A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF LORLATINIB (PF-06463922) MONOTHERAPY VERSUS CRIZOTINIB MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED ALK-POSITIVE NON-SMALL CELL LUNG CANCER
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Pfizer

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CLINICAL PROTOCOL
A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF LORLATINIB 
(PF-06463922) MONOTHERAPY VERSUS CRIZOTINIB MONOTHERAPY IN THE 
FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED ALK-POSITIVE
NON-SMALL CELL LUNG CANCER
Investigational Product Number:
PF-06463922
Investigational Product Name:
Lorlatinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-003315-35
Protocol Number:
B7461006
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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 and Rationale
Original Protocol
05 October 2016
Not Applicable 
Amendment 1
21 February 2017

Schedule of Activities updated for 
consistency with relevant protocol 
sections.

Instructions added in Table 4. PR 
Interval Prolongation Management that 
in case of complete heart block not 
followed by pacemaker placement, 
lorlatinib is permanently discontinued.

Ophthalmology examination updated to 
be consistent with data collection in the 
crizotinib studies.

Pharmacogenomics Section 7.13. 
removed to avoid duplicate sample 
collection.

DATA ANALYSIS/STATISTICAL 
METHODS Section 9. amended to 
specify how homogeneity of treatment 
effect across centers will be 
investigated.
Amendment 2
16 April 2018

Schedule of Activities (SoA) modified 
to allow use of available results for 
assessments performed prior to the 
Informed Consent being obtained.

Pre screening activities to determine 
ALK status included in SoA and related 
protocol sections.

SoA updated for consistency with 
relevant protocol sections.

Time window added for Laboratory 
exams in SoA: Explanatory notes for 
Triplicate ECG reported in SoA.

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Document
Version Date
Summary of Changes and Rationale

Time window added for ECHO and 
Muga at Screening and further 
assessment.

Trans Thoracic Echocardiogram to 
assess Pulmonary Arterial Pressure and 
right heart functionality added in SoA 
and paragraph 7.4.6 upon demand of
France and Germany Health Authorities.

Clarification provided in SoA and § 
7.1 for patients continuing treatment 
beyond disease.

SoA and related § 6.1 updated to 
confirm suitability of cytological 
sampling and Endobronchial Ultrasound 
Transbronchial biopsies.

The Footnotes # 23 and # 24 in the
SoA for Beck Depression Inventory II
Scale and the Columbia Suicide
Severity Rating Scale updated.

1.2.5.3 Clinical Data section updated 
providing the most recent enrollment 
status for the pivotal study B7461001.

1.2.8 Summary of Benefit/Risk 
Assessment section revised with regards 
to the updated list of lorlatinib identified 
risks.

Inclusion Criteria #1 reworded for the 
sake of clarity.

Inclusion Criteria #2 reworded in 
alignment with the Inclusion Criteria #1.

Exclusion Criteria # 7 revised to be
exclusionary of vascular (both arterial
and venous) and non-vascular
conditions.

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Document
Version Date
Summary of Changes and Rationale

Exclusion Criteria # 10 revised to allow 
in situ malignancies which do not 
currently require treatment.

Exclusion Criteria #11 updated for the 
CYP 3A inhibitors//inducers list per 
new FDA classification.

Exclusion Criteria #16 revised based on 
the updated safety contraception 
language.  Section 4.3.1 Contraception 
updated accordingly.

Sunlight exposure warning removed, 
based on phototoxicity results in rats.

Stratification Factors at § 5.1.1 clarified 
for allocation to Asian or Non Asian 
stratum.

Additional information/guidance 
provided in §5.4.3 and §7.2 in case 
patient continues to be treated with 
study drug after Progression of Disease 
and for drug provison after the study 
ends.

A revised list of suitable statins 
provided (§5.5.1.1) to support 
Investigator in the management of 
elevated lipid levels.

Guidance provided in §5.5.2.6 for data 
collection in case of Severe Visual 
Loss.

Section 5.9.1.1 Inhibitors and Inducers 
of CYP Enzymes updated according to 
new FDA classification.

Minor updates in section 9.

Updates to Appendix 4.

