessment 
Questionnaire; PD-L1 = programmed death-ligand 1; PET = positron emission tomography; PFS2 = progression-free survival 2; PRO-CTCAE = patient-reported outcome Common Terminology 
Criteria for Adverse Events; RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases; SAE = serious adverse event; SoA = Schedule of Activities; V = visit. 
a 
Short-term follow-up begins when the patient and investigator agree that the patient will no longer continue study treatment:  

All patients in Part A should complete V801 and will not complete V201. 

Patients in Arm B that may potentially crossover will enter V201.
o
V201 has no maximum time duration. 
o
Patients in Arm B who will crossover to selpercatinib more than 37 days (30 days +/- 7days) after the last dose of study treatment should complete V201 assessments. If a patient in
V201 that has completed the V201 assessments does not enter crossover (V300), they do not need to complete the V801 assessments, but will need to complete V802 assessments. 
o
Patients in Arm B who will crossover to selpercatinib in 37 days or less should discontinue from V201 when the decision to be screened for crossover is made. They will not complete 
the V201 assessments, but rather enter visit 300 and complete the screening assessments for crossover.
o
Patients in Arm B who will not potentially crossover to selpercatinib should not enter V201. They will not complete the V201 assessments, but rather subsequently enter V801 and 
complete the V801 assessments. 
b 
Long-term follow-up begins when short-term follow-up period is completed and continues until death, study withdrawal, or the patient is lost to follow-up. In all cases, no follow-up procedures will 
be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent. 
Note: Baseline/screening assessments and laboratory values drawn within the indicated window of C1D1 may be used for both screening/baseline and C1D1 assessments. There is not a defined interval 
required from randomization to C1D1. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
26 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Applicable only for patients initially randomly assigned to Arm B (platinum-based therapy with pemetrexed with or without 
pembrolizumab) who have progression that is confirmed by the blinded independent central review (BICR) and who are eligible for 
crossover treatment.  
Study Period 
Crossover Baseline 
Study Treatment (Cycle = 21 days) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening (V300) 
Cycle 301 
Cycle 302-n 
Short-
Term 
Follow-upa 
Long-
Term 
Follow-
upb 
Visit 
duration/window 
Up to 42 days 
-3 days
±3 
days 
±3 
days 
± 3 days 
±3 days 
±3 days 
30±7 days 
90±7 
days 
Relative Day 
within Dosing 
Cycle 
≤42 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
V801 
V802-X 
Procedure 
Informed consent 
X 
ICF must be signed before any protocol-specific 
procedures are performed. See Appendix 1. 
Inclusion/exclusion 
criteria for 
crossover phase 
X 
See Section 5.2.2. 
Optional 
postprogression 
tumor biopsy 
See 
Instructions 
Can be obtained any time prior to the start of next 
therapy 
Concomitant 
medication 
X 
X 
X 
Record all premedication, supportive care, and 
concomitant medication throughout crossover 
treatment. 
Physical 
examination 
X 
X 
X 
X 
Physical examination and review of relevant systems at 
Screening. Symptom-directed physical examinations, 
including measurement of weight may be performed at 
other time points. 
Weight and vital 
signs 
X 
X 
X 
X 
Includes weight, blood pressure, pulse rate, pulse 
oximetry, and temperature. Can be done at C301D1. 
All patients should have their blood pressure optimized 
(if necessary) prior to initiation of study drug to a 
reading of ≤140/90 mmHg. 
ECG 
X 
X 
X 
See 
Instructions 
Obtain triplicate local ECGs at Screening, C301D1, 
C301D8, and C302-6D1. It is preferable to obtain 
approximately 2 hours after dosing. See Section 8.2.1 
for additional information, including requirements for 
potential adjudication. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
27 
Study Period 
Crossover Baseline 
Study Treatment (Cycle = 21 days) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening (V300) 
Cycle 301 
Cycle 302-n 
Short-
Term 
Follow-upa 
Long-
Term 
Follow-
upb 
Visit 
duration/window 
Up to 42 days 
-3 days
±3 
days 
±3 
days 
± 3 days 
±3 days 
±3 days 
30±7 days 
90±7 
days 
Relative Day 
within Dosing 
Cycle 
≤42 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
V801 
V802-X 
Procedure 
ECOG performance 
status 
X 
X 
X 
X 
Karnofsky 
performance scale  
X 
X 
X 
X 
For RANO-BM assessment. 
AE collection 
X 
X 
X 
Collect throughout Crossover Treatment. Use CTCAE 
Version 5.0. Only SAEs related to study treatment or 
protocol procedures are reported in long-term follow-
up. 
Radiologic imaging 
and measurement 
of palpable or 
visible lesions (X-
ray, CT scan with 
bone windows, 
MRI, bone 
scintigraphy 
[preferred], PET 
scan or PET 
component of 
PET/CT scan) 
See Instructions 
See 
Instructions 
X 
Perform within 35 days prior to the first dose of 
selpercatinib in the crossover period. Perform 
assessments at 6 weeks (±7 days) and 12 weeks (±7 
days) and then every 9 weeks (±7 days) for the first 48 
weeks following C301D1 and then every 12 weeks (±7 
days) thereafter until progression, the start of a new 
anticancer therapy, death, or study completion. For 
patients with nonmeasurable bone disease bone 
scintigraphy (preferred) or PET scan or PET 
component of PET/CT scan may be obtained every 24 
weeks (±7 days) or more often if clinically indicated. 
Scans obtained prior to the signing of the crossover 
consent may be used. See Section 8.1. 
Intracranial 
evaluation with CT 
or MRI 
See Instructions 
See 
Instructions 
X 
Required for all patients. Should be obtained at 
baseline and then at the same frequency as other 
radiologic imaging and as clinically indicated. See 
Section 8.1. 
Submit scans 
X 
See 
Instructions 
X 
All scans taken for tumor assessment (e.g., 
radiographic, bone, and intracranial) should be 
submitted to Lilly’s designee for central review by the 
BICR.  
Pregnancy test 
X 
See Instructions 
X 
Perform within 24 hours prior to the first dose of 
selpercatinib in the crossover period. Applies only to 
women of childbearing potential. Note: during study 
treatment, perform at least monthly or as required per 
local regulations and/or institutional guidelines. See 
Appendix 2. 
Approved on 15 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJC(e) 
28 
Study Period 
Crossover Baseline 
Study Treatment (Cycle = 21 days) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening (V300) 
Cycle 301 
Cycle 302-n 
Short-
Term 
Follow-upa 
Long-
Term 
Follow-
upb 
Visit 
duration/window 
Up to 42 days 
-3 days
±3 
days 
±3 
days 
± 3 days 
±3 days 
±3 days 
30±7 days 
90±7 
days 
Relative Day 
within Dosing 
Cycle 
≤42 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
V801 
V802-X 
Procedure 
Hematology 
X 
X 
X 
X 
X 
X 
Additional assessments may be obtained at the 
discretion of the investigator. See Appendix 2. 
Coagulation 
X 
X 
Additional assessments may be obtained at the 
discretion of the investigator. See Appendix 2. 
Urinalysis 
X 
X 
See 
Instructions 
X 
For Cycles 302-n, as clinically indicated for 
subsequent cycles. See Appendix 2. 
Clinical chemistry 
X 
X 
X 
X 
X 
Should be performed on C302D1, C303D1, and then 
D1 of every subsequent cycle (e.g., C302, C303). 
Additional assessments may be obtained at the 
discretion of the investigator. See Appendix 2. 
Hepatic monitoring  
X 
See 
Instructions 
Including AST, ALT, total/direct bilirubin, and ALP. 
Should be performed on C301D15, C302D15, and 
C303D15. Additional assessments may be obtained at 
the discretion of the investigator 
Thyroid function 
X 
See 
Instructions 
Starting in Cycle 302 and every other cycle for the first 
8 cycles (e.g., Cycles 2, 4, 6, 8). Thereafter should be 
collected at the investigator’s discretion. See Appendix 
2. 
Plasma for cfDNA 
analysis and 
exploratory 
biomarkers 
X (pre-
dose) 
X 
X 
X 
Blood sample for 
pharmacokinetics 
X 
X 
Samples to be drawn prior to the morning dose (-2 to 
0 hr) in Cycles 301 to 306. See Sections 8.5 and 8.6. 
Survival 
information 
X 
Survival information may be collected by contacting 
the patient or family directly (e.g., via telephone) if no 
procedures are required. This should be collected 
approximately every 90 days from the end of short-
term follow up. 
Collection of 
poststudy-treatment 
anticancer therapy 
information 
X 
Perform every 90 days from the end of short-term 
follow up for the first 2 years after discontinuation 
from study treatment and every 6 months (±14 days) 
thereafter until death or study completion. 
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Study Period 
Crossover Baseline 
Study Treatment (Cycle = 21 days) 
Poststudy Treatment 
Discontinuation 
Instructions 
Cycle/Visit 
Screening (V300) 
Cycle 301 
Cycle 302-n 
Short-
Term 
Follow-upa 
Long-
Term 
Follow-
upb 
Visit 
duration/window 
Up to 42 days 
-3 days
±3 
days 
±3 
days 
± 3 days 
±3 days 
±3 days 
30±7 days 
90±7 
days 
Relative Day 
within Dosing 
Cycle 
≤42 
≤14 
D1 
D8 
D15 
D1 
D8 
D15 
V801 
V802-X 
Procedure 
EORTC QLQ-C30 
X 
X 
X 
The patient will complete electronically at the clinic 
site. See Section 8.9. 
EORTC IL19 
X 
X 
X 
X 
X 
X 
The patient will complete electronically on the 
provided electronic device at home (not at the clinic 
site). Items 1 to 5 of the IL19 will be collected. See 
Section 8.9. 
NSCLC-SAQ 
X 
X 
X 
X 
X 
X 
The patient will complete electronically on the 
provided electronic device at home (not at the clinic 
site). See Section 8.9. 
PRO-CTCAE 
X 
X 
X 
X 
X 
X 
The patient will complete electronically on the 
provided electronic device at home (not at the clinic 
site). Selected items will be collected. See Section 8.9. 
FACT-GP5 
X 
X 
X 
X 
X 
X 
The patient will complete electronically on the 
provided electronic device at home (not at the clinic 
site). See Section 8.9. 
EQ-5D-5L 
X 
X 
X 
X 
The patient will complete electronically at the clinic 
site. In Long-term follow-up, completion is only 
required if the patient is physically in clinic (e.g. for 
radiographic assessment). See Section 8.9. 
Premedication 
X 
X 
As appropriate for the therapy and following local 
practice and labels. See Section 6.1. 
Patient dosing diary 
X 
Provide patient diary Day 1. Completed daily by 
patient. Review at each study visit. 
Dispense 
selpercatinib 
X 
See Section 6.1. 
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Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BICR = blinded independent central review; C = cycle; 
cfDNA = circulating cell-free DNA; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; 
EORTC IL19 = European Organisation for Research and Treatment of Cancer, item library 19; EQ-5D-5L = EuroQol Five Dimension Five Level; FACT-GP5 = Functional Assessment of Cancer 
Therapy-Side Effects; hr = hour; ICF = informed consent form; MRI = magnetic resonance imaging; NSCLC-SAQ = Non-small Cell Lung Cancer-Symptom Assessment Questionnaire; PET = 
positron emission tomography; PRO-CTCAE = patient-reported outcome Common Terminology Criteria for Adverse Events; RANO-BM = Response Assessment in Neuro-Oncology Brain 
Metastases; SAE = serious adverse event; V = visit. 
a 
Short-term follow-up begins when the patient and investigator agree that the patient will no longer continue study treatment and lasts approximately 30 days (±7 days). 
b 
Long-term follow-up begins when short-term follow-up period is completed and continues until death, study withdrawal, or the patient is lost to follow-up. In all cases, no follow-up procedures will 
be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent. 
Note: Crossover baseline/screening assessments and laboratory values drawn within the indicated window of C301D1 may be used for both crossover screening/baseline and C301D1 assessments. 
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Continued Access SoA for All Patients 
Visit 
Study Treatment 
30-Day Follow-Upa
Instructions 
501-5XX
901 
Procedureb 
AE collection 
X 
X 
Per CTCAE v5.0., for posttreatment follow-up, the investigator should only collect SAEs 
related to the study treatment regimen or protocol procedures. 
Collect throughout the study. 
Administer study intervention 
X 
See Section 6.1 for Study Intervention administration details and guidelines. 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event. 
a 
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access period and lasts approximately 30 days. In all 
cases, no follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent. 
b 
Efficacy assessments will be done at the investigator’s discretion based on the standard of care. 
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2.
Introduction
2.1. 
Study Rationale 
Patients with RET fusion-positive non-small cell lung cancer (NSCLC) represent a population 
with high unmet need. Combination chemotherapy has short-term palliative potential in 
advanced NSCLC. While antiprogrammed cell death protein 1 (anti-PD-1) monoclonal 
antibodies (e.g., nivolumab and pembrolizumab) have extended progression-free survival (PFS) 
and recently been approved for patients with NSCLC in some geographies, they may be less 
effective as monotherapy in tumors marked by single-gene driver oncogenic kinase alterations 
(including kinase fusions) with otherwise low mutation burdens and low neoantigen production 
(Borghaei et al. 2015; Rizvi et al. 2015; Gainor et al. 2016; Herbst et al. 2016).  
Agents targeting specific alterations such as EGFR and BRAF activating mutations and ALK and 
ROS1 gene fusions have demonstrated compelling efficacy in patients with cancers that harbor 
the respective activating genetic alteration (Lindeman et al. 2018; Pakkala and Ramalingam 
2018).  
Selpercatinib, a selective RET tyrosine kinase inhibitor (TKI), has demonstrated a favorable 
safety profile and evidence of durable antitumor activity in patients with advanced RET fusion-
positive NSCLC (both treatment naïve and those previously treated with approved first-line 
chemotherapy with or without immunotherapy [Drilon et al. 2018; Oxnard et al. 2018, Wirth et 
al. 2018]). As a result, selpercatinib may be of benefit as an initial treatment with advanced or 
metastatic RET fusion-positive NSCLC. 
2.2. 
Background 
Lung cancer is the most common form of cancer and the most common cause of cancer deaths 
worldwide, with 2.09 million new cases and 1.76 million deaths in 2018. Approximately 80% to 
85% of lung cancers are NSCLCs (American Lung Association 2019, Lung Cancer Fact Sheet).  
Standard of care (SOC) first-line treatment for patients with NSCLC remains, in most cases, 
platinum-based chemotherapy regimens. Typical response rates to platinum-based therapies are 
20% to 30%, with a median PFS (mPFS) of approximately 5 months (Paz-Ares et al. 2018). 
Recent studies have demonstrated that addition of an immune checkpoint inhibitor (e.g., anti-PD-
1 or PD-L1 antibody) to platinum-based regimens will improve responses and PFS. As an 
example, patients treated with the combination of pembrolizumab plus pemetrexed plus platinum 
demonstrated better outcomes compared to those treated with control arm of pemetrexed plus 
platinum in response rates (47.6% vs. 18.9%), PFS (8.8 months vs. 4.9 months), and overall 
survival (OS) (not reached vs. 11.3 months [Gandhi et al. 2018]), respectively. The benefits were 
observed regardless of PD-L1 status. For patients with high PD-L1 expression (tumor proportion 
score [TPS] of 50% or greater), monotherapy with a PD-L1 inhibitor may be sufficient (Reck et 
al. 2016): in a randomized Phase 3 trial, patients treated with pembrolizumab monotherapy 
achieved better outcomes compared to those treated with chemotherapy (mPFS of 10.3 months 
vs. 6.0 months, respectively; hazard ratio [HR] 0.50). Recent data indicate that immune 
checkpoint inhibitors may be less effective in patients with oncogenic driver-positive NSCLC, 
including patients with RET alterations.  
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The identification of mutually exclusive, activating genetic alterations in specific tyrosine 
kinases has led to a new classification of NSCLC based on molecular genotype rather than 
histology. Matching a specific targeted TKI to the specific driver mutation identified has led to a 
paradigm shift in the treatment of NSCLC, with targeted therapy considered the preferred initial 
treatment for patients with NSCLC with EGFR and BRAF activating mutations and ALK and 
ROS1 gene fusions, and chemotherapy and immunotherapy saved for later lines of therapy. 
Molecular profiling of NSCLC tumors is recommended by international consensus guidelines as 
part of routine evaluation in newly diagnosed patients to identify these known driver mutations 
(EGFR, ALK, and ROS1) as well as a second group of genes that should be included in any 
expanded panel that is offered for lung cancer patients including BRAF, MET, RET, ERBB2 
(HER2), and KRAS (Lindeman et al. 2018). 
Given the high efficacy and differentiated toxicity (compared to platinum-based chemotherapy 
regimens) observed for these TKIs, ongoing clinical trials are examining whether newer selective 
TKIs can also benefit patients with NSCLC whose cancers harbor activating genetic alteration in 
other kinases (Mok et al. 2009; Zhang et al. 2017). The RET receptor tyrosine kinase is 
oncogenically activated by chromosomal rearrangements producing RET gene fusions in 1% to 
2% of patients with NSCLC (Ju et al. 2012; Kohno et al. 2012; Lipson et al. 2012; Takeuchi et 
al. 2012; Kato et al. 2016). Several multikinase inhibitors (MKI) with some degree of anti-RET 
activity and approved for other cancers demonstrated modest activity in RET fusion-positive lung 
cancer in Phase 2 studies, with response rates of 16% to 53% (depending on the specific MKI 
and patient population), but PFS of only 3.6 to 7.3 months (Drilon et al. 2018; Oxnard et al. 
2018; Wirth et al. 2018). The efficacy of these MKIs in patients is ultimately limited by 
incomplete inhibition of RET in tumors, significant toxicity from stronger inhibition of other 
targets (e.g., KDR/VEGFR2, EGFR, and MET), and poor pharmacokinetics (PK) (i.e., significant 
drug accumulation and long half-life contributing to toxicity but not efficacy). As a result, most 
patients treated with these agents experience significant toxicities requiring dose interruptions, 
reductions, and/or treatment cessation.  
Selpercatinib is a highly potent and specific small-molecule inhibitor of the RET kinase, with 
minimal inhibition of other kinase and nonkinase targets. A Phase 1/2 study (Drilon et al. 2018; 
Oxnard et al. 2018; Wirth et al. 2018) was designed to assess the safety, PK, and antitumor 
activity of selpercatinib in patients with RET-altered solid tumors. The Phase 1 portion of the 
study has been completed and the Phase 2 portion is currently ongoing. The recommended Phase 
2 dose was established as 160 mg twice a day (BID). Please see the Investigator’s Brochure (IB) 
for the most current safety information.  
As of 30 March 2019, 422 patients were enrolled in Study LOXO-RET-17001 (LIBRETTO-001) 
and received treatment with selpercatinib across 9 dose levels ranging from 20 mg once daily 
(QD) to 240 mg BID, treatment-emergent adverse events (TEAEs) occurring in ≥15% patients 
were dry mouth (30.8%), diarrhea (27.7%), hypertension (27.3%), fatigue (22.3%), constipation 
(21.8%), aspartate aminotransferase (AST) increased (21.6%), alanine aminotransferase (ALT) 
increased (20.4%), headache (18.7%), nausea (18.0%), edema peripheral (17.3%), and blood 
creatinine increased (14.9%).The most common Grade ≥3 TEAEs included hypertension (12.3), 
ALT increased (6.2%), AST increased (4.7%), hyponatremia (4.3%), electrocardiogram (ECG) 
QT prolonged (2.8%), dyspnea and lymphopenia (each 2.6%), and diarrhea and 
thrombocytopenia (each 2.1%).All other Grade ≥3 TEAEs occurred in less than 2% of patients 
overall. During dose escalation, 2 dose-limiting toxicities (DLTs) were reported, both at the 
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240 mg BID dose level: 1 DLT of Grade 3 tumor lysis syndrome and 1 DLT of Grade 3 
thrombocytopenia. 
As presented at World Conference on Lung Cancer 2018 and American Thyroid Association 
2018, with a data cutoff of 19 July 2018, among the first 82 patients enrolled in LIBRETTO-001, 
the overall response rate (ORR) was 68% (95% confidence interval [CI] 50% to 82%, n=26/38) 
in RET fusion-positive NSCLC, 78% (95% CI 40% to 97%, n=7/9) in RET fusion-positive 
thyroid (nonmedullary thyroid cancer [MTC]), 50% (n=1/2) in RET fusion-positive pancreatic, 
59% (95% CI 39% to 77%, n=17/29) in RET-mutant MTC, and 0% (n=0/4) in patients without a 
known activating RET alteration in their cancers (Drilon et al. 2018; Wirth et al. 2018). 
Responses did not differ by fusion partner, mutation (including the V804M gatekeeper resistance 
mutation), or prior therapies, including MKIs with anti-RET activity. Confirmed intracranial 
responses were achieved in 100% (n=5/5: 1 complete response, 4 partial responses) of patients 
with measurable brain metastases. The median duration of response was not reached. A total of 
96% (49/51) of responding patients were still on treatment (median follow-up of responders - 
8.8 months). 
2.3. 
Benefit/Risk Assessment 
The benefit-risk assessment for selpercatinib is considered in the context of the significant unmet 
medical need for patients with metastatic RET-fusion positive NSCLC who require systemic 
therapy. Patients who have driver alterations that can be matched with a targeted agent (e.g., 
erlotinib, osimertinib, crizotinib, alectinib) have demonstrated improved outcomes relative to 
patients who receive nonspecific therapy such as chemotherapy. Although patients with RET-
fusion-positive NSCLC have an identifiable driver alteration, they currently receive the same 
SOC treatment as patients with NSCLC who do not have a driver alteration, as there are no RET-
specific approved therapies. The magnitude and durability of the responses observed in RET 
fusion positive NSCLC patients in the Phase 1 study LIBRETTO-001 suggest that selpercatinib 
provides meaningful clinical efficacy. The benefits demonstrated with selpercatinib are 
consistent and meaningful across multiple endpoints, including among fusion partners. 
The safety profile of selpercatinib is well-tolerated, clinically manageable, and distinct from 
available therapies, with the low rates of study drug discontinuation due to adverse events (AEs), 
particularly when compared to platinum-based SOC treatment regimens. As outlined in the IB, 
the most common toxicities associated with selpercatinib are monitorable and reversible and 
include dry mouth, diarrhea, hypertension, fatigue, constipation, AST/ALT elevation, headache, 
nausea, peripheral edema, and increased blood creatinine. The majority of events were Grade 1 
or 2. Events of special interest include hypersensitivity, liver-function test abnormalities, 
thrombocytopenia, and hypertension. 
Although the study procedures in Study JZJC are generally consistent with SOC, increased 
monitoring of vital signs (including blood pressure), hematology, hepatic panels, and ECGs 
occur in the initial cycles to monitor for potential toxicities of interest. Additionally, an 
Independent Data Monitoring Committee (IDMC) will assess unblinded safety data during the 
trial on a regular basis. The IDMC will evaluate all safety-related data provided for each meeting 
to determine whether a change in the conduct of the trial is warranted for the safety of patients.  
Given the high unmet need for additional therapies to treat RET fusion-positive NSCLC, the 
clinical safety profile of selpercatinib, and the clinical efficacy observed in patients with RET-
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altered solid tumors (including NSCLC) in the ongoing Phase 1/2 trial, the risk/benefit 
assessment supports evaluation of selpercatinib in the proposed patient population. 
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated AEs of selpercatinib is to be found in the IB. 
More detailed information about the known and expected benefits and risks of carboplatin, 
cisplatin, pemetrexed, and pembrolizumab may be found in the Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics. 
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3.
Objectives and Endpoints
Objectives 
Endpoints 
Primary 

