Clinical trial NCT04541706
Conditions: Advanced Non-Small Cell Lung Cancer
Sponsor: Pfizer
Start date: 2020-08-27; Completion date: 2022-07-20
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Lorlatinib is a third-generation, oral, reversible, ATP-competitive, macrocyclic TKI of ALK and ROS1. Lorlatinib was specifically designed to penetrate the CNS and to overcome known secondary resistance mutations in the ALK tyrosine kinase domain.

This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to evaluate the safety and tolerability of lorlatinib in adult participants with unresectable advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment.

This study is being conducted as a post approval study to fulfill Central Drugs Standard Control Organization (CDSCO) request relating to additional information on use of Lorlatinib in Indian patients.

Detailed description:

Arms: arm 1: The recommended dosage of lorlatinib is 100 mg orally once daily, with or without food, until disease progression, unacceptable toxicity, or participant refusal/lost to follow-up. About 100 participants will be enrolled in this study.
Interventions: intervention 1: Lorlatinib
Intervention descriptions: intervention 1: Lorlatinib will be supplied for oral administration as 25 mg tablets. The recommended dosage of lorlatinib is 100 mg orally once daily.

Protocol documents:
Prot_000.pdf: 
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SINGLE-ARM STUDY TO EVALUATE THE SAFETY OF LORLATINIB IN ALK 
INHIBITOR-TREATED UNRESECTABLE ADVANCED AND/OR RECURRENT 
ALK-POSITIVE NON-SMALL CELL LUNG CANCER PARTICIPANTS IN INDIA
Protocol Number:
B7461030
Medicinal product:
Lorlatinib
United States (US) Investigational New 
Drug (IND) Number: 
N/A (Not Applicable)
European Clinical Trial Database 
(EudraCT) Number:
N/A (Not Applicable)
Universal Trial Number:
N/A (Not Applicable)
Phase:
4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Original protocol
30 March 2020
Not Applicable (N/A)


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ABBREVIATION
Abbreviation
Definition
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AV
atrioventricular
bpm
beat per minute
BUN
blood urea nitrogen
CAP
chest abdomen pelvis
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
Clinical Study Agreement
CT
computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome
DCIS
ductal carcinoma in situ
DoR
duration of response
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic CRF
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
FDG
fluorodeoxyglucose
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HRT
hormonal replacement therapy
IC-DoR
intracranial duration of response
IC-ORR
intracranial objective response rate
ICH
International Council for Harmonisation
ILD
interstitial lung disease
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IVRS
interactive voice response system
IWRS
interactive web response system
LDL
low-density lipoprotein
LPFV
last participant last visit
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
N
number of participants
NCI
National Cancer Institute
NTI
narrow therapeutic index
NSCLC
non-small-cell lung cancer


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Abbreviation
Definition
ORR
objective response rate
P-gp
permeability glycoprotein
PASS
post-authorization safety study
PD
progressive disease
PET
positron emission tomography
PR
partial response
PS
performance status
PT
prothrombin time
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval calculated using Fridericia’s correction factor
PVC
premature ventricular complex
RECIST
Response Evaluation Criteria in Solid Tumor
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SRSD
Single Reference Safety Document
TEAE
treatment-emergent adverse event
TG
triglyceride
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
WBC
white blood cell
WOCBP
woman of childbearing potential


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PROTOCOL SUMMARY
Background
Lung cancers that harbor chromosomal rearrangements of anaplastic lymphoma kinase
(ALK) constitute about 3-5% of non-small-cell lung cancers (NSCLCs) and are highly 
responsive to small-molecule tyrosine kinase inhibitors (TKIs) that target ALK.  Standard 
treatment of patients with advanced ALK-positive NSCLC has recently shifted from 
sequential crizotinib followed by more potent second-generation ALK TKIs to front-line 
second-generation TKIs.  Whereas most patients derive clinical benefit from 
second-generation ALK TKIs, acquired resistance invariably develops and leads to clinical 
relapse.1
Lorlatinib is a third-generation, oral, reversible, adenosine triphosphate (ATP)-competitive, 
macrocyclic TKI of ALK and ROS1.  Compared with second-generation inhibitors, lorlatinib 
was specifically designed to penetrate the central nervous system (CNS) and to overcome 
known secondary resistance mutations in the ALK tyrosine kinase domain.  Preclinical 
studies demonstrate that lorlatinib is more potent than earlier-generation TKIs against 
nonmutant ALK and retains potency against most known single ALK resistance mutations, 
including the highly refractory ALK G1202R solvent front mutation.2  
In the pivotal single arm, multicenter Phase 2 study, treatment with lorlatinib showed 
clinically relevant response rates and durable response in patients with ALK-positive NSCLC 
who had previously received at least 1 ALK TKI, including the second-generation drugs 
ceritinib and alectinib.1  In the cohort of patients previously treated with a second-generation 
ALK TKI (number of patients [N]=28), objective responses were observed in 9 patients (32% 
[95% confidence interval [CI]: 15.9-52.4]). Substantial intracranial activity was also 
observed in these patients suffering from frequent brain metastases. The proportion of 
patients with objective intracranial response to lorlatinib was 55.6% (95% CI: 21.2-86.3) in 
patients with at least 1 measurable brain lesion at baseline (N=9). The overall and
intracranial median duration of response (DoR) were not reached (95% CI: 4.1 months – not
reached; duration of follow-up 7 months).  
Rationale
On the basis of pivotal Phase 1/2 Study B7461001, lorlatinib received conditional marketing 
authorization by the Indian Ministry of Health for the treatment of ALK fusion gene-positive 
unresectable advanced and/or recurrent NSCLC with resistance or intolerance to ALK 
TKI(s).  
In view of the lack of Indian participants from Study B7461001 and of the limited number 
from the ongoing Phase 3 Study B7461006 (CROWN), the Indian Ministry of Health 
requested the Sponsor to conduct a post-approval study to obtain additional data on 
participants in India.  The study will be conducted as a post-authorization safety study 
(PASS).  


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Study Objectives and Endpoints
Primary Objective

To evaluate the safety and tolerability of single-agent lorlatinib in participants with 
unresectable advanced and/or recurrent ALK-positive NSCLC with resistance or
intolerance to at least 1 prior ALK inhibitor treatment.  
Secondary Objective

To evaluate overall and intracranial antitumor activity of single-agent lorlatinib in 
participants with unresectable advanced and/or recurrent ALK-positive NSCLC with 
resistance or intolerance to at least 1 prior ALK inhibitor treatment.  
Primary Endpoint

Incidence of adverse events (AEs).  
Secondary Endpoints

Confirmed objective response rate (ORR), confirmed intracranial objective response 
rate (IC-ORR), DoR and intracranial duration of response (IC-DoR) as assessed by 
the Investigator using Response Evaluation Criteria in Solid Tumor (RECIST) 
version 1.1.  
Study Design
This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to 
evaluate the safety and tolerability of lorlatinib in adult participants with unresectable 
advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 
1 prior ALK inhibitor treatment.
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  
Study Treatments
Participants will take lorlatinib at the approved dose of 100 mg once daily (QD).  Participants
will be treated until disease progression, participant refusal/lost to follow-up, or unacceptable 
toxicity. 
At the end of study, participants who are on treatment and benefiting from lorlatinib 
treatment will be moved to commercially available lorlatinib (if considered appropriate by 
the Investigator) as soon as feasible.  


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Statistical Methods
The study’s objectives are to evaluate the safety, tolerability and antitumor activity of 
single-agent lorlatinib.  This study will enroll enough participants to ensure that 
100 participants are treated with lorlatinib.  With 100 participants, any AE rate can be 
estimated with the maximum standard error of 0.05.  All participants who receive at least 
1 dose of lorlatinib will be included in the safety and antitumor activity analyses, unless 
otherwise specified.
Analysis of Primary Endpoint
AEs will be graded by the Investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE
summaries will be on treatment-emergent adverse events (TEAEs), those with an initial onset 
or increasing in severity after the first dose of study medication to at most 35 days post last 
dosing date or the date of initiation of a new anticancer therapy.  The number and percentage 
of participants who experienced any AE, serious adverse event (SAE), treatment-related AE, 
and treatment-related SAE will be summarized.  
Additional Safety Analyses
Other safety parameters, including study treatment exposure, laboratory, electrocardiogram 
(ECG), vital signs measurements, dose reductions due to AEs, and temporary and permanent 
discontinuations due to AEs, will be summarized descriptively.  
Analysis of Secondary Endpoints
The following analyses of response will be performed according to the Investigator 
assessment using RECIST version 1.1. 
ORR
ORR is defined as the percent of participants with best overall response as confirmed 
complete response (CR) or confirmed partial response (PR) according to RECIST 
version 1.1.  ORR will be provided along with the corresponding 95% CI based on Wilson’s 
Score Method.  
IC-ORR
IC-ORR is defined as the percent of participants with intracranial response (ie, best overall 
intracranial response as confirmed CR or confirmed PR considering only intracranial lesions) 
relative to participants with CNS metastases at study entry.  IC-ORR will be provided along 
with the corresponding 95% CI based on Wilson’s Score Method.  


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DoR
DoR is defined as the time from the first documentation of objective tumor response 
(confirmed CR or confirmed PR) to the first documentation of disease progression or death 
due to any cause, whichever occurs first.  For participants whose responses proceed from PR 
to CR, the onset of PR is taken as the onset of response.  DoR will be summarized in the 
population of participants with a confirmed CR or confirmed PR using the Kaplan Meier 
method and will be displayed graphically where appropriate.  The median event time (if 
appropriate) and 2-sided 95% CI for the median will be provided.  Censoring for DoR will be 
described in the statistical analysis plan (SAP).  In case the number of participants with 
progressive disease (PD) after a confirmed CR or confirmed PR is small, the use of Kaplan 
Meier method may be limited and descriptive statistics may be provided.
IC-DoR
IC-DoR is defined as the time from the first documentation of an intracranial objective 
response in the subgroup of participants with brain metastasis at baseline.  Analyses similar 
to DoR will be repeated for IC-DoR considering participants with intracranial response (ie, 
best overall intracranial response as confirmed CR or confirmed PR considering only 
intracranial lesions).  
End of Study
The end of study is defined as 1 year after the “last participant first visit” (LPFV) date in the 
study.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed
information on each procedure and assessment required for compliance with the protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed on the 
Schedule of Activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the participant.  
Visit Identifier
Screening
Cycle 1
(28 days)
Visit on Day 1 of Every Cycle
End of 
Treatment
Follow-Up8
Visit Window
≤28 days
Day 1
±2 days
±7 days
Informed consent1
X
Tumor history
X
Medical history
X
Physical examination and 
vital signs
X
X
X
X
Body weight
X
X
X
ECOG performance status
X
X
X
X
Contraception check2 (as 
appropriate)
X
X
X
X
Laboratory
Hematology
X
(X)
X
X
Blood chemistry
X
(X)
X
X
Lipids
X
(X)
X
X
Pregnancy test3
X
X
X 
X
X
Cardiac Monitoring
12-Lead ECG4
X
(X)
X (every cycle up to Cycle 5)
X
Treatment
Lorlatinib
Orally once daily, continuously
Tumor Assessments
CT or MRI imaging5
X
X (every 12 weeks ±1 week)
X
Other Clinical Assessments
Serious and non-serious 
AEs6
X
X
X
X
X
Concomitant 
medications and
non-drug supportive 
interventions7
X
X
X
X
X
(X): No need to repeat if assessment performed within 7 days prior to Cycle 1 Day 1.
Abbreviations: AE=adverse event; CAP=chest abdomen pelvis; CRF=case report form; CT=computed 
tomography; CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; MRI=magnetic resonance imaging; NCI=National Cancer 
Institute; QTc=QT interval corrected for heart rate; RECIST=Response Evaluation Criteria in Solid Tumor;
SAE=serious adverse event.  
1.
Informed consent must be obtained prior to undergoing any study-specific procedures that are not 
considered standard of care.
2.
Contraceptive check: participant may be contacted by phone to confirm contraception is still appropriate 
per the protocol.


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3.
Pregnancy test: for female participants of childbearing potential, a serum or urine pregnancy test will be 
performed at Screening and at the Cycle 1 Day 1 visit.  Results must be available before investigational 
product administration.  Pregnancy tests will be also routinely repeated at every cycle during the active 
treatment period, at the end of treatment, at the short-term follow-up visit, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
4.
12-lead ECGs: 3 consecutive 12-lead ECGs pre-dose will be performed approximately 2 minutes apart to 
determine mean PR interval and QTc interval at baseline (screening and Cycle 1 Day 1 if the ECG at 
screening is performed more than 7 days before Cycle 1 Day 1) and single ECGs will be performed at Day 
1 of every cycle up to Cycle 5 and at the end of treatment.  Additional ECGs may be collected as clinically 
indicated.
5.
Tumor assessment: tumor assessments will include all known or suspected disease sites.  CT or MRI scans 
of CAP and MRI of the brain will be performed at Screening and repeated every 12 weeks (±1 week).  For 
all tumor assessments, the method of assessment that was used at Screening should be the same method 
used throughout the study. Responses will be confirmed ≥4 weeks after first occurrence of response, 
according to RECIST version 1.1 criteria.  Tumor assessment should be repeated at the end of treatment if 
more than 6 weeks have passed since the last evaluation.  
6.
AE assessments: AEs should be documented and recorded into the electronic CRF at each visit using NCI 
CTCAE version 4.03.  For AEs and SAEs, the active collection period to Pfizer or its designated 
representative begins from the time that the participant provides informed consent, through and including at 
least 28 calendar days and no more than 35 days after the last administration of the investigational product.  
If a participant begins a new anticancer therapy, the reporting period for non-serious AEs ends at the time 
the new treatment is started.  SAEs and Death must be reported if it occurs during the SAE reporting period 
after the last dose of investigational product, irrespective of any intervening treatment.  
7.
Concomitant medications and non-drug supportive interventions: all concomitant medications and 
non-drug supportive interventions should be recorded in the CRF from 28 days prior to start of study 
treatment and up to at least 28 days and no more than 35 days after the last dose of study treatment.
8.
Follow-up: at least 28 days, and no more than 35 days after discontinuation of treatment, participants will 
return to undergo contraception check, pregnancy test, review of concomitant medications, AE 
assessments, and review for resolution of any treatment-related toxicity.