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Version Date
Summary of Changes and Rationale
•
Appendix 7 specific for France 
included.
Amendment 3 
16 January 2019
•
Section 4.3 Lifestyle Requirements. 
This section was updated as per lifestyle 
guidance reported in the new protocol 
template and as per contraception 
requirements of updated product labels. 
Exclusion criteria 15 (it was #16 in the 
PA2) was updated accordingly.
•
Section 5.4.3 Treatment duration. Text 
was modified to clarify that patients, 
continuing the treatment beyond 
confirmed progression by BICR, should 
undergo the same assessments foreseen 
during the active treatment period. As 
far as tumor assessments, if 
only extracranial progression was 
documented, with intracranial lesions 
stable or in response, intracranial 
assessments should be performed until 
intracranial PD; once intracranial PD is 
documented no further tumor 
assessments are required.
•
Section 5.9 Concomitant Treatments. 
Text was updated to align the wording 
with lorlatinib core data sheet and IB.  
Exclusion Criteria 11 and 12, were 
updated accordingly. 
•
Section 7.2 Expedited Blinded 
Independent Central Review for Disease 
Progression. Text was modified to 
clarify that for investigator-assessed 
disease progression every effort should 
be made to keep the patient on study 
treatment and have all the assessments 
performed as per SoA until the BICR 
has completed the radiographic image 
review and confirmed progression.
 
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•
Schedule of Activities, footnote 31. 
Text was modified to clarify that the 
Post Treatment Follow Up visit will 
continue until PD or until the time of 
initiation of new anticancer treatment, 
with the exception of patients 
continuing to experience treatment 
related toxicities that will continue to be 
followed at least every 4 weeks until 
resolution or determination, in the 
clinical judgment of the Investigator, 
that no further improvement is expected.  
 
 
 
 
 
Amendment 4
4 October 2019
The group-sequential design of the study 
based on the primary PFS endpoint as 
assessed by BICR has been modified by 
replacing the planned futility analysis, that 
was to be conducted at 60% information 
fraction (IF), with an interim efficacy 
analysis to be conducted at 75% IF.
•
As a result, Section 9.1 Sample Size 
Determination and Section 9.6 Interim 
Analysis, have been revised by 
replacing the Lan-DeMets 
(O’Brien-Fleming) spending function to 
determine the non-binding futility 
boundary at the interim analysis of PFS
with the Lan-DeMets 
(O’Brien-Fleming) α-spending function 
to determine the efficacy boundaries at 
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the interim and final analysis of PFS.
 
 
 
 
 
•
Section 9.3.2.7 Clinical Benefit 
Response has been removed and CBR 
has been eliminated from the list of 
secondary endpoints since the protocol 
already includes more relevant efficacy 
endpoints.
•
The actual patient enrollment has also 
been provided in Section 3 STUDY 
DESIGN as enrollment has been closed.
•
Section 2. and 9.3: IC-DR and IC-TTR 
added.
•
Section 4.1 Inclusion Criteria,
clarification added on the Lung Cancer 
Staging System.
•
Section 4.2 Exclusion Criteria and 4.3 
Contraception: female contraception
period after the last lorlatinib dose
extended from 21 to 35 days to align 
with the Lorviqua SmPC (CHMP 
Opinion on 28 February 2019 and 
Commission Decision 06 May 2019).
•
Section 7.2 Expedited Blinded 
Independent Central Review for Disease 
Progression.  The process has been 
clarified.
•
Schedule of Activities, the collection of 
subsequent anticancer treatment has 
been clarified.
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Version Date
Summary of Changes and Rationale