To compare PFS of selpercatinib with the
combination of platinum-based (carboplatin or
cisplatin) therapy, pemetrexed, and
pembrolizumab in patients with advanced or
metastatic RET fusion-positive NSCLC

To compare PFS of selpercatinib with the
combination of platinum-based (carboplatin or
cisplatin) and pemetrexed therapy, with or
without pembrolizumab, in patients with
advanced or metastatic RET fusion-positive
NSCLC

PFS per RECIST 1.1 by BICR
Secondary 

To compare the efficacy of selpercatinib with
the combination of platinum-based (carboplatin
or cisplatin) therapy, pemetrexed, and
pembrolizumab in patients with advanced or
metastatic RET fusion-positive NSCLC

To compare the efficacy of selpercatinib with
the combination of platinum-based (carboplatin
or cisplatin) and pemetrexed therapy, with or
without pembrolizumab, in patients with
advanced or metastatic RET fusion-positive
NSCLC

PFS per RECIST 1.1 by investigator

ORR/DOR/DCR per RECIST 1.1 by BICR

ORR/DOR/DCR per RECIST 1.1 by
investigator

Intracranial ORR/DOR per RECIST 1.1 by
BICR

Time to CNS progression per RECIST 1.1. by
BICR

Intracranial ORR/DOR per RANO-BM by
BICR

OS

PFS2

Time to deterioration in pulmonary symptoms:
cough, chest pain, and dyspnea as measured by
the NSCLC-SAQ

To assess safety and tolerability of
selpercatinib compared to platinum-based and
pemetrexed therapy with pembrolizumab

To assess safety and tolerability of
selpercatinib compared to platinum-based and
pemetrexed therapy with or without
pembrolizumab

Including but not limited to SAEs, AEs, deaths,
and clinical laboratory abnormalities per
CTCAE v5.0
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
To assess/evaluate performance of RET local
laboratory tests compared to a single central
test

RET fusion status
Tertiary/Exploratory 

To compare patient-reported tolerability
outcomes, including symptomatic adverse
events and overall side-effect bother between
patients treated with selpercatinib versus the
combination of platinum-based (carboplatin or
cisplatin) and pemetrexed therapy, with or
without pembrolizumab

Symptomatic Adverse Events: PRO-CTCAE

Overall Side-effect Bother (FACT-GP5)

To compare patient-reported Physical
Functioning and HRQoL between patients
treated with selpercatinib versus the
combination of platinum-based (carboplatin or
cisplatin) and pemetrexed therapy, with or
without pembrolizumab

Physical Functioning: EORTC QLQ-C30
Physical Functioning Subscale (and EORTC
IL19)

Other HRQoL Outcomes: EORTC QLQ-C30

To compare RET fusion status in tumor and
blood samples

RET fusion status

To assess the relationship between biomarkers
and clinical outcomes

Biomarkers assessed from blood or tissue
samples, unless precluded by local regulations

Clinical outcomes data

To assess efficacy of selpercatinib in patients
randomly assigned to Arm B who crossed over
to selpercatinib

PFS/ORR/DOR/DCR after crossover

To assess the pharmacokinetics of selpercatinib

Predose plasma concentrations at Day 8 of
Cycle 1, and at Day 1 of Cycles 2 through 6.
Abbreviations: AE = adverse event; BICR = blinded independent central review; CNS = central nervous system; 
CTCAE = Common Terminology Criteria in Adverse Events; DCR = disease control rate; DOR = duration of 
response; EORTC IL19 = European Organisation for Research and Treatment Item Library 19; 
EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 Version 3.0.; FACT-GP5 = Functional Assessment of Cancer Therapy-Side Effects; 
HRQoL = health-related quality of life; NSCLC = non-small cell lung cancer; NSCLC-SAQ = Non-small Cell 
Lung Cancer Symptom Assessment Questionnaire; ORR = overall response rate; OS = overall survival; 
PFS = progression-free survival; PRO = patient-reported outcome; PRO-CTCAE = patient-reported outcome 
Common Terminology Criteria for Adverse Events; RANO-BM = Response Assessment in Neuro-Oncology 
Brain Metastases; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event. 
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4.
Study Design
4.1. 
Overall Design 
This is a global, multicenter, randomized, open-label, controlled Phase 3 study comparing 
selpercatinib (Arm A) to platinum-based and pemetrexed therapy with or without 
pembrolizumab (Arm B) in patients with advanced or metastatic, RET fusion-positive 
nonsquamous NSCLC.  
Patients will be stratified based on: 

geography (East Asia vs. non-East Asia),

brain metastases per investigator assessment (presence vs. absence or unknown), and

investigator’s choice of treatment with or without pembrolizumab. This decision must be
determined at the time of randomization.
Adult patients with histologically confirmed, unresectable, locally advanced or metastatic 
nonsquamous NSCLC with no previous systemic therapy for metastatic disease will be eligible. 
Patients will be required to have a documented RET fusion in tumor and/or blood identified via 
NGS and/or PCR assays, as performed in the routine course of clinical care. Laboratories used 
for RET testing must have certification by Clinical Laboratory Improvement Amendments 
(CLIA), International Organization for Standardization/Independent Ethics Committee 
(ISO/IEC), College of American Pathologists (CAP), or other similar certification. After 
confirmation of eligibility, approximately 250 patients will be randomly assigned in a 2:1 ratio 
to:  

Arm A: treated with selpercatinib (160 mg BID continuously in 21-day cycles) or

Arm B: treated with pemetrexed (500 mg/m2 IV) every 3 weeks plus the investigator’s
discretion of the following treatments administered every 3 weeks:
o
4 cycles of carboplatin (AUC 5, maximum dose 750 mg IV) or cisplatin (75
mg/m2 IV)
o
with or without pembrolizumab (200 mg IV) up to 35 cycles
After the completion of 4 cycles of chemotherapy without progressive disease, patients randomly 
assigned to Arm B will receive maintenance therapy with pemetrexed (500 mg/m2) with or 
without pembrolizumab (200 mg) every 3 weeks according to the decision made at the time of 
randomization. Patients with the intent by the investigator to be treated without pembrolizumab 
will be restricted to 20%. Treatment will continue until radiographic disease progression 
confirmed by BICR, unacceptable toxicity, withdrawal of consent, or death.  
Patients randomly assigned to Arm B who discontinue treatment for radiographic disease 
progression that is confirmed by BICR may be eligible for crossover to selpercatinib (see Section 
5.2.2). Crossover treatment will be optional at the discretion of the investigator.  
The primary efficacy population is defined as all randomized patients with investigator’s intent-
to-treat (ITT) with pembrolizumab if randomized to Arm B (ITT-pembrolizumab population; 
defined in Section 9.3); patients will be analyzed according to assigned treatment group without 
regard to received treatment.  
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The primary endpoint of PFS per RECIST 1.1 by BICR in the ITT-pembrolizumab population 
will act as a gatekeeper for the endpoint of PFS by BICR in the ITT population, i.e., PFS in the 
ITT population will be tested conditionally on achieving statistical significance for PFS in the 
ITT-pembrolizumab population. The study will be considered to be a positive study if a 
statistically significant improvement in PFS by BICR in the ITT-pembrolizumab population is 
observed. Progression-free survival by BICR in the ITT population, in turn, will act as a 
gatekeeper for testing OS in the ITT population, i.e., the OS in ITT population will be tested 
conditionally on achieving statistical significance for the PFS in the ITT population. This 
ordering of the endpoint hierarchy is driven by the need to satisfy certain country-specific 
regulatory and payer expectations. Testing strategy of other secondary endpoints will be further 
described in the SAP. 
4.2. 
Scientific Rationale for Study Design 
This study is a head-to-head comparison of selpercatinib vs. a SOC for the treatment of advanced 
or metastatic nonsquamous NSCLC. The SOC arm consists of platinum-based therapy (cisplatin 
or carboplatin) with pemetrexed, with or without pembrolizumab. Patients with squamous 
NSCLC will be excluded to be consistent with the pemetrexed label. Although pembrolizumab in 
combination with platinum-based chemotherapy has been approved for patients with NSCLC in 
some geographies, it is not considered a global SOC. There are geographical differences in the 
frequency with which pembrolizumab is used based on individual patient characteristics that may 
influence the expected efficacy and safety (e.g., contraindications, PD-L1 expression, the 
potential for subsequent therapy with targeted agents whose toxicity profile may be affected by 
prior treatment with pembrolizumab). Additionally, not all patients are suitable to receive an 
immune checkpoint inhibitor such as pembrolizumab (e.g., patients with a history of interstitial 
lung disease (ILD) or interstitial pneumonitis, an active autoimmune disease, or requiring 
concurrent treatment with supraphysiologic doses of immunosuppressive agents). The design of 
Study JZJC, which allows the platinum doublet to be administered with or without 
pembrolizumab, provides flexibility for the investigator to select the regimen most well-suited 
for each specific patient. The preliminary results evaluating selpercatinib in RET-fusion-positive 
NSCLC have been previously described. Efficacy appears independent of line of therapy. 
Response rates and duration of therapy compare favorably to SOC therapies (Gandhi et al. 2018). 
Given these results, a comparative trial of selpercatinib vs. SOC appears justified. 
The study will allow crossover of patients whose disease has progressed on chemotherapy with 
or without pembrolizumab. The preliminary results from a prior study in NSCLC suggest that 
selpercatinib will be effective in patients who have received prior treatment (Drilon et al. 2018; 
NCT03157128). The crossover design will therefore allow patients whose disease progresses on 
SOC therapy to receive selpercatinib.  
4.3. 
Justification for Dose 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in murine 
xenograft models, meaningful inhibition of RET in tumors is expected to be achievable with oral 
dose regimens at total daily doses ≥40 mg/day. The dosage of 160 mg BID was selected as the 
recommended Phase 2 dose based on safety data (N=82) and preliminary efficacy data in 
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64 evaluable patients treated at doses from 20 mg QD through 240 mg BID (Drilon et al. 2018, 
NCT03157128). See the IB for additional information. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally. 
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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Type of Participant and Disease Characteristics 
1. Histologically or cytologically confirmed Stage IIIB-IIIC or Stage IV NSCLC that is not
suitable for radical surgery or radiation therapy (Amin et al. 2017). The histology of the
tumor must be predominantly nonsquamous. Squamous cell and/or mixed small
cell/non-small cell histology is not permitted.
2. Must have a RET gene fusion in tumor using PCR or NGS. Results in blood using NGS
are also acceptable.

The RET gene fusion result should be generated from a laboratory with CLIA,
ISO/IEC, CAP, or other similar certification that clearly denotes the presence of a
RET alteration. Blood results must be determined on a platform that meets these
standards and is also Lilly approved.

In all cases, the presence of the RET fusion must be confirmed upon review of the
pathology report by Lilly or designee prior to enrollment.
3. Must have measurable disease per RECIST 1.1 (Eisenhauer et al. 2009) as assessed by
the investigator. Target lesions situated in a previously irradiated area are considered
measurable if progression has been determined in such lesions, and the location of
previously irradiated lesions is clearly documented.
4. Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0
to 2 (Oken et al. 1982).
5. Must have life expectancy of at least 3 months.
6. Must have adequate organ function, as defined subsequently. These values must be met
during the baseline visit prior to randomization.
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System 
Laboratory Value 
Hematologic 
ANC 
1.5×109/L
Platelets 
100×109/L
Hemoglobin 
9 g/dL 
Note: transfusions to increase a participant’s hemoglobin level or initiation of erythropoietin or G-CSF therapy 
to meet enrollment criteria are not allowed in the 28 days preceding the first dose of study drug. 
Coagulation 
INR or PT 
≤1.5X ULN unless the subject is receiving 
anticoagulation therapy 
aPTT or PTT 
≤1.5X ULN unless the subject is receiving 
anticoagulation therapy 
Hepatic 
Total bilirubin 
1.5X ULN 
Except participants with a documented history of 
Gilbert syndrome who must have a total bilirubin 
level of <3.0X ULN
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5X ULN
ALT and AST 
<2.5X ULN OR
5X ULN if the liver has tumor involvement
Renal 
Measured creatinine clearance OR 
50 mL/min 
Calculated creatinine clearance (Appendix 7) 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; dL = deciliter; G-CSF = granulocyte-colony-stimulating 
factor; g = gram; INR = international normalized ratio; L= liter; mL = milliliter; min = minute; PT = prothrombin 
time; PTT = partial thromboplastin time; ULN= upper limit of normal.  
7. Ability to swallow capsules.
Contraception
8. Men with partners of childbearing potential or women of childbearing potential must
agree to use a highly effective contraceptive method (e.g., intrauterine device or birth
control pill) during treatment with study drug and for 6 months following the last dose of
study drug. See Appendix 3. In addition, male subjects on selpercatinib should use a
condom while on study treatment and males randomized to Arm B should use a condom
while on study treatment and for 91 days following the last dose of pemetrexed.
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Note: Unless not allowed by local regulations, women of childbearing potential who are 
abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must agree to either 
remain abstinent or stay in a same-sex relationship without sexual relationships with 
males. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
9. Women of childbearing potential must:

Have a negative pregnancy test (serum or urine, consistent with local regulations)
documented within 24 hours prior to treatment with study drug.

Not be breast-feeding during treatment and for at least 4 months after the last dose
of study drug.
Informed consent 
10. The participant must be capable of demonstrating an understanding of the nature,
significance, and implications of participation in the trial and giving signed informed
consent as described in Appendix 1, which includes compliance with the requirements
and restrictions listed in the informed consent form (ICF) and in this protocol.
Age 
11. Are of an acceptable age to provide informed consent according to local regulations and
are at least 18 years of age.
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
12. Have additional validated oncogenic drivers in NSCLC, if known: e.g., activating
mutations of EGFR, BRAF, or KRAS, MET exon 14 mutations or high-level MET
amplification or fusions of ALK, ROS, or NTRK 1/2/3.
13. Have symptomatic CNS) metastases, carcinomatous meningitis, or untreated spinal cord
compression. Any previous definitive treatment or glucocorticoid therapy to treat CNS
metastases must be completed at least 2 weeks prior to randomization and patients must
be neurologically stable for 2 weeks prior to randomization.
14. Have clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of study treatment or prolongation of the
QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 msec on
more than 1 ECG obtained during the baseline period.
Note: Patients with implanted pacemakers may enter study without meeting
corrected QT interval (QTc) criteria due to nonevaluable measurement.
15. Have uncontrolled, disease-related, pericardial effusion or pleural effusion.
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16. Have a history of human immunodeficiency virus ([HIV]; known HIV 1/2 antibodies
positive). If the medical history, symptoms, and/or laboratory values suggest the patient
may have HIV, appropriate assessments should be conducted to determine if the patient
should be excluded.
17. Have known active Hepatitis B or C.

Patients with serological evidence of chronic hepatitis B virus (HBV) infection
who have no known underlying liver cirrhosis (screening not required) and an
HBV viral load below the limit of quantification with or without concurrent viral
suppressive therapy (at a stable dose) are allowed. Patients with detectable HBV
DNA and controlled disease may be permitted on therapy with sponsor approval.
Concurrent viral suppressive therapy will be required for patients with detectable
HBV DNA.

Patients with a history of hepatitis C virus (HCV) infection who have completed
viral suppressive therapy and have a viral load below the limit of quantification
are allowed.

If the medical history, symptoms, and/or laboratory values suggest that the patient
may have active hepatitis B or C, appropriate assessment should be conducted to
determine if the patient should be excluded.
18. Have active, uncontrolled, systemic bacterial, viral, or fungal infection that requires
treatment or have serious ongoing intercurrent illness that is not controlled, despite
optimal treatment (e.g., hypertension, diabetes, clinically active diverticulitis, intra-
abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis). Screening
for chronic conditions is not required.
19. Have clinically significant active malabsorption syndrome or other condition likely to
affect gastrointestinal absorption of the study drug.
20. Other malignancy unless nonmelanoma skin cancer, carcinoma in situ of the cervix or
other in situ cancers, or a malignancy diagnosed ≥2 years previously and not currently
active. Patients receiving adjuvant hormone therapy for breast or prostate cancer with no
evidence of disease are eligible.
Prior/Concomitant Therapy 
21. Has had any of the following prior to randomization:

Prior systemic therapy (chemotherapy, immunotherapy, or biological therapy) for
metastatic disease. Patients who received adjuvant or neoadjuvant therapy are
eligible if the last dose of the systemic treatment was completed at least 6 months
prior to randomization.