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TABLE OF CONTENTS
ABBREVIATION......................................................................................................................3
LIST OF TABLES...................................................................................................................13
APPENDICES .........................................................................................................................14
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................16
3. STUDY DESIGN.................................................................................................................16
4. PARTICIPANT SELECTION.............................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................18
4.3. Life Style Guidelines...............................................................................................20
5. STUDY INTERVENTION..................................................................................................20
5.1. Allocation to Intervention/Treatment......................................................................21
5.2. Drug Supplies..........................................................................................................21
5.2.1. Dosage Form(s) and Packaging..................................................................21
5.3. Administration.........................................................................................................21
5.4. Drug Storage ...........................................................................................................22
5.5. Drug Accountability................................................................................................23
5.6. Concomitant Treatments .........................................................................................23
5.6.1. Prohibited Concomitant Treatments...........................................................24
5.6.2. Permitted Concomitant Treatments............................................................26
6. STUDY PROCEDURES .....................................................................................................27
6.1. Screening.................................................................................................................27
6.2. Study Period ............................................................................................................27
6.3. Follow-up Visit .......................................................................................................27
6.4. Participant Withdrawal............................................................................................27
7. ASSESSMENTS..................................................................................................................28
7.1. Antitumor Activity Assessments.............................................................................28
7.2. Safety Assessments .................................................................................................28
7.2.1. Physical Examination .................................................................................29


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7.2.2. Electrocardiogram.......................................................................................29
7.2.3. ECOG Performance Status .........................................................................29
7.2.4. Clinical Safety Laboratory Assessments ....................................................29
7.2.5. Pregnancy Testing ......................................................................................29
8. ADVERSE EVENT REPORTING......................................................................................30
8.1. Adverse Events........................................................................................................30
8.2. Reporting Period .....................................................................................................30
8.3. Definition of An Adverse Event..............................................................................31
8.4. Medication Errors....................................................................................................32
8.4.1. Treatment of Overdose ...............................................................................32
8.5. Abnormal Test Findings..........................................................................................32
8.6. Serious Adverse Event ............................................................................................33
8.6.1. Protocol-Specified Serious Adverse Events...............................................34
8.6.2. Potential Case of Drug-Induced Liver Injury.............................................34
8.7. Hospitalization ........................................................................................................35
8.8. Severity Assessment................................................................................................36
8.9. Causality Assessment..............................................................................................36
8.10. Exposure During Pregnancy..................................................................................37
8.11. Withdrawal Due to Adverse Events (See Also Section on participant 
Withdrawal)...............................................................................................................38
8.12. Eliciting Adverse Event Information ....................................................................38
8.13. Reporting Requirements........................................................................................38
8.13.1. Serious Adverse Event Reporting Requirements .....................................38
8.13.2. Non-serious Adverse Event Reporting Requirements..............................39
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................39
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................39
9.1. Estimands and Statistical Hypotheses.....................................................................39
9.1.1. Estimands....................................................................................................39
9.2. Sample Size Determination.....................................................................................40
9.3. Data Sources............................................................................................................40
9.4. Antitumor Activity Analysis ...................................................................................40
9.4.1. Analysis of Primary Endpoint ....................................................................40


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9.4.2. Analysis of Secondary Endpoints...............................................................40
9.5. Analysis of Other Endpoints ...................................................................................41
9.6. Safety Analysis........................................................................................................41
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................42
11. DATA HANDLING AND RECORD KEEPING .............................................................43
11.1. Case Report Forms/Electronic Data Record .........................................................43
11.2. Record Retention...................................................................................................43
12. ETHICS..............................................................................................................................44
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................44
12.2. Ethical Conduct of the Study ................................................................................44
12.3. Participant Information and Consent.....................................................................44
12.4. Participant Recruitment.........................................................................................45
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH
GCP ...........................................................................................................................46
13. DEFINITION OF END OF STUDY.................................................................................46
13.1. End of Study in Participating Country..................................................................46
14. SPONSOR DISCONTINUATION CRITERIA ................................................................46
15. PUBLICATION OF STUDY RESULTS..........................................................................46
15.1. Communication of Results by Pfizer ....................................................................46
15.2. Publications by Investigators ................................................................................46
16. REFERENCES ..................................................................................................................48
LIST OF TABLES
Table 1.
Study Intervention(s) Administered .....................................................................20
Table 2.
Dose Modification Recommendation for Adverse Reactions of Lorlatinib.........22
Table 3.
Pharmacokinetic Properties of Statins..................................................................52
Table 4.
Pharmacokinetic properties of Lipid Lowering Agents........................................53
Table 5.
Response Evaluation Criteria in Solid Tumors ....................................................58
Table 6
Protocol Required Safety Laboratory Assessments..............................................63


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APPENDICES
Appendix 1. Contraceptive Guidance......................................................................................49
Appendix 2. Pharmacokinetic Properties of Statins and Lipid Lowering Agents...................51
Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria7.............................................54
Appendix 4. ECG Findings of Potential Clinical Concern......................................................60
Appendix 5. ECOG Classification of Performance Status ......................................................62
Appendix 6. Clinical Laboratory Tests....................................................................................63


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Lorlatinib is a third-generation, oral, reversible, ATP-competitive, macrocyclic TKI of ALK 
and ROS1.  Compared with second-generation inhibitors, lorlatinib was specifically designed
to penetrate the CNS and to overcome known secondary resistance mutations in the ALK 
tyrosine kinase domain.  
1.2. Background and Rationale
Lung cancers that harbor chromosomal rearrangements of ALK constitute about 3-5% of 
NSCLCs and are highly responsive to small-molecule TKIs that target ALK.  Standard
treatment of patients with advanced ALK-positive NSCLC has recently shifted from 
sequential crizotinib followed by more potent second-generation ALK TKIs to front-line 
second-generation TKIs.  Whereas most patients derive clinical benefit from 
second-generation ALK TKIs, acquired resistance invariably develops and leads to clinical 
relapse.1
Preclinical studies demonstrate that lorlatinib is more potent than earlier-generation TKIs 
against nonmutant ALK and retains potency against most known single ALK resistance 
mutations, including the highly refractory ALK G1202R solvent front mutation.2
In the pivotal single arm, multicenter Phase 2 study, treatment with lorlatinib showed 
clinically relevant response rates and durable response in patients with ALK-positive NSCLC 
who had previously received at least 1 ALK TKI, including the second-generation drugs 
ceritinib and alectinib.1  In the cohort of patients previously treated with a second-generation 
ALK TKI (N=28), objective responses were observed in 9 patients (32%, 95% CI:
15.9-52.4). Substantial intracranial activity was also observed in these patients suffering 
from frequent brain metastases.  The proportion of patients with objective intracranial 
response to lorlatinib was 55.6% (95% CI: 21.2-86.3) in patients with at least 1 measurable 
brain lesion at baseline (N=9).  The overall and intracranial median DoR were not reached 
(95% CI: 4.1 months - not reached; duration of follow-up 7 months).  
On the basis of pivotal Phase 1/2 Study B7461001, lorlatinib received conditional marketing 
authorization by the Indian Ministry of Health for the treatment of ALK fusion gene-positive 
unresectable advanced and/or recurrent NSCLC with resistance or intolerance to ALK 
TKI(s).  
In view of the lack of participants in India from the Study B7461001 and of the limited 
number from the ongoing Phase 3 Study B7461006 (CROWN), the Indian Ministry of Health
requested the Sponsor to conduct a post-approval study to obtain additional data on 
participants in India.  The study will be conducted as a PASS.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Indian product label. 


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2. STUDY OBJECTIVES AND ENDPOINTS
Objective
Estimands
Endpoints
Primary

To evaluate the safety and 
tolerability of single-agent 
lorlatinib in participants with 
unresectable advanced and/or
recurrent ALK-positive 
NSCLC with resistance or 
intolerance to at least 1 prior 
ALK inhibitor treatment.  

The primary estimand is the 
incidence of AEs from the
time of first dose to at most
35 days post last dosing date 
or the date of initiation of a 
new anticancer therapy for all 
participants who receive at 
least 1 dose of lorlatinib, 
regardless of dosing 
interruptions or dosing 
compliance.

Incidence of AEs.  
Secondary

To evaluate overall and 
intracranial antitumor activity 
of single-agent lorlatinib in 
participants with unresectable 
advanced and/or recurrent 
ALK-positive NSCLC with 
resistance or intolerance to at 
least 1 prior ALK inhibitor 
treatment.  

The secondary estimand is the
treatment effect of lorlatinib 
as assessed by the investigator 
from time of first dose (ORR 
and IC-ORR) or time of first
response (DoR and IC-DoR) 
until progression is met, death 
or subsequent anticancer 
therapy is administered for all 
participants who receive at 
least 1 dose of lorlatinib 
without regard to tolerability 
or discontinuation from 
treatment.  

Confirmed ORR, confirmed 
IC-ORR, DoR and IC-DoR 
as assessed by the 
Investigator using RECIST 
version 1.1.  
3. STUDY DESIGN
This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to 
evaluate the safety and tolerability of lorlatinib in adult participants with unresectable 
advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 
1 prior ALK inhibitor treatment.
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  
4. PARTICIPANT SELECTION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom the protocol
intervention is considered appropriate by their health care provider.
4.1. Inclusion Criteria
Participant eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before participants are included in the study.


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Participants must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Evidence of histologically or cytologically confirmed diagnosis of unresectable 
advanced and/or recurrent NSCLC that carries an ALK rearrangement, as detected by 
an appropriate test.
2. Disease progression or intolerance to 1 previous treatment with ALK TKI.  
participants may have also had prior chemotherapy for their advanced and/or 
recurrent disease.
3. Participants with asymptomatic CNS metastases (including participants controlled 
with stable or decreasing steroid use within the last 2 weeks prior to study enrollment) 
will be eligible.  
4. Age ≥18 years. 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2.  
6. Adequate hematologic and renal function as defined as:
a.
Absolute neutrophil count (ANC) ≥1,000/mm3;
b. Platelets ≥50,000/mm3;
c.
Hemoglobin ≥8 g/dL;
d. Estimated creatinine clearance ≥30 mL/min as calculated using the method 
standard for the institution.
7. Adequate liver function, including:
a.
Total serum bilirubin ≤1.5 × upper limit of normal (ULN); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN (≤5.0 × ULN in case of liver metastases).
8. Adequate pancreatic function, including:
a.
Serum total amylase ≤1.5 × ULN.*
b. Serum lipase <1.5 × ULN.
*if total amylase >1.5 × ULN, but pancreatic amylase is within the ULN, the 
participant may be enrolled.


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9. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade 
<1 except for AEs that in the Investigator’s judgment do not constitute a safety risk 
for the participant.  
10. Systemic anticancer therapy completed within a minimum of 5 half-lives of study 
enrollment (unless clinically meaningful tumor flare per discretion of the Investigator, 
in which discussion with the Sponsor is warranted). 
11. Evidence of a personally signed and dated informed consent document indicating that 
the participant (or a legally acceptable representative) has been informed of all 
pertinent aspects of the study.  
12. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures.
13. Pregnancy test for females of childbearing potential negative at Screening or female 
participants who are not of childbearing potential (refer to Appendix 1 for definition).  
Male and female participants of childbearing potential and at risk for pregnancy must 
agree to use a highly effective method of contraception from the time of Screening, 
throughout the study and for 3 months after the last dose of assigned treatment, 
6 months if female participants. 
4.2. Exclusion Criteria
Participants presenting with any of the following will not be included in the study:
1. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study 
enrollment. Palliative radiation (<10 fractions) must have been completed at least 
48 hours prior to study enrollment.  Stereotactic or small field brain irradiation must 
have completed at least 2 weeks prior to study enrollment.  Whole brain radiation 
must have completed at least 4 weeks prior to study enrollment.  Prior irradiation to 
>25% of the bone marrow.
2. Major surgery within 4 weeks prior to enrollment.  Minor surgical procedures (eg, 
port insertion) are not excluded, but sufficient time should have passed for adequate 
wound healing.
3. Known prior or suspected severe hypersensitivity to study drug or any component in
its formulation.
4. Active and clinically significant bacterial, fungal, or viral infection. 
5. Clinically significant vascular (both arterial and venous) and non-vascular cardiac 
conditions (active or within 3 months prior to enrollment), which may include, but are 
not limited to:
a.
Arterial disease such as cerebral vascular accident/stroke (including transient 
ischemic attack [TIA]), myocardial infarction, unstable angina;


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b. Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary 
embolism;
c.
Non-vascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥II), second degree or third degree 
atrioventricular (AV) block (unless paced) or any AV block with PR interval 
>220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, 
uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 beats per 
minute (bpm) (unless participant is otherwise healthy such as long distance 
runners, etc.), machine read ECG with QT interval corrected for heart rate (QTc) 
>470 msec, or congenital long QT syndrome.
6. History or known presence of interstitial fibrosis, interstitial lung disease (ILD), 
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative 
bronchiolitis, and pulmonary fibrosis.
7. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the participant 
inappropriate for enrollment in this study.
8. Evidence of active malignancy (other than current NSCLC, non-melanoma skin 
cancer, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ 
[DCIS] of the breast or localized and presumed cured prostate cancer) within the last 
3 years prior to enrollment.
9. Concurrent use of any of the following food or drugs (consult the Sponsor if in doubt 
whether a food or a drug falls into any of the categories described below) within 
12 days prior to the first dose of lorlatinib:
a.
Known strong cytochrome (CYP)3A inducers (eg, carbamazepine, enzalutamide, 
mitotane, rifampin, St. John’s Wort).  
b. Known strong CYP3A inhibitors (eg, grapefruit juice or grapefruit/grapefruit 
related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat,
clarithromycin, conivaptan, diltiazem, idelalisib, indinavir, itraconazole, 
ketoconazole, lopinavir, nelfinavir, paritaprevir, posaconazole, ritonavir alone and 
with elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or 
dasabuvir or saquinavir or tipranavir, telaprevir and voriconazole).  The topical 
use of these medications (if applicable), such as 2% ketoconazole cream, is 
allowed.  
c.
Known CYP3A substrates with narrow therapeutic index, such as pimozide, 
quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including 
transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine).  


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d. Known permeability glycoprotein (P-gp) substrates with a narrow therapeutic 
index (eg, digoxin).  
10. Participants who are investigational site staff members directly involved in the 
conduct of the study and their family members, site staff members otherwise 
supervised by the Investigator, or participants who are Pfizer employees directly
involved in the conduct of the study. 
11. Participation in other studies involving investigational drug(s) (Phases 1-4) during 
study participation. 
12. Breastfeeding female participants.  
4.3. Life Style Guidelines
See Appendix 1 for mandatory contraception information.  
Refrain from consumption of grapefruit/grapefruit related citrus fruits (eg, Seville oranges
pomelos) from 1 day before the start of study intervention until after the final dose.   
Lorlatinib has moderate influence on the ability to drive and use machines.  Caution should 
be exercised when driving or operating machinery as participants may experience CNS 
effects.
5. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.  
Table 1.
Study Intervention(s) Administered
ARM name
Lorlatinib 100 mg QD
Intervention name
Lorlatinib
Type
Small molecule
Dosage form
Tablet
Dose strength
25 mg
Dosage
100 mg QD
Route of administration
Oral
Sourcing
Provided centrally by the Sponsor
Packaging and labeling
Study intervention will be provided in bottles.  Each bottle will be labeled as 
required per country requirement.
Current/former name(s) or 
alias(es)
PF-06463922/lorlatinib
Abbreviation: QD=once daily.  


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5.1. Allocation to Intervention/Treatment
This is an open-label study; however, the specific intervention to be taken by a participant 
will be assigned using an interactive voice response system (IVRS)/interactive web response 
system (IWRS).  The site will contact the IVRS/IWRS prior to the start of study intervention 
administration for each participant.  The site will record the intervention assignment on the 
applicable case report form (CRF), if required.
5.2. Drug Supplies
5.2.1. Dosage Form(s) and Packaging
Lorlatinib (PF-06463922) will be supplied by Pfizer Global Clinical Supply for oral 
administration as 25 mg tablets in high-density polyethylene (HDPE) bottles with desiccant 
and labeled according to local regulatory requirements. 
Drug supplies will be shipped to the study sites with a Drug Shipment and Proof of Receipt
form.  This form will be completed and filed, as directed on the bottom of the Drug Shipment 
and Proof of Receipt form.  The Investigator shall take responsibility for and shall take all
steps to maintain appropriate records and ensure appropriate supply, storage, handling,
distribution, and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.
5.3. Administration
The product will be administered in accordance with the label.  
The recommended dosage of lorlatinib is 100 mg orally QD, with or without food, until 
disease progression, unacceptable toxicity, or participant refusal/lost to follow-up.  Tablets 
should be swallowed whole.  Tablets should not be chewed, crushed, or split.  Tablets should 
not be taken if they are broken, cracked, or otherwise not intact.  Lorlatinib should be taken
at the same time each day.  If a dose is missed, then the missed dose should be taken unless 
the next dose is due within 4 hours.  Two (2) doses should not be taken at the same time to 
make up for a missed dose.  An additional dose should not be taken if vomiting occurs after 
lorlatinib but the next scheduled dose should be continued.  Dosing interruption or dose 
reduction may be required based on individual safety and tolerability.
Lorlatinib dose reduction levels are summarized below:

First dose reduction: 75 mg taken orally QD; 

Second dose reduction: 50 mg taken orally QD.  
Lorlatinib should be permanently discontinued if the participant is unable to tolerate the 
50 mg dose taken orally QD.  Dose modification recommendations for adverse reactions are 
provided in Table 2.  