Typos fixed.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
LIST OF FIGURES .................................................................................................................14
APPENDICES .........................................................................................................................15
SCHEDULE OF ACTIVITIES (SOA)....................................................................................21
1. INTRODUCTION ...............................................................................................................31
1.1. Mechanism of Action/Indication.............................................................................31
1.2. Background and Rationale ......................................................................................31
1.2.1. NSCLC .......................................................................................................31
1.2.2. ALK Alterations in NSCLC .......................................................................31
1.2.3. Resistance Mechanisms..............................................................................32
1.2.4. Crizotinib (XALKORI®) ............................................................................33
1.2.5. Lorlatinib (PF-06463922)...........................................................................35
1.2.5.1. Preclinical Data .........................................................................36
1.2.5.2. Teratogenicity............................................................................36
1.2.5.3. Clinical Data..............................................................................36
1.2.6. Study Rationale...........................................................................................40
1.2.7. Rationale for Starting Dosing Regimens....................................................41
1.2.8. Summary of Benefit/Risk Assessment .......................................................41
...........................................................42
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................43
3. STUDY DESIGN.................................................................................................................44
3.1. Study Treatment ......................................................................................................44
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................45
4.1. Inclusion Criteria.....................................................................................................45
4.2. Exclusion Criteria....................................................................................................47
4.3. Lifestyle Requirements ...........................................................................................50
4.3.1. Contraception..............................................................................................50
4.3.1.1. Woman of Childbearing Potential (WOCBP)...........................51
4.3.1.2. Methods of Contraception.........................................................52
4.4. Sponsor’s Qualified Medical Personnel..................................................................52
5. STUDY TREATMENTS.....................................................................................................53
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5.1. Allocation to Treatment ..........................................................................................53
5.1.1. Stratification Factors...................................................................................53
5.2. Patient Compliance .................................................................................................54
5.3. Investigational Product Supplies.............................................................................54
5.3.1. Dosage Forms and Packaging.....................................................................55
5.3.1.1. Lorlatinib (PF-06463922) .........................................................55
5.3.1.2. Crizotinib...................................................................................55
5.3.2. Preparation and Dispensing........................................................................55
5.3.2.1. Lorlatinib (PF-06463922) .........................................................55
5.3.2.2. Crizotinib...................................................................................55
5.4. Administration.........................................................................................................56
5.4.1. Lorlatinib (PF-06463922)...........................................................................56
5.4.2. Crizotinib....................................................................................................56
5.4.3. Treatment Duration.....................................................................................57
5.5. Recommended Dose Modifications ........................................................................57
5.5.1. Lorlatinib Dose Modifications....................................................................58
5.5.1.1. Hyperlipidemia..........................................................................62
5.5.1.2. PR Interval Prolongation...........................................................62
5.5.2. Crizotinib Dose Modifications ...................................................................63
5.5.2.1. Nausea and Emesis....................................................................68
5.5.2.2. Diarrhea.....................................................................................68
5.5.2.3. Bradycardia ...............................................................................68
5.5.2.4. Pneumonitis/Pneumonia............................................................68
5.5.2.5. Renal Cysts................................................................................69
5.5.2.6. Severe Visual Loss....................................................................69
5.6. Management of Overdose .......................................................................................70
5.7. Investigational Product Storage ..............................................................................70
5.8. Investigational Product Accountability...................................................................71
5.8.1. Destruction of Investigational Product Supplies ........................................71
5.9. Concomitant Treatments .........................................................................................71
5.9.1. Inhibitors and Inducers of CYP Enzymes ..................................................71
5.9.1.1. Arm A Lorlatinib.......................................................................72

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5.9.1.2. Arm B Crizotinib.......................................................................73
5.9.2. Other Anti-Tumor/Anti-Cancer or Experimental Drugs ............................74
5.9.3. Other Prohibited Concomitant Medications and Therapies........................74
5.9.4. Hematopoietic Growth Factors...................................................................74
5.10. Concomitant Surgery.............................................................................................75
5.11. Concomitant Radiotherapy....................................................................................75
6. STUDY PROCEDURES .....................................................................................................75
6.1. Screening.................................................................................................................75
6.1.1. Tumor Biospecimens..................................................................................75
6.1.1.1. Determination of ALK Status ...................................................76
............................................................77
6.2. Treatment Period.....................................................................................................77
6.3. End of Treatment/Withdrawal and Post-Treatment Follow-Up..............................77
6.4. Patient Withdrawal..................................................................................................77
6.5. Survival Follow up Visits........................................................................................78
7. ASSESSMENTS..................................................................................................................78
7.1. Tumor Response Assessments ................................................................................79
7.2. Expedited Blinded Independent Central Review for Disease Progression .............79
7.3. Pregnancy Testing...................................................................................................80
7.4. Safety Assessments .................................................................................................80
7.4.1. Adverse Events ...........................................................................................80
7.4.2. Laboratory Safety Assessment ...................................................................80
7.4.3. Vital Signs and Physical Examinations......................................................81
7.4.4. (12-Lead) Electrocardiograms....................................................................81
7.4.5. Echocardiograms/MUGA Scans.................................................................82
7.4.6. Transthoracic echocardiogram (France and Germany only) ......................82
......................................83
 