Major surgery (excluding placement of vascular access) within 3 weeks prior to
planned start of study treatment.

Radiotherapy for palliation within 1 week of the first dose of study treatment or
any radiotherapy within 6 months prior to the first dose of study treatment if more
than 30 Gy to the lung.
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
Any unresolved toxicities from prior therapy greater than Common Terminology
Criteria in Adverse Events (CTCAE) Grade 1 at the time of starting study
treatment except for alopecia and Grade 2, prior therapy related neuropathy.
22. Are taking a concomitant medication that is known to cause QTc prolongation (e.g., see
Attachment 5).
23. Criteria #23 has been removed.
24. Criteria #24 has been removed.
25. Require chronic treatment with steroids. Intermittent use of inhaled steroids for asthma or
local steroid injections is allowed. Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
is not considered a form of chronic treatment and does not need to be excluded. The use
of topical, ophthalmic, inhaled, and intranasal corticosteroids is permitted. However,
immunosuppressive therapy within 1 week prior to the first dose of study medication is
not permitted.
26. Have received a live vaccine within 30 days prior to the first dose of trial treatment.
Seasonal flu vaccines that do not contain live virus are permitted.
27. Are unable to interrupt nonsteroidal anti-inflammatory drugs (NSAIDs) 2 days before
(5 days for long-acting NSAIDs), the day of, and 2 days following administration of
pemetrexed.
Prior/Concurrent Clinical Study Experience 
28. Are currently enrolled in any other clinical study involving an investigational product or
any other type of medical research judged not to be scientifically or medically compatible
with this study.
29. Have participated, within the past 30 days (4 months for studies conducted in Japan;
3 months for studies conducted in the UK), in a clinical study involving an
investigational product. If the previous investigational product has a long half-life, 5 half-
lives or 30 days (4 months for studies conducted in Japan; 3 months for studies conducted
in the UK [whichever is longer]) should have passed. Exceptions will be considered on a
case-by-case basis by the Lilly clinical research physician (CRP)/clinical research
scientist (CRS).
Other Exclusions 
30. Have a known hypersensitivity to any of the excipients of selpercatinib, platinum-
containing drugs, or pemetrexed.
31. Are unable or unwilling to take folic acid, dexamethasone, or vitamin B12
supplementation.
5.2.1. 
Exclusion Criteria for Participants on Pembrolizumab 
The following exclusion criteria should apply only for participants on Arm B who the 
investigator plans on treating with pembrolizumab:  
32. Have a history of ILD or interstitial pneumonitis, including clinically significant radiation
pneumonitis.
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33. Have active autoimmune disease or any illness or treatment that could compromise the
immune system within the past 2 years, or a syndrome or condition that requires
corticosteroids or immunosuppressive agents. Replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and does not need to be
excluded.
34. Use of escalating or chronic supraphysiologic doses of corticosteroids or
immunosuppressive agents (such as, exceeding 10 mg/day of prednisone or equivalent).
Use of topical, ophthalmic, inhaled, and intranasal corticosteroids permitted.
35. Have previously received pembrolizumab or have a known hypersensitivity to any of the
excipients of pembrolizumab.
5.2.2. 
Enrollment Criteria for Crossover Treatment 
Patients who are randomly assigned to Arm B who discontinue treatment for radiographic 
disease progression that is confirmed by BICR may be eligible for crossover to selpercatinib if 
they meet the following criteria: 
a) Have radiographic disease progression using RECIST 1.1 as assessed by BICR and
stopped their initial treatment with platinum-based therapy and pemetrexed with or
without pembrolizumab.
b) Are willing and able to provide written informed consent to crossover treatment.
c) Have adequate hematologic, hepatic, and renal function as defined within the inclusion
and exclusion criteria for initial eligibility (Sections 5.1 and 5.2).
d) Have all toxicities attributed to platinum-based chemotherapy with or without
pembrolizumab resolved to ≤Grade1 (CTCAE v5.0) or baseline, with the exception of
alopecia, Grade 2 platinum therapy-related neuropathy, or controlled Grade 2
hypothyroidism or hypertension.
e) Have not received any other anticancer systemic therapy since platinum-based
pemetrexed therapy with or without pembrolizumab.
f)
Have an ECOG performance status of 0 to 2.
Patients are eligible to be considered for crossover if: 

they meet the criteria above and

they can initiate treatment with selpercatinib within 42 days the time of BICR confirmed
progression.
Exceptions may be made on a case-by-case basis following approval from the sponsor. 
Patients that may crossover should not: 

complete V801 at the end of their initial treatment, but should enter V201 and V300 prior
to starting selpercatinib (SoA [Section 1.3]). Visit 201 will allow for the collection of
Arm B posttreatment safety information for patients that do not crossover to selpercatinib
within 30 (+/-7 days) of the last dose of study treatment.

initiate selpercatinib any earlier than 21 days after their last dose of study treatment.
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5.3. 
Lifestyle Considerations 
Not applicable. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number. The interval 
between rescreening should be ≥2 weeks. Each time rescreening is performed, the individual 
must sign a new ICF and will be assigned a new identification number. Repeating of laboratory 
tests during the screening period or repeating screening tests to comply with the 
protocol-designated screening period does not reconstitute rescreening. 
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6.
Study Intervention
Study intervention is defined as any medicinal product(s) medical device(s) intended to be 
administered to or used by a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Arm A 
(selpercatinib) 
Arm B 
(Investigator’s discretion of carboplatin or cisplatin + pemetrexed 
± pembrolizumab) 
Intervention 
Selpercatinib 
Carboplatin 
Cisplatin 
Pemetrexed 
Pembrolizu
mab 
(investigator
’s choice) 
Dose 
160 mg 
AUC 5 
(maximum 
dose 750 mg) 
75 mg/m2 
500 mg/m2  
(with vitamin 
supplementation
) 
200 mg 
Schedule 
BID 
continuously in 
21-day cycles
Day 1 Q3W 
for 4 cycles 
Day 1 Q3W 
for 4 cycles 
Day 1 Q3W 
Day 1 Q3W 
up to 35 
cycles 
Route 
Oral 
IV 
IV 
IV 
IV 
Authorized as defined by 
EU Clinical Trial 
Regulation 
Authorized and 
used according 
to EU 
authorization 
Authorized 
and used 
according to 
EU 
authorization 
Authorized 
and used 
according to 
EU 
authorization 
Authorized and 
used according 
to EU 
authorization 
Authorized 
and used 
according to 
EU 
authorizatio
n 
Abbreviations: AUC = area under the concentration versus time curve; BID = twice a day; IV = intravenous; 
m = meter; mg = milligrams; Q3W = every 3 weeks. 
6.1.1. 
Selection and Timing of Doses 
A cycle is defined as an interval of 21 days. A delay of a cycle due to holiday, weekend, bad 
weather, or other unforeseen circumstances will be permitted for a maximum of 7 days and not 
counted as a protocol deviation. 
The actual doses of cisplatin and pemetrexed to be administered will be determined by 
calculating the patient’s body surface area (BSA) at the beginning of each cycle. Although it is 
acceptable to recalculate more frequently, if the patient’s weight does not fluctuate by more than 
10% from the weight used to calculate the prior cycle or from baseline, the BSA will not need 
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to be recalculated. A 10% variance in the calculated total dose will be allowed for ease of dose 
administration. 
Arm A: Selpercatinib doses will be administered at approximately the same times on each day, 
and BID dosing will be separated by approximately 12 hours (a minimum of 6 hours between 
consecutive doses). See Section 6.5.1.1 and Appendix 5 for concomitant therapy considerations 
(including food and beverage intake). In all other instances not listed in Section 6.5.1.1, 
selpercatinib can be taken with or without food.  
Participants randomized to selpercatinib treatment must keep a daily diary to record dosing 
compliance, which will also be assessed at clinic visits by means of a capsule count in the 
returned bottle(s). Late doses (i.e., 4 or more hours after scheduled time) should be noted in the 
diary. Doses that are late by more than 6 hours should be skipped and recorded in the dosing 
diary as missed. Vomiting after dosing should be noted in the diary, and a vomited dose should 
not be redosed or replaced. 
Arm B: Patients will begin dosing with investigator’s choice of carboplatin or cisplatin, 
pemetrexed, and pembrolizumab (if applicable) on C1D1. After the completion of 4 cycles of 
chemotherapy without progressive disease, patients randomly assigned to Arm B will receive 
maintenance therapy with pemetrexed and pembrolizumab (if applicable) every 3 weeks. 
Guidance for administration is provided below, but it is acceptable to administer pre- or post-
medications and study drugs per local practice and/or labels. 
Drug 
Administration 
Pembrolizumab 

Investigator’s choice determined at the time of randomization.

If applicable, administered as IV infusion over approximately 30 min on Day 1 prior to pemetrexed and
platinum.

It is recommended that any chemotherapy premedications not be administered until at least 30 minutes
after the completion of the pembrolizumab infusion.

If applicable, pembrolizumab will be discontinued after completion of approximately 2 years of
treatment (completion of 35 treatments with pembrolizumab).
Pemetrexed 

IV infusion over approximately 10 minutes on Day 1. Should occur at a minimum 30 minutes after
pembrolizumab.

All patients must receive the appropriate supplementation of vitamin B12, folic acid, and corticosteroid
as shown below or per local practice and/or labels.

Folic acid supplementation: To reduce toxicity, patients treated with pemetrexed must be
instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily
basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first
dose of pemetrexed and dosing should continue during the full course of therapy and for 21 days
after the last dose of pemetrexed.

Vitamin B12 supplementation (1000 µg): Will be administered as an intramuscular injection
approximately 1 to 2 weeks prior to the first dose of pemetrexed and repeated approximately
every 9 weeks until 3 weeks after the last dose of study therapy.

Dexamethasone prophylaxis (4 mg, orally BID – or equivalent): Taken the day before, day of, and
day after pemetrexed administration. Higher or additional doses are permitted for reasons other
than routine rash prophylaxis (e.g., antiemetic prophylaxis).
Cisplatin 

Administered as an IV infusion approximately 30 minutes after the pemetrexed infusion for the first 4
cycles.

Cisplatin therapy should be immediately preceded and followed by hydration procedures and
administered according to local practice and labels. Similarly, antiemetic therapy should follow local
guidelines and labels.
Carboplatin 

Administered as an IV infusion over 15 to 60 minutes (approximately 30 minutes) after pemetrexed for
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the first 4 cycles as per local practice and labels. 

Doses should be calculated using the Calvert formula (Calvert et al. 1989) and should not exceed
750 mg.

Antiemetic therapy should follow local guidelines and labels.
Abbreviations: BID = twice a day; IV = intravenous; min = minutes. 
6.1.2. Packaging and Labeling
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
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6.2. 
Preparation/Handling/Storage/Accountability 
Please consider the following for study intervention preparation/handling/storage/accountability: 
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received; any discrepancies are to be
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study intervention
must be stored in a secure, environmentally controlled, and monitored (manual or
automated) area in accordance with the labeled storage conditions prior to dispensing,
with access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions
are provided in the Pharmacy Manual.
5. Investigators should consult the study drug information provided in the Pharmacy
Manual or the product label for the specific administration information (including
warnings, precautions, contraindications, adverse reactions, and dose modifications).
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. However, Lilly will not have unblinded access to aggregate data 
from the clinical database, to preserve the integrity of the trial. An IDMC will monitor aggregate 
safety during the course of the trial on a regular basis. Details will be specified in a separate 
IDMC charter. 
To minimize investigator bias, PFS will be determined based on the assessment of a BICR (see 
Section 8.1.2). Patients on Arm B will be allowed to cross over to selpercatinib only after 
progression has been confirmed by the BICR. Details of the BICR will be described in a separate 
BICR charter.  
Patients will be randomly assigned to 1 of 2 treatments arms, stratified based on geography (East 
Asia vs. non-East Asia), brain metastases per investigator assessment (presence vs. absence or 
unknown), and investigator’s choice of treatment (with or without pembrolizumab). 
6.4. 
Study Intervention Compliance 
For participants randomly assigned to selpercatinib treatment, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned capsules, and reviewing patient diaries. Deviation(s) from the prescribed 
dosage regimen should be recorded in the electronic case report form (eCRF). 
A patient will be considered noncompliant if he or she takes <75% of the planned doses for 
assigned study drug in a cycle. A patient will also be considered noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken ≥125% of the planned doses 
of study drug over the course of the patient’s treatment.  
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Study intervention that is administered intravenously will be administered only at the 
investigational sites by the authorized study site personnel. As a result, treatment compliance is 
ensured. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 

reason for use

dates of administration including start and end dates
The Lilly CRP/CRS should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Prohibited Concomitant Therapy 
Except as indicated in Section 6.5.2, patients are not allowed to receive concomitant systemic 
anticancer agents (including herbal drugs known to have antitumor activity), drugs with 
immunosuppressant properties, or any other investigational agents not specified in this protocol. 
Any disease progression requiring other forms of specific antitumor therapy will necessitate 
early discontinuation from the study. 
Chronic treatment (>7 days) with steroids is not permitted except to treat symptoms from an 
immune-related AE or brain metastases. Changes in steroid use or doses, especially in the 
context of steroids used to treat brain metastases, should be recorded on the eCRF to facilitate 
assessment of Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). 
Intermittent use of inhaled steroids for asthma or local steroid injections is allowed. Similarly, 
the use of topical, ophthalmic, and intranasal corticosteroids is permitted. Similarly, limited use 
of systemic corticosteroids (≤7 days) is permitted where it is considered SOC (e.g., as 
premedication for contrast allergy or for chronic obstructive pulmonary disease exacerbation). 
Replacement doses of steroids (e.g., prednisone 10 mg daily) are permitted while on study.  
The concurrent use of drugs known to prolong QTc is prohibited (Appendix 5). Drugs with a 
possible or conditional risk should be avoided if possible.  
Live vaccines should not be administered while on study treatment or within 90 days after the 
last dose of study treatment. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, bacillus 
Calmette-Guérin, and typhoid. Seasonal flu vaccines that do not contain live virus are permitted. 
6.5.1.1. Concomitant Therapy Considerations for Arm A 
Avoid concomitant use of a PPI, H2 receptor antagonists, or locally-acting antacids with 
selpercatinib. If concomitant use cannot be avoided: 

Take selpercatinib with food (at least 400 calories) when co-administered with a PPI

Take selpercatinib 2 hours before or 10 hours after administration of an H2 receptor
antagonist
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
Take selpercatinib 2 hours before or 2 hours after administration of a locally-acting
antacid
Concomitant use of selpercatinib with a strong or moderate CYP3A inhibitor increases 
selpercatinib plasma concentrations, which may increase the risk of selpercatinib adverse 
reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate 
CYP3A inhibitors with selpercatinib. If concomitant use of strong and moderate CYP3A 
inhibitors cannot be avoided, reduce the selpercatinib dosage and monitor the QT interval with 
ECGs more frequently. 
Concomitant use of selpercatinib with a strong or moderate CYP3A inducer decreases 
selpercatinib plasma concentrations, which may reduce selpercatinib antitumor activity. Avoid 
coadministration of strong or moderate CYP3A inducers with selpercatinib. 
Selpercatinib is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of 
selpercatinib with CYP2C8 and CYP3A substrates increases their plasma concentrations, which 
may increase the risk of adverse reactions related to these substrates. Avoid coadministration of 
selpercatinib with CYP2C8 and CYP3A substrates where minimal concentration changes may 
lead to increased adverse reactions. If coadministration cannot be avoided, follow 
recommendations for CYP2C8 and CYP3A substrates provided in their approved product 
labeling. 
Please refer to the IB for additional details. 
6.5.1.2.Concomitant Therapy Considerations for Arm B 
Ibuprofen (up to 400 mg daily QD) can be administered with pemetrexed in patients with normal 
renal function (creatinine clearance [CrCl] >80 mL/min); caution should be used while 
administering ibuprofen concurrently with pemetrexed to patients with mild to moderate renal 
insufficiency (CrCl from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency 
should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the 
day of, and 2 days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with 
longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days 
before, the day of, and 2 days following pemetrexed administration. If concomitant 
administration of an NSAID is necessary, patients should be monitored closely for toxicity, 
especially myelosuppression, renal, and gastrointestinal toxicity. 
6.5.2. 
Palliative Medicine and Supportive Care for Arm A and Arm B 
Standard supportive medications may be used in accordance with institutional guidelines and 
investigator discretion. These may include: 

hematopoietic growth factors to treat neutropenia, anemia, or thrombocytopenia in
accordance with American Society for Clinical Oncology (ASCO) or European Society
for Medical Oncology (ESMO) guidelines.

red blood cells and platelet transfusions.

antiemetic, analgesic, and antidiarrheal medications.

electrolyte repletion (e.g., calcium and magnesium) to correct low electrolyte levels.
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
brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use is
considered SOC (e.g., as premedication for chemotherapeutic agents specified in the
protocol, contrast allergy, short courses to treat asthma, chronic obstructive pulmonary
disease). Replacement doses of steroids (e.g., prednisone 10 mg daily) are permitted
while on study.

thyroid replacement therapy for hypothyroidism.

bisphosphonates, denosumab, and other medications for the treatment of osteoporosis,
prevention of skeletal-related events from bone metastases, and/or hypoparathyroidism.
Continuation of medications that the patient has been on for the previous 28 days is allowed, 
provided they are not on the list of prohibited concomitant medications (refer to Appendix 5). 
Such therapy may include hormonal therapy for patients with prior:  

prostate cancer (e.g., gonadotropin-releasing hormone [GnRH] or luteinizing hormone-
releasing hormone [LHRH] agonists) or

breast cancer (e.g., GnRH/LHRH agonists, aromatase inhibitors, selective estrogen
receptor modulators, or degraders)
Local treatment while receiving study treatment (e.g., palliative radiation therapy or surgery for 
bone metastases) is permitted with sponsor approval. If the lesion that is to be treated is a target 
lesion, the lesion will be censored at the time of treatment. However, the patient may be eligible 
to remain on study drug treatment provided there are other lesions that can be followed up for 
progression. Additionally, the patient must not be considered to be clinically or radiographically 
progressing. Patients should have recovered from the acute effects of radiation or surgery prior to 
restarting treatment. For patients on Arm A, sponsor recommends holding selpercatinib for 
approximately 5 half-lives (approximately 7 days) before and after radiation therapy or surgery. 
Recent guidance has encouraged a re-evaluation of common eligibility criteria to make clinical 
trials more representative of real world populations and provide great accessibility to clinical 
trials, especially for rare populations (Kim et al. 2017; FDA 2019; Forde et al. 2020). As a result, 
the exclusion criterion for hepatitis B and C was updated with amendment b to allow patients 
who are positive for either HBsAg or Anti-HBc to be enrolled in certain circumstances as 
outlined in Criteria 17. It is recommended that patients who are positive for either HBsAg or 
Anti-HBc and have an HBV viral load below the limit of quantification have concurrent viral 
suppressive therapy. It is also recommended these patients undergo regular monitoring of 
HBsAg and HBV DNA and if HBV DNA becomes detectable, prophylactic anti-HBV treatment 
be initiated (if the patient is not currently on viral suppressive therapy). Concurrent viral 
suppressive therapy will be required for patients with detectable HBV DNA and regular 
monitoring of HBsAg and HBV DNA is recommended. 
6.6. 
Dose Modification Guidelines for Arm A and Arm B 
The following rules should guide dosing: 

Toxicity must resolve to Grade ≤1 or baseline prior to resuming the next cycle except
AEs with no immediate medical consequence that can be controlled with adequate
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treatment (e.g., pain, alopecia, neuropathy, fatigue, nausea, vomiting, diarrhea, Grade 2 
hypothyroidism, dry mouth, or Grade 2 hypertension). 