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Table 2.
Dose Modification Recommendation for Adverse Reactions of Lorlatinib
Adverse Reaction
Lorlatinib Dosing
CNS Effect
Grade 1
Continue lorlatinib at same dose or withhold the 
dose until recovery to baseline.  Resume lorlatinib at 
the same dose or at a reduced dose.
Grade 2 or Grade 3
Withhold dose until Grade 0 or 1.  Resume lorlatinib 
at a reduced dose. 
Grade 4
Permanently discontinue lorlatinib.  
Hyperlipidemia
Grade 4 hypercholesterolemia or Grade 4 
hypertriglyceridemia
Withhold lorlatinib until recovery of 
hypercholesterolemia and/or hypertriglyceridemia to 
less than or equal to Grade 2. Resume lorlatinib at 
the same dose.  If severe hypercholesterolemia 
and/or hypertriglyceridemia recurs, resume lorlatinib 
at a reduced dose.
AV block
Second-degree AV block
Withhold lorlatinib until PR interval is less than 
200 msec.  Resume lorlatinib at a reduced dose.
First occurrence of complete AV block
Withhold lorlatinib until:

pacemaker placed, or

PR interval less than 200 msec.
If a pacemaker is placed, resume lorlatinib at the 
same dose.  If no pacemaker is placed, resume 
lorlatinib at a reduced dose.
Recurrent complete AV block
Place pacemaker or permanently discontinue 
lorlatinib.
ILD/Pneumonitis
Any grade treatment–related ILD/Pneumonitis
Permanently discontinue lorlatinib.  
Other adverse reactions
Grade 1 or Grade 2
Continue lorlatinib at same dose or reduced dose.  
Grade 3 or Grade 4
Withhold lorlatinib until symptoms resolve to less 
than or equal to Grade 2 or baseline.  Resume 
lorlatinib at reduced dose.
Grade based on NCI CTCAE version 4.0. 
Abbreviations: AV=atrioventricular; CNS=central nervous system; CTCAE=Common Terminology Criteria 
for Adverse Events; ILD=interstitial lung disease; NCI=National Cancer Institute.  
5.4. Drug Storage
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are 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 with 
access limited to the Investigator and authorized site staff.  At a minimum, daily 
minimum and maximum temperatures for all site storage locations must be 


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documented and available upon request.  Data for nonworking days must indicate the 
minimum and maximum temperature since previously documented for all site storage 
locations upon return to business.
3. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.
4. Study interventions should be stored in their original containers and in accordance
with the labels.
5. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
6. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention 
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion.  Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation.  Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the investigational product manual.
5.5. Drug Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).  All study interventions will be
accounted for using an investigational product accountability form/record.  Further guidance 
and information for the final disposition of unused study interventions are provided in the 
investigational product manual. 
The Sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the investigator site, 
the Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.  
5.6. Concomitant Treatments
The use of permitted concomitant medication must be in accordance with the study drug
label.
All concomitant medications and non-drug supportive interventions should be recorded in the 
CRF from 28 days prior to start of study treatment and to at least 28 days and no more than 
35 days after the last dose of study treatment.


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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 and dates of
administration including start and end dates.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
5.6.1. Prohibited Concomitant Treatments
Concomitant treatment considered necessary for the participant’s wellbeing may be given at 
discretion of the treating physician.  Prior to giving any concomitant medication, the 
following lorlatinib drug interaction information should be considered.
Lorlatinib is a substrate of CYP3A.  This is supported by drug interaction studies in healthy 
volunteers, in which lorlatinib exposure was decreased by a strong CYP3A inducer
(rifampin) and increased by a strong CYP3A inhibitor (itraconazole).  
Thus, the following cautions are provided: 

Lorlatinib metabolism may be inhibited by strong CYP3A inhibitors leading to a
potential increase in lorlatinib toxicities.  Concomitant administration of lorlatinib 
with strong CYP3A inhibitors (eg, boceprevir, cobicistat, clarithromycin, conivaptan, 
diltiazem, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nelfinavir, 
paritaprevir, posaconazole, ritonavir alone and with elvitegravir or indinavir or 
lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, 
telaprevir and voriconazole) may increase lorlatinib plasma concentrations.  
Grapefruit products may also increase lorlatinib plasma concentrations and should be 
avoided.  An alternative concomitant medicinal product with less potential to inhibit 
CYP3A should be considered.  If a strong CYP3A inhibitor must be co-administered, 
the starting lorlatinib dose of 100 mg QD should be reduced to 75 mg dose QD.  In 
participants who have had a dose reduction to 75 mg orally QD due to adverse 
reactions and who initiate a strong CYP3A inhibitor, reduce lorlatinib dose to 50 mg 
orally QD.  If concurrent use of the strong CYP3A inhibitor is discontinued, lorlatinib 
should be resumed at the dose used prior to the initiation of the strong CYP3A 
inhibitor and after a washout period of 3 to 5 half-lives of the strong CYP3A 
inhibitor.  The participant should be closely monitored for safety and reduction of the 
lorlatinib dose if necessary.  
In the B7461011 study, in which lorlatinib was co-administered with rifampin, significant 
increases in AST and ALT were observed.  In subsequent studies in cynomolgus monkeys, 
lorlatinib in combination with carbamazepine demonstrated similar AST and ALT elevations 
as well.  


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Thus, the following clinical guidance is provided: 

The use of a strong CYP3A inducer (eg, carbamazepine, enzalutamide, mitotane, 
rifampin, St. John’s Wort) with lorlatinib is contraindicated, as they may also reduce 
lorlatinib plasma concentration.  Furthermore, when lorlatinib was coadministered 
with rifampin (Study B7461011), increases in AST and ALT were noted.  
Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A 
inducer prior to initiating lorlatinib and until study treatment discontinuation.  In 
addition, use with moderate CYP3A inducers should be avoided due to the potential 
reduction in lorlatinib exposure.  
In vivo results show that lorlatinib 100 mg QD at steady state is a moderate inducer of 
CYP3A.  In addition, a drug interaction study conducted in NSCLC participants indicated 
that lorlatinib is a moderate inducer of P-gp.
Thus, the following clinical guidance is provided:  

Lorlatinib is a net moderate inducer of CYP3A at steady state.  Thus, concurrent 
administration of lorlatinib with CYP3A substrates with narrow therapeutic indices 
(NTIs), including but not limited to alfentanil, ciclosporin dihydroergotamine,
ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and 
tacrolimus, should be avoided since the concentration of these medicinal products 
may be reduced by lorlatinib. However, if it is absolutely necessary to use, Sponsor
approval is required and the dose of the CYP3A substrate may need to be increased.  
The narrow NTI CYP3A substrate should be started only after at least 14 days of
continuous lorlatinib dosing.  If there is a change in the lorlatinib dosing regimen 
such as a dosing interruption or dose reduction, the administration of the NTI CYP3A
substrate should be stopped and resumed at a readjusted dose only after at least 14
days of resumed lorlatinib dosing.

Lorlatinib is a net moderate inducer of P-gp at steady state. The concurrent use of 
drugs which are P-gp substrates with NTI, such as digoxin is not permitted at study 
entry.  The use of these drugs during the study is not recommended and alternate 
medications should be considered.  If absolutely necessary to use during the study, it 
should be initiated following sponsor approval, and be used then with caution. 
Other Antitumor or Experimental Drugs
No additional systemic antitumor therapy will be permitted while participants are receiving 
a study therapy.  Additionally, the concurrent use of select herbal supplements (St John’s 
wort, ginseng, and goldenseal) is not permitted. 
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first cycle but they may be used to treat treatment-emergent neutropenia as per standard 
of care.  


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If approved and available for use per country regulations, erythropoietin may be used at the 
Investigator’s discretion for the supportive treatment of anemia.
5.6.2. Permitted Concomitant Treatments
Bisphosphate Therapy
Bisphosphonate therapy for metastatic bone disease is permitted.  Bisphosphonate therapy 
should be given as per local medical practice.
Lipid-Lowering Therapy
Since statins can be metabolized or inhibited by the same CYP450 pathways as lorlatinib 
(Appendix 2), pitavastatin or pravastatin followed by rosuvastatin should be the agents to use 
concomitantly with lorlatinib since they are the least involved with the CYP450 enzyme
systems. However, no clinical drug-drug interactions have been formally studied with 
lorlatinib and careful monitoring is advised.  
If hypertriglyceridemia requires treatment beyond a statin that was administered for 
hypercholesterolemia, fenofibrate or fish oils followed by nicotinic acid should be 
administered as they have the least involvement with the CYP450 enzyme systems 
(Appendix 2).  No clinical drug-drug interactions have been formally conducted with 
lorlatinib and agents listed in Appendix 2, so careful monitoring is advised. 
Radiotherapy

Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing the lesions were known at the time of study entry and the Investigator 
clearly indicates that the need for palliative radiotherapy is not indicative of disease 
progression.  In view of the current lack of data about the interaction of lorlatinib with 
radiotherapy, lorlatinib treatment should be interrupted during palliative radiotherapy, 
stopping 1 day before and resuming treatment after recovery from acute radiation 
toxicities to baseline.
Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study. The
appropriate interval of time between surgery and lorlatinib required to minimize the risk of 
impaired wound healing and bleeding has not been determined. Stopping lorlatinib is 
recommended at least 2 days prior to surgery.  Postoperatively, the decision to reinitiate 
lorlatinib treatment should be based on a clinical assessment of satisfactory wound healing 
and recovery from surgery.


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6. STUDY PROCEDURES
6.1. Screening
All participants being considered for the study and eligible for screening must sign an 
informed consent for the study before completing any study-specific procedures.  Participants 
will be screened within 28 days prior to first dosing of lorlatinib to confirm that they meet the
eligibility criteria for the study.  The required screening assessments are summarized in the 
Schedule of Activities and Section 7 Assessments.  
6.2. Study Period
For study treatment period procedures, see Schedule of Activities and Section 7 Assessments.  
6.3. Follow-up Visit
At least 28 days, and no more than 35 days after discontinuation of treatment, participants 
will return to undergo contraception check, pregnancy test, review of concomitant
medications, AE assessments, and review for solution of any treatment-related toxicity.  
6.4. Participant Withdrawal

Participants who request to discontinue study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further 
contact with him/her or persons previously authorized by participant to provide this 
information.  Participants should notify the Investigator of the decision to withdraw 
consent from future follow-up in writing, whenever possible.  The withdrawal of 
consent should be explained in detail in the medical records by the Investigator, as to 
whether the withdrawal is from further treatment with study drug only or also from 
study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 

All reasonable efforts must be made to locate participants to determine and report 
their ongoing status.  This includes follow-up with persons authorized by the 
participant as noted above.  Lost to follow-up is defined by the inability to reach the 
participant after a minimum of 3 documented phone calls, faxes, or emails as well as 
lack of response by participant to 1 registered mail letter.  All attempts should be 
documented in the participant’s medical records.  If it is determined that the 
participant has died, the site will use permissible local methods to obtain the date and
cause of death.  If Investigator’s use of third-party representative to assist in the 
follow-up portion of the study has been included in the participant’s informed 
consent, then the Investigator may use a Sponsor retained third-party representative to 
assist site staff with obtaining participant’s contact information or other public vital 
status data necessary to complete the follow-up portion of the study.  The site staff 
and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If after all 
attempts, the participant remains lost to follow-up, then the last known alive date as 


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determined by the Investigator should be reported and documented in the 
participant’s medical records.
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator. 
If a participant does not return for a scheduled visit, every effort should be made to contact
the participant.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s medical record. In any 
circumstance, every effort should be made to document participant’s outcome, if possible.  
The Investigator should inquire about the reason for withdrawal, request the participant to 
return for a final visit, if applicable, and follow up with the participant regarding any 
unresolved AEs.
If the participant withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should 
be collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.  
7. ASSESSMENTS
7.1. Antitumor Activity Assessments
Tumor assessments will include all known or suspected disease sites. Computed tomography 
(CT) or magnetic resonance imaging (MRI) scans of chest abdomen pelvis (CAP) and MRI
of the brain will be performed at Screening.  Gadolinium contrast enhanced MRI must be 
used for assessment of CNS lesions with contingent slices of 1 mm for lesions 5 mm to 
10 mm in size, 5 mm for lesions greater than 10 mm.  For all tumor assessments, the method 
of assessment that was used at Screening should be the same method used throughout the 
study.  CT and MRI scans to be done at every 12 weeks ±1 week till the end of treatment.  
Tumor assessment should be repeated at the end of treatment if more than 6 weeks have 
passed since the last evaluation.  Moreover, radiological tumor assessments will be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration).  
Assessment of response will be made using RECIST version 1.1 (Appendix 3).  
Confirmation of response will be required at least 4 weeks after initial response is observed.
All participants’ files and radiologic images must be available for source verification.
7.2. Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 


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7.2.1. Physical Examination

Participants will have a physical examination to include major body systems, body 
weight, blood pressure, pulse rate, and assessment of ECOG performance status at the 
time points described in the Schedule of Activities.  Blood pressure and pulse rate 
should be taken with the participant in the seated position after the participant has 
been sitting quietly for at least 5 minutes. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
7.2.2. Electrocardiogram

ECG will be obtained as outlined in the Schedule of Activities using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  

PR interval prolongation and AV block have been reported in participants receiving 
lorlatinib. If at any time the mean PR interval is prolonged (≥200 msec) or QTc is 
prolonged (≥470 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  

ECG values of potential concern are listed in Appendix 4. Dose modifications for 
AV block is provided in Table 2.  
7.2.3. ECOG Performance Status
Refer to Appendix 5 for ECOG PS criteria.  
7.2.4. Clinical Safety Laboratory Assessments
The required laboratory tests are listed in Appendix 6. 

Hematology and blood chemistry will be collected at the time points described in the 
Schedule of Activities and analyzed at local laboratories. They may also be 
performed when clinically indicated.  Local laboratory certification(s) and reference 
ranges should be provided to the Sponsor prior to study participant screening activity.
7.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in woman of childbearing potential 
(WOCBP) at the times listed in the Schedule of Activities.  Following a negative pregnancy 
test result at Screening, appropriate contraception must be commenced, and a second 
negative pregnancy test result will be required at Cycle 1 Day 1 prior to the participant’s 
receiving the study intervention.  Pregnancy tests will also be repeated at every cycle during 
the active treatment period, at the end of treatment, and at the short-term follow-up visit to be 
performed at least 28 days and no more than 35 days after the last dose.  Pregnancy tests will 
also be done whenever 1 menstrual cycle is missed during the active treatment period (or 


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when potential pregnancy is otherwise suspected). If a urine test cannot be confirmed as 
negative (eg, an ambiguous result), a serum pregnancy test is required.  In such cases, the 
participant must be excluded if the serum pregnancy result is positive.  
In the case of a confirmed pregnancy, the participant will be withdrawn from study 
medication and from the study.  
Pregnancy tests may also be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations. 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of suspected causal relationship to the 
investigational product(s) will be reported as described in the following sections.  
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the 
AE.  The Investigator is required to assess causality. Follow-up by the Investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
Investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For AEs and SAEs, the active reporting period to Pfizer or its designated representative 
begins from the time that the participant provides informed consent, which is obtained prior 
to the participant’s participation in the study, ie, prior to undergoing any study-related
procedure and/or receiving investigational product, through and including at least 28 calendar
days and no more than 35 days after the last administration of the investigational product.  
SAEs occurring to a participant after the active reporting period has ended should be reported 
to the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.
If a participant begins a new anticancer therapy, the AE reporting period for nonserious AEs 
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.


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8.3. Definition of An Adverse Event
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure; 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.  


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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong participant, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the AE CRFs 
and on the SAE form when appropriate.  In the event of medication dosing error, the Sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error and, if applicable, any associated AE(s) are captured on an 
AE CRF page (refer to Section 8 Adverse Event Reporting section for further details).  
8.4.1. Treatment of Overdose
For this study, any dose of lorlatinib greater than 100 mg within a 24-hour time period will
be considered an overdose.  Sponsor does not recommend specific treatment for an overdose.  
There is no antidote for lorlatinib.  
In the event of an overdose, the Investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AE/SAE and given the dose dependent effect 
on PR interval, ECG monitoring is recommended.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to safety only when associated with a SAE.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Event
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria (CTC) 
Grade 5 (see Section 8.8 Severity Assessment). 

Lack of efficacy should be reported as an AE when it is associated with an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  The important medical event should be reported as serious, 
if it is determined that the event may jeopardize the participant or may require intervention to
prevent 1 of the other AE outcomes.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.  


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8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
Investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements).  
8.6.2. Potential Case of Drug-Induced Liver Injury
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the participant’s individual baseline values and underlying conditions.  
Participants who present with the following laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values:

participants with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT values ≥3 × ULN concurrent with 
a total bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value ≤2 × ULN or not available;

For participants with preexisting ALT or AST or total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For participants with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).