.................................................................................................83
.........84
.................................................84
..............................................................................................85
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..............85
.............................................................................................85
....................................................................................86
7.9. Patient-Reported Outcome Assessments.................................................................86
7.10. Assessment of Mood .............................................................................................87
7.11. Assessment of Suicidal Ideation and Behavior.....................................................88
7.12. Ophthalmologic Examinations..............................................................................88
8. ADVERSE EVENT REPORTING......................................................................................88
8.1. Requirements...........................................................................................................88
8.1.1. Additional Details on Recording Adverse Events on the CRF...................90
8.1.2. Eliciting Adverse Event Information..........................................................90
1.1.1. Withdrawal From the Study Due to Adverse Events (Also See 
Section 6.4 Patient Withdrawal) ......................................................................90
8.1.3. Time Period for Collecting AE/SAE Information......................................90
8.1.3.1. Reporting SAEs to Pfizer Safety...............................................90
8.1.3.2. Recording Non-Serious AEs and SAEs on the CRF.................91
8.1.4. Causality Assessment .................................................................................91
8.1.5. Sponsor’s Reporting Requirements to Regulatory Authorities ..................91
8.2. Definitions...............................................................................................................91
8.2.1. Adverse Events ...........................................................................................91
8.2.2. Abnormal Test Findings .............................................................................92
8.2.3. Serious Adverse Events ..............................................................................93
8.2.4. Hospitalization............................................................................................93
8.3. Severity Assessment................................................................................................95
8.4. Special Situations ....................................................................................................95
8.4.1. Protocol-Specified Serious Adverse Events...............................................95
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................95
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................97
8.4.3.1. Exposure During Pregnancy......................................................97
8.4.3.2. Exposure During Breastfeeding ................................................99
8.4.3.3. Occupational Exposure .............................................................99
8.4.4. Medication Errors .......................................................................................99
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8.4.4.1. Medication Errors......................................................................99
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................100
9.1. Sample Size Determination...................................................................................100
9.2. Analysis Sets .........................................................................................................101
9.2.1. Full Analysis Set.......................................................................................101
9.2.2. Safety Analysis Set...................................................................................101
.................................................................101
9.2.4. PRO Analysis Set .....................................................................................101
9.2.5. Biomarker Analysis Set............................................................................102
9.3. Efficacy Analysis ..................................................................................................102
9.3.1. Analysis of the Primary Endpoint.............................................................102
9.3.2. Analysis of Secondary Endpoints.............................................................103
9.3.2.1. Overall Survival ......................................................................103
9.3.2.2. Objective Response.................................................................103
9.3.2.3. Intracranial Objective Response..............................................104
9.3.2.4. Intracranial Time to Progression.............................................104
9.3.2.5. Duration of Response..............................................................104
9.3.2.6. Time to Tumor Response ........................................................105
9.3.2.7. Progression-Free Survival 2....................................................105
9.3.2.8. Patient-Reported Outcomes.....................................................105
9.4. Analysis of Other Endpoints .................................................................................107
........................................................................107
9.4.2. Pharmacokinetic and Exposure-Response Analysis.................................107
9.4.3. Biomarker Analysis for Secondary 
 Endpoints...............107
9.5. Safety Analysis......................................................................................................107
9.5.1. Adverse Events .........................................................................................107
9.5.2. Laboratory Abnormalities.........................................................................108
9.5.3. Electrocardiograms...................................................................................108
9.5.4. Left Ventricular Ejection Fraction............................................................108
9.5.5. Ophthalmologic Data................................................................................109
9.5.6. Mood and Suicidal Ideation and Behavior Analyses................................109
9.6. Interim Analysis ....................................................................................................109
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9.7. Data Monitoring Committee .................................................................................110
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................110
11. DATA HANDLING AND RECORD KEEPING ...........................................................111
11.1. Case Report Forms/Electronic Data Record .......................................................111
11.2. Record Retention.................................................................................................111
12. ETHICS............................................................................................................................112
12.1. Institutional Review Board/Ethics Committee....................................................112
12.2. Ethical Conduct of the Study ..............................................................................112
12.3. Patient Information and Consent.........................................................................112
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................113
13. DEFINITION OF END OF TRIAL.................................................................................114
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................114
15. PUBLICATION OF STUDY RESULTS........................................................................114
15.1. Communication of Results by Pfizer ..................................................................114
15.2. Publications by Investigators ..............................................................................115
16. REFERENCES ................................................................................................................117
LIST OF TABLES
Table 1.
Lorlatinib Dose Levels for Intra-patient Dose Modifications ..................58
Table 2.
Arm A Patients: Lorlatinib Dose Modifications for 
Lorlatinib-Related Toxicities....................................................................59
Table 3.
PR Interval Prolongation Management ....................................................62
Table 4.
Crizotinib Dose Levels for Intra-patient Dose Modifications ..................63
Table 5.
Arm B Patients: Crizotinib Dose Modifications for 
Crizotinib-Related Toxicity......................................................................64
Table 6.
Stopping Boundaries for PFS .................................................................109
LIST OF FIGURES
Figure 1.
Study B7461006 Design...........................................................................19