Reduction of only 1 chemotherapy drug is appropriate if in the opinion of the
investigator, the toxicity is clearly related to 1 drug. If the toxicity is deemed to be related
to more than 1 drug, then the dose of each drug should be reduced. If a dose reduction of
a chemotherapy drug is required, the dose may not be re-escalated. Patients on Arm A
who have been dose reduced and who tolerate selpercatinib without toxicity for at least 1
cycle may be re-escalated. Please see Section 6.6.1. and the IB for guidance on specific
AEs. If more than 2 dose reductions are required for any agent on Arm A or Arm B, that
drug should be discontinued. If the investigator deems it in the best interest of patients,
those on selpercatinib with clinical benefit who have had 2 dose reductions may be
allowed to continue treatment with additional reductions (e.g., recurrent AST or ALT
increase) with CRP/CRS approval.

If toxicity is clearly attributed to 1 chemotherapy drug, that drug alone may be
discontinued. If patients experience toxicity attributed to cisplatin or carboplatin, the
respective agent should be discontinued. Switching between platinum agents is permitted.
Patients treated with platinum-based and pemetrexed therapy with or without
pembrolizumab may have platinum and/or pemetrexed discontinued and continue
pembrolizumab alone. Similarly, pembrolizumab may be discontinued and chemotherapy
continued, if appropriate.
o
For patients in Arm A: Selpercatinib may be withheld for up to 28 days from the
last dose to allow time to recover from toxicity.
o
For patients in Arm B: Initiation of a dose of chemotherapy may be delayed for
a maximum of 21 days (42 days from prior dose) to allow a patient sufficient time
for recovery from study treatment-related toxicity (e.g., a delay of 21 days from
the planned Day 1 of the cycle). Pembrolizumab may be delayed for up to
12 weeks.
o
For patients in Arm A or Arm B: In exceptional circumstances, a longer delay
is permitted upon agreement between the investigator and the Lilly CRP/CRS.

Cycles are 21 days in duration regardless of dose interruption unless the dose interruption
includes D1 of the next cycle, in which case the next cycle will start with resumption of
study drug.
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Dose reductions should be made according to the following table. In addition, the dose 
can be delayed or adjusted at the investigator’s discretion as clinically indicated.  
Dose reduction for study interventions 
Arm A 
(selpercatinib) 
Arm B 
(Investigator’s discretion of carboplatin or cisplatin + pemetrexed ± 
pembrolizumab) 
Intervention 
Selpercatinib 
Carboplatin 
Cisplatin 
Pemetrexed 
Pembrolizumab 
(investigator’s 
choice) 
Dose Level 0 
(Starting Dose) 
160 mg BID 
AUC 5  
Max dose = 750 mg 
75 mg/m2 
500 mg/m2 
200 mg 
Dose Level -1 
120 mg BID 
AUC 3.75  
Max dose = 562.5 mg 
56 mg/m2 
375 mg/m2 
Not permitted 
Dose Level -2 
80 mg BID 
AUC 2.5  
Max dose = 375 mg 
38 mg/m2 
250 mg/m2 
Not permitted 
Dose Level -3 
40 mg BIDa 
Discontinue 
Discontinue 
Discontinue 
Not permitted 
Abbreviations: AE = adverse event; AUC = area under the concentration versus curve; BID = twice daily; 
LFT = liver function test; m = meter; mg = milligrams. 
a 
For some AEs (e.g., hypersensitivity reactions and LFT increases), an alternative re-escalation strategy should be 
followed. Additional information is provided in Section 6.6.1 of this protocol as well as Section 6 of the 
selpercatinib IB, Summary of Data and Guidance for the Investigator.  
6.6.1. 
Dose Modifications and Toxicity Management Guidelines for Arm A 
A patient who experiences a clinically significant AE may have selpercatinib dosing withheld to 
evaluate the AE and to allow for recovery (to Grade 1 or baseline level). Upon recovery, the 
patient may restart therapy if it is considered in his/her best interest to continue therapy. Upon 
restarting, the patient may have the dose reduced by at least 1 dose level. Please see Section 
8.2.1. for guidance on dose adjustments related to prolonged QTcF. 
Dose Modifications for Selpercatinib Hypersensitivity 
Please refer to the IB for the most current guidance on management of selpercatinib 
hypersensitivity reactions. Recommended actions are shown below. 
If selpercatinib drug hypersensitivity is suspected, study drug should be withheld and treatment 
with steroids at 1 mg/kg prednisone (or equivalent) should be initiated. Upon resolution, 
selpercatinib may be resumed at a reduced dose of 40 mg BID while continuing steroids at the 
same dose. Note that this dose reduction does not require sponsor approval. Hypersensitivity has 
recurred in some patients, typically at 3 to 6 hours following drug administration. Follow the 
guidelines below if hypersensitivity recurs:  
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
Discontinue selpercatinib for recurrent clinically significant hypersensitivity

After a minimum of 7 days and in the absence of clinically significant recurrent drug
hypersensitivity, the dose of selpercatinib may be escalated sequentially to 80 mg BID,
120 mg BID, and 160 mg BID. Once the patient has tolerated treatment for a minimum of
7 days at the final dose, steroids may be tapered slowly.
Dose Modifications for Selpercatinib Liver Function Test Abnormalities 
If a patient experiences ≥Grade 3 elevated liver function test (LFT) increases, study drug should 
be withheld and evaluation for potential alternative causes should be conducted (e.g., history of 
other hepatotoxic medications/substances, viral serologies, liver imaging). A repeat value 3 to 5 
days after the initial finding of elevation of LFTs should be obtained to confirm the abnormality 
and to confirm if it is increasing or decreasing. Thereafter, LFTs should be monitored at least 
weekly until resolution to normal/baseline (depending on the clinical situation, resolution to 
Grade 1 if baseline is acceptable but waiting until normalization is preferable). If the LFT 
abnormalities do not begin to resolve (or worsen) within 5 days of the AE, a hepatology 
consultation should be considered to evaluate the need for a liver biopsy. 
Upon resolution, for patients who received 160 mg BID or 120 mg BID, the selpercatinib dose 
should be reduced by 2 dose levels (80 mg BID or 40 mg BID, respectively) with weekly LFT 
monitoring. In the absence of recurrent LFT abnormalities, the dose of selpercatinib may be 
escalated sequentially to the next highest dose (120 mg BID or 80 mg BID, respectively) after a 
minimum of 2 weeks and again to the original dose and after a minimum of an additional cycle. 
Once the patient has been treated at a stable dose of selpercatinib for a minimum of 1 cycle 
without recurrent LFT abnormalities, the frequency of LFT monitoring may be decreased (e.g., 
midcycle for 2 cycles and then at the start of every cycle thereafter). For patients who experience 
≥Grade 3 elevated LFTs at 80 mg BID, the sponsor should be contacted for additional guidance 
regarding dose modification. If the patient experiences ≥Grade 3 elevated LFTs at a dose of 
40 mg BID, selpercatinib should be discontinued. Please refer to Section 8.2.2 for additional 
monitoring that may need to be initiated.  
Dose Modifications for Thrombocytopenia 
If a patient is discovered to have thrombocytopenia ≥Grade 3, study drug should be withheld and 
the patient should be evaluated for alternative causes (medications/substances, viral studies). A 
hematology consultation may be considered, as necessary, to understand the etiology and to 
consider a role for concomitant steroid therapy. The patient should undergo weekly complete 
blood count (CBC) testing until the event resolves and CBC level returns to normal/baseline. 
Upon recovery, the patient should resume selpercatinib with a dose reduction of at least 1 level 
with weekly CBC surveillance for 1 full cycle.  
Dose Modifications for Hypertension 
Hypertension is defined as: 

a sustained increase in blood pressure from baseline, as evidenced by ≥2 readings on ≥2
separate occasions, or

a clinically significant elevation requiring acute treatment.
If hypertension occurs, study drug may be interrupted at the discretion of the investigator while: 
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
a new antihypertensive medication regimen is initiated, or

a preexisting regimen is optimized to a reproducible reading of ≤140/90 mmHg.
If study drug is interrupted, it may be resumed at the same or a lower dose at the discretion of the 
investigator. In all cases, the patient should continue to undergo regular blood pressure 
monitoring to ensure adequate blood pressure control. Dose re-escalation to the patient’s original 
dose can be considered once adequate BP control has been obtained; with clinically appropriate 
monitoring.  
Dose Modification for Selpercatinib Interstitial Lung Disease/Pneumonitis 
For Grade 2, withhold selpercatinib until resolution. Resume at next lower dose. Discontinue 
selpercatinib for recurrent ILD/pneumonitis. 
For Grade 3 or 4, discontinue selpercatinib. 
6.6.2. 
Dose Modification and Toxicity Management Guidelines for Arm B 
6.6.2.1.
Dose Modification for Chemotherapy 
Please refer to the product label for the current dose modification and toxicity management 
guidelines for carboplatin, cisplatin, and pemetrexed. If a dose reduction for toxicity occurs with 
any agent, the dose may not be re-escalated. The following information provides 
recommendations for dose adjustments. These serve as a guide and do not replace investigator 
judgment and applicable local label recommendations if more stringent. 
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Recommended Dose Modifications for Chemotherapy: Hematological Toxicity 
Platelets 
ANC 
Pemetrexed 
Cisplatin/Carboplatin 
Dose Level (DL) from the Dose reduction for 
study interventions table 
≥50x 109/L AND 
≥0.5 x 109/L 
DL 0 
DL 0 
≥50 x 109/L AND 
<0.5 x 109/L 
DL -1 
DL -1 
<50 x 109/L without 
bleeding AND 
ANY 
DL -1 
DL -1 
<50 x 109/L with 
Grade ≥2 bleeding 
AND 
ANY 
DL -2 
DL -2 
ANY AND 
neutropenic fever 
DL -1 
DL -1 
Recommended Dose Modifications for Chemotherapy: Nonhematological Toxicity 
Event 
CTCAE 
Grade 
Pemetrexed 
Cisplatin 
Carboplatin 
Dose Level (DL) from the Dose reduction for study 
interventions table 
Nausea or vomitinga 
Grade 3 or 4 
DL 0 
DL 0 
DL 0 
Diarrhea 
Grade 3 or 4 
DL -1 
DL -1 
DL 0 
Mucositis 
Grade 3 or 4 
DL -2 
DL 0 
DL 0 
Neurotoxicity 
Grade 2 
DL 0 
DL -2 
DL 0 
Grade 3 or 4 
DL -1 
Discontinue 
DL -1 
Transaminase elevation 
Grade 3 
DL -1 
DL -1 
DL -1 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other nonhematological 
toxicityb 
Grade 3 or 4 
DL -1 
DL -1 
DL -1 
Abbreviations: CTCAE = Common Terminology Criteria in Adverse Events. 
a 
Despite maximal treatment. 
b 
Of medical consequence that cannot be controlled with treatment. 
For patients who develop a clinically significant pleural or peritoneal effusions (on the basis of 
symptoms or clinical examination) during initiation of pemetrexed therapy, consideration should 
be given to draining the effusion prior to dosing. However, if, in the investigator’s opinion, the 
effusion represents progression of disease, the patient should be discontinued from study therapy. 
No dosage adjustment is needed in patients with CrCl >45 mL/min. Insufficient numbers of 
patients have been studied with CrCl <45 mL/min to give a dose recommendation. Therefore, 
pemetrexed/platinum should not be administered to patients whose CrCl is <45 mL/min. 
6.6.2.2.
Dose Modification for Pembrolizumab 
An immune-related adverse event (irAE) may be defined as an AE consistent with an 
immune-mediated chronic inflammatory reaction associated with drug exposure. These irAEs 
may occur shortly after the first dose or several months after the last dose of drug and may affect 
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more than 1 body system simultaneously. Therefore, early recognition and initiation of treatment 
are critical to reduce complications. Based on existing clinical study data, most irAEs are 
reversible and can be managed with interruptions of therapy, administration of corticosteroids, 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, and skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue therapy and administer corticosteroids. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks. Dose modification and toxicity management guidelines for potential 
irAEs are provided in the following table. 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. 
Institutional guidelines and applicable local recommendations should be followed for the 
management of pembrolizumab infusion reactions.  
Please refer to the product label, ESMO guidelines (Haanen et al. 2017), ASCO guidelines 
(Brahmer et al. 2018), and local guidance for the current dose modification and toxicity 
management guidelines for pembrolizumab. The following information provides 
recommendations for dose adjustments. They serve as a guide and do not replace investigator 
judgment and applicable local label recommendations if more stringent.  
Immune-Related Adverse 
Reactions 
Severity 
Treatment Modification 
Pneumonitis 
Grade 2 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade 3 or 4, or recurrent Grade 2 
Permanently discontinue. 
Colitis 
Grade 2 or 3 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade 4 or recurrent Grade 3 
Permanently discontinue. 
Nephritis 
Grade 2 with creatinine >1.5 to ≤3 
times upper limit of normal (ULN) 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade ≥3 with creatinine >3 times 
ULN 
Permanently discontinue. 
Endocrinopathies 
Symptomatic hypophysitis 
Type 1 diabetes associated with Grade ≥3 
hyperglycemia (glucose >250 mg/dL or 
>13.9 mmol/L) or associated with
ketoacidosis hyperthyroidism Grade ≥3 
Withhold until adverse reactions 
recover to Grades 0 to 1.a For 
patients with Grade 3 or 4 
endocrinopathy that improved to 
Grade 2 or lower and is controlled 
with hormone replacement, if 
indicated, continuation of 
pembrolizumab may be considered 
after corticosteroid taper, if 
needed. Otherwise treatment 
should be discontinued. 
Hypothyroidism may be 
managed with replacement 
therapy without treatment 
interruption. 
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Immune-Related Adverse 
Reactions 
Severity 
Treatment Modification 
Hepatitis 
Grade 2 with aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) 
>3 to 5 times ULN or total bilirubin >1.5
to 3 times ULN 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade ≥3 with AST or ALT >5 times 
ULN or total bilirubin >3 times ULN 
Permanently discontinue. 
In case of liver metastasis with baseline 
Grade 2 elevation of AST or ALT, 
hepatitis with AST or ALT increases 
≥50% and lasts ≥1 week 
Permanently discontinue. 
Skin reactions 
Grade 3 or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade 4 or confirmed SJS or TEN 
Permanently discontinue. 
Other immune-related adverse 
reactions 
Based on severity and type of reaction 
(Grade 2 or Grade 3) 
Withhold until adverse reactions 
recover to Grades 0 to 1.a 
Grade 3 or 4 myocarditis 
Grade 3 or 4 encephalitis 
Grade 3 or 4 Guillain-Barré syndrome 
Permanently discontinue. 
Grade 4 or recurrent Grade 3 
Permanently discontinue. 
Infusion-related reactions 
Grade 3 or 4 
Permanently discontinue. 
a If treatment-related toxicity does not resolve to Grade 0 to 1 within 12 weeks after the last dose of 
pembrolizumab, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day 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 the table above or as outlined per local guidelines and 
regulations.  
6.7. 
Intervention after the End of the Study 
The end of study is defined in Section 4.4. Investigators will continue to follow the SoA 
provided in Section 1.3 until notified by Lilly that the end of the study has occurred. 
6.7.1. 
Treatment after Study Completion
Study completion occurs after the clinical trial database is locked and final analysis of primary 
and secondary endpoints has been performed. Investigators will continue to follow SoA (Section 
1.3) for all patients until notified by Lilly that study completion has occurred. 
6.7.2. 
Continued Access
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention if they are experiencing clinical benefit and no undue risks. 
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The continued access period will apply to this study only if at least 1 participant is still on study 
treatment when study completion occurs. Lilly will notify investigators when the continued 
access period begins. 
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol. 
The participant’s continued access to study intervention will end when a criterion for 
discontinuation is met (Section 7). Continued access follow-up will begin when the participant 
and the investigator agree to discontinue study intervention and lasts approximately 30 days. 
Follow-up procedures will be performed as shown in the Continued Access SoA. 
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the 30-day short-term follow-up visit is completed. 
Crossover and long-term follow-up do not apply. 
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up. 
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent. 
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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
7.1. 
Discontinuation of Study Intervention 
Possible reasons leading to permanent discontinuation of investigational product: 

The participant or the participant’s designee, e.g., legal guardian requests to discontinue
investigational product.

A clinically significant finding is identified (e.g., a change from baseline in QT interval
or LFT abnormality) after enrollment. In such cases, the investigator or qualified
designee will determine if the participant can continue in the study and if any change in
participant management is warranted.
In addition, participants will be discontinued from using the investigational product under the 
following circumstances: 

The patient becomes pregnant during the study

The patient is significantly noncompliant with study procedures and/or treatment

Disease progression (radiographic or clinical progression). Exceptions for continuing
study treatment beyond BICR-confirmed radiographic progression may be made on a
case-by-case basis for patients who are believed to be clinically benefiting from study
treatment, and the investigator and Lilly CRP/CRS agree that continuing study treatment
is in the patient’s best interest

Unacceptable toxicity

The patient, for any reason, requires treatment from another therapeutic agent that has
been demonstrated to be effective for treatment of the study indication (except as noted in
Section 6.5.2). Discontinuation from study treatment will occur prior to introduction of
the new agent. If medically appropriate, the short-term follow-up procedures should also
be completed prior to introduction of the new agent (even if the interval is less than
30 days from the last dose of study treatment)

The investigator decides that the patient should be discontinued from study intervention
Participants discontinuing from using the investigational product for any reason should complete 
AE per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and Serious Adverse 
Events), and Section 8.2 (Safety Assessments) of the protocol. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Participants will be discontinued under the following circumstances: 

Participation in the study needs to be stopped for medical, safety, regulatory,
or other reasons consistent with applicable laws, regulations, and good clinical
practice (GCP)

Patient’s decision
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o
The patient or the patient’s designee requests to be withdrawn from the
study
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments) of the protocol. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Patients 
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from using the study treatment 
unless there are extenuating circumstances that make it medically necessary for the patient to 
continue on study treatment.  
If the investigator and the sponsor CRP/CRS agree it is medically appropriate to continue, the 
investigator must obtain documented approval from the sponsor CRP/CRS to allow the 
inadvertently enrolled participant to continue in the study with or without treatment with 
investigational product.  
Safety follow-up is as outlined in Section 1.3 (Schedule of Activities), Section 8.3 (Adverse 
Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) of the protocol. 
For sites located in the United Kingdom (UK) and Germany, refer to Appendix 6 for country-
specific discontinuation guidelines. 
7.3. 
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. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
Discontinuation of specific sites or of the study as a whole is described in Section 10.1.8.2. 
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8.
Study Assessments and Procedures
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results. Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards: 

Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon
occurrence or awareness to determine if the participant should continue or discontinue
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is
essential and required for study conduct.

All screening evaluations must be completed and reviewed by the appropriate site
personnel 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.