Concurrent with:

For participants with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased by 1 × ULN or ≥3 × ULN (whichever is smaller).
The participant should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  


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Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test abnormalities identified at the time, 
should be considered potential Hy’s law cases irrespective of availability of all the results of 
the investigations performed to determine etiology of the abnormal liver function tests.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, participant has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);


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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual participant;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
AEs will be graded by the Investigator according to the CTCAE version 4.03.  
Grade
Clinical Description of Severity
1
Mild adverse event
2
Moderate adverse event
3
Severe adverse event
4
Life-threatening consequences; urgent intervention indicated
5
Death related to adverse event
8.9. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An Investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided. If the Investigator does not know whether or not the investigational product 
caused the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the Sponsor (see Section 8.13 Reporting Requirements).  If 
the Investigator’s causality assessment is “unknown but not related to investigational 
product,” this should be clearly documented on study records.  
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.


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8.10. Exposure During Pregnancy
For investigational products and for marketed products, an EDP occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.  An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman 
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).
2. A male participant has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy. 
If a study participant or study participant’s partner becomes or is found to be pregnant during 
the study participant’s treatment with the investigational product, the Investigator must 
submit this information to the Pfizer drug safety unit on a SAE Report Form and EDP 
supplemental form, regardless of whether an SAE has occurred.  In addition, the Investigator 
must submit information regarding environmental exposure to a Pfizer product in a pregnant 
woman (eg, a participant reports that she is pregnant and has been exposed to a cytotoxic 
product by inhalation or spillage) using the EDP supplemental form.  This must be done
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion or until pregnancy termination and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to investigational product. 
Additional information regarding the EDP may be requested by the Investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
Investigator will provide the study participant with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the source
documents that the participant was given the Pregnant Partner Release of Information Form 
to provide to his partner.
8.11. Withdrawal Due to Adverse Events (See Also Section on Participant Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a participant withdraws because of an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study participant or legally acceptable representative.  In addition, each study participant 
or legally acceptable representative will be questioned about AEs.
8.13. Reporting Requirements
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of Investigator awareness of the 
event.  
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP and exposure via breastfeeding cases.  
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study participant initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.


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For all SAEs, the Investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an Investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a participant death, 
a summary of available autopsy findings must be submitted as soon as possible to Pfizer or 
its designated representative.
8.13.2. Non-serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in an SAP, which will be maintained by the Sponsor.  This document 
may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Estimands and Statistical Hypotheses
The primary objective of the study is to evaluate the safety and tolerability of single-agent 
lorlatinib in participants with unresectable advanced and/or recurrent ALK-positive NSCLC 
with resistance or intolerance to at least 1 prior ALK inhibitor treatment.  
The secondary objective of the study is to evaluate overall and intracranial antitumor activity 
of single-agent lorlatinib in participants with unresectable advanced and/or recurrent 
ALK-positive NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor
treatment.  
9.1.1. Estimands
The primary estimand is the incidence of Adverse Events from the time of first dose to at 
most 35 days post last dosing date or the date of initiation of a new anticancer therapy for all 
participants who receive at least one dose of lorlatinib, regardless of dosing interruptions or 
dosing compliance.


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The secondary estimand is the treatment effect of lorlatinib as assessed by the investigator 
from time of first dose (ORR and IC-ORR) or time of first response (DoR and IC-DoR) until 
progression is met, death or subsequent anticancer therapy is administered for all participants 
who receive at least one dose of lorlatinib without regard to tolerability or discontinuation 
from treatment.
9.2. Sample Size Determination
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  With 100 participants, any AE rate can be estimated with the maximum standard 
error of 0.05. All participants who receive at least 1 dose of lorlatinib in this study will be 
included in the safety and antitumor activity analyses unless otherwise specified.
9.3. Data Sources
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 site.
Data reported on the CRF or entered in the electronic CRF (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.  
9.4. Antitumor Activity Analysis
All antitumor activity analyses will be performed on the safety set.  Participants with 
inadequate baseline or no follow-up assessments will be considered as non-responders.  
9.4.1. Analysis of Primary Endpoint
Not applicable.  
9.4.2. Analysis of Secondary Endpoints
The following analyses of response will be performed according to the Investigator 
assessment using RECIST version 1.1. 
ORR
ORR is defined as the percent of participants with best overall response as confirmed CR or 
confirmed PR according to RECIST version 1.1.  ORR will be provided along with the 
corresponding 95% confidence interval based on Wilson’s Score Method. 
IC-ORR
IC-ORR is defined as the percent of participants with intracranial response (ie, best overall 
intracranial response as confirmed CR or confirmed PR considering only intracranial lesions) 
relative to participants with CNS metastases at study entry. IC-ORR will be provided along 
with the corresponding 95% CI based on Wilson’s Score Method. 


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DoR
DoR is defined as the time from the first documentation of objective tumor response 
(confirmed CR or confirmed PR) to the first documentation of disease progression or death 
due to any cause, whichever occurs first.  For participants whose responses proceed from PR 
to CR, the onset of PR is taken as the onset of response.  DoR will be summarized in the 
population of participants with a confirmed CR or confirmed PR using the Kaplan Meier 
method and will be displayed graphically where appropriate.  The median event time (if 
appropriate) and 2-sided 95% CI for the median will be provided. Censoring for DoR will be
described in the SAP.  In case the number of participants with PD after a confirmed CR or 
confirmed PR is small, the use of Kaplan Meier method may be limited and descriptive 
statistics may be provided.
IC-DoR
IC-DoR is defined as the time from the first documentation of an intracranial objective 
response in the subgroup of participants with brain metastasis at baseline.  Analyses similar 
to DoR will be repeated for IC-DoR considering participants with intracranial response (ie, 
best overall intracranial response as confirmed CR or confirmed PR considering only 
intracranial lesions).  
9.5. Analysis of Other Endpoints
Not applicable.  
9.6. Safety Analysis
All safety analysis will be conducted on the safety set. 
Primary Endpoint
AEs will be graded by the Investigator according to the CTCAE version 4.03 and coded 
using the MedDRA.  The focus of AE summaries will be on TEAEs, those with an initial 
onset or increasing in severity after the first dose of study medication up to at most 35 days 
post last dosing date or the date of initiation of a new anticancer therapy.  The number and 
percentage of participants who experienced any AE, SAE, treatment-related AE, and 
treatment-related SAE will be summarized.  
Adverse events leading to death or discontinuation of study treatment, events classified as
NCI CTCAE version 4.03 Grade ≥3, study drug-related events, SAEs, dose reductions due to 
AEs, and temporary and permanent discontinuations due to AEs will be summarized.
Detailed information collected for each AE will be listed with a description of the event, 
duration, whether the AE was serious, intensity, relationship to study treatment, action taken, 
and clinical outcome.


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Study Treatment Exposure
Drug exposure will be summarized using descriptive statistics.  The number and percentage 
of participants with drug interruptions and the corresponding reasons will be summarized.  
The number and percentage of participants with dose reductions and the corresponding 
reasons will also be summarized.
Laboratory Abnormalities
Laboratory test results will be graded according to NCI CTCAE version 4.03.  Data will be 
summarized by the type of laboratory test.  Summary of laboratory abnormalities will be 
presented by maximum CTCAE grade.  For laboratory tests without an NCI CTCAE grade 
definition, results will be categorized as normal (within normal ranges), abnormal, or not 
done.  Shift tables will be provided to examine the distribution of laboratory abnormalities.
Vital Signs
Vital signs data will be summarized using descriptive statistics (mean, standard deviation, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (ie, unscheduled assessments will be excluded). 
Electrocardiograms
All ECGs obtained during the study will be evaluated for safety.  The triplicate pre-dose data 
will be averaged. Summary statistics and data presentations for pre-dose will use the 
averaged data.  Any data obtained from ECGs repeated for safety reasons after the nominal 
time points will not be averaged along with the preceding.
QT intervals will be corrected for heart rate using standard correction factors (ie, Fridericia’s 
[default correction], Bazett’s [if necessary], and possibly a study-specific factor, as 
appropriate).  However, safety assessments as to QTc prolongation will be based on the 
Fridericia's correction formula.  Data will be summarized and listed for QT, HR, RR, PR, 
QRS, QTc.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) of QTc 
and other ECG parameters will be used to summarize absolute values and changes from 
baseline on treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT, PR, and QRS and the maximum post-baseline corrected QT 
interval.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.


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The study site may be subject to review by the Institutional Review Board (IRB)/Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included participant.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the participant’s chart in the hospital or the 
physician’s office.  In these cases, data collected on the CRFs must match the data in those 
charts.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating participants (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Council for Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer. The investigator must ensure that the records continue to be stored 
securely for so long as they are retained.


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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the participants. 
In that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World
Medical Association 1996 & 2008) and Schedule Y, Drug and Cosmetics Act 1940 and 
Rules 1945. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local India regulatory requirements and laws.
12.3. Participant Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant personal data.
Such measures will include omitting participant names or other directly identifiable data in 
any reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 


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study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data is compiled for transfer to Pfizer and other authorized parties, 
participant names, addresses, and other identifiable data will be replaced by a numerical code
consisting of a numbering system provided by Pfizer in order to de-identify study 
participants.  The study site will maintain a confidential list of participants who participated 
in the study linking their numerical code to the participant’s actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of participant 
personal data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study participant, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  
Whenever consent is obtained from a participant’s legally acceptable representative, the 
participant’s assent (affirmative agreement) must subsequently be obtained when the 
participant has the capacity to provide assent, as determined by the IRB/EC. If the 
investigator determines that a participant’s decisional capacity is so limited he/she cannot 
reasonably be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the participant’s assent may be waived with source documentation 
of the reason assent was not obtained.  If the study participant does not provide his/her own 
consent, the source documents must record why the participant did not provide consent (eg, 
minor, decisionally impaired adult), how the investigator determined that the person signing 
the consent was the participant’s legally acceptable representative, the consent signer’s 
relationship to the study participant (eg, parent, spouse) and that the participant’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant or the participant’s legally acceptable representative, when 
applicable, before any study-specific activity is performed.  The investigator will retain the 
original of each participant’s signed consent document.  
12.4. Participant Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.


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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
13. DEFINITION OF END OF STUDY
13.1. End of Study in Participating Country
End of study in participating country is defined as 1 year after the LPFV date in the study.  
At the end of study, participants who are on treatment and benefiting from lorlatinib 
treatment will be moved to commercially available lorlatinib (if considered appropriate by 
the Investigator) as soon as feasible.  
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating participants 
and the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), www.ctri.nic.in (Clinical Trials 
Registry-India) and other public registries in accordance with applicable local 
laws/regulations.
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product. 
15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational drug.  


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However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the Study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive 
non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 
2018;19(12):1654-67. 
2. Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and 
Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 
2016;6(10):1118-33.
3. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: 
mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80(6):565-81.
4. Miller M. “What Are the Effects of Statins on Triglycerides and What Are the Results of 
Major Outcomes Studies?” 2009 Mar 12; http://www.medscape.org/viewarticle/589010.
5. Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacy and safety profiles of a novel 
synthetic HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 2003;21(3):199-215.
6. Schaefer EJ, McNamara JR, Tayler T, et al. Comparisons of effects of statins 
(atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and 
postprandial lipoproteins in patients with coronary heart disease versus control subjects. 
Am J Cardiol 2004;93(1):31-9.
7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.


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Appendix 1. Contraceptive Guidance 
Definition
WOCBP: A woman is considered fertile following menarche and until becoming
post-menopausal unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before 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, (eg, mullerian agenesis, androgen insensitivity), Investigator 
discretion should be applied to determining study entry.  
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in 
the participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high FSH level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or HRT.

Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-estrogen 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
Contraception – For Women
Female participants must use highly effective contraception while taking study intervention 
and for at least 6 months after stopping study intervention.
Lorlatinib may reduce the effectiveness of hormonal contraceptive methods; therefore, 
hormonal contraceptives may not be considered highly effective.  If hormonal contraception 
is unavoidable, it must be used in combination with a condom.
Highly effective methods that have low user dependency includes:  
1. Intrauterine device (IUD).
2. Bilateral tubal occlusion.
3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Contraception – For Men
Male participants must use a condom while taking study intervention and for at least 
3 months after stopping study intervention. 


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Appendix 2. Pharmacokinetic Properties of Statins and Lipid Lowering Agents
The PK properties of statins and lipid lowering agents are provided in Table 3 and Table 4, 
respectively.  


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Table 3.
Pharmacokinetic Properties of Statins
Generic Name
Pitavastatin
Pravastatin
Rosuvastatin
Atorvastatin
Simvastatin
Lovastatin
Fluvastatin
Metabolism†
++
+
+
+++
+++
+++
+++
Metabolizing CYP enzyme
(of lactone or acid form)
(2C9)
(3A4)
2C9 (2C19)
3A4 (2C8)
3A4 2C8
3A4 2C8
2C9
Inhibitor of CYP3A4‡
-
-
+
+
+
+
+
Inhibitor of CYP2C9‡
-
-
(+)
-
-
-
+
Triglyceride lowering effect
22%-31%**
11%-14%*
17%*
14%-19%*
10%-14%*
13%*
5%***
Adapted from Neuvonen et al, 2006.3
Parentheses indicate minor significance.
†Three (3) plus signs indicate extensively metabolized, and 1 plus sign indicates limited metabolism, eliminated mainly unchanged.
‡A plus sign indicates yes, and a minus sign indicates no.
*Baseline TG 100-200 mg/dL; Effect of Statins vs Placebo on Triglyceride Levels in 10 Primary and Secondary Placebo-Controlled Outcome Trials table in 
Miller 2009.4
**Baseline TG 150 mg/dL; Kajinami et al, 2003.5
***Schaefer et al, 2004.6
Abbreviations:  CYP=cytochrome P450; TG=triglyceride.  


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Table 4.
Pharmacokinetic properties of Lipid Lowering Agents
Fibric Acids
Fish Oils
Generic Name
Nicotinic Acid
Gemfibrozil
Fenofibrate
Ethyl esters of omega-3 
fatty acids
Dose
100–2000 mg QD
600 mg BID
200 mg QD
4 gm QD/2 gm BID
Metabolism‡
-
-
-
-
Metabolizing CYP enzymes 
(of lactone or acid form)‡
-
-
-
-
Inhibitor of CYP3A4‡
-
-
-
-
Inhibitor of CYP2C9‡
-
+++
++
-
Inhibitor of CYP2C19‡
-
++
+
-
Inhibitor of CYP1A2‡
-
+
-
-
Triglyceride lowering effect
(TG 150 mg/dL)
20%-50%*
20%-50%*
36%-55%e
45%
Drug interactions
Caution should be used 
when prescribing niacin with
statins
Concomitant administration 
with statins is 
contraindicated
May increase exposure to 
pravastatin and its metabolite 
(13%-26%) when used 
concomitantly
-
‡A plus sign indicates yes, and a minus sign indicates no.
*NCEP-ATP III, 2001.
Abbreviations: BID=twice daily; QD=once daily.
a.
PI, 4/2015.
b.
PI, 11/2014.
c.
PI, 12/2014.
d.
PI, 05/2014.
e.
Primary hypertriglyceridemia – severe hypertriglyceridemia (baseline TG levels 500 to 1500 mg/dL).


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Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria7
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or not, according to the criteria summarized below.  
1. Measurable Lesions
Lesions that can be accurately measured in at least 1 dimension (longest diameter in
the plane of measurement is to be recorded) with a minimum size of:  

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan 
slice thickness no greater than 5 mm);

10 mm for lesions assessed clinically by caliper measurement (lesions which 
cannot be accurately measured with calipers should be recorded as 
non-measurable);

20 mm for lesions assessed by chest X-ray;

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). 
2. Non-measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or 
pathological lymph nodes with a ≥10 but <15 mm short axis) as well as truly 
non-measurable lesions.  Truly non-measurable lesions include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses identified by physical 
examination and not measurable by reproducible imaging techniques.   
Nodes that have a short axis <10 mm are considered non-pathological and should not 
be recorded or followed. 
3. Special Considerations Regarding Specific Lesions
Bone lesions

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such 
as CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.


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
Blastic bone lesions are non-measurable.
Cystic lesions

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above.  However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions.
Lesions with prior local treatment

Tumor lesions situated in a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion.
Solitary lesions

If a measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. 
One (1) exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as 
2 dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The 
smaller of these measures is the short axis. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present”, “absent”, or in rare cases “unequivocal progression”.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the CRF (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
Definition of Tumor Response
Target Lesions
Response in target lesions is defined as follows:  

CR: disappearance of all target lesions. 

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.

PD: at least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  The appearance of 1 or more new 
lesions is also considered a sign of progression.

Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of “0” on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.  
Response in non-target lesions is defined as follows:  

CR: disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (<10 mm short axis).  


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
Non-CR/Non-PD: persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.  

PD: unequivocal progression of existing non-target lesions. (Note: the appearance of 
one or more new lesions is also considered progression).  
Cytology, Histology
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or SD and PD.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF.  Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF. 
New Lesions
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
The use of fluorodeoxyglucose (FDG)-PET is sometimes reasonable to complement a CT 
scan assessment of a PD (particularly for possible “new” disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up.  

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.


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Confirmation of Tumor Response
Confirmation of response is required for non-randomized trials with primary endpoint of 
response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data.  
Determination of Overall Response by RECIST Version 1.1
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in 
Table 5.  
Table 5.
Response Evaluation Criteria in Solid Tumors
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, 
NE=none-evaluable
Best Overall Response
The best overall response is determined once all the data for the patient is known.  Best 
response in trials in which confirmation of CR or PR is not required (ie, randomized trials) is 
defined as the best response across all time points (for example, a patient who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall response
of PR).  When SD is believed to be the best response, it must also meet the protocol-specified 
minimum time from baseline.  If the minimum time is not met when SD is otherwise the best 
time point response, the patient’s best response depends on the subsequent assessments.  For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD.  The same patient lost to follow-up after the 
first SD assessment would be considered non-evaluable. 
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  CR or PR may be claimed only if the criteria for each are met at a following 
time point as specified in the protocol (generally 4 weeks later).


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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy.  The objective 
response status of such patients is to be determined by evaluation of target and non-target 
lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. 


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Appendix 4. ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >200 msec.

New prolongation of QTcF to >470 msec (absolute) or by ≥60 msec from baseline.

New onset atrial flutter or fibrillation, with controlled ventricular response rate, ie, 
rate <120 bpm.

New onset Type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New onset left bundle branch block (QRS >120 msec).

New onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 


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pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the Investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
Abbreviations: AE=adverse event; AV=atrioventricular; ECG=electrocardiogram; PVC=premature 
ventricular complex; QTcF=QT interval calculated using Fridericia’s correction factor; SAE=serious adverse 
event.  


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Appendix 5. ECOG Classification of Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead


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Appendix 6. Clinical Laboratory Tests
The laboratory tests detailed in Table 6 will be performed by the local laboratory and must be 
performed in fasted condition.  Investigators must document their review of each laboratory 
safety report.
Pregnancy testing:  

Refer to Section 4.1 Inclusion Criteria for screening pregnancy criteria.

For details of timing of recommended pregnancy testing see Section 7.2.5.  
Table 6
Protocol Required Safety Laboratory Assessments
Hematology
Clinical Chemistry1
Other Tests
Platelet count
Hemoglobin
WBC count with differential:
Neutrophils2
Lymphocytes2
Monocytes2
Eosinophils2
Basophils2
BUN or urea
Creatinine
Glucose (fasting)
Uric acid
Potassium
Sodium
Total calcium
Magnesium
AST
ALT
Alkaline phosphatase
Albumin
Total bilirubin
Phosphorus or phosphate
Serum total amylase3
Serum lipase
Highly sensitive serum or urine hCG 
pregnancy test (as needed for women of 
childbearing potential).  
Lipids: total cholesterol, LDL,4 HDL, 
and triglycerides.  
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CRF=case report form; hCG=human chorionic gonadotropin; HDL=high-density lipoprotein; INR=international 
normalized ratio; LDL=low-density lipoprotein; SAE=serious adverse event; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=woman of childbearing potential.  
1.
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR 
>1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE.  
2.
Values in percentages (%) are acceptable.  
3.
Pancreatic isoenzyme required if serum total amylase not within normal limits per local institutional ranges.
4.
A measured LDL value is preferable instead of calculated LDL.  If LDL value is calculated from 
Friedewald equation, this can be considered only in absence of the following circumstances: plasma 
dysbetalipoproteinemia (Type III hyperlipoproteinemia).  

SAP_001.pdf: 
Protocol B7461030 (PF-06463922) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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Protocol B7461030 
 
 
 
 
SINGLE-ARM STUDY TO EVALUATE THE SAFETY OF LORLATINIB IN ALK 
INHIBITOR-TREATED UNRESECTABLE ADVANCED AND/OR RECURRENT 
ALK-POSITIVE NON-SMALL CELL LUNG CANCER PARTICIPANTS IN INDIA 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
1 
 
Date:  
03 June 2020 


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................4 
APPENDICES ...........................................................................................................................4 
1. VERSION HISTORY ............................................................................................................5 
2. INTRODUCTION .................................................................................................................5 
2.1. Study Objectives, Endpoints, and Estimands ............................................................6 
2.1.1. Primary Estimand .........................................................................................6 
2.1.2. Secondary Estimands ....................................................................................7 
2.1.3. Additional Estimand .....................................................................................9 
2.2. Study Design .............................................................................................................9 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9 
3.1. Primary Endpoint ......................................................................................................9 
3.2. Secondary Endpoints .................................................................................................9 
3.2.1. Confirmed Objective Response Rate (ORR) ................................................9 
3.2.2. Confirmed Intracranial Objective Response Rate (IC-ORR) .......................9 
3.2.3. Duration of Response (DoR) ......................................................................10 
3.2.4. Intracranial Duration of Response (IC-DoR) .............................................10 
3.3. Other Endpoint ........................................................................................................10 
3.4. Baseline Variables ...................................................................................................10 
3.5. Safety Endpoints .....................................................................................................11 
3.5.1. Treatment Exposure ....................................................................................11 
3.5.2. Adverse Event of Special Interest (AESI) ..................................................11 
3.5.3. Laboratory Data ..........................................................................................11 
3.5.4. Vital Signs ..................................................................................................11 
3.5.5. ECG ............................................................................................................12 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................12 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................12 
5.1. Hypotheses and Decision Rules ..............................................................................12 
5.1.1. Hypotheses and Sample Size ......................................................................12 
5.1.2. Decision Rules ............................................................................................12 
5.2. General Methods .....................................................................................................12 
5.2.1. Definition of Study Day..............................................................................12 


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5.2.2. Definition of Cycle and Cycle Day ............................................................13 
5.2.3. Definition of Start of New Anticancer therapy ...........................................13 
5.2.4. Date of Last Contact ...................................................................................14 
5.2.5. Measurable Disease ....................................................................................14 
5.2.6. Tumor Assessment Date .............................................................................15 
5.2.7. Sum of Lesion Diameters ...........................................................................15 
5.2.8. Adequate Baseline Tumor Assessment ......................................................15 
5.2.9. Adequate Post-baseline Tumor Assessment ...............................................15 
5.2.10. Nominal and Unscheduled Visits .............................................................15 
5.2.11. Standard Derivations and Reporting Conventions ...................................15 
5.2.12. Analyses for Continuous and Qualitative Variables .................................16 
5.2.13. Analyses for Time-to-Event Endpoints ....................................................16 
5.3. Methods to Manage Missing Data ..........................................................................16 
5.3.1. Missing ECG Data ......................................................................................16 
5.3.2. Handling of Incomplete or Missing Dates ..................................................17 
5.3.2.1. Adverse Events ..........................................................................17 
5.3.2.2. Exposure ....................................................................................18 
5.3.2.3. Date of Death ............................................................................18 
5.3.2.4. Date of Start of New Anticancer Therapy .................................18 
5.3.2.5. Other Dates ................................................................................20 
5.3.3. Missing Toxicity Grade of Adverse Events ................................................20 
6. ANALYSES AND SUMMARIES ......................................................................................21 
6.1. Primary Endpoint ....................................................................................................21 
6.1.1. Adverse Events ...........................................................................................21 
6.1.1.1. Main Analysis ...........................................................................21 
6.1.1.2. Additional Analysis ...................................................................23 
6.2. Secondary Endpoints ...............................................................................................23 
6.2.1. Confirmed OR ............................................................................................23 
6.2.2. Confirmed IC-OR .......................................................................................25 
6.2.3. DoR .............................................................................................................25 
6.2.4. IC-DoR .......................................................................................................27 
6.3. Other Endpoint(s) ....................................................................................................27 
Not applicable. ...............................................................................................................27 


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6.4. Subset Analyses .......................................................................................................27 
Not applicable. ...............................................................................................................27 
6.5. Baseline and Other Summaries and Analyses .........................................................27 
6.5.1. Baseline Summaries ....................................................................................27 
6.5.2. Study Conduct and Participant Disposition ................................................28 
6.5.2.1. Disposition ................................................................................28 
6.5.2.2. Protocol Deviations ...................................................................29 
6.5.3. Study Treatment Exposure .........................................................................29 
6.5.3.1. Exposure to lorlatinib ................................................................29 
6.5.3.2. Dose Reductions and Interruptions ...........................................29 
6.5.4. Concomitant Medications and Non-drug Treatments .................................30 
6.5.5. Subsequent Anticancer Therapies/Procedures ............................................31 
6.6. Safety Summaries and Analyses .............................................................................31 
6.6.1. Laboratory Data ..........................................................................................31 
6.6.2. Vital Signs ..................................................................................................34 
6.6.3. Electrocardiograms .....................................................................................35 
6.6.4. Performance Status .....................................................................................37 
6.6.5. Physical Examination .................................................................................37 
7. INTERIM ANALYSES .......................................................................................................37 
7.1. Introduction .............................................................................................................37 
7.2. Interim Analyses and Summaries ............................................................................37 
8. APPENDICES .....................................................................................................................38 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................5 
Table 2. 
Outcome and event dates for DoR analyses .............................................26 
Table 3. 
Censoring Reasons and Hierarchy for DoR analyses ...............................26 
 
APPENDICES 
Appendix 1. List of Abbreviations...........................................................................................38 
 


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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study B7461030 is based on the protocol version 1 
dated 30Mar2020.   
Table 1. 
Summary of Changes  
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1/ 
03 June 2020 
Original 30 
March 2020 
N/A 
N/A 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B7461030.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
Any deviations from this analysis plan will be described in the Clinical Study Report. 
All summaries and analyses will include all data in the database at the end of the study which  
is defined as 1 year after the last participant first visit date in the study.   


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2.1. Study Objectives, Endpoints, and Estimands 
Objective 
Estimands 
Endpoints 
Primary 
• 
To evaluate the safety and 
tolerability of single-agent 
lorlatinib in participants with 
unresectable advanced 
and/or recurrent ALK-
positive Non-Small Cell 
Lung Cancer (NSCLC) with 
resistance or intolerance to 
at least 1 prior ALK 
inhibitor treatment.   
• 
The primary estimand is the 
incidence of Adverse Events 
(AEs) from the time of first 
dose to at most 35 days post 
last dosing date or the date 
of initiation of a new 
anticancer therapy for all 
participants who receive at 
least 1 dose of lorlatinib, 
regardless of dosing 
interruptions or dosing 
compliance. 
• 
Incidence of AEs.   
Secondary 
• 
To evaluate overall and 
intracranial antitumor 
activity of single-agent 
lorlatinib in participants with 
unresectable advanced 
and/or recurrent ALK-
positive NSCLC with 
resistance or intolerance to 
at least 1 prior ALK 
inhibitor treatment.   
• 
The secondary estimand is 
the treatment effect of 
lorlatinib as assessed by the 
investigator from time of first 
dose (Objective Response 
Rate (ORR) and Intra 
Cranial-Objective Response 
Rate (IC-ORR)) or time of 
first response (Duration of 
Response (DoR) and 
Intracranial Duration of 
Response (IC-DoR)) until 
progression is met, death or 
subsequent anticancer 
therapy is administered for 
all participants who receive 
at least 1 dose of lorlatinib 
without regard to tolerability 
or discontinuation from 
treatment.   
• 
Confirmed ORR, confirmed 
IC-ORR, DoR and IC-DoR 
as assessed by the 
Investigator using Response 
Evaluation Criteria in Solid 
Tumors (RECIST) 
version 1.1.   
 
 
2.1.1. Primary Estimand 
The primary estimand is the incidence of Adverse Events from the time of first dose to 35 
days post last dosing date or the date prior to initiation of a new anticancer therapy, 
whichever occurs first for all participants who receive at least one dose of lorlatinib, 
regardless of dosing interruptions or dosing compliance.  It includes the following 4 
attributes: 
• Population: Participants with unresectable advanced and/or recurrent ALK-positive 
NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment as 
defined by the inclusion and exclusion criteria, and who receive at least one dose of 
Lorlatinib 


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• Variable: Binary indicator of whether any AE occurring at least once 
• Intercurrent event: All data after the intercurrent event “initiation of a new anticancer 
therapy (-1 day)” or “treatment discontinuation (+35 days post last dosing date)” will be 
excluded. Dosing interruptions or dosing compliance are not considered as intercurrent 
event for this analysis.. 
• Population-level summary: Adverse event incidence rate from the time of first dose to 35 
days post last dosing date or the date prior to initiation of a new anticancer therapy, 
whichever occurs first.  AE incidence rate is the number of patients with any AE 
occurring at least once in the study population. 
2.1.2. Secondary Estimands 
A secondary estimand is the treatment effect of Lorlatinib as assessed by the investigator 
from the time of first dose until progression is met, death or subsequent anticancer therapy is 
administered regardless of tolerability or duration on treatment. It includes the following 4 
attributes: 
• Population: Participants with unresectable advanced and/or recurrent ALK-positive 
NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment as 
defined by the inclusion and exclusion criteria, and who receive at least one dose of 
lorlatinib  
• Variable: Confirmed Objective Response (OR) according to RECIST 1.1 per investigator, 
defined as confirmed partial response (PR) or confirmed complete response (CR) from the 
date of first dose until progressive disease (PD), death, or start of new anticancer therapy  
• Intercurrent event: All data after the intercurrent event “start of subsequent anticancer 
therapy” will be excluded.  All tumor assessments are considered regardless of gaps in 
assessments.  Treatment interruptions is not an intercurrent event. 
• Population-level summary: ORR, ie percentage of participants with confirmed CR or 
confirmed PR and corresponding 95% confidence interval (CI) based on Wilson’s Score 
Method.  
Another secondary estimand is the durability of treatment effect of Lorlatinib as assessed by 
the investigator from the time of first response until progression is met, death or subsequent 
anticancer therapy is administered regardless of tolerability or duration on treatment for 
participants showing a confirmed OR per investigator. It includes the following 4 attributes: 
• Population: Participants with unresectable advanced and/or recurrent ALK-positive 
NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment as 
defined by the inclusion and exclusion criteria, who receive at least one dose of lorlatinib 
and showing a confirmed OR per investigator  
• Variables: DoR 


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• Intercurrent event: All data after the intercurrent events “start of subsequent anticancer 
therapy” or “extended gap in tumor assessment prior to progression or death” will be 
excluded. Treatment interruptions is not an intercurrent event. 
• Population-level summary: Kaplan-Meier Median of DoR and 2-sided 95% CI 
Another secondary estimand is the intracranial treatment effect of Lorlatinib as assessed by 
the investigator from the time of first dose until intracranial progression is met per 
investigator, death or subsequent anticancer therapy is administered regardless of tolerability 
or duration on treatment. It includes the following 4 attributes: 
• Population: Participants with unresectable advanced and/or recurrent ALK-positive 
NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment as 
defined by the inclusion and exclusion criteria, who receive at least one dose of lorlatinib 
and having Central Nervous System (CNS) metastases at study entry  
• Variable: Confirmed Intracranial-Objective Response (IC-OR) according to RECIST 1.1 
per investigator, defined as confirmed Intracranial Partial Response (IC-PR)  or 
Intracranial Complete Reponse (IC-CR) from the date of first dose until PD, death, or start 
of new anticancer therapy  
• Intercurrent event: All data after the intercurrent event “start of subsequent anticancer 
therapy” will be excluded.  All tumor assessments are considered regardless of gaps in 
assessments.  Treatment interruptions is not an intercurrent event. 
• Population-level summary: IC-ORR, ie percentage of participants with confirmed IC-CR 
or confirmed IC-PR and corresponding 95% confidence interval based on Wilson’s Score 
Method. 
Another secondary estimand is the durability of intracranial treatment effect of Lorlatinib as 
assessed by the investigator from the time of first intracranial response until intracranial 
progression is met, death or subsequent anticancer therapy is administered regardless of 
tolerability or duration on treatment for participants showing a confirmed IC-OR per 
investigator. It includes the following 4 attributes: 
• Population: Participants with unresectable advanced and/or recurrent ALK-positive 
NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment as 
defined by the inclusion and exclusion criteria, who receive at least one dose of lorlatinib, 
having CNS metastases at study entry and showing a confirmed IC-OR per investigator 
• Variable: IC-DoR according to RECIST 1.1 per investigator  
• Intercurrent event: All data after the intercurrent events “start of subsequent anticancer 
therapy” or “extended gap in tumor assessment prior to progression or death” will be 
excluded.   Treatment interruptions is not an intercurrent event. 
• Population-level summary: Kaplan-Meier Median of IC-DoR and 2-sided 95% CI 