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APPENDICES
Appendix 1. Abbreviations....................................................................................................121
Appendix 2. Eastern Cooperative Oncology Group (ECOG) Classification of 
Performance Status .................................................................................125
Appendix 3. RECIST Version 1.1 - Modified to Include Assessment of CNS 
Metastases...............................................................................................126
Appendix 4. Required Laboratory Tests................................................................................130
Appendix 5. Medications with Potential PR Interval Prolongation Effect............................132
Appendix 6. PRO Instruments...............................................................................................133
Appendix 7. Specific for France............................................................................................141

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PROTOCOL SUMMARY
Background and Rationale
Non-small cell lung cancer (NSCLC) is the most common cause of fatal malignancy 
globally, most often diagnosed in advanced stages, where surgery and local radiotherapy are 
no longer curative or indicated.1,2 Standard therapy in advanced stages of disease is 
primarily palliative in nature, involving the use of cytotoxic chemotherapy with or without 
radiation therapy or immunotherapy.3,4,5 Targeted therapies such as tyrosine kinase inhibitors 
(TKIs) may be used for appropriate patients.  In spite of these treatments, 5-year survival is 
only about 17% for advanced-stage NSCLC patients, highlighting the need for novel 
therapies and treatment regimens.6,7
Molecularly targeted therapy has been successful in NSCLC patients who have tumors that 
harbor various alterations, including the fusion protein EML4-ALK.  The first approved
agent for anaplastic lymphoma kinase (ALK)-positive NSCLC was crizotinib.  Although 
most patients with ALK-positive NSCLC derive substantial clinical benefit from crizotinib, 
some ALK-positive NSCLC patients will not derive any benefit (intrinsic resistance), while 
other patients who initially derive benefit will develop resistance (acquired resistance).  In 
the case of crizotinib-resistant ALK-positive NSCLC, the rate of resistance due to mutations 
in the ALK kinase domain is typically reported in the range of 35-40%.31 In response to 
causes of crizotinib treatment failure, next-generation ALK/ROS1TKIs are being developed. 
The second-generation ALK inhibitors, which have demonstrated activity in a 
crizotinib-refractory or resistant treatment setting, may have the potential for even greater 
activity in treatment-naïve patients.  Data from both alectinib1,21 and ceritinib25 have shown 
that using these more potent agents in the first-line advanced ALK-positive NSCLC 
treatment setting may exceed the median progression-free survival (PFS) time for crizotinib. 
Lorlatinib is a selective, brain-penetrant ALK TKI with potent activity against ALK and 
ROS1 fusions, including those harboring resistance mutations.  Lorlatinib has demonstrated 
clinically meaningful anti-tumor activity in patients with brain metastases after treatment 
with ALK inhibitors including crizotinib.30 Further, lorlatinib appears to be the only ALK 
TKI active against certain mutations that are the most difficult to inhibit, such as the G1202R 
mutation.
Lorlatinib has the potential to improve PFS in the treatment-naïve advanced ALK-positive 
NSCLC treatment setting based on its greater potency against ALK and its broad coverage 
against all known single point mutations that mediate resistance to crizotinib and 
second-generation ALK inhibitors.29

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STUDY OBJECTIVES and ENDPOINTS
Primary Objective
•
To demonstrate that lorlatinib as a single agent (Arm A) is superior to crizotinib alone 
(Arm B) in prolonging progression-free survival (PFS) in advanced ALK-positive 
NSCLC patients who are treatment naïve.
Secondary Objectives: 
•
To compare Arm A with Arm B in treatment-naïve advanced ALK-positive NSCLC 
patients with respect to overall survival (OS);
•
To evaluate the antitumor activity in each treatment arm;
•
To evaluate the safety and tolerability in each treatment arm;
•
To evaluate patient-reported outcomes (PROs) of health-related quality of life, 
disease/treatment-related symptoms of lung cancer, and general health status for each 
treatment arm;
•
To evaluate candidate biomarkers of sensitivity or resistance to single-agent crizotinib 
or lorlatinib in pre-treatment tumor tissue;
•
To evaluate candidate biomarkers of sensitivity or resistance to single-agent crizotinib 
or lorlatinib in peripheral blood.
Exploratory Objectives:
 