Procedures conducted as part of the participant’s routine clinical management (e.g., blood
count, scans, RET testing) and obtained before signing of the ICF may be utilized for
screening or baseline purposes, provided the procedures met the protocol-specified
criteria and were performed within the time frame defined in the SoA.
8.1. 
Efficacy Assessments 
8.1.1. 
Imaging 
To evaluate PFS, tumor assessments will be performed for each patient at the times shown in the 
SoA (Section 1.3) or whenever clinically indicated. Radiologic assessments obtained previously 
as part of routine clinical care and obtained prior to consent may be used as baseline assessment, 
provided they are of diagnostic quality and were done no more than 28 days before the first dose 
of study drug. 
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT. Intravenous and oral contrast is 
strongly recommended unless not feasible/medically contraindicated. 
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast). A PET scan alone or as part of a PET-CT 
may be performed for additional analyses but cannot be used to assess response according to 
RECIST 1.1 (Eisenhauer et al. 2009). 
The method of tumor assessment used at baseline must be used consistently throughout the 
study. Radiologic scan of the thorax, abdomen, and pelvis is required, as well as any other areas 
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with suspected disease involvement. A baseline intracranial evaluation with CT or MRI is 
required for all patients. A bone scintigraphy (preferred) or PET scan or PET component of 
PET/CT scan should be obtained for patients with known nonmeasurable bone lesions. Note that 
RECIST 1.1 emphasizes bone scintigraphy is not adequate to measure bone lesions; however, 
bone scintigraphy can be used to confirm the presence or disappearance of bone lesions. Please 
see the Site Imaging Manual for guidelines on how the various imaging studies should be 
performed and transmitted for central review. It is recommended to confirm presence of 
malignant cells before determining progressive disease on imaging alone. Some patients 
receiving selpercatinib have been reported to have effusions and/or ascites which have 
subsequently been found to be chylous in nature (See Section 8.2.2.2 and IB for additional 
details). 
Progression-free survival after next line of treatment (PFS2) will also be assessed. For patients 
who cross over to selpercatinib, tumor assessments will be performed for each patient at the 
times shown in the SoA (Section 1.3, Optional Crossover Treatment). For patients who do not 
cross over to selpercatinib, it is recommended that, to the extent it is feasible, the scan interval of 
approximately every 6 weeks for the first 2 assessments and then every 9 weeks for the next 
48 weeks and then every 12 weeks thereafter is maintained during the subsequent line of therapy 
to adequately characterize PFS2. 
8.1.2. 
BICR Assessment 
Response assessments, including verification of partial response (PR) or complete response (CR) 
and disease progression, will be assessed by the BICR. These data will constitute the primary 
assessment for PFS and ORR analyses. The BICR will conduct 2 assessments of tumor response 
using RECIST 1.1: 1 for the overall systemic disease (based on target/nontarget and new lesions) 
and 1 solely for the evaluation of CNS endpoints (based on brain metastases only). The BICR 
will also conduct 1 assessment using RANO-BM (Lin et al. 2015) for the evaluation of CNS-
related endpoints. 
Following each scan in the main study, the investigator will assess for progression using 
RECIST 1.1 and submit the scan for BICR review as outlined in Section 1.3. It is anticipated that 
the BICR assessment to confirm progression will be completed prior to the next scheduled scan. 
In the rare cases where this is not the case, the patient should continue on the scan schedule until 
the BICR assessment is provided to the site. The following table outlines the potential actions 
following BICR review. 
Investigator assessment 
BICR assessment 
Actions 
Progressive Diseasea 
Progression verified 
Discontinue study treatment OR
Continue therapy with sponsor approval and
signing of post-progression consent if the
patient is believed to be clinically benefiting
OR
Crossover (only patients progressing on
Arm B are eligible for crossover) OR
Continue treatment per iRECIST (only for
patients in Arm B receiving pembrolizumab)
Progression not verified 
Continue on study treatment if the patient is
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Investigator assessment 
BICR assessment 
Actions 
believed to be clinically benefiting (sponsor 
approval is not necessary) until a criterion for 
discontinuation is met OR 
Discontinue study treatment; imaging should
continue until (1) radiographic disease is
verified by the BICR, (2) the start of a new
anticancer therapy, (3) death, (4) withdrawal
of consent, or (5) study completion. Note that
these patients would be eligible to cross over
upon BICR documentation of progression.
Nonprogression 
In the case of investigator-
assessed nonprogression, results 
are not reported back to 
investigator as BICR 
assessment is only used for 
endpoint assessment 
Continue on study treatment until progressive
disease or another criterion for
discontinuation is met
Abbreviations: BICR = blinded independent central review; iRECIST = immune Response Evaluation Criteria in 
Solid Tumors; PD = progressive disease. 
a 
For patients where the investigator assessment is PD, it is at the discretion of the investigator if treatment is 
continued until the BICR assessment is received. 
In the crossover period, scans will be collected and stored for future review, if needed. However, 
the BICR does not provide progression confirmation in the crossover period and progression is 
determined solely on investigator assessment. 
For patients in Arm B who are receiving pembrolizumab, treatment decisions should be made 
using investigator-assessed immune Response Evaluation Criteria in Solid Tumors (iRECIST) 
(RECIST 1.1 for Immune-based Therapeutics; Seymour et al. 2017). For patients who have 
initial evidence of radiological progressive disease (PD) using RECIST 1.1 (i.e., unconfirmed PD 
by iRECIST), it is at the discretion of the investigator whether to continue a patient on study 
treatment until repeat imaging is obtained (using iRECIST for patient management). Study 
treatment may continue until criteria for confirmed PD are met (Seymour et al. 2017).  
8.2. 
Safety Assessments 
8.2.1. 
Electrocardiograms 
Electrocardiogram monitoring should be performed as outlined in the SoA (Section 1.3). QTcF 
values should be recorded on the case report form (CRF). The following actions should be taken 
if the QTcF is greater than 500 msec on at least 2 of 3 ECGs and the triplicate average QTcF is 
greater than 500 msec or >60 msec longer than baseline: 

Manually review to confirm accuracy. Electrocardiograms will be interpreted by a
qualified physician (the investigator or qualified designee) at the site for immediate
patient management.
Assess for alternative causes (concomitant medications, electrolyte abnormalities,
presence of pacemaker). Potassium should be ≥4 mEq/L and less than upper limit of
normal (ULN) and magnesium and calcium should be within normal limits. If a potential
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alternative cause is identified, the sponsor should be consulted for dose reduction 
guidance. 
Institutional guidelines or SOC measures for management of QTcF interval >500 msec
and/or associated arrhythmias should be initiated.
Clinical chemistry should be assessed and if electrolytes are abnormal, they should be
repleted as indicated.
If the patient is on Arm A, selpercatinib should be reduced at least 1 dose level.
If the patient is on Arm B, dose adjustments should occur per label/institutional
guidelines.
If a patient experiences QTcF >500 msec as defined earlier despite 2 dose reductions and if the 
investigator deems it in the best interest of the patient, he/she may continue treatment with study 
drug with CRP/CRS approval. In addition, Lilly may request copies of the ECGs for 
adjudication). 
8.2.2. 
Clinical Safety Laboratory Assessments 

Blood will be collected so that Lilly may analyze safety laboratory values using a central
vendor. Lilly or its designee will provide the investigator with the results of safety
laboratory tests analyzed by a central vendor.
o
See Appendix 2 for the list of clinical laboratory tests to be performed and Section 1.3
(SoA) for the timing and frequency.
o
The investigator should review any clinically significant abnormal laboratory
findings, and assess relevance to patient care. If the laboratory findings are clinically
significant, the investigator should document the findings as an AE in the CRF (if not
previously documented using local laboratories). The laboratory reports must be filed
with the source documents. Clinically significant abnormal laboratory findings are
based on investigator’s judgment.

In addition, investigator sites may use local laboratories to determine patient eligibility
and treatment decisions.

Regardless of whether or not central or local laboratory tests are used to determine patient
care decisions, all laboratory tests with values considered clinically significantly
abnormal during participation in the study or until completion of V801 should be
repeated until the values return to normal or baseline or are no longer considered
clinically significant by the investigator.
o
If such values do not return to normal/baseline within a period of time judged
reasonable by the investigator, the etiology should be identified and the sponsor
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be
conducted in accordance with the laboratory manual and the SoA.
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8.2.2.1.
Hepatic Safety Monitoring 
In Study Participants with Baseline ALT/AST <1.5X ULN 
If a study participant enrolled with baseline ALT/AST <1.5X ULN experiences elevated 
ALT/AST ≥3X ULN and elevated total bilirubin (TBL) ≥2X ULN, or ALT/AST≥5X ULN, liver 
testing (Appendix 4) including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase, 
and creatine kinase should be repeated within 3 to 5 days to confirm the abnormality and to 
determine if it is increasing or decreasing. If the abnormality persists or worsens, clinical and 
laboratory monitoring and evaluation for possible causes of abnormal liver tests should be 
initiated by the investigator in consultation with the study CRP/CRS. Monitoring of ALT, AST, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
In Study Participants with Baseline ALT/AST ≥1.5X ULN 
If a study participant enrolled with baseline ALT/AST ≥1.5X ULN experiences elevated 
ALT/AST≥ 3X baseline or ALT/AST ≥2X baseline and TBL ≥2X ULN, liver testing (Appendix 
4) including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase
should be repeated within 3 to 5 days to confirm the abnormality and to determine if it is
increasing or decreasing. If the abnormality persists or worsens, clinical and laboratory
monitoring and evaluation for possible causes of abnormal liver tests should be initiated by the
investigator in consultation with the study CRP/CRS. Monitoring of ALT, AST, and TBL should
continue until levels normalize or return to approximate baseline levels.
8.2.2.1.1. 
Special Hepatic Safety Data Collection 
Hepatic data (Appendix 4) should be collected in the event that 1 (or more) of the following 
conditions is met for the patient during the course of the study:  

Patients enrolled with baseline ALT/AST <1.5X ULN:
a.
elevated ALT/AST ≥3X ULN and elevated TBL ≥2X ULN
b. ALT/AST ≥5X ULN on 2 consecutive tests

Patients enrolled with baseline ALT/AST ≥1.5X ULN (regardless of whether or not
they have hepatic metastasis):
a.
elevated ALT/AST ≥2X baseline and elevated TBL ≥2X ULN
b. elevated ALT/AST ≥3X baseline on 2 consecutive tests

All patients:
a.
discontinuation from study treatment due to a hepatic event or
abnormality of liver tests
b. occurrence of a hepatic event considered to be an SAE
8.2.2.2.
Chylothorax and Chylous Ascites Monitoring 
If a patient develops a pleural effusion or abdominal ascites or both while on selpercatinib, fluid 
sampling and testing should be considered as part of the management algorithm whenever 
possible. The etiology of this finding varies and distinguishing chylous fluid from malignant (as 
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well as other causes such as infectious) may impact management significantly (for example, 
presumption of disease progression with premature discontinuation of therapy). Additionally, a 
diagnosis of chylous effusions or ascites or both may indicate a role for conservative measures 
such as fluid replacement, dietary alteration or medical therapy or both (for example, 
somatostatin analogue) prior to consideration of more invasive measures. Selpercatinib 
interruption and dose modification should follow the general strategy as outlined in Section 6.6 
(Dose Modification), based upon severity and causality of the event. 
8.2.2.3.
Renal Safety Monitoring 
In vitro, selpercatinib is an inhibitor of the drug transporter MATE1 and may reduce the 
clearance of MATE1 substrates (for example, creatinine). Selpercatinib may increase serum 
creatinine due to inhibition of the renal tubular secretion transporter MATE1, without affecting 
glomerular function. Complementary markers such as blood urea nitrogen (BUN), cystatin C, or 
calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered 
to determine whether renal function is impaired 
8.2.2.4.
Thyroid Function Monitoring 
Hypothyroidism was reported in patients receiving selpercatinib in clinical trials. Monitor 
patients for hypothyroidism and treat as medically appropriate. Baseline laboratory measurement 
of thyroid function is recommended in all patients. Patients with preexisting hypothyroidism 
should be treated as per standard medical practice prior to the start of selpercatinib treatment. All 
patients should be observed closely for signs and symptoms of thyroid dysfunction during 
selpercatinib treatment. Thyroid function should be monitored periodically throughout treatment 
with selpercatinib. Patients who develop thyroid dysfunction should be treated as per standard 
medical practice. However, patients could have an insufficient response to substitution with 
levothyroxine (T4), as selpercatinib may inhibit the conversion of levothyroxine to liothyronine 
(T3) and supplementation with liothyronine may be needed. 
8.3. 
Adverse Events and Serious Adverse Events 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant. The investigator is responsible for 
the appropriate medical care of participants during the study.  
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study. The participant should be followed up until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise explained. The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator. Lack of drug effect is 
not an AE in clinical studies, because the purpose of the clinical study is to establish treatment 
effect. 
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
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the disease under treatment in the study. In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. The investigator should provide AE verbatim terms 
and then the terms will be mapped by Lilly or its designee to corresponding terminology within 
the Medical Directory for Regulatory Activities lower level term dictionary. The investigator 
will use CTCAE v5.0 to assign AE severity grades.  
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure or investigational product, via CRF. The investigator will interpret and document 
whether or not an AE has a reasonable possibility of being related to study treatment, or a study 
procedure, taking into account the disease, concomitant treatment, or pathologies. A “reasonable 
possibility” means that there is a cause and effect relationship between the investigational 
product, and/or study procedure and the AE. The investigator answers yes/no when making this 
assessment. 
Disease progression of the primary tumor in and of itself is captured as an efficacy assessment 
and should not be captured as an AE (including fatal AEs) unless the disease progression is 
assessed as related to study treatment. If a new primary malignancy appears, it will also be 
considered an AE. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment.  
Adverse events 

An AE is any untoward medical occurrence in a participant administered a pharmaceutical
product and which does not necessarily have a causal relationship with the study
intervention. An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of a medicinal (investigational) product, or investigational
combination product, whether or not related to the medicinal (investigational) product or
investigational combination product.

An AE is any untoward medical occurrence, unintended disease or injury, or untoward
clinical signs (including abnormal laboratory finding) in study participants, users, or
other persons, whether or not related to the investigational device.
Events meeting the AE definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments, for example, ECG, radiological scans, and vital signs
measurements, including those that worsen from baseline, considered clinically
significant in the medical and scientific judgment of the investigator, that is, not related to
progression of underlying disease.

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
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
New condition detected or diagnosed after study intervention administration even though
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical
sequelae.

Lack of efficacy or failure of expected pharmacological action per se will not be reported
as an AE or SAE. Such instances will be captured in the efficacy assessments. However,
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be
reported as AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT meeting the AE definition 

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, for example, endoscopy, appendectomy. The condition
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the start of the study that do not worsen.
Serious Adverse Events 
An SAE is any AE from this study that results in 1 of the following outcomes: 

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in
death or hospitalization but may jeopardize the participant or may require
intervention to prevent 1 of the other outcomes listed in the definition above.
Examples of such medical events include allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the development of
drug dependency or drug abuse
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria. 
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received investigational product. However, if an SAE occurs after signing the ICF, but prior to 
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receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 8.3.1) if it is considered reasonably possibly 
related to study procedure. 
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms. This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE
information. Participants with a serious hepatic AE should have additional data collected using
the CRF (see Section 8.2.2).
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE. However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure. 
United States 21 Code of Federal Regulations (CFR) 312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received study drug. 
However, if an SAE occurs after signing the ICF, but prior to receiving study treatment, it needs 
to be reported ONLY if it is considered reasonably possibly related to study procedures.  
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE CRF, not the Medical History CRF. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of investigator awareness. The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available. Serious adverse 
events, including death, caused by disease progression should not be reported unless the 
investigator deems them to be possibly related to study treatment. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.3.2. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed up until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 1.3).  
8.3.3. 
Regulatory Reporting Requirements for SAEs 

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical
investigation. The sponsor will evaluate the reported SAEs, including confirmation of
relatedness and assessment of expectedness. The sponsor has processes for safety reports
for identification, recording, and expedited reporting of SUSARs according to local
regulatory requirements. The sponsor will comply with country-specific regulatory
requirements relating to safety reporting to the regulatory authority, Institutional Review
Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

An investigator who receives an investigator safety report describing a SAE or other
specific safety information (e.g., summary or listing of SAEs) from the sponsor will
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC,
if appropriate according to local requirements.
8.3.4. 
Pregnancy 

Details of all pregnancies in female participants and, if indicated, female partners of male
participants will be collected after the start of study intervention and until the completion
of V801 or 120 days following the last dose of pembrolizumab.

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 3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs.

Additional requirements for pregnancy testing during and after study intervention are
located in Appendix 3.

The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
8.3.5. 
Cardiovascular and Death Events 
No additional reporting is required. 
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8.3.6. 
Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
8.4. 
Treatment of Overdose 
Refer to the IB and/or product label for selpercatinib, cisplatin, carboplatin, pemetrexed, and 
pembrolizumab for available information on the signs, symptoms, and treatment of overdose. 
8.5. 
Pharmacokinetics 
At the visits and times specified in the SoA (Section 1.3), blood samples of approximately 2 mL 
each will be collected to determine the plasma concentrations of selpercatinib in Arm A only.  
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor. Instructions for the 
collection and handling of blood samples will be provided by the sponsor. The actual date and 
time (24-hour clock time) of each sampling and prior dose will be recorded. 
Blood for PK assessment will be collected on C1D8, and at the first day of each consecutive 
cycle up to Cycle 6. Samples are to be drawn within 2 hours prior to dose, and exact time of 
sample collection should be recorded. In addition, time of previous dose should be recorded. 
Additional PK may also be assessed in patients when considered necessary by the investigator to 
understand exposure in relationship to possible safety.  
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 2 years following last 
participant visit for the study. During this time, samples remaining after the bioanalyses may be 
used for exploratory analyses, such as metabolism, transport and/or protein binding work.  
8.6. 
Pharmacodynamics 
Not applicable 
8.7. 
Genetics 
8.7.1. 
Whole Blood Sample for Pharmacogenetic Research 
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples may be used to investigate variable response to selpercatinib, to 
investigate genetic variants thought to play a role in NSCLC and to determine whether genetic 
alterations identified in tumor samples are somatic or germline variants. Assessment of variable 
response may include evaluation of AEs or differences in efficacy. 
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All samples will be coded with the patient number. These samples and any data generated can be 
linked back to the patient only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ethical review boards 
(ERBs)/IRBs impose shorter time limits. This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of selpercatinib or after selpercatinib becomes commercially 
available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome and exome 
sequencing, genome-wide association studies, and candidate gene studies. Regardless of 
technology utilized, data generated will be used only for the specific research scope described in 
this section. 
8.8. 
Biomarkers 
8.8.1. 
Samples for Retrospective Evaluation of RET Status 
If available, an unstained, archived tumor tissue sample in a sufficient quantity to allow for 
retrospective central analysis of RET fusion status should be provided as outlined in the Schedule 
of Activities: 
a) Tumor samples must be formalin fixed and paraffin embedded (FFPE). Blocks should be
provided wherever possible, but unstained slides are also permitted. Acceptable sample
collection methods include, but are not limited to, surgical resection (preferred), core
biopsy, endobronchial ultrasound bronchoscopy procedure (EBUS), or FFPE fine needle
aspiration (FNA). Cell blocks or cytology samples in FFPE are acceptable. Biopsy
samples taken from bone metastasis are unsuitable for testing and are not acceptable.
Samples may be collected from primary or metastatic tumor sites.
b) The investigator site will be asked to provide at least 1 of the following, if available:
a.
FFPE tumor tissue blocks, or
b. Preferably, at least 11 unstained FFPE slides. However, it is strongly
recommended that 20 FFPE slides be submitted. Preferably, each section should
be approximately 5 µm thick.
If it is considered safe to perform, patients who do not have sufficient available tumor tissue may 
undergo a fresh tumor biopsy/FNA.  
Patients must have RET gene fusion as outlined in Section 5.1. For all patients, a redacted 
molecular pathology report or other report(s) describing tumor RET (and other) fusion analysis 
should be submitted to the sponsor, designee, and central laboratory to confirm trial eligibility. In 
regions or sites where RET testing is not SOC and/or an acceptable local test (as defined by 
Lilly) is not available, a prescreening consent will be used to provide information to the patient 
regarding testing to determine tumor RET status. The results of the initial or retrospective 
evaluation will include other genes. These genes include, but are not limited to, EGFR, ALK, 
ROS1, KRAS, BRAF, HER2, MET, NTRK1, NTRK2, or NTRK3. 
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8.8.2. 
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, resistance mechanisms, variability of 
participant response (including safety), and clinical outcome. Sample collection is incorporated 
into clinical studies to enable examination of these questions through measurement of 
biomolecules including but not limited to deoxyribonucleic acid (DNA), cell free DNA, RNA, 
proteins, lipids, and other cellular elements. 
Blood and tissue samples for biomarker research will be collected at the times specified in the 
SoA (Section 1.3) where local regulations allow. Whole blood will be collected to compare RET 
fusion status in tumor and cfDNA samples. It is possible that biomarker data for patients in the 
study have already been generated from samples that were collected and analyzed prior to 
enrolling in this study. This may include pathology reports and data generated from genetic 
analyses. If available, these data may be requested from medical records for use in the research 
described in Sections 8.7 and 8.8.  
Samples will be used for research on the drug target, disease process, variable response to 
selpercatinib, pathways associated with NSCLC and the mechanism of action of selpercatinib. 
These samples may also be used to develop related research methods or to validate diagnostic 
tools or assays.  
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
An optional tissue biopsy may be collected at the time of progression (either on initial therapy 
and/or crossover) if it can be safely performed. 
Lilly has a right to retain a portion of the submitted tissue. Archival blocks will be sectioned and 
returned to the study site. Slides and tissue samples collected on-study will not be returned. For 
biopsies performed in the setting of disease progression, the sponsor should be contacted to 
inform them of the planned biopsy.  
Samples will be retained at a facility selected by Lilly for a maximum 15 years after the last 
participant visit for the study, or for a shorter period if local regulations and IRB/ERBs impose 
shorter time limits. This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of selpercatinib or after selpercatinib becomes commercially available. 
Technologies are expected to improve during the 15-year storage period and, therefore, cannot 
be specifically named. Existing approaches, including mutation profiling, copy number 
variability analysis, gene expression assays, multiplex assays, whole genome sequencing, whole 
exome sequencing, RNA sequencing, and/or immunohistochemistry may be performed on these 
tissue samples to assess potential associations between these biomarkers and clinical outcomes. 
8.9. 
Medical Resource Utilization and Health Economics 
8.9.1. 
Patient-Reported Outcomes and Health Care Resource Utilization 
Patient-reported questionnaires will be administered electronically according to the SoA 
(Section 1.3) in countries where the questionnaires have been translated into the native language 
of the region and linguistically validated. Patients that are illiterate or have religious restrictions 
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are not required to complete the questionnaires. The patient-reported outcomes will be used to 
compare pulmonary symptoms (NSCLC-Symptom Assessment Questionnaire [SAQ]) between 
treatment arms.  
While individual patients may vary in their response time, it is estimated that 20 items (similar to 
this study) can be completed in an average of less than 4 minutes using an electronic device. Two 
recent publications have evaluated survey completion times. Of note, the number of items in this 
study are significantly lower than those studied. In this study, 67 items were completed in an 
average of 15 minutes, and 100% of patients reported the completion time as “about right” and 
79% were willing to answer more questions (Girgis et al. 2017). The current study will apply 
much fewer items than investigated in these studies.  
NSCLC-SAQ 
This instrument measures overall severity of cough, pain, dyspnea, fatigue, and appetite 
(McCarrier et al. 2016). An electronic-based delivery method will be used in this study. The 
7-day recall period requires weekly assessment by the patient via the provided device. Sites will
not administer this instrument.
PRO-CTCAE 
These items have been developed to assess select symptomatic AEs from the patient perspective 
associated with cancer therapy, to complement the CTCAE data collected at the site level (Basch 
et al. 2014; Bennet et al. 2016). 
The reported outcome-CTCAE will be administered electronically directly to the patient via the 
electronic device provided on a weekly basis. Sites will not administer this instrument. 
FACT-GP5 
This is a single item from the Functional Assessment of Cancer Therapy-Side Effects general 
scale to assess the overall burden of the items reported via the PRO-CTCAE. This item will be 
administered electronically directly to the patient via the electronic device provided on a weekly 
basis. Sites will not administer this instrument. 
EORTC QLQ-C30 and EORTC IL19 
Health-related quality of life will be assessed using the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30; 
Aaronson et al. 1993). 
The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covered by 1 
of 3 dimensions: 