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2.1.3. Additional Estimand 
Not applicable. 
2.2. Study Design 
This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to 
evaluate the safety and tolerability of lorlatinib in adult participants with unresectable 
advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 
1 prior ALK inhibitor treatment. 
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.   
Participants will continue with the assigned study treatment until disease progression, 
participant refusal/lost to follow-up, or unacceptable toxicity.  At the end of the study, 
participants who are on treatment and benefiting from Lorlatinib treatment will be moved to 
commercially available Lorlatinib (if considered appropriate by the Investigator) as soon as 
feasible.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
The primary endpoint is the incidence of AEs.  AEs will be graded by the Investigator 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events  
(NCI CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The focus of AE summaries will be on treatment-emergent adverse 
events (TEAEs) defined in section 3.5.1.   
3.2. Secondary Endpoints 
3.2.1. Confirmed Objective Response Rate (ORR) 
Objective Response (OR) based on investigator assessment is defined as CR or PR according 
to RECIST v1.1 from date of first dose until documented PD or start of new anticancer 
therapy without regard to discontinuation from treatment. Both CR and PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met. Participants without a CR or PR or with death prior to first post-
baseline assessment, inadequate baseline assessment, new anticancer therapy started prior to 
first post-baseline assessment, and all post-baseline disease assessments missing will be 
considered as non-responders.  
ORR is defined as the percent of participants with best overall response (BOR) as confirmed 
CR or confirmed PR according to RECIST version 1.1   BOR is defined in section 6.2.1. 
3.2.2. Confirmed Intracranial Objective Response Rate (IC-ORR) 
Intracranial OR based on investigator assessment is defined as IC-CR or IC-PR according to 
RECIST v1.1 from date of first dose until documented Intracranial Progressive Disease (IC-
PD) or start of new anticancer therapy without regard to discontinuation from treatment. Both 


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IC-CR and IC-PR must be confirmed by repeat assessments performed no less than 4 weeks 
after the criteria for response are first met. Participants without IC-CR or IC-PR or with death 
prior to first post-baseline assessment, inadequate baseline assessment, new anticancer 
therapy started prior to first post-baseline assessment, and all post-baseline disease 
assessments missing will be considered as non-responders.  
IC-ORR is defined as the percent of participants with intracranial response (ie, best overall 
intracranial response as confirmed CR or confirmed PR considering only intracranial lesions) 
relative to participants with CNS metastases at study entry. 
3.2.3. Duration of Response (DoR) 
DoR is defined as the time from the first documentation of objective tumor response 
(confirmed CR or confirmed PR) to the first documentation of disease progression or death 
due to any cause, whichever occurs first. The censoring rules for DOR are presented in 
section  6.2.3. 
3.2.4. Intracranial Duration of Response (IC-DoR)  
IC-DoR is defined as the time from the first documentation of an intracranial objective 
response in the subgroup of participants with brain metastasis at baseline.  The censoring 
rules for DoR will be used for IC-DoR. 
3.3. Other Endpoint 
Not applicable. 
3.4. Baseline Variables 
Start and end dates of study treatment:  
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
the study drug. 
The date of last dose of study treatment is the latest date of non-zero dosing of the study 
drug. 
Definition of baseline:  
No windowing will be applied when defining baseline, except as noted in Section 5.2.8 for 
tumor assessments.  Any deviations from the protocol specified window will be documented 
as protocol deviations.   A separate definition of adequate baseline will be provided for tumor 
assessment related antitumor activity endpoints.  
For antitumor activity analyses and baseline characteristics associated with tumor 
assessments the last assessment prior to treatment start date will serve as the baseline 
assessment. 
For safety (including laboratory, vital signs and Eastern Cooperative Oncology Group 
(ECOG) performance status) the last assessment performed on or prior to date of the first 


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dose of study treatment will serve as the baseline assessment.  If there are no observations 
meeting these criteria, then baseline is considered missing.   
Participants who start treatment and discontinue from the study on the same day may have 
two different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
Triplicate electrocardiograms (ECGs) are collected pre-dose; therefore, the baseline for each 
ECG measurement is the average of the latest pre-dose triplicate measurements.  
Unscheduled assessments will not be included in the calculation of the average.  
3.5. Safety Endpoints 
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.  Safety data collected outside the on-treatment period as described below will be 
listed but not summarized. 
3.5.1. Treatment Exposure 
On-treatment is defined as the time from the first dose of study treatment through end of 
safety follow-up period, ie 35 days after discontinuation of treatment, or start of new 
anticancer therapies (follow-up systemic therapy, follow-up radiation therapy to target or 
non-target lesions or follow-up surgery to target or non-target lesions), whichever occurs 
first. Adverse events occurring on the same day as the first dose of study treatment will be 
considered to have occurred during the on-treatment period.  
An adverse event is considered treatment emergent (TEAE) if: 
• the event occurs for the first time during the effective duration of study treatment and 
was not observed prior to the start of study treatment (e.g., during screening), or 
• the event was observed prior to the start of study treatment but increased in severity 
during the effective duration of study treatment. 
3.5.2. Adverse Event of Special Interest (AESI) 
AESIs include events such as CNS (mood, speech, cognition) events. These events will be 
defined based on a list of MedDRA Preferred Terms  (PTs) specified in the Safety Review 
Plan for lorlatinib. A final list will be provided to programming prior to database release. 
3.5.3. Laboratory Data 
Hematology, chemistry, and lipids results will be programmatically graded according to the 
NCI CTCAE version 4.03 for relevant parameters. A shift summary of baseline grade by 
maximum post-baseline grade will be presented. Parameters which cannot be graded will be 
summarized relative to the normal range (ie, normal range high or normal range low). 
Additional details are provided in Section 6.6.1. 
3.5.4. Vital Signs 
Vital signs data will be summarized using descriptive statistics (mean, standard deviation 
(Std Dev), median, quartiles, minimum, and maximum) of actual values and change from 


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baseline for each nominal visit over time (ie, unscheduled assessments will be excluded).  
Additional details are provided in Section 6.6.2. 
3.5.5. ECG 
Descriptive statistics (n, mean, median, Std Dev, minimum, and maximum) of corrected QT 
(QTc) and other ECG parameters will be used to summarize absolute values and changes 
from baseline on treatment. Categorical analysis will be conducted for the maximum change 
from baseline in QTc, PR, and QRS and the maximum post-baseline QTc interval.  
Additional details are provided in Section 6.6.3.  
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures. 
Only participants who signed informed consent will be included in the analysis sets below. 
Population 
Description 
Enrolled 
All participants who sign the informed consent document.  
Safety 
All participants who receive at least 1 dose of lorlatinib.  
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
All analyses will be performed at study participant data set release at the end of study, 
defined as 1 year after the last participant first visit (LPFV) date in the study. 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and Sample Size  
The primary objective of the study is to evaluate the safety and tolerability of single-agent 
lorlatinib in participants with unresectable advanced and/or recurrent ALK-positive NSCLC 
with resistance or intolerance to at least 1 prior ALK inhibitor treatment.  No formal 
statistical hypothesis testing is planned for the primary objective.  
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib. 
5.1.2. Decision Rules 
There is no decision rule for the primary objective. 
5.2. General Methods 
5.2.1. Definition of Study Day 
Start day of study treatment is the day of the first dose of study treatment. 


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The study day for assessments occurring on or after the first dose of study treatment (e.g., 
adverse event onset, tumor measurement) will be calculated as: 
 
Study day = Date of the assessment/event - start date of study treatment + 1.  
The study day for assessments occurring prior to the first dose of study treatment (e.g., 
baseline characteristics, medical history) will be negative and calculated as: 
 
Study day = Date of the assessment/event –start date of study treatment. 
The study day will be displayed in all relevant data listings. 
5.2.2. Definition of Cycle and Cycle Day 
Cycle start and end dates are derived per participant. Treatment will be dispensed at the 
beginning of every 28-day cycle. 
 
• 
For Cycle X, the actual cycle start date for each participant is: 
o the earliest start date of dosing (dose>0 at that visit) in Cycle X visit Case 
Report Form (CRF) exposure page 
• 
For all but the last cycle,  
o actual cycle stop date is calculated as the start date of the next cycle minus 
one day.  
o actual cycle duration is calculated from Day 1 of a cycle to the day prior to 
Day 1 of the next cycle, as follows:  
 
 
Actual Cycle Duration (weeks) = (cycle stop date – cycle start date + 1) / 7 
• 
For the last cycle, actual cycle duration is calculated as follows:  
o Actual Cycle Duration (weeks) = (last date of study treatment– cycle start date 
+ 1) /7  
The cycle day will be calculated as: 
Cycle day = Date of the assessment/event – cycle start date + 1. 
5.2.3. Definition of Start of New Anticancer therapy 
Start date of new anticancer therapy (drug, radiation, surgery) is used for definition of on-
treatment in safety analyses (see Section 3.5.1) and for censoring in antitumor activity 
analyses (see Section 6.2.3). 
The start date of new anticancer therapy is the earliest date after first dose of Lorlatinib 
amongst the following: 
• Start date of anticancer drug therapy recorded in the ‘Concomitant Medications’ CRF 
pages with ‘Category of medication’ = ‘Follow-up Cancer Therapy’ 


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• Start date of radiation therapy recorded in ‘Radiation Treatment’ CRF page with 
‘Subcategory’ = ‘Curative in intent’ 
• Surgery date recorded in ‘Non-drug Treatments’ CRF pages with ‘Category’ = 
‘Cancer Surgery’ and ‘Outcome of Procedure’ = ‘Resected’ or ‘Partially Resected’.   
When start date of anticancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.2.4 should be applied using ‘Concomitant Medications’, ‘Radiation 
Treatment’, and ‘Non-drug Treatments’ CRF pages. 
5.2.4. Date of Last Contact 
The date of last contact will be derived for participants not known to have died at end of the 
study using the latest complete date (i.e. imputed dates will not be used in the derivation) 
among the following: 
• All participant assessment dates e.g. tumor assessments, 
• Start and stop dates of concomitant therapies including non-drug treatments or 
procedures, 
• Start and end dates of anticancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries, 
• AE start and end dates, 
• Date of first and last dose, 
• Vital sign, ECG, laboratory and weight assessment dates 
• Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death). 
Only dates associated with actual examinations of the participant will be used in the 
derivation.   
5.2.5. Measurable Disease 
A participant will be considered to have measurable disease if there is at least one target 
lesion identified at baseline meeting the following criteria:  
• Non lymph node lesions with longest diameter ≥ 10 mm by Computerized 
Tomography (CT) scan,  
• Non lymph node lesions with longest diameter ≥ 10 mm caliper measurement by 
clinical exam,  
• CNS lesions with longest diameter ≥5 mm provided by gadolinium contrast enhanced 
Magnetic Resonance Imaging (MRI) performed with contingent slices of 1 mm, or  


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• Lymph nodes with short axis ≥ 15 mm when assessed by CT.  
5.2.6. Tumor Assessment Date 
The Date of Tumor Assessment at each nominal timepoint as provided by the investigator on 
the Investigator Overall Tumor Assessment (IOTA) CRF will be utilized for the respective 
analyses. 
5.2.7. Sum of Lesion Diameters 
For lesions that are assessed as ‘too small to measure’, 5 mm will be imputed and used in the 
calculation of the sum of the lesion diameters. 
5.2.8. Adequate Baseline Tumor Assessment 
Adequate baseline is defined using the following criteria: 
• 
All baseline assessments must be within 35 days prior to and including the date of 
first dose.  
• 
All documented lesions must have non-missing assessments (i.e. non missing 
measurements for target lesions and non-missing lesions status at baseline for non-
target lesions). 
• 
Measurable disease at baseline (see Section 5.2.5 for the definition of measurable 
disease)  
5.2.9. Adequate Post-baseline Tumor Assessment 
An adequate assessment is defined as an assessment where a response of CR, PR, Stable 
Disease (SD), non-CR/non-PD, or PD has been provided by the investigator.  Timepoints 
where the response is not evaluable, or no assessment was performed will not be used for 
determining the censoring date. 
5.2.10. Nominal and Unscheduled Visits 
For all algorithms and analyses, visit labels as specified on the CRF will be used as the 
nominal timepoint (i.e. assessment will not be slotted). 
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables 
by nominal visit/timepoint. Unscheduled assessments will be used when deriving baseline 
and worst case on-treatment for adverse events laboratories and vital signs assessments. 
Additionally, unscheduled tumor assessments will be used for antitumor activity analyses 
(e.g. defining date of progression/censoring, best overall response, date of last contact). 
5.2.11. Standard Derivations and Reporting Conventions 
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Demographics and physical measurements: 
• Age [years]:  


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o (year of given informed consent - year of birth) 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and Std Dev should be displayed to two more decimal places 
than the raw data. Percentages will be reported to one decimal place. The rounding will be 
performed to closest integer / first decimal using the common mid-point between the two 
consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be 
rounded to an integer of 6. 
5.2.12. Analyses for Continuous and Qualitative Variables 
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, Std Dev, 
minimum, maximum, first and third quartile (Q1 and Q3) and inter-quartile range.  
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants with an assessment at that visit, unless otherwise specified. 
5.2.13. Analyses for Time-to-Event Endpoints 
Time to event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate. Graphs will describe the 
number of participants at risk over time. The median, quartiles, and probabilities of an event 
at particular points in time will be estimated by the Kaplan-Meier method. Confidence 
intervals for medians and quartiles are based on the Brookmeyer-Crowley method.  
Summaries of the number and percentages of participants with an event will also be provided 
on summary tables and figures. 
5.3. Methods to Manage Missing Data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
Any imputations will occur at the analysis dataset level.  Additionally, in all data listings 
imputed values will be presented and flagged as imputed. 
Missing statistics, e.g. when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’.  
5.3.1. Missing ECG Data 
For QTc analyses, no values will be imputed for missing data.  
For pre-dose measurements, if one or two of the triplicate measurements for an ECG 
parameter are missed, the average of the remaining two measurements or the single 


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measurement can be used in the analyses. If all triplicate measurements are missing at a 
timepoint for an ECG parameter, no values will be imputed.  If the triplicate needs to be 
repeated because of an artifact, then the repeated triplicate will be reported on an 
unscheduled CRF page.  Based on a review of the data these unscheduled assessments may 
be used in place of the assessments for pre-dose. Data review and consultation with the study 
team is required to flag these cases. 
5.3.2. Handling of Incomplete or Missing Dates 
5.3.2.1. Adverse Events 
AE Onset Date: 
The following imputation rules apply if the event is unique for a participant or it is the first of 
a series of similar events; otherwise, the AE Onset Date will not be imputed: 
• If the AE Collection Date is not missing, is less than the Date of First Exposure to 
Treatment, and is less than the AE Stop Date, then AE Onset Date is set to the Date of 
AE Collection. 
• If the Previous Visit Date is greater than the Date of First Exposure to Treatment and 
less than the AE Stop Date, the AE Onset Date is set to the previous visit date. 
• If the Date of First Exposure to Treatment is greater than the previous visit date and 
less than the AE Stop Date, the AE Onset Date is set to the Date of First Exposure to 
Treatment. 
• Otherwise AE Onset date is set to the AE Stop date. 
AE Stop Date: 
Ongoing events will have the AE Stop Date set to one of the following values: 
• Date of Death, if the participant died and a date of death exists. 
• Maximum of (Withdraw date, AE Onset Date, AE Collection Date) if the participant 
withdrew from the study and a date of withdraw exists. 
• Maximum of (AE Onset Date, Subject Summary Collection Date, AE Collection 
Date) if the Subject Summary CRF page exists but a date of withdraw does not exists. 
• Maximum of (Last Treatment Date, AE Onset Date) if no Subject Summary page 
exits. 
Imputation will only occur if event is unique for the participant, or it is the last of a series of 
similar events; otherwise the Stop Date will not be imputed.  Adverse Events are deemed 
similar if they have the same verbatim term. 
Resolved events will have the AE Stop Date set to the maximum of the AE collection date 
and the AE Onset date. 