 
 
Primary Endpoint: 
•
PFS based on Blinded Independent Central Review (BICR) assessment (RECIST 
v.1.1, see Appendix 3).
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Secondary Endpoints: 
•
Efficacy: OS, PFS based on Investigator’s assessment, Objective Response (OR) 
based on BICR and on Investigator’s assessment; intracranial OR (IC-OR), IC-time to 
progression (IC-TTP), Duration of Response (DR) and IC-DR, Time to Tumor 
Response (TTR), and IC-TTRall by BICR (RECIST v. 1.1), and PFS2;
•
Safety: Adverse Events (AEs), as graded by NCI CTCAE (National cancer Institute 
Common Terminology Criteria for Adverse Events) v.4.03; laboratory abnormalities 
(as graded by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate) and body 
weight; electrocardiograms (ECGs); echocardiogram or MUGA (multigated 
acquisition) scan; ophthalmologic data;
•
PRO as assessed by EORTC (European Organisation for Research and Treatment of 
Cancer) QLC-C30, EORTC QLQ-LC13, EQ-5D-5L;
•
Tumor tissue biomarkers including, but not limited to, ALK gene rearrangement 
and/or mutations as measured by next-generation sequencing (NGS) and/or 
immunohistochemistry (IHC);
•
Peripheral blood cfDNA (circulating free Deoxyribonucleic acid) biomarkers 
including, but not limited to, ALK gene rearrangement and/or ALK kinase domain 
mutations.
Exploratory Endpoints:
 
 
 
STUDY DESIGN
Study Overview
This is a Phase 3, multinational, multicenter (at approximately 160 sites), randomized, 
open-label, parallel 2-arm study in which approximately 280 previously untreated patients 
with advanced ALK-positive NSCLC were to be randomized 1:1 to receive lorlatinib 
monotherapy or crizotinib monotherapy according to the study design illustrated in Figure 
1 below (296 patients were actually randomized).
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Figure 1.
Study B7461006 D

Patients will be stratif

Presence of brain 

Ethnic origin (Asi

Crossover between tre
Study Treatments
This study was to randomize 

Arm A: Lorlatinib mo
100 mg QD (quaque d
continuously; or

Arm B: Crizotinib mo
administered as 1 x 25

Each cycle duratio
Study treatment may continu
refusal, patient lost to follow
sponsor, whichever comes fir
ctober 2019
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Design
fied according to: 
metastases (Yes vs. No); 
ian vs. non-Asian).
eatment arms will not be permitted.
280 patients in a 1:1 ratio to receive either:
onotherapy at the Recommended Phase 2 dose (R
die; every day), administered as 4 x 25 mg oral t
onotherapy at the registered starting dose of 250
50 mg oral capsules, twice daily, continuously.
on will be 28 days. 
ue until confirmed disease progression assessed b
-up, unacceptable toxicity, or the study is termin
rst.
RP2D) of 
tablets, 
mg BID, 
by BICR, patient 
nated by the 

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Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.
Sample Size Determination
The primary objective of this study is to demonstrate that lorlatinib (Arm A) is superior to 
crizotinib (Arm B) in prolonging PFS by BICR assessment per RECIST v1.1.  A key 
secondary objective of the study is to demonstrate that lorlatinib is superior to crizotinib in
prolonging OS.
The study is designed to test H0: HRPFS ≥1 vs. HA: HRPFS <1, where HRPFS is the hazard ratio 
(Arm A/Arm B) of PFS.
Approximately 280 patients (140 in each arm) were to be randomized using a 1:1 ratio 
stratified by presence of brain metastases and ethnic origin. As of 28 February, 2019 
enrollment was closed with 296 patients randomized. One hundred seventy seven (177) PFS 
events will be required to have at least 90% power to detect a hazard ratio (HR) of 
0.611 using a one-sided stratified log-rank test at a significance level of 0.025, and a 2-look 
group-sequential design with a Lan-DeMets (O’Brien-Fleming) α-spending function to 
determine the efficacy boundaries
The planned sample size was determined based on the assumption of a HR of 0.611 under the 
alternative hypothesis which, under an exponential model, assumes a median PFS of 
11 months in the crizotinib arm and 18 months in the lorlatinib arm.  
 