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, cognitive, or
social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea,
insomnia, appetite loss, constipation, diarrhea, or financial impact)
Electronic versions of the questionnaires will be used and will be available to the patient on the 
provided electronic device. The full scale will be completed electronically on Day 1 of each 
cycle at the clinic site prior to receiving study treatment.  
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Note: The EORTC QLQ-C30 Physical Functioning score (items 1-5) will also be completed 
weekly by the patient using the device provided (not at the clinic site). In these instances, the 
physical functioning scale is referred to as the EORTC IL19 in order to comply with copyright 
requirements.  
EQ-5D-5L 
Health status will be assessed using the EuroQol Five Dimension Five Level questionnaire (EQ-
5D-5L) (Janssen et al. 2008). These utility measures are an important input for economic 
evaluations concerning the value of treatment interventions. Patients will complete the 5-
dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), 5-level 
(no problem, slight, moderate, severe, or extreme problem) assessment according to the SoA. A 
unique EQ-5D health state is defined by combining 1 level from each of the 5 dimensions. 
Additionally, patients will indicate their current health status by marking on a visual analog scale 
ranging from 100 (best imaginable health state) to 0 (worst imaginable health state). The recall 
period is “today”. The EQ-5D-5L is designed for self-completion by respondents and is 
cognitively simple, taking only a few minutes to complete, and will be administered 
electronically at the study site on Day 1 of each cycle prior to receiving study treatment. EQ-5D-
5L responses may be incorporated into cost utility analyses, but will not be included in the 
clinical study report (CSR). 
Health Care Resource Utilization 
Health care resource utilization will be collected in the CRF by the investigator and study site 
personnel for all participants throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. 
The data collected will include: 

hospitalization (yes or no) and duration of hospitalization (admission and discharge dates)

emergency room visits (yes and number of events, or no)

supportive care medications (granulocyte-colony-stimulating factor [G-CSF] use, analgesics,
transfusions)
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9.
Statistical Considerations
9.1. 
Statistical Hypotheses 
Treatment of patients with advanced or metastatic RET fusion-positive nonsquamous NSCLC 
with selpercatinib in the first-line setting will provide a clinically meaningful increase in PFS 
over treatment with platinum-based chemotherapy and pemetrexed in combination with or 
without pembrolizumab.  
9.2. 
Sample Size Determination 
The primary efficacy endpoints are progression-free survival (PFS) per BICR in the ITT-
pembrolizumab and in the ITT population (defined in Section 9.3) with hypothesis testing 
conducted via the stratified log-rank test. Approximately 250 patients will be randomized at a 
ratio of 2:1 to selpercatinib versus control. The percentage of patients with the intent not to 
receive pembrolizumab (by investigator’s choice) will be capped at 20% of the ITT population. 
As a result, a minimum of 200 patients will be enrolled in the ITT-pembrolizumab population. 
Under an alternative hazard ratio (HR) assumption of 0.563 (and the interim analysis plan 
specified in Section 9.5), a total of 140 PFS events in the ITT-pembrolizumab population are 
required to yield 89% overall statistical power at a 1-sided type I error rate of 0.025. If a mPFS 
of 9 months is assumed for patients in the Arm B (Gandhi et al. 2018), with exponentially 
distributed PFS, the hazard ratio assumption of 0.563 would correspond to an increase in mPFS 
of approximately 7 months associated with selpercatinib treatment (9 vs. 16 months with control 
vs. selpercatinib, respectively). Observation of the requisite PFS events in the ITT-
pembrolizumab population will trigger the interim and final analyses of BICR PFS.  
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Entered 
All participants who sign informed consent 
Intention to treat (ITT)/Enrolled 
All randomized patients, even if a patient does not take the assigned treatment, 
does not receive the correct treatment, or otherwise does not follow the protocol. 
Patients will be analyzed according to the treatment group they were assigned to 
regardless of what actual treatment they receive. 
ITT-pembrolizumab 
All randomized patients with investigator’s intent to treat with pembrolizumab if 
randomized to control arm. Patients will be analyzed according to the treatment 
group they were assigned to regardless of what actual treatment they receive. 
Evaluable 
Defined in the following specific subsections if applicable. 
Safety 
All randomized patients who take at least 1 dose (including a partial dose) of 
study treatment. Analysis of safety data will be based on the actual treatment a 
patient received on the first study treatment administration regardless of which 
treatment they were randomized to receive (“as treated”). 
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9.4. 
Statistical Analyses 
9.4.1. 
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated. 
Continuous variables will be summarized using descriptive statistics (i.e., number of patients, 
mean, median, standard deviation, minimum, and maximum). Categorical variables will be 
summarized by frequency and its corresponding percentage. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the CSR. Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Handling of missing, unused, and/or spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and/or SAP, where appropriate. Adjustments to the 
planned analyses are described in the final CSR. 
9.4.2. 
Treatment Group Comparability 
9.4.2.1. 
Participant Disposition 
A detailed description of participant disposition will be provided according to the CONSORT 
publishing requirements. 
9.4.2.2. 
Participant Characteristics 
Patient demographic and baseline characteristics will be summarized. Baseline disease 
characteristics, prior anticancer therapies, historical illness, and preexisting conditions will also 
be summarized. 
9.4.2.3. 
Concomitant Therapy 
A summary of preferred names of concomitant medication by treatment arm by decreasing 
frequency will be generated.  
9.4.2.4.
Treatment Compliance: Selpercatinib Treatment Only 
Applicable for patients randomly assigned to selpercatinib treatment only (Arm A). Compliance 
will be assessed as the proportion of treatment that is actually taken, relative to what is expected, 
after accounting for protocol-defined dose adjustments. Study treatment taken will be derived 
from the difference between the total number of capsules dispensed and returned over the course 
of the patient’s treatment. A patient will be considered noncompliant if he or she takes <75% or 
≥125% of the planned doses.  
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9.4.2.5.
Extent of Exposure 
The duration on therapy, dose omissions, dose reductions, dose delays, and dose intensity for 
each drug will be summarized for all treated patients by arms. 
9.4.2.6.
Post-Study Treatment Therapy 
The numbers and percentages of patients receiving poststudy anticancer therapies will be 
provided by type of therapy (surgery, radiotherapy, or systemic therapy), by drug class and/or 
name, overall, and by line of therapy. 
9.4.3. 
Efficacy Analyses 
All efficacy analyses will be performed using the ITT-pembrolizumab population and the ITT 
population, unless otherwise specified. 
9.4.3.1. 
Primary Analysis 
The primary endpoints are BICR PFS in the ITT-pembrolizumab population and BICR PFS in 
the ITT population. BICR PFS is defined as the time from randomization until the occurrence of 
documented disease progression by the BICR, per RECIST 1.1 criteria, or death from any cause 
in the absence of BICR-documented progressive disease. Patients known to be alive and without 
disease progression will be censored at the time of the last adequate tumor assessment (a detailed 
PFS event/censoring scheme will be provided in the statistical analysis plan [SAP]). The BICR-
PFS will be compared between treatment arms using a stratified log-rank test, stratified by the 
randomization strata (interactive web-response system data). The corresponding HR between 
treatment arms will be estimated using a stratified Cox regression model (Cox 1972), stratified 
by randomization strata. The PFS survival curves, mPFS, and PFS rates at various time points 
with 95% CI for each treatment arm will be estimated using the Kaplan-Meier method (Kaplan 
and Meier 1958). Sensitivity analyses for PFS will be described in the SAP. 
The analysis of BICR PFS is event driven. The interim PFS analysis will be conducted when 
approximately 93 events have been observed in the ITT-pembrolizumab population. Details are 
provided in Section 9.5. Approximately 140 BICR PFS events in the ITT-pembrolizumab 
population will trigger the final PFS analysis. Conditional on achieving statistical significance 
for the BICR PFS, the other primary endpoint, BICR PFS in the ITT population will be tested at 
interim and final analysis. To preserve the overall type I error rate at the 1-sided significance 
level of 0.025, O’Brien-Fleming boundaries will be used. A detailed alpha spending scheme will 
be provided in the statistical analysis plan. The study will be considered to be a positive study if 
PFS by BICR in the ITT-pembrolizumab population achieves the critical boundaries at interim or 
final analysis.  
9.4.3.2. 
Key Secondary Analysis 
Overall survival in ITT population is an error-controlled, key secondary endpoint. Overall 
survival is defined as the time from randomization until death from any cause. If the patient is 
alive or lost to follow-up at the time of data analysis, OS data will be censored on the last date 
the patient is known to be alive. Overall survival will be compared between treatment arms using 
a stratified log-rank test, stratified by the randomization strata. The corresponding HR between 
treatment arms will be estimated using a stratified Cox regression model (Cox 1972), stratified 
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by the randomization strata. Overall survival curves, the median and survival rates at various 
time points with 95% CI, for each treatment arm will be estimated using the Kaplan-Meier 
method (Kaplan and Meier 1958). Sensitivity analyses for OS will be described in the SAP. 
Conditional on achieving statistical significance for both of the primary endpoints of BICR PFS 
in the ITT-Pembrolizumab and ITT populations, OS in the ITT population will be tested at the 
interim analysis, the final BICR PFS analysis or a separate final OS analysis. The final OS 
analysis (if needed) will be triggered upon observation of approximately 175 deaths, allowing a 
censoring rate of approximately 30% given the ITT sample size of 250. To preserve the overall 
type I error rate at the 1-sided significance level of 0.025, O’Brien-Fleming boundaries will be 
used. A detailed alpha spending scheme will be provided in the statistical analysis plan. 
9.4.3.3.  Supportive Secondary Analyses 
Overall Survival in the ITT-Pembrolizumab population is defined according to the same criteria 
as OS in the ITT population. OS in the ITT-Pembrolizumab population will be compared 
between treatment arms using a stratified log-rank test, stratified by the randomization strata. 
The corresponding HR between treatment arms will be estimated using a stratified Cox 
regression model (Cox 1972), stratified by the randomization strata. Overall survival curves, the 
median and survival rates at various time points with 95% CI, for each treatment arm will be 
estimated using the Kaplan-Meier method (Kaplan and Meier 1958).  
Progression-free survival per investigator assessment is defined according to the same criteria 
and will be analyzed using the same methodology as for BICR PFS.  
Overall response rate (ORR) is defined as the number of patients who achieve a best overall 
response (BOR) of CR or PR divided by the total number of patients randomized to each 
treatment arm. Intracranial ORR is defined as the number of patients who achieve CR or PR of 
intracranial lesions divided by the total number of patients with baseline brain metastases and 
randomized to each treatment arm. The ORR and intracranial ORR, with 95% CI, will be 
summarized for each treatment arm. Best overall response is determined from a sequence of 
responses assessed. Two objective status determinations of CR before progression are required 
for a best response of CR. Two determinations of PR or better before progression, but not 
qualifying for a CR, are required for a best response of PR.  
Overall response rate and intracranial ORR will be compared between Arm A and Arm B using a 
Cochran-Mantel-Haenszel test stratified by the randomization strata. The ORR according to both 
BICR and investigator-assessed BOR will be evaluated per RECIST 1.1 criteria. Intracranial 
ORR will be assessed by BICR (no investigator assessment) per RECIST 1.1 and RANO-BM 
criteria. 
Duration of response (DOR) is defined as the time from the date that measurement criteria for 
CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent 
or documented disease progression is observed, or the date of death from any cause in the 
absence of documented disease progression or recurrence. The DOR according to both BICR and 
investigator-assessed BOR will be evaluated per RECIST 1.1 criteria. Intracranial DOR will be 
assessed by BICR (no investigator assessment) per RECIST 1.1 and RANO-BM criteria. 
Disease control rate (DCR) is defined as the number of patients who achieve a best overall 
response of CR, PR, or SD lasting 16 or more weeks divided by the total number of patients 
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randomized to each treatment arm. The DCR according to both BICR and investigator-assessed 
BOR will be evaluated. 
Time to CNS progression is defined as the time from randomization to the occurrence of 
documented CNS progression by the BICR. Central nervous system progression is defined as 
progression due to newly developed intracranial lesions and/or progression of pre-existing 
intracranial lesions per RECIST 1.1. Non-CNS progression and death are completing events, 
because once a patient has systemic disease progression or death, no further scans are required 
per protocol. Time to CNS progression will be compared between Arm A and Arm B using a 
stratified log-rank test, computed on the basis of cause-specific hazard functions. The 
corresponding cause-specific HRs will be estimated using a stratified Cox regression model. 
Gray’s test (Gray 1988; Fine and Gray 1999) to compare the risk of CNS progression between 
treatment arms will also be performed. 
Progression-free survival 2 is defined as the time from randomization to disease progression on 
the next line of treatment or death from any cause in the absence of observed disease 
progression. If the patient is alive at the cutoff date for the analysis, and disease progression has 
not been observed, PFS2 data will be censored on the latest date of last progression-free 
assessment or start of the next line of treatment.  
Time to deterioration in pulmonary symptoms assessed by NSCLC-SAQ will be described using 
the method of Kaplan-Meier and a comparative analyses between the 2 arms using a log-rank 
test. Further details will be provided in the SAP. 
The error-controlled testing strategy of supportive secondary endpoints will be described in the 
SAP. 
9.4.4. 
Safety Analyses 
The safety population will consist of all randomized patients who receive at least 1 dose of any 
study drug(s). A baseline measurement and at least 1 laboratory or other safety-related 
measurement obtained after treatment of study drug may be required for inclusion in the analysis 
of a specific safety parameter. The safety analyses will be performed on the patients who receive 
at least 1 dose of any study drug in the ITT-pembrolizumab population and in the ITT population. 
The IDMC will monitor the overall safety of the study. An early safety analysis will be 
performed after approximately 50 patients have been randomized and had the opportunity to be 
treated for 2 cycles. The IDMC will meet and review data approximately every 6 months 
thereafter. Detailed information on the role of the IDMC and frequency of meetings will be 
provided in the IDMC charter separate from this protocol. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Selpercatinib plasma concentrations will be summarized by descriptive statistics. Additional 
analysis utilizing the population PK approach may also be conducted if deemed appropriate. 
The relationship between selpercatinib plasma exposure and selected efficacy and safety 
outcomes may be explored. 
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9.4.6. 
Other Analyses 
9.4.6.1. 
Patient-Reported Outcomes and Health Care Resource Utilization 
For each instrument, percentage compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments. Data will be separately summarized 
using descriptive statistics. 
Further details will be provided in the SAP for each patient-reported outcome (PRO) instrument, 
respectively. 
Frequency counts of hospitalizations, emergency room visits, G-CSF use, transfusions, and 
analgesic use will be reported descriptively for each treatment arm by cycle. 
9.4.6.2. 
Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category of the following subgroups (defined based on eCRF 
data): 

Age category (≤65 vs. >65 years)

ECOG Performance Scale (0 to 1 vs. 2)

Sex (female vs. male)

Race (Asian vs. non-Asian)

Geography (East Asia vs. non-East Asia)

Smoking status (never vs. former/current smokers)

Brain metastasis status at baseline (absence or unknown vs. presence)

Disease stage (Stage IVA vs. Stage IVB)

PD-L1 expression (TPS <1% vs. TPS ≥1% vs. unknown)

Liver metastases (absence vs. presence)