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5.3.2.2. Exposure 
No imputation will be done for first dose date.  Date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows: 
• If the last date of study treatment is completely missing and there is no EOT CRF 
page and no death date, the participant should be considered to be ongoing and use 
the data cutoff date for the analysis as the last dosing date; or 
• If the last date of study treatment is completely or partially missing and there is 
EITHER an EOT CRF page OR a death date available (on or prior to the data cutoff 
date), then impute this date as the last dose date: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, 
death date), 
= Last day of the month, if both Year and Month are available and Year = Year 
of min (EOT date, death date) and Month < the month of min (EOT date, death 
date), or 
= min (EOT date, death date), for all other cases. 
5.3.2.3. Date of Death 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as the day after the date of last contact  
• If the day or both day and month is missing, death will be imputed to the maximum of 
the full (non-imputed) day after the date of last contact and the following: 
o Missing day: 
 
 
1st day of the month and year of death 
o Missing day and month: 
January 1st of the year of death 
5.3.2.4. Date of Start of New Anticancer Therapy 
Incomplete dates for start date of new anticancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for antitumor 
activity analyses and in the derivation of the end of on-treatment period.  PD date below 
refers to PD date by investigator assessment. 
• The end date of new anticancer therapy will be included in the imputations for start date 
of new anticancer therapy.  If the end date of new anticancer therapy is 
o completely missing then it will be ignored in the imputations below 
o partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anticancer therapy 
o partially missing with only month and year available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new 
anticancer therapy 


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• For participants who have not discontinued study treatment at the analysis cutoff date, 
last dose of study treatment is set to the analysis cutoff date in the imputations below.  
• If the start date of new anticancer therapy is completely or partially missing, then the 
imputed start date of new anticancer therapy is derived as follows: 
o Start date of new anticancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anticancer therapy] 
o Only year (YYYY) for start of anticancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anticancer therapy]  
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anticancer therapy] 
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anticancer therapy]  
THEN imputed start date = 01JANYYYY 
o Both Year (YYYY) and Month (MMM) for start of anticancer therapy are available 
IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy],  AND 
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anticancer therapy]  
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY ; 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy],  AND 
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anticancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anticancer therapy]); 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy],  AND 


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MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anticancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy] 
THEN  
imputed start date = 01 MMM YYYY. 
5.3.2.5. Other Dates 
Imputation methods for other partial dates as follows:  
• If the day of the month is missing for a start date used in a calculation, the first day of 
the month will be used to replace the missing date.  
• If both the day and month are missing, the first day of the year is used.  
• For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively.  
• If the date is completely missing, no imputation will be performed. 
5.3.3. Missing Toxicity Grade of Adverse Events 
Prior to Study Treatment: If no toxicity grade is available or the grade is reported as 
unknown for an adverse event prior to the first study treatment, then Grade 1 will be assumed 
for purposes of defining a baseline grade. 
In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed. Missing grade will only be displayed for cases where a participant reported 
only one event and the grade is missing. 


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6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint 
6.1.1. Adverse Events 
6.1.1.1. Main Analysis 
Analysis set: Safety: All enrolled participants who take at least 1 dose of Lorlatinib 
Analysis methodology:   
• AE incidence rate is the number of patients with any AE occurring at least once in the 
study population . 
• All Adverse Events (AEs) will be coded using the MedDRA.  
• All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in Section 3.5.1. 
 
Intercurrent events and missing data: 
• All data after the intercurrent event “start of subsequent anticancer therapy (-1 day)” 
or “35 days after treatment discontinuation” will be excluded from summaries but 
will be listed regardless of dosing interruptions or dosing compliance. 
 
Summaries used for reporting: 
• High-level summaries of adverse events (both All Causality and Treatment Related) 
will include the number and percent of participants with:  
o Any Adverse Event;  
o Serious AE;  
o Adverse Events with CTCAE Grade 3-4;  
o Grade 5 events;  
o AEs associated with dose interruptions;  
o AEs associated with dose reductions;  
o AEs associated with withdrawal;  
 
Additionally, the number of events reported for each of the categories above will be 
provided. Each unique adverse event at the PT level for a participant is included in 
the count. Seriousness, relatedness, toxicity grade, action taken (interruption, 
reduction, and withdraw) are as reported by the investigator on the adverse event 
CRF.  
• Summaries by System Organ Class (SOC) and PT in decreasing frequency will be 
provided for:  
o Treatment Emergent Events by Maximum Toxicity Grade (All Causality);  
o Treatment Emergent Events by Maximum Toxicity Grade (Treatment 
Related);  


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o Serious Treatment Emergent by Maximum Toxicity Grade Events (All 
Causality);  
o Serious Treatment Emergent by Maximum Toxicity Grade Events (Treatment 
Related);  
 
An event will be considered treatment related if the investigator considered the event 
related to the study drugs or this information is unknown.  
 
• Clustered adverse events will be summarized by maximum CTCAE grade and 
causality (all-causality and treatment-related) together with other adverse events. 
Adverse Events pertaining to each cluster will be summarized separately, by cluster. 
The clustered events are described in a list in the product’s Safety Review Plan 
maintained by the Sponsor.  
 
The following summaries will be provided by PT/Cluster Term (summaries will not 
include SOC) in decreasing frequency:  
o Treatment Emergent Events (All Causality) by Preferred Term and Maximum 
Toxicity Grade;  
o Treatment Emergent Grade 1-2, 3-4 and 5 Events (All Causality) by Preferred 
Term and Maximum Toxicity Grade;  
o Treatment Emergent Adverse Events Associated with Dose Interruptions (All 
Causality);  
o Treatment Emergent Adverse Events Associated with Dose Reductions (All 
Causality);  
o Treatment Emergent Adverse Events Associated with Withdrawal (All 
Causality);  
o Treatment Emergent Adverse Events Associated with Dose Interruptions 
(Treatment Related);  
o Treatment Emergent Adverse Events Associated with Dose Reductions 
(Treatment Related);  
o Treatment Emergent Adverse Events Associated with Withdrawal (Treatment 
Related);  
o Serious Treatment Emergent Events (All Causality).  
o Serious Treatment Emergent Events (Treatment Related).  
 
Each participant will be counted only once within each SOC, Cluster Term and PT.  
 
As described in section 5.3.3, in case a participant has events with missing and non-
missing toxicity grades, the maximum of the non-missing grade will be displayed. 
Missing grade will only be displayed in the event that only one event has been 
reported for a participant and the grade is missing. 


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• Detailed information collected for each AE will be listed with a description of the 
event, duration, whether the AE was serious, intensity, relationship to study 
treatment, action taken, and clinical outcome. 
• For AEs of special interest as specified in 3.5.2, these analyses will be performed:  
o Treatment Emergent Events by Maximum Toxicity Grade (All Causality);  
o Treatment Emergent Events by Maximum Toxicity Grade (Treatment 
Related); 
• Regarding deaths, the following analysis will be performed:   
o The frequency (number and percentage) of participants in the safety analysis 
set who died and who died within 28 days after last dose of study treatment as 
well as the primary reason for death, will be tabulated based on information 
from the ‘Notice of Death’.  
o The frequency (number and percentage) of participants in the safety analysis 
set who died within 30 days of first dose of study treatment will also be 
provided.  
o Date and cause of death will be provided in individual participant data listing 
together with selected dosing information (date of first / last administration, 
dose).  
6.1.1.2. Additional Analysis 
Basic Results  
For summaries required for basic results disclosures in the US and EU the following 
additional summaries will be provided:  
• Treatment Emergent Non-Serious Adverse Events by SOC and PT in >5% of 
participants;  
• Treatment Emergent Non-Serious Adverse Events by SOC and PT;  
• Treatment Emergent Serious Adverse Events by SOC and PT; and  
• Fatal Adverse Events by SOC and PT.  
 
Each of the above summaries will include a count of the number of participants with all 
causality events and the number of participants with treatment related events.  
6.2. Secondary Endpoints 
6.2.1. Confirmed OR 
Analysis set: Safety: All enrolled participants who take at least 1 dose of Lorlatinib 
Analysis methodology: 
• Objective Response Rate (ORR) defined as the percentage of participants with a 
confirmed best overall response (BOR) of CR or PR according to RECIST v1.1.  
BOR will be determined based on reported overall responses at different evaluation 
timepoints by the investigator from the date of treatment start until documented 


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disease progression or start of new anticancer therapy, according to the following 
rules: 
o CR = at least two determinations of CR at least 4 weeks apart and documented 
before progression and start of new anticancer therapy 
 
o PR = at least two determinations of PR or better (and not qualifying for a CR) 
at least 4 weeks apart and before progression and start of new anticancer 
 
o SD (for participants with at least one measurable lesion at baseline) = at least 
one SD assessment (or better and not qualifying for CR or PR) ≥ 6 weeks after 
date of treatment start and before progression and the start of new anticancer 
therapy 
 
o Non-CR/Non-PD (for participants with only non-target disease at baseline) = 
at least one Non-CR/Non-PD assessment (or better and not qualifying for CR 
≥ 6 weeks after date of treatment start and before progression and the start of 
new anticancer therapy 
 
o PD = progression ≤ 13 weeks after date of treatment start and not qualifying 
for CR, PR or SD 
 
o Not Evaluable (NE) = all other cases. 
 
Clinical deterioration will not be considered as documented disease progression. 
 
• participants without documented CR or PR will be considered as non-responders 
• 95% CI interval for ORR using the Wilson’s Score method 
Intercurrent events and missing data: 
• data on response after subsequent anticancer therapy is administered will be excluded 
• participants with death prior to first post-baseline assessment, inadequate baseline 
assessment, new anticancer therapy started prior to first post-baseline assessment, and 
all post-baseline disease assessments missing will also be considered as non-
responders. 
Summaries used for reporting: 
• The frequency (number and percentage) of participants with BOR of CR, PR, SD, 
PD, non-CR/non-PD (applicable only to participants with non-measurable disease at 
baseline), and NE (not evaluable) 
• ORR estimated by dividing the number of participants with OR (CR or PR) by the 
number of participants in the safety set 
• corresponding 2-sided 95% CIs 


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6.2.2. Confirmed IC-OR 
Analysis set: Participants with CNS metastases based on Investigator Assessment  
Analysis methodology:  
The IC-OR will be summarized similar to OR (as described above in section 6.2.1), in Safety 
Population with CNS metastases based on investigator assessment. Surgery or radiotherapy 
of extracranial lesions will not affect the determination of IC-OR. 
6.2.3. DoR  
Analysis set: Subset of Participants with confirmed objective response 
Analysis methodology:  
DoR will be calculated on every participant showing OR as follows:  
DoR (months) = [first date of PD or death/censoring – first date of CR/PR 
subsequently confirmed+1]/30.4375  
DoR data will be censored as follows:  
• For participants who start a new anticancer therapy prior to an event, censoring will 
be at the last adequate tumor assessment (see Section 5.2.9) prior to the start of new 
anticancer therapy. Note: if date of progression occurs on the same date as the start of 
new anticancer therapy, the progression will be counted as an event.  
• For participants with documented progression or death after two or more missing 
tumor assessments, censoring will occur at the last adequate tumor assessment prior 
to the missing assessments. In this study antitumor activity will be assessed through 
radiological tumor assessments conducted at screening and every 12 weeks until 
disease progression regardless of initiation of subsequent anticancer therapy. The 
allowable time window for disease assessments is ±1week while on treatment and 
whenever disease progression is suspected (eg, symptomatic deterioration). Therefore 
time without adequate assessment is defined as 24 weeks plus 2 weeks.  
• All other participants alive without objective progression will be censored on the date 
of the last adequate tumor assessment.  
The date of tumor response at each nominal timepoint based on the investigator assessments 
will be used for determining the dates of last adequate assessment for censoring purposes.  
The censoring and event date options to be considered for the DoR analysis are presented in 
Table 2. 
 


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Table 2. 
Outcome and event dates for DoR analyses 
Scenario 
Date of event/censoring 
Outcome 
Progression or death ≤ 26 
weeks after last adequate 
tumor assessment 
Date of progression or death  Event  
Progression or death > 26 
weeks after the last adequate 
tumor assessment 
Date of last adequate 
assessment documenting no 
PD prior to anticancer 
therapy or missed 
assessments  
Censored  
No progression  
New anticancer therapy 
given prior to PD  
 
Intercurrent events and missing data: data on response after subsequent anticancer therapy 
is administered will be excluded. 
Summaries used for reporting: Kaplan-Meier estimates (product-limit estimates) will be 
presented together with a summary of associated statistics including the median DoR time 
with two-sided 95% CIs. The CIs for the median will be calculated according to Brookmeyer 
and Crowley.  
When the number of participants with PD after a confirmed CR or PR is small, the use of 
Kaplan-Meier method is limited due to high number of censored observation, so the DoR 
will be summarized using number (%) of participants with events and of participants 
censored with DoR in the following categories: less than 6 months, ≥6 - <9 ,≥9-<12, ≥12-
<15, ≥15-<18, ≥18-<21, ≥21-<24, and ≥24 months. 
Frequency (number and percentage) of participants with each event type (PD or death) and 
censoring reasons will be presented along with the overall event and censor rates.  
Reasons for censoring will be summarized according to the categories in Table 3. If a 
participant meets multiple definitions for censoring the list will be used to define the 
hierarchy. 
Table 3. 
Censoring Reasons and Hierarchy for DoR analyses 
Hierarchy Condition 
Censoring Reason 
1  
Event more than 26 weeks from last adequate 
post-baseline tumor assessment/start date 
Event after missing 
assessments a 
2 
No event and [withdrawal of consent date ≥ 
start date OR End of study (EOS) = Subject 
refused further follow-up]  
Withdrawal of consent 
3 
No event and lost to follow-up in any 
disposition page  
Lost to follow-up 
4  
No event and none of the conditions in the prior 
hierarchy are met  
Ongoing without an event 


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a more than 26 weeks after last adequate tumor assessment.   
 
6.2.4. IC-DoR 
Analysis set: Subset of Safety Participants with confirmed Intracranial objective response 
Analysis methodology: IC-DoR (months) = [first date of PD in brain lesions or 
death/censoring – first date of IC-OR (CR/PR subsequently confirmed)+1]/30.4375  
For participants whose IC-OR proceeds from PR to CR, the onset of PR is taken as the onset 
of response. 
Censoring for IC-DoR will be identical to the censoring rules presented above for DoR.  
 
Intercurrent events and missing data: data on response after subsequent anticancer therapy 
is administered will be excluded.  
 
Summaries used for reporting: The IC-DoR will be summarized similar to DoR (as 
described above in section 6.2.3), in Participants with CNS metastases. Surgery or 
radiotherapy of extracranial lesions will not affect the determination of IC-DoR.  
6.3. Other Endpoint(s) 
Not applicable. 
6.4. Subset Analyses 
Not applicable. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
• Demographic and Physical Characteristics  
The following demographic and baseline characteristics will be summarized by number 
and percentage:  
o Gender (male, female)  
o Age (18-<45; 45- <65; ≥65)  
o ECOG Performance status  
Age (continuous) and weight (kg) will be summarized with descriptive statistics (mean, 
median, Std Dev, minimum, and maximum, inter quartile range). 
• Disease Characteristics 
The following baseline disease characteristics will be summarized by number and 
percentage:  
o Measurable disease at baseline (yes/no) (see Section 5.2.5)  


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o Involved tumor sites at baseline.  
o Number of sites of disease at baseline (1, 2, ≥3)  
Involved tumor sites at baseline will be derived from target and non-target lesions at 
baseline. Each participant will be counted once per organ. Similarly, number of sites of 
disease at baseline will be derived by counting the number of unique organ sites from target 
and non-target lesions at baseline. “Other” will be counted as one organ site. 
• Medical History  
Medical history will be coded using the most current version of MedDRA and summarized 
by MedDRA’s SOC and PT. Each participant will be counted only once within each PT or 
SOC. Summaries will be ordered by primary SOC and PT in descending order of frequency. 
Separate summaries will be provided for past and present conditions. 
• Prior Anticancer Treatments  
Prior anticancer treatments include systemic therapy, radiation, and surgery. The number and 
percentage of participants in each of the following anticancer therapy categories will be 
tabulated:  
o Participants with at least one type of prior anticancer treatment;  
o Participants with at least one prior anticancer drug therapy;  
o Participants with at least one prior anticancer radiotherapy; 
o Participants with at least one prior anticancer surgery.  
Prior anticancer drug therapy will be summarized as follows based on the number and 
percentage of participants:  
o Number of prior anticancer therapy regimens: missing / 1 / 2 / 3 / ≥4;  
o Number of participants who received prior chemotherapy  
o Number of participants who received 1st generation (Crizotinib) or 2nd 
generation (Alectinib, Certinib or Brigatinib) ALK Inhibitor (ALKi) as Prior 
ALKi  
The prior anticancer drugs will be coded in the World Health Organization (WHO) Drug 
coding dictionary. 
6.5.2. Study Conduct and Participant Disposition 
6.5.2.1. Disposition 
A summary of the number of participants enrolled by site will be provided for the Enrolled 
analysis set. 
Discontinuations from study will be summarized using the Enrolled set. Discontinuations 
from study treatment will be summarized using the Safety analysis set. 