  
 
 
 
The sample size further assumed a 15% drop-out rate within each 
treatment arm at 30 months and a non-uniform patient accrual over approximately 15 months 
and follow-up after the last patient is randomized of approximately 18 months
This sample size will also allow comparison of OS between the 2 treatment arms, provided 
that superiority of lorlatinib over crizotinib with respect to PFS has been demonstrated.  If the 
true HR is 0.70 under the alternative hypothesis (under an exponential model, assumes 
median OS of 48 months on the crizotinib arm and 68.6 months on the lorlatinib arm), a total 
of 198 deaths will be required to have 70% power using a one-sided stratified log-rank test at 
a significance level of 0.025, and a 3-look group-sequential design with  Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundaries.
These calculations further assumed a 15% drop-out rate for OS on either treatment arm at 
120 months and a follow-up of approximately 110 months after the last patient is 
randomized.
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SCHEDULE OF ACTIVITIES (SOA)
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the 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 in the Schedule of Activities table in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
CYCLE 1
28 days
CYCLE 2
28 days
CYCLES 3
(28 days per 
cycle)
END of TREATMENT (EOT)/FOLLOW-UP
Visit Identifiera
Screening1
(28 days prior 
to 
randomization)
Day 1
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal30
Post-Treatment 
Follow-Up31
(every 4 weeks until 
PD)
Survival
Follow-Up32 (every
4 months up to 
3 years, then every 
6 months thereafter)
Visit Time Window 
(days)
N/A
1
1
2
2
3
±7
7
Informed consent2
X
Tumor history, including 
ALK status 
determination3
X
Medical/oncological 
history (including prior 
medications and smoking 
history)
X
Physical examination 
X
(full PE at 
screening only)
X
X
X
X
X
Baseline signs and 
symptoms4
X
Ophthalmologic 
examination5
X
To be repeated during the study in case of visual disturbances CTCAE grade increase, or 
as clinically indicated
Height
X
Weight6
X
X
X
X
Vital signs6
X
X
X
X
X
X
X

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CYCLE 1
28 days
CYCLE 2
28 days
CYCLES 3
(28 days per 
cycle)
END of TREATMENT (EOT)/FOLLOW-UP
Visit Identifiera
Screening1
(28 days prior 
to 
randomization)
Day 1
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal30
Post-Treatment 
Follow-Up31
(every 4 weeks until 
PD)
Survival
Follow-Up32 (every
4 months up to 
3 years, then every 
6 months thereafter)
Visit Time Window 
(days)
N/A
1
1
2
2
3
±7
7
ECOG performance 
status7
X
X
X
X
X
Contraception check8
X
X
X
X
X
X
X
X
Laboratory
Hematology9
X
X( - 7 days)
X
X
X
X
X
X
Blood Chemistry10
X
X (-7 days)
X
X
X
X
X
X
HBV, HCV (if 
applicable)
X
Lipids11
X
X(- 7 days)
X
X
X
X
X
X (at 30 days)
Coagulation12
X
X (-7 Days)
X
X
X
X
Urinalysis13
X
X(-7 days)
(X)
(X)
X
X
Pregnancy test14
X
X
X
X
X
Triplicate (12-lead) 
ECGs15
X
X (pre and 1-4 hs 
post dose for Arm 
A and pre-dose for 
Arm B)
X 
(1-4 hs 
post 
dose for 
Arm A 
only)
X(1-4 hs 
post dose 
for Arm 
A only)
X(1-4 hs 
post dose 
for Arm A 
only and 
2-6 hs post 
dose for 
Arm B)
X (single 
reading, 
pre-dose, on 
Day 1 of 
every other 
cycle for both 
Arms)
X (Triplicate ECG for 
both Arms)
LVEF assessment 
(Echocardiogram or 
MUGA scan)16
X
X (pre- dose- not 
to be repeated if 
normal and 
performed 
<2 weeks prior to 
randomization)
X (pre-dose, 
on Day 1 of 
every other 
cycle; a time 
window of 
1 week prior 
to Day 1 is 
permitted)