Tissue vs. blood RET fusion detection

KIF5B vs. no-KIF5B fusion partner

Investigator’s choice of treatment with vs. without pembrolizumab
If a level of a factor includes fewer than 5% of the ITT population, analysis within that level will 
be omitted. Additional subgroup analyses may be performed as deemed appropriate. 
9.4.6.3.
Biomarker Analysis 
Biomarker results will be summarized and may be analyzed for correlations with clinical 
outcomes. 
9.4.6.4. 
Evaluation of RET Testing Results 
The consistency between the RET results based on local laboratory tests and a single, central test will be 
evaluated to assess the performance of RET fusion testing at local laboratories.  
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9.4.6.5. 
PFS/ORR/DOR/DCR after Crossover 
Progression-free survival after crossover in patients randomly assigned to Arm B who crossed 
over to selpercatinib is defined as the time from start of selpercatinib treatment until the 
occurrence of disease progression or death from any cause. Patients known to be alive and 
without disease progression will be censored at the time of the last adequate tumor assessment. 
Overall response rate is defined as the number of patients who achieve a BOR of CR or PR with 
respect to the crossover baseline tumor assessment, divided by the total number of patients who 
assigned to Arm B and crossed over to selpercatinib. Duration of response is defined as the time 
from the date that measurement criteria for CR or PR (whichever is first recorded) are first met 
until the first date that disease is recurrent or documented disease progression is observed, or the 
date of death from any cause in the absence of documented disease progression or recurrence 
during crossover period. Disease control rate is defined as the number of patients who achieve a 
BOR of CR, PR, or SD lasting 16 or more weeks, divided by the total number of patients who 
assigned to Arm B and crossed over to selpercatinib. Further details will be provided in the SAP. 
9.5. 
Interim Analyses 
A single interim efficacy analysis for BICR PFS is planned at 67% information fraction 
(approximately 93 events) in the ITT-pembrolizumab population. The sequential monitoring 
approach of Lan and DeMets (1983) with the O’Brien-Fleming function will be used to control 
the type I error rate associated with the multiple looks. The event numbers, cumulative type I 
error rates, critical values and associated boundary crossing probabilities are provided in the 
table below. The HR and p-value boundaries are for reference only and they will be updated 
based on the actual number of events observed at the time of interim and final analysis. The 
interim boundary associated with the O’Brien-Fleming spending function was specifically 
chosen within the present context because it is generally considered conservative in terms of 
declaring early success at interim. This is desirable as there are substantial risk-benefit 
considerations beyond the primary endpoint. It is important to note that the interim HR boundary 
of 0.575 corresponds to a minimum of approximately 7 additional months of mPFS and a p-value 
< 0.006, indicating a stringent threshold for clinically/statistically significant PFS findings 
required to conclude success at interim analysis. With the O’Brien-Fleming function, there is an 
approximately 54% chance of the correct conclusion of early success under the alternative 
hazard ratio assumption of 0.563.  
At the interim analysis, the other primary endpoint BICR PFS in the ITT population will only be 
tested if interim success is achieved in the ITT-pembrolizumab population. The observed number 
of events and corresponding boundary are to be updated at the time of analysis. Further details 
will be provided in the SAP.
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Planned Analysis Stopping Rules 
Analysis 
Number 
of Events 
Information 
Fraction 
Cumulative 
Type I 
Error 
Probability 
Critical 
HR 
Boundary 
Critical 
p-Value
Boundary
Boundary Crossing 
Probabilities 
𝑯𝟎: 
𝑯𝑹= 𝟏
𝑯𝟏: 
𝑯𝑹= 𝟎. 𝟓𝟔𝟑
Interim 
93 
67% 
0.006 
0.575 
0.006 
0.006 
0.540 
Final 
140 
100% 
0.025 
0.700 
0.023 
0.019 
0.351 
Abbreviations: H0 = null hypothesis; H1 = alternative hypothesis; HR = hazard ratio. 
The interim efficacy and overall safety of this study will be monitored by an IDMC. Efficacy 
will be evaluated based on prespecified stopping rules in the preplanned interim analyses. If the 
criterion for early efficacy is met at the time of an interim analysis, the IDMC may recommend 
stopping the study in accordance with the terms of the IDMC charter.  
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10.
Supporting Documentation and Operational Considerations
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
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) GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and
approved by the IRB/IEC before the study is initiated

Any amendments to the protocol will require IRB/IEC approval before implementation of
changes made to the study design, except for changes necessary to eliminate an
immediate hazard to study participants

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014
for clinical studies (if applicable), and all other applicable local regulations
o
Reporting to the sponsor or designee significant issues related to participant safety,
participant rights, or data integrity
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative. 
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study. 
10.1.2. 
Informed Consent Process 

The investigator or his/her representative will explain the nature of the study, including
the risks and benefits, to the participant or his/her legally authorized representative and
answer all questions regarding the study.
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
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, local regulations, ICH guidelines, Health
Insurance Portability and Accountability Act requirements, where applicable, and the
IRB/IEC or study center.

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 ICF.

Participants must be reconsented to the most current version of the ICF(s) during their
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally
authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF. 
10.1.3. 
Data Protection 

Participants will be assigned a unique identifier by the sponsor to protect the
participant’s personal data . Any participant information, such as records, datasets or
tissue samples that are transferred to the sponsor will contain the identifier only.
Participant names or any information which would make the participant identifiable
will not be transferred.

The participant must be informed that the participant’s 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 the participant who will be required to give
consent for their data to be used as described in the informed consent. This is done
by the site personnel through the informed consent process.

The participant must be informed through the informed consent by the site personnel
that their medical records may be examined by Clinical Quality Assurance auditors
or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC
members, and by inspectors from regulatory authorities.

The sponsor has processes in place to ensure information security, data integrity, and
data protection. These processes address management of data transfer, and
prevention and management of unauthorized access, disclosure, dissemination,
alteration or loss of information or personal data. These processes include
appropriate contingency plan(s) for appropriate and timely response in the event of a
data security breach.

The transfer of personal data is subject to appropriate safeguards through contractual
agreements and processes. The sponsor’s processes are compliant with local privacy
laws and relevant legislations including the General Data Protection Regulation
(GDPR).
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10.1.4. 
Committee Structure 
The primary endpoint, PFS, will be assessed by BICR. Blinded independent central review will 
consist of independent radiologists to perform response assessments and determination of disease 
progression per RECIST 1.1. 
10.1.5. 
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly and international 
policies. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
10.1.6. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following: 

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study
coordinators. This training will give instruction on the protocol, the completion of
the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by
mail, telephone, and/or fax

review and verify data reported to detect potential errors
In addition, the sponsor or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by the sponsor or 
its representatives and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs. 
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
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An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, electronic Clinical Outcome Assessment (eCOA) data questionnaires and scales 
will be directly recorded by the patient, into an instrument (e.g., an electronic device). The eCOA 
data will serve as the source documentation and the investigator does not maintain a separate 
written or electronic record of these data. 
Data collected via the sponsor-provided data capture system will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and results will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
10.1.7. 
Source Documents 

Source documents provide evidence for the existence of the participant and substantiate
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source
documents must be consistent with the source documents or the discrepancies must be
explained. The investigator may need to request previous medical records or transfer
records, depending on the study. Also, current medical records must be available.
10.1.8. 
Study and Site Closure 
10.1.8.1. Discontinuation of the Study 
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 
10.1.8.2. Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP. 
10.1.9. 
Provisions for Changes in Study Conduct During Emergencies 
There may be times due to exceptional circumstances where it may not be feasible for patients to 
come to investigator sites for study-required visits. To mitigate the risk of patients missing visits 
to allow patients to safely continue to receive care and maintain the data integrity of the study, 
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the following may be allowed on a case-by-case basis following approval from the sponsor and if 
permitted by local regulations: 

Remote/virtual visits and/or extended visit windows may be used. Medically qualified
site personnel may collect study required information (e.g., AEs, concomitant
medications, ECOG status, and study treatment compliance) via videoconference
(preferred) or phone. Visit or cycle windows as defined in the schedule of activities may
be extended to facilitate the ability to perform study-specific assessments at the site,
which is preferred to remote/virtual visits. Every effort should be made to return to in-
clinic visits as soon as reasonably possible and safe for the patient and investigator/site
staff.

Labs, ECGs and/or tumor imaging may be obtained at a local (nonstudy) site. Laboratory
results (including reference ranges), ECGs and/or scans obtained at a local lab must be
filed and reviewed by the study investigator or qualified designee in a timely manner.

For patients that meet the protocol criteria to continue or restart dosing, local processes
may be leveraged to deliver drug directly to patients. Note that the IV agents on Arm B
must be administered at the clinic.

A remote informed consent process may be implemented.
Site personnel are responsible for documenting in the source records all changes in study 
conduct, relevant communications (patient and sponsor), and dispensing/shipment records of IP 
and indicating the actions taken as a result of exceptional circumstances mitigation. If 
mitigations are approved by the sponsor, additional instructions on the process and 
documentation will be provided to the site. Additional mitigations may be approved by the 
sponsor and will be tracked as protocol deviations as required. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 

The tests detailed below will be performed by the indicated laboratory.

Local laboratory results are required only in the event that the central laboratory results
are not available in time for inclusion/exclusion determination, study intervention
administration, and/or response evaluation. If a local sample is required or used for
treatment decisions (e.g., delay the start of a cycle), it is important that the sample for
central analysis is obtained at the same time. Additionally, if the local laboratory results
are used to make either a study intervention decision or response evaluation, this should
be reported into the CRF as an AE. If there is an abnormal laboratory value or abnormal
value for any other diagnostic or screening test (e.g., blood pressure increased,
neutrophils decreased, etc.) and it is known to be related to a diagnosis (e.g.,
hypertension, neutropenia, etc.) this should be reported into the CRF as an AE. Do not
enter the test abnormality, enter the disease diagnosis or categorical term.

Additional tests may be performed at any time during the study as determined necessary
by the investigator or required by local regulations, and clinically significant findings
should be reported in the CRF as an AE.
Enrollment and treatment decisions may be based upon local laboratory results. Discrepancies 
between local and central laboratory results will not be considered a protocol deviation. 
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Clinical Laboratory Tests 
Hematologya – Local laboratory 
Leukocytes (WBC) 
Basophils 
Neutrophils 
Erythrocytes (RBC) 
Lymphocytes 
Hemoglobin (HGB) 
Monocytes 
Hematocrit (HCT) 
Eosinophils 
Platelets (PLT) 
Coagulationa – Local laboratory 
PT/INR 
PTT/aPTT 
Clinical chemistryb,c – Central laboratory 
Serum concentrations of: 
Alanine aminotransferase (ALT) 
Chloride 
Albumin 
Creatinine 
Alkaline phosphatase 
Glucose (random) 
Aspartate aminotransferase (AST) 
Magnesium 
Bilirubin, direct 
Potassium 
Bilirubin, total 
Protein 
Blood urea nitrogen (BUN) or blood urea 
Sodium 
Calcium 
Hepatic monitoring – Central laboratoryb 
Alanine aminotransferase (ALT) 
Bilirubin, direct 
Aspartate aminotransferase (AST) 
Bilirubin, total 
Alkaline phosphatase 
Urinalysisa – Local laboratory 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Urine leukocyte esterased 
pH 
Pregnancy Teste – Local laboratory 
Urine pregnancy test 
Serum pregnancy test 
Thyroid panelb - Central laboratory 
Triiodothyronine (T3) 
Thyroid-stimulating hormone (TSH) 
Thyroxine (T4) 
Abbreviations: aPTT = activated partial thromboplastin time; CRF = case report form; PT/INR = prothrombin time/international 
normalized ratio; PTT = partial thromboplastin time; RBC= red blood cell; WBC = white blood cell. 
a 
Local or investigator-designated laboratory. 
b 
Treatment and enrollment decisions may be based on local laboratory results. Investigators may use central laboratory results 
to guide treatment and enrollment decisions if local laboratories are not available. Local laboratory results are not required to 
be recorded on a CRF if a sample is sent to the central laboratory at the same time.  
Note: Neutrophils reported by automated differential hematology instruments include both segmented and band forms. When a 
manual differential is needed to report the neutrophils, the segmented and band forms should be added together and reported 
on the CRF, unless the CRF specifically provides an entry field for bands. 
c 
Central laboratory may be used for Lilly investigational analysis. 
d 
Urine microscopy may be used in the place of the urine leukocyte esterase assessment to test for the presence of WBCs. 
e 
For female patients of childbearing potential. 
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10.3. 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a postmenopausal state in women not using hormonal contraception
or hormonal replacement therapy (HRT). However, in the absence of 12 months of
amenorrhea, confirmation with more than 1 FSH measurement is required.

Females on HRT and whose menopausal status is in doubt will be required to use 1 of
the nonestrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
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Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb that Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device

Intrauterine hormone-releasing systemc

Bilateral tubal occlusion

Vasectomized partner

(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is
approximately 90 days.)
Highly Effective Methodsb that Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of
ovulationc
o
oral
o
intravaginal
o
transdermal
o
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
o
oral
o
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of
the participant.)
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those that inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure with friction). 
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Collection of Pregnancy Information 
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s
female partner who becomes pregnant while the male participant is in this study. This
applies only to male participants who receive selpercatinib.

After obtaining the necessary signed informed consent from the pregnant female partner
directly, the investigator will record pregnancy information on the appropriate form and
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The
female partner will also be followed up to determine the outcome of the pregnancy.
Information on the status of the mother and child will be forwarded to the sponsor.
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal status
(presence or absence of anomalies) or indication for the procedure.
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who
becomes pregnant while participating in this study. Information will be recorded on the
appropriate form and submitted to the sponsor within 24 hours of learning of a
participant’s pregnancy.