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Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing, the event will be considered 
related to treatment. If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment.  
6.5.2.2. Protocol Deviations 
Protocol deviations will be compiled prior to database closure and will be summarized by 
category (n(%)) for the Enrolled Analysis Set.  Categories will be assigned by the study 
Clinician. 
6.5.3. Study Treatment Exposure 
6.5.3.1. Exposure to lorlatinib  
Exposure will be summarized for the Safety analysis set.  
The summary of treatment exposure for lorlatinib will include the following information:  
• Treatment duration (days) 
• Cumulative dose (mg)  
• Dose intensity (mg/day)  
• Relative dose intensity (%).  
 
The duration of lorlatinib (in days) is defined as:  
Treatment duration (days) = (last dose date – first dose date + 1)  
 
The cumulative dose (mg) of lorlatinib is the sum of the actual dose levels that the participant 
received (i.e., total dose administered (mg)).  
 
The dose intensity (DI) and the relative dose intensity (RDI) of lorlatinib will be calculated 
for each participant during the study. The DI (mg/day) of lorlatinib during the study is 
defined as  
DI (mg/day) = [cumulative dose (mg)]/[treatment duration (days)]  
 
The RDI of lorlatinib is defined as the ratio of the DI and planned dose intensity d and 
expressed in %  
RDI (%) = 100× [DI (mg/day]/[d (mg/day)].  
 
6.5.3.2. Dose Reductions and Interruptions  
A dose reduction is defined as a non-zero dose that is less than the prior dose.  
The number and percentage of participants with at least one dose reduction as well as a 
breakdown of dose reductions (1 / 2 / 3 / ≥4) will be summarized.  
Reasons for dose reductions will also be summarized. Participants can contribute to more 
than one reason if multiple dose reductions occurred for different reasons but will only be 


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counted once per reason. Percentages will be calculated based on the total number of 
participants in safety analysis set.  
An interruption is defined as a 0 mg dose administered on one or more days. (Note: A dose 
interruption is not considered a dose reduction). The number and percentage of participants 
with dose interruptions and the corresponding reasons will be summarized. Participants can 
contribute to more than one reason if multiple dose interruptions occurred for different 
reasons but will only be counted once per reason. Percentages will be calculated based on the 
total number of participants in safety analysis set.  
The following define how dose interruptions will be counted in the case of multiple dose 
interruptions:  
• If an interruption occurs consecutively for at least two days due to the same reason, 
then it will be counted only once.  
• If an interruption occurs consecutively for at least two days due to different reasons, 
then it will be counted for each reason.  
• If an interruption occurs for more than one day due to the same reason, but the days 
are not consecutive, i.e. there is at least one dosing day in between, then each dose 
interruption will be counted as a different occurrence.  
6.5.4. Concomitant Medications and Non-drug Treatments 
Concomitant medications and non-drug treatments received by participants during the study 
will be summarized for the Safety Analysis Set.  
Concomitant medications refer to all medications which started prior to first dose of study 
treatment and continued during the on-treatment period (see section 3.5.1) as well as those 
started during the on-treatment period. Concomitant medications will be coded in the WHO 
Drug coding dictionary and will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification level 2 and preferred term in descending order of frequency. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. A 
participant will be counted only once within a given drug class and within a given drug 
name, even if he/she received the same medication at different times. Preferred Terms will be 
reported under each ATC class that it is included under within WHO Drug (no primary path 
is available in WHO Drug). 
Concomitant non-drug treatments refer to all non-drug treatments administered during the 
on-treatment period. Non-drug treatments will be coded with the most current version of 
MedDRA and will be summarized by MedDRA’s SOC and PT in descending order of 
frequency.  
Participants will be counted only once per PT even if he/she received the same treatment 
multiple times.  


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Any medications or non-drug treatments, aside from anticancer treatments described in 
section 6.5.5, which were only administered prior to treatment start will be listed but not 
summarized. 
6.5.5. Subsequent Anticancer Therapies/Procedures  
Subsequent Anticancer Therapies and Procedures are defined as therapies entered on the 
short term follow up in the following: 
• ‘Concomitant Medications’ CRF page with ‘Category of Medication’ = ‘Follow-up 
Cancer Therapy’) 
• ‘Radiation Treatment’ CRF page with ‘Subcategory’ = ‘Curative in intent’ 
• ‘Non-drug Treatments’ (with ‘Category’ = ‘On-study Cancer Surgery’ and ‘Outcome 
of Procedure’ = ‘Resected’ or ‘Partially Resected’).  
The number and percentage of participants within each category (medication therapy, 
radiation therapy, and surgeries) will be provided.  
Medications will be coded using the WHO Drug coding dictionary and will be tabulated by 
preferred term in descending order of frequency.  
Analyses will be based on the safety analysis set. 
6.6. Safety Summaries and Analyses 
Summaries of safety parameters will be based on the safety analysis set.  
6.6.1. Laboratory Data 
Laboratory results will be converted to International System of Units (Système International 
d'unités, SI) units which will be used for applying toxicity grades and for all summaries.  
Quantitative data will be summarized using simple descriptive statistics (mean, Std Dev, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (i.e. unscheduled assessments will be excluded). The total 
number of participants for change from baseline will include all participants who have both a 
baseline and a value at the nominal visit.   
As described in Section 3.4, baseline will be defined as the last assessment performed on or 
prior to date of the first dose of study treatment.  If there are multiple assessments that meet 
the baseline definition on the same day without the ability to determine which was truly last, 
then the worst grade will be assigned as the baseline grade.  Several of the CTCAE terms 
(including Hypo/Hypercalcemia, Chronic Kidney Disease, and Activated Partial 
Thromboplastin) can be derived using several laboratory tests (analytes).  


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Results collected as strict inequalities (e.g., >10, <10) will be converted to numeric values 
subtracting a factor of <0.001>.  Expressions of the form” ≥” or “≤” will be converted to the 
end point.  These numeric values will be evaluated for clinically significant abnormalities but 
will not be included in calculations of summary statistics.  
Additionally, laboratory results will be programmatically classified according to NCI-
CTCAE version 4.03 grade.  Non-numerical qualifiers will not be taken into consideration in 
the derivation of grade (e.g. hypokalemia Grade 1 and Grade 2 are only distinguished by a 
non-numerical qualifier and therefore Grade 2 will not be derived). In summary statistics the 
number and percentage of participants corresponding to grades that only include non-
quantitative criteria will be displayed as a blank or NA (not assessed) rather than 0.  If there 
is any overlap between grade criteria (e.g. CTCAE grading criteria for Creatinine Increased – 
a value can fall into one range based on comparison to Upper Limit of Normal (ULN) and 
another range based on comparison to baseline), the highest (worst) grade would be assigned 
to that record. Grade 5 is defined in the CTCAE criteria guidance as an event with an 
outcome of death. Since laboratory data does not collect an outcome, Grade 5 is not used 
when programmatically grading laboratory data. 
Grade 0 or Outside Toxicity Reference (OTR) is not defined specifically by in the CTCAE 
guidance. However, programmatically this is used as a category to represent those 
participants who did not meet any of the Grades 1 to 4 criteria.  If the laboratory value is 
evaluable for CTCAE criteria grading (numeric value is present, valid units and ranges are 
present as required to allow conversion to standard units and grading), and does not qualify 
for any of the Grade 1-4 criteria for a given lab test, then the value is assigned as Grade 0 or 
OTR. 
Several of the CTCAE terms (including Hypo/Hypercalcemia, Chronic Kidney Disease, and 
Activated Partial Thromboplastin) can be derived using several laboratory tests (analytes).   
Abnormalities will be described using the worst grade by scheduled timepoint and overall.  
Worst case overall will be determined from scheduled and unscheduled visits.  Several 
laboratory tests have bi-directional grading criteria defined so that both low (hypo) and high 
(hyper) values can be graded separately.  Each criterion will be summarized separately.  In 
the cases where a value is graded as a Grade 1, 2, 3, or 4 for one of the directions, that value 
will also be assigned as a Grade 0 for the opposite direction for that test.  For example, a 
value meeting the criteria for Grade 3 Hypercalcemia will be classified as a Grade 0 
Hypocalcemia. For CTCAE terms that can be derived using one of several laboratory tests, 
the maximum post-baseline grade for a given participant and CTCAE term will be the 
maximum across all possible laboratory tests. 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the following categories by scheduled timepoint as well as overall:  below normal limit, 
within normal limits, and above normal limits. In the unlikely event that for a given 
participant, clinically significant abnormalities are noted in both directions (e.g., > ULN  and 
< Lower Limit of Normal (LLN)), then both abnormalities are counted.  


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Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
Alkaline Phosphatase (ALP), and total bilirubin (TBILI) are used to assess possible drug 
induced liver toxicity. The ratios of test result over the ULN will be calculated and classified 
for these three parameters during the on-treatment period.    
Summary of liver function tests will include the following categories.  The number and 
percentage of participants with each of the following during the on-treatment period will be 
summarized: 
• ALT ≥ 3×ULN, ALT ≥ 5xULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT 
or AST) ≥ 20×ULN 
• TBILI ≥ 2×ULN 
• Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP ≤ 2×ULN or 
missing 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e., a participant with an elevation of AST ≥10×ULN will 
also appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible 
Hy’s Law cases will be summarized using frequency counts and percentages.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying 
• peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN.  
• peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at  
AST=3×ULN and total bilirubin=2×ULN.  
In addition, a listing of all TBILI, ALT, AST and ALP values for participants with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 


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6.6.2. Vital Signs 
Vital signs data includes weight, pulse, systolic blood pressure, and diastolic blood pressure. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  Measurements were only to be provided once per timepoint. If 
multiple assessments are provided per timepoint, the maximum value will be used for 
reporting. 
Vital signs data will be summarized using simple descriptive statistics (mean, Std Dev, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (i.e. unscheduled assessments will be excluded). The total 
number of participants for change from baseline will include all participants who have both a 
baseline value and a value at the nominal visit.  Baseline will be selected as defined in 
Section 3.4 . 
The number and percent of participants in each of the following minimum and maximum 
blood pressure, body weight, and pulse categories will be presented: 
• Increase in Systolic Blood Pressure ≥40 mmHg 
• Decrease in Systolic Blood Pressure ≥ 40 mmHg 
• Increase in Diastolic Blood Pressure ≥20 mmHg 
• Decrease in Diastolic Blood Pressure ≥20 mmHg 
• Increase in Diastolic Blood Pressure ≥60 mmHg  
• Maximum Pulse Rate > 120 bpm 
• Minimum Pulse Rate < 50 bpm 
• Maximum increase in pulse rate ≥ 30 bpm 
• Maximum decrease in pulse rate ≥ 30 bpm 
• Decrease in Body Weight ≥ 10% 
• Increase in Body Weight between 10% and 20% 
• Increase in Body Weight  ≥ 20%  
All assessments, including unscheduled assessments will be considered.  A participant can be 
included in multiple categories if different criteria are met at different timepoints.    


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6.6.3. Electrocardiograms 
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.   
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted by QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate.  
Fridericia’s correction (QTcF) will be programmatically derived using the following formula: 
3
/
1
(sec)
/
sec)
(
sec)
(
RR
m
QT
m
QTcF
=
 
and Bazett’s correction (QTcB) will be programmatically derived using the following 
formula: 
(sec)
sec)
(
sec)
(
RR
m
QT
m
QTcB
=
, 
where RR represents the RR interval of the ECG, in seconds.   
The correlation between RR and QTcF will be explored graphically.  If these are correlated 
and there are a sufficient number of participants (e.g. >30) with baseline ECGs, a study 
specific correction (QTcS) will be performed as follows: 
• b will be estimated from ln(QT)=a+b*ln(RR) 
• and QTcS will be derived as QTcS=QT(msec)\(RR(sec))^1\b 
Data will be summarized using QTcB and QTcF. However, if these are not appropriate for 
the data set due to an observed large correlation between corrected QT and HR using the 
baseline assessments, the results will also be summarized using QTcS.   
QT, heart rate, QTcB and QTcF will be summarized using simple descriptive statistics 
(mean, Std Dev, median, quartiles, minimum, and maximum) of actual values and change 
from baseline for each nominal visit over time (i.e. unscheduled assessments will be 
excluded). The total number of participants for change from baseline will include all 
participants who have both a baseline and a value at the nominal visit. Baseline will be 
selected as defined in Section 3.4 . 
The mean absolute QTc, QTcB, QTcF, RR, PR, and QRS will be presented with two-sided 
95% confidence intervals and the baseline adjusted mean QTc, QTcB, QTcF, RR, PR, and 
QRS will be presented with two-sided 90% confidence intervals. 


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Additionally, QTcB and QTcF (and QTcS if applicable) will be summarized by maximum 
on-treatment values using the following categories  
• ≤ 450 msec 
• > 450 msec but ≤ 480 msec;  
• > 480 msec but ≤ 500 msec;  
• > 500 msec. 
Unscheduled assessments will be utilized in addition to planned assessments.   
Shift tables will be provided for baseline value versus worst on-treatment value.   
Additionally maximum increases from baseline (including scheduled and unscheduled 
assessments) will be summarized based on the following categories: 
• Change > 60 msec,  
• Change >30 msec but ≤ 60 msec,  
• Change ≤ 30 msec 
For QRS maximum increases from baseline, the following categories will be applied: 
• QRS change ≥50% if absolute baseline value was <100 msec, 
• QRS change ≥25% if absolute baseline value was ≥100 msec 
For PR interval, the number (%) of subjects with maximum post-dose PR interval values and 
maximum increases from baseline in the following categories will be tabulated: 
Absolute Value (msec) 
< 160 
≥160 - < 180 
≥180 - <200 
≥200 - <220 
≥220 - <240 
≥240 – 260 
≥260 
Absolute Change (msec) 
40 - <60 


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≥60 - <80 
≥80 
Relative Change from baseline 
>25% 
6.6.4. Performance Status 
ECOG performance status with shift from ECOG=0 or 1 to ECOG 2 or higher will also be 
presented in a data listing. 
6.6.5. Physical Examination 
Physical examination findings will only be listed. 
7. INTERIM ANALYSES 
7.1. Introduction 
Not applicable. 
7.2. Interim Analyses and Summaries 
Not applicable. 
 


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8. APPENDICES 
Appendix 1. List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
DI 
Dose Intensity 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
EGFR 
Epidermal Growth Factor Receptor 
EOS 
End of Study 
EOT 
End of Treatment 
IC-CR 
Intracranial Complete Response 
IC-DoR 
Intracranial Duration of Response 
IC-OR 
Intracranial Objective Response 
IC-ORR 
Intracranial Objective Response Rate 
IC-PD 
Intracranial Progressive Disease 
IC-PR 
Intracranial Partial Response 
IOTA 
Investigator Overall Tumor Assessment 
LLN 
Lower Limit of Normal 
LPFV 
Last Participant First Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
N/A 
Not Applicable 
ND 
Not Done 
NE 
Not Evaluable 
NR 
Not Reached 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Objective Response 
ORR 
Objective Response Rate 


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Abbreviation 
Term 
OTR 
Outside Toxicity Reference 
PD 
Progressive Disease 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval calculated using Fridericia’s correction factor 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SI 
International System of Unit 
SOC 
System Organ Class 
Std Dev 
Standard Deviation 
TBILI 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHO  
World Health Organization