The participant will be followed up to determine the outcome of the pregnancy. The
investigator will collect follow-up information on the participant and the neonate and the
information will be forwarded to the sponsor. Generally, follow-up will not be required
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies)
or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy will be reported as an AE or SAE. A
spontaneous abortion is always considered to be an SAE and will be reported as such.
Any poststudy pregnancy-related SAE considered reasonably related to the study
intervention by the investigator will be reported to the sponsor as described in
Section 8.3.2. While the investigator is not obligated to actively seek this information in
former study participants, he or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will
discontinue study intervention or be withdrawn from the study.
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10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the Lilly CRP/CRS, or his/her 
designee. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin time 
WBC 
Prothrombin time, INR 
Neutrophils, segmented 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
Hepatitis B core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
ALT 
Antinuclear Antibodya 
AST 
GGT 
Alkaline Phosphatase Isoenzymesa 
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; HBV = hepatitis B virus; HCV = hepatitis C virus; 
Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cell; WBC = white blood cell. 
a Assayed by Lilly-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability, this may include 
HBV/HCV DNA or RNA. 
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10.5. 
Appendix 5: Restricted and Prohibited Concomitant Medication 
The following table(s) describes the drug class and associated medications that will be prohibited, 
restricted, or be used with caution during the study treatment period. Patients who, in the 
assessment by the investigator, require the use of any of the prohibited treatments for clinical 
management should be removed from the study. In general, all strong and moderate CYP3A4 
inhibitors, strong and moderate inducers of CYP3A4, sensitive CYP2C8 substrates, and proton 
pump inhibitors (PPI’s) are to be used with caution during the study treatment period. Agents 
known to cause QTc prolongation are prohibited during the study treatment period. Please see 
Section 6.5 for additional information.  
This is not an all-inclusive list. 
Note: Nonsystemic (e.g., topical creams, eye drops, mouthwashes, etc.) applications of the 
following are permissible. 
Inhibitors of CYP3A4 
Strong Inhibitorsa 
Moderate Inhibitorsb 
boceprevir 
amprenavir 
clarithromycin 
atazanavir 
conivaptan 
ciprofloxacin 
grapefruit juicec 
darunavir 
indinavir 
diltiazem 
itraconazole 
erythromycin 
ketoconazole 
fluconazole 
lopinavir 
fosamprenavir 
mibefradil 
imatinib 
nefazodone 
verapamil 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4. 
a Increases the AUC of sensitive index substrates of a given metabolic pathway by ≥5-fold. 
b Increases the AUC of sensitive index substrates of a given metabolic pathway by 2- to 5-fold. 
c When excessive amounts are consumed. 
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Inducers of CYP3A4 
Strong Inducersa 
Moderate Inducersb 
Avasimibe 
bosentan 
carbamazepine 
efavirenz 
Enzalutamide 
etravirine 
Phenytoin 
modafinil 
Rifampin 
nafcillin 
St John’s wort 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4. 
a Decreases the AUC of the sensitive index substrates of a given metabolic pathway by ≥80%. 
b Decreases the AUC of the sensitive index substrates of a given metabolic pathway by 50% to 80%. 
Sensitive CYP2C8 substrates 
Repaglinide 
Dasabuvir 
Selexipag 
Abbreviation: CYP2C8 = Cytochrome P4502C8. 
Examples of PPIs 
omeprazole 
pantoprazole 
esomeprazole 
rabeprazole 
lansoprazole 
dexlansoprazole 
Abbreviation: PPI = proton pump inhibitor. 
Examples of H2 blocking agents 
famotidine 
cimetidine 
ranitidine 
nizatidine 
Note: The above lists are not exhaustive. 
See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm0936
64.htm.
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Examples of Agents Known to Cause QTc Prolongation 
Amiodarone 
ibogaine 
Anagrelide 
ibutilide 
Azithromycin 
levofloxacin 
Chloroquine 
levomepromazine (methotrimeprazine) 
Chlorpromazine 
levosulpiride 
Cilostazol 
methadone 
Ciprofloxacin 
moxifloxacin 
Citalopram 
ondansetron 
Clarithromycin 
papaverine HCl (intracoronary) 
Cocaine 
pentamidine 
Disopyramide 
pimozide 
Dofetilide 
procainamide 
domperidone 
propofol 
Donepezil 
quinidine 
Dronedarone 
roxithromycin 
Droperidol 
sevoflurane 
Erythromycin 
sotalol 
Escitalopram 
sulpiride 
Flecainide 
sultopride 
Fluconazole 
terlipressin 
halofantrine 
terodiline 
Haloperidol 
thioridazine 
hydroquinidine, dihydroquinidine 
Note: The above list is not exhaustive. 
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10.6. 
Appendix 6: Country-Specific Requirements 
Discontinuation of Inadvertently Enrolled Patients in the United Kingdom and Germany 
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment and 
safety follow up should be performed as outlined in Section 1.3 (Schedule of Activities), Section 
8.3 (Adverse Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) of the 
protocol. 
Time Period and Frequency for Collecting SAE information for Patients in Germany 
All SAEs, regardless of causality, should be reported for the entire duration of the clinical trial. 
Since survival is a secondary endpoint and patients are followed after discontinuation of study 
treatment, SAEs should be reported until patient death. 
Hepatitis B, Hepatitis C and HIV testing for Patients in Germany: 
If the HIV, Hepatitis B, or Hepatitis C status is not known, suitable testing should be carried 
prior to the initiation of therapy to determine if exclusion criteria 16 or 17 are met. 
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10.7. 
Appendix 7: Creatinine Clearance Formula 
Note: This formula has to be used for calculating CrCl from local laboratory results only. 
For serum creatinine concentration in mg/dL: 
CrCl 
= 
(140 – agea) × (wt) × 0.85 (if female), or × 1.0 (if male) 
(mL/min) 
72 × serum creatinine (mg/dL) 
For serum creatinine concentration in μmol/L: 
CrCl   
= 
(140 – agea) × (wt) × 0.85 (if female), or × 1.0 (if male) 
(mL/min) 
       0.81 × serum creatinine (μmol/L) 
a Age in years, weight (wt) in kilograms. 
Source: Cockcroft and Gault 1976. 
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10.8. 
Appendix 8: Abbreviations and Definitions 
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
ALT 
alanine aminotransferase 
ASCO 
American Society for Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, 
which is used as an investigational medicinal product 
BICR 
blinded independent central review 
BID 
twice a day 
BOR 
best overall response 
BSA 
body surface area 
BUN 
blood urea nitrogen, 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
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Term 
Definition 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer. 
CRS 
clinical research scientist 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria in Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
eCOA 
electronic Clinical Outcome Assessment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
EORTC 
European Organisation for Research and Treatment of Cancer Quality of Life 
questionnaire 
EORTC IL19 
European Organisation for Research and Treatment of Cancer item library 19 
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Term 
Definition 
EQ-5D-5L 
EuroQol Five Dimension Five Level 
ERB 
ethical review board 
ESMO 
European Society for Medical Oncology 
FACT-GP5 
Functional Assessment of Cancer Therapy-Side Effects 
FNA 
fine needle aspiration 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
G-CSF
granulocyte colony-stimulating factor 
GDPR 
EU General Data Protection Regulation 
GFR 
glomerular filtration rate 
GnRH 
gonadotropin-releasing hormone 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
informed consent 
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed, and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
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Term 
Definition 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
immune Response Evaluation Criteria in Solid Tumors 
ISO/IEC 
International Organization for Standardization/Independent Ethics Committee 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (i.e., the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
LFT 
Liver function test 
LNRH 
Luteinizing hormone-releasing hormone 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors: 
• dose omission associated with an AE or a product complaint
• dispensing or use of expired medication
• use of medication past the recommended in-use date
• dispensing or use of an improperly stored medication
• use of an adulterated dosage form or administration technique inconsistent with the
medication's labeling (for example, Summary of Product Characteristics, IB, local
label, protocol), or
• shared use of cartridges, prefilled pens, or both.
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MKI 
multikinase inhibitor 
mPFS 
median progression-free survival 
MRI 
magnetic resonance imaging 
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Term 
Definition 
MTC 
medullary thyroid cancer 
NGS 
next generation sequencing 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PPI 
Proton pump inhibitor 
PR 
partial response 
PRO 
patient-reported outcomes 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAQ 
Symptom Assessment Questionnaire 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
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Term 
Definition 
SoA 
schedule of activities 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed by 
the sponsor and or study investigator as being unexpected, serious, and as having a 
reasonable possibility of a causal relationship with the study intervention. 
TBL 
total bilirubin level 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
TKI 
tyrosine kinase inhibitor 
TPS 
tumor proportion score 
UK 
United Kingdom 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment (d) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
This amendment incorporates changes to include additional endpoints to further characterize the 
intracranial activity of selpercatinib compared to the control arm. In addition, this amendment 
includes changes made to correct and clarify information for sites. This amendment also corrects 
typographical errors and inconsistencies that were noted in Study JZJC amendment (c). 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Updated newly added endpoints to match 
the updated endpoints in Section 3 
To align with Section 3 
1.2 Schema and throughout 
Changed coprimary to primary or deleted 
coprimary 
To align with intent of original 
protocol; only one of the 
endpoints needs to be positive, not 
both 
1.3 Schedule of Activities 
Prescreening 
Added information about the possibility of 
using a fresh biopsy to determine 
eligibility to the schedule of activities 
Clarification 
1.3 Schedule of Activities 
Main and crossover 
Deleted the requirement for ECG to be 
obtained after Cycle 6 
To align with IB 
1.3 Schedule of Activities 
Main and crossover 
Added Karnofsky performance status 
To enable intracranial assessment 
by RANO-BM 
1.3 Schedule of Activities 
Main and crossover 
Intracranial evaluation with CT or MRI is 
required for all patients 
To align with newly added 
endpoints 
1.3 Schedule of Activities 
Note regarding blood sample for 
pharmacokinetics was corrected 
Correction to align with schedule 
1.3 Schedule of Activities 
Main 
Information regarding archived tumor 
tissue or fresh biopsy was moved to the 
screening visit 
To clarify that a biopsy may be 
obtained during screening to 
determine eligibility 
3 Objectives and Endpoints 
Included additional endpoints 
In order to evaluate the potential 
protective effect of selpercatinib 
to prevent or delay brain 
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Section # and Name 
Description of Change 
Brief Rationale 
metastases 
To describe efficacy after 
crossover with additional 
endpoints 
4.1 Overall Design 
And 
9.4.3.1.  Primary Analysis 
Added language to indicate the study will 
be considered positive if a statistically 
significant improvement in PFS by BICR 
in the ITT-pembrolizumab population is 
observed 
Clarification 
5.2 Exclusion criteria 
(criterion 25) 
And 
6.5.1 Prohibited Concomitant 
Therapy 
Added “The use of topical, ophthalmic, 
inhaled, and intranasal corticosteroids is 
permitted.”  
Clarification 
6.5.1 Prohibited Concomitant 
Therapy 
Added statement that changes in steroid 
use/doses should be recorded in eCRF 
To facilitate assessment of 
RANO-BM 
8.1.1 Imaging 
Added recommendation to confirm 
presence of malignant cells before 
determining progressive disease on 
imaging alone 
For consistency with the IB 
8.1.2 BICR assessment 
Added RANO-BM assessment 
For the evaluation of CNS related 
endpoints 
9.4.3.3 Supportive Secondary 
Analyses 
Added information about how the newly 
added endpoints would be analyzed 
To align with new endpoints 
9.4.6.2 Subgroup Analyses 
Added refinements to subgroup analyses 
Remove the subgroups that are not 
feasible based on current data 
collection 
9.4.6.5 PFS/ORR/DOR/DCR 
after Crossover 
Added definition for newly added 
endpoints 
To align with new endpoints 
Amendment (c) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union  
Overall Rationale for the Amendment: 
This amendment corrects typographical errors and inconsistencies that were noted in JZJC 
amendment (b). 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Updated rationale regarding immunotherapy 
Updated text to be consistent with 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.2 
1.3 SOA 
Adjusted timing and description of PRO 
Correction and clarifications 
1.2 Schema and 4.1 Overall 
Design 
Corrected language regarding percentage of 
patients with intent to not receive 
pembrolizumab 
Typographical error 
4.1 Overall Design 
Modified language of testing strategy for 
coprimary and secondary endpoints 
Clarification 
1.1 Synopsis and 3 Objectives 
and Endpoints 
Clarified endpoints and description of PRO 
objectives and updated secondary endpoints 
in Objectives/Endpoints Table 
Clarification 
8.3 AE and SAE 
Removed conflicting language 
Clarification 
8.9.1. Patient Reported 
Outcomes and Health Care 
Resource Utilization  
Updated health-related quality of life 
assessments 
Clarification 
9.2 Sample Size Determination 
Clarified language regarding percentage of 
patients with intent to not receive 
pembrolizumab 
Clarification 
9.4.3.2 Key Secondary 
Analyses and 9.4.3.3 
Supportive Secondary 
Analyses 
Clarified OS testing strategy; Added 
targeted number of deaths for final OS 
analyses 
Clarification 
9.4.3.3 Supportive Secondary 
Analyses 
Added language of analyzing methodology 
for PFS by investigator. Added OS 
definition in the ITT pembro population and 
moved disease control definition after 
duration of response 
Clarification 
9.4.6.1. Patient Reported 
Outcomes and Health Care 
Resource Utilization 
Moved Kaplan-Meier method assessment to 
section 9.4.3.3. 
Clarification 
9.4.6.4. Evaluation of RET-
Testing Results 
Modified language of RET-testing 
evaluation 
Clarification 
9.4.6.5. PFS after Crossover 
Added this section for consistency with 
Section 3, where PFS after crossover is one 
of the exploratory endpoints 
Clarification 
9.5 Interim Analysis 
Added how to update the boundaries at 
analysis 
Clarification 
Throughout the protocol 
Minor formatting and editorial changes 
Minor, therefore not detailed 
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Amendment (b) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union  
Overall Rationale for the Amendment: 
This amendment incorporates changes requested by regulatory agencies. In addition, this 
amendment includes changes made to correct and clarify information for sites. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis 
(Objectives and 
Endpoints) 
Updated primary objective; updated 
secondary objectives and end points 
To meet country-specific 
regulatory and payer 
expectations 
Section 1.1. Synopsis 
(Overall Design) 
Added a sentence related to 
randomization ratio 
Minimize patients treated on 
control arm (based on 
regulatory agency feedback 
and LIBRETTO-001 data) 
Section 1.1. Synopsis 
(Overall Design) 
Changed primary endpoint 
Clarification 
Section 1.1. Synopsis 
(Number of Participants) 
Updated number of participants 
Minimize patients treated on 
control arm (based on 
regulatory agency feedback 
and LIBRETTO-001 data) 
Section 1.2. Schema 
Updated sample size, randomization, 
and primary objective; modified 
footnote a and added footnote c 
Based on regulatory agency 
feedback and payer 
expectations 
Section 1.3. Schedule of 
Activities 
Added test results language to 
instructions for prescreening ICF 
To clarify that RET is not the 
only result that will be 
provided 
Section 1.3. Schedule of 
Activities 
Updated archived tumor or fresh 
biopsy and optional postprogression 
tumor biopsy collection instructions 
Clarification 
Section 1.3. Schedule of 
Activities 
Duration of ECG monitoring update 
For consistency with updated 
IB 
Section 1.3. Schedule of 
Activities 
Clarified hepatic safety monitoring 
also includes direct bilirubin  
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. Schedule of 
Activities 
Updated sample collection timelines 
for PK instructions 
To provide more flexibility 
based on feasibility feedback 
from sites 
Section 1.3. Schedule of 
Activities 
Duration of ECG monitoring update 
in crossover SOA 
For consistency with updated 
IB 
Section 1.3. Schedule of 
Activities 
Updated timing of radiologic 
imaging and measurement of 
palpable or visible lesion 
instructions in crossover SoA 
To match the expectations in 
main protocol  
Section 1.3. Schedule of 
Activities 
Clarified instructional guidance for 
intracranial evaluation with CT or 
MRI in crossover SoA 
Clarification 
Section 1.3. Schedule of 
Activities 
Updated sample collection timelines 
for PK instructions in crossover SoA 
To provide more flexibility 
based on feasibility feedback 
from sites 
Section 1.3. Schedule of 
Activities 
Correction of time point and 
clarified hepatic safety monitoring 
also includes direct bilirubin in 
crossover SoA 
Clarification 
Section 1.3. Schedule of 
Activities 
Corrected the instructional guidance 
for EQ-5D-5L in crossover SoA 
Correction 
Section 1.3. Schedule of 
Activities 
Added note related to usage of 
crossover baseline/screening 
assessments 
Clarification 
Section 1.3 Schedule of 
Activities 
Modified language around scan 
submissions 
Clarification 
Section 1.3 Schedule of 
Activities 
Added premedication procedure to 
screening period 
Clarification 
Section 1.3 Schedule of 
Activities 
Updated table notes for 
baseline/screening assessments 
during on-study treatment period 
Clarification 
Section 3. Objectives and 
Endpoints 
Updated primary objective; updated 
secondary objective and end points; 
added tertiary/exploratory objective 
To meet country-specific 
regulatory and payer 
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Section # and Name 
Description of Change 
Brief Rationale 
and end point related to PK 
expectations 
Section 4.1. Overall 
Design 
Updated sample size, stratification 
factor related to platinum therapy, 
randomization, primary endpoint, 
and number of patients that will be 
assigned to treatment without 
pembrolizumab 
To meet country-specific 
regulatory and payer 
expectations and based on 
additional LIBRETTO-001 
data 
Section 4.2. Scientific 
Rationale for Study 
Design 
Modified pembrolizumab language 
Updated based on recent 
publications and data 
Section 5.1. Inclusion 
Criteria 
Clarified language for histological 
diagnosis in Inclusion Criterion 1 
Clarification 
Section 5.1. Inclusion 
Criteria 
Removed tissue sample 
requirements in Inclusion Criterion 2 
Based on a change in 
regulatory agency 
requirements 
Section 5.1. Inclusion 
Criteria 
Specified timeline for organ function 
lab values in Inclusion Criterion 6 
Clarification 
Section 5.1. Inclusion 
Criteria 
Modified language on male 
contraception in Inclusion Criterion 
8 
Based on regulatory agency 
feedback 
Section 5.1. Inclusion 
Criteria 
Removed legally authorized 
representative from informed 
consent requirements 
Clarification 
Section 5.2. Exclusion 
Criteria 
Modified pleural effusion language 
in Exclusion Criterion 15 
Clarification 
Section 5.2. Exclusion 
Criteria 
Updated Hepatitis B and C status in 
Exclusion Criterion 17 
Based on investigator 
feedback and newly 
published guidance 
Section 5.2. Exclusion 
Criteria 
Added in situ cancers as exceptions 
to Exclusion Criterion 20 
Clarification 
Section 5.2. Exclusion 
Criteria 
Updated prior therapy criteria in 
Exclusion Criterion 21 
Based on investigator 
feedback 
Section 5.2. Exclusion 
Exclusion Criteria 23 and 24 
New data indicated these 
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Section # and Name 
Description of Change 
Brief Rationale 
Criteria 
removed due to change in study 
design 
exclusions were not required 
Section 5.2. Exclusion 
Criteria 
Clarified steroid treatment definition 
in Exclusion Criterion 25 
Clarification 
Section 5.2. Exclusion 
Criteria 
Clarified prior treatment 
Clarification 
Section 6.1.1 Selection 
and Timing of Doses 
Added pre- or postmedication 
guidance  
Clarification 
Section 6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Clarified stratification factor related 
to investigator’s choice of treatment 
Clarification 
Section 6.5.1. Prohibited 
Concomitant Therapy 
Updated steroid treatment language 
and removed CYP3A4 inhibitors as 
prohibited concomitant use 
New data resulted in updated 
guidance  
Section 6.5.1. Prohibited 
Concomitant Therapy 
Updated steroid treatment 
exclusions 
Clarification 
Section 6.5.1.1. 
Concomitant Therapy 
Considerations for Arm 
A 
Modified language regarding 
concomitant therapy with PPIs and 
CYP3A inhibitors 
New data resulted in updated 
guidance 
Section 6.5.1.1. 
Concomitant Therapy 
Considerations for Arm 
A 
Deleted language on discontinuation 
of CYP3A4 inducer prior to study 
administration 
New data resulted in updated 
guidance 
Section 6.5.2. Palliative 
Medicine and Supportive 
Care for Arms A and 
Arm B 
Removed sentence related to 
needing sponsor approval for 
physiologic dose of corticosteroid 
usage and updated study drug half-
lives before and after RT or surgery 
Sponsor approval is not 
needed and clarification 
Section 6.5.2. Palliative 
Medicine and Supportive 
Care for Arm A and Arm 
B 
Added guidance for patients with 
hepatitis B or C 
Based on investigator 
feedback and newly 
published guidance 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6. Dose 
Modification Guidelines 
for Arm a and Arm B 
Added dose reduction and re-
escalation instructions and updated 
Dose reduction for study 
interventions table 
Clarification 
Section 6.6. Dose 
Modification Guidelines 
for Arm a and Arm B 
Updated Dose reduction for study 
interventions table and updated 
footnote for Dose Level 3 
discontinuation 
Clarification 
Section 6.6.1. Dose 
Modifications and 
Toxicity Management 
Guidelines for Arm A 
Removed recommended lab testing 
for selpercatinib drug 
hypersensitivity; updated dose 
modifications for selpercatinib liver 
function test abnormalities; updated 
dose modifications for 
thrombocytopenia; updated dose 
modifications for hypertension; 
amended dose modification 
guidelines for patients on Arm A 
For consistency with updated 
IB 
Section 8.1.1. Imaging 
Clarified scan interval schedule 
Clarification 
Section 8.2.1. 
Electrocardiograms 
Clarified QTcF values that require 
action 
Clarification 
Section 8.5. 
Pharmacokinetics 
Updated sample collection time 
point 
Clarification and consistency 
with SoA. 
Section 8.8.1. Samples 
for Retrospective 
Evaluation of RET Status 
Modified sample language and 
removed required slides to 
determine RET status; added 
language around results of testing 
Based on a change in 
regulatory agency 
requirements 
Section 8.8.2. Biomarkers Added language related to whole 
blood collection 
Clarification 
Section 8.9.1. Patient-
reported Outcomes and 
Health Care Resource 
Utilization 
Modified language around 
completing questionnaires 
Clarification 
Section 9.1. Statistical 
Hypotheses 
Updated primary hypothesis 
To meet country-specific 
regulatory and payer 
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Section # and Name 
Description of Change 
Brief Rationale 
expectations 
Section 9.2. Sample Size 
Determination 
Updated language around sample 
size, randomization and cap on 
investigator’s choice of 
chemotherapy and coprimary 
endpoints 
Minimize patients treated on 
control arm (based on 
regulatory agency feedback 
and LIBRETTO-001 data) 
Section 9.3. Populations 
for Analyses 
Updated description of the ITT-
pembrolizumab population 
Clarification 
9.4.3. Efficacy Analyses 
Revised efficacy analyses 
population 
Clarification 
Section 9.4.3.1. Primary 
Analysis 
Amended details related to the 
primary analysis 
To meet country-specific 
regulatory and payer 
expectations 
Section 9.4.3.2. 
Secondary Analysis 
Amended details related to 
numerous secondary analyses 
To meet country-specific 
regulatory and payer 
expectations 
Section 9.4.4. Safety 
Analyses 
Clarified population to perform 
safety analyses on 
Clarification 
Section 9.5 Interim 
Analyses 
Added a single interim efficacy 
analysis and provided details for this 
analysis; removed previously 
described interim analyses 
To meet country-specific 
regulatory and payer 
expectations 
Section 10.2. Appendix 
2: Clinical Laboratory 
Tests 
Updated required sample 
instructions for treatment decisions 
and local lab results recording 
Section 10.5. Appendix 
5: Restricted and 
Prohibited Concomitant 
Medication 
Added guidance related to CYP 
usage 
For consistency with updated 
IB 
Section 10.5. Appendix 
5: Restricted and 
Prohibited Concomitant 
Medication 
Modified list of moderate CYP3A4 
inhibitors 
Correction 
Section 10.5. Appendix 
Removed guidance related to 
For consistency with updated 
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Section # and Name 
Description of Change 
Brief Rationale 
5: Restricted and 
Prohibited Concomitant 
Medication 
timeframe of PPI usage 
IB 
Section 10.6. Appendix 
6: Country-Specific 
Requirements 
Added guidance related to SAE 
collection for German patients 
To meet country-specific 
regulatory requirements 
Section 10.6. Appendix 
6: Country-Specific 
Requirements 
Added guidance related to Hepatitis 
and HIV testing for German patients 
To meet country-specific 
regulatory requirements 
Throughout the protocol 
Changed the name of LOXO-292 to 
selpercatinib 
Regulatory approval of drug 
name 
Throughout the protocol 
Minor formatting and editorial 
changes  
Minor, therefore not detailed 
Amendment (a) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union  
Overall Rationale for the Amendment: 
This amendment incorporates changes requested by regulatory agencies. In addition, this 
amendment includes changes made to correct and clarify information for sites. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
Added requirement for 
adequate tissue for central 
confirmation and removed 
FISH as a possible testing 
method; added inclusion 
criteria related to breast-
feeding 
Based on regulatory agency 
feedback 
3. Objectives
Added secondary objective to 
assess/evaluate performance 
of RET local laboratory tests 
compared to a single, central 
test 
Based on regulatory agency 
feedback 
9.4.6.4. Evaluation of RET 
Added subsection regarding 
evaluation of RET testing 
Based on regulatory agency 
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Section # and Name 
Description of Change 
Brief Rationale 
Testing Results 
results 
feedback 
8.8. Biomarkers 
Updated samples required for 
eligibility section regarding 
mandatory tissue requirements 
for central RET fusion 
confirmation 
Based on regulatory agency 
feedback 
2.3. Benefit Risk Assessment 
Added additional information 
and context to risk benefit 
assessment 
Based on regulatory agency 
feedback 
5.1. Inclusion Criteria 
Modified Contraception 
section to indicate participants 
must use a highly effective 
method of contraception and 
align with pemetrexed label 
language; modified Informed 
Consent section regarding 
language on participant's 
ability to understand 
implications of participation in 
a trial 
Based on regulatory agency 
feedback 
5.2. Exclusion Criteria 
Modified Medical Condition 
section. Clarified HIV and 
Hepatitis B exclusion criteria 
Based on regulatory agency 
feedback 
6.5. Concomitant Therapy 
Modified language on vaccine 
administration 
Based on regulatory agency 
feedback 
6.6. Dose Modification for 
Arm A and Arm B 
Modified recommended 
assessments following a 
hypersensitivity reaction 
Based on regulatory agency 
feedback 
1.3. Schedule of Activities 
Added test range for 
pregnancy tests during study 
treatment 
Based on regulatory agency 
feedback 
5.1. Inclusion Criteria 
Added clarification that all 
RET testing is required to be 
authorized by an appropriate 
accreditation body 
Based on regulatory agency 
feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
Updated ECG instructions and 
added timepoints for Arm A 
and Arm B; added sponsor 
approval language for scan 
submission; updated archived 
tissue instructions, updated 
pharmacokinetics sample 
instructions; updated 
collection of cfDNA 
Clarification 
4.1. Overall Design 
Clarified brain metastases 
assessment stratification 
language 
Clarification 
5.2. Exclusion Criteria 
Clarified timing of prior 
neoadjuvant/adjuvant therapy 
Clarification 
10.5. Appendix 
Added list of H2 blocking 
agents 
Clarification 
Throughout the protocol 
Updated drug name to 
selpercatinib 
Clarification 
Throughout the protocol 
Minor formatting and editorial 
changes 
Minor, therefore not detailed 
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11.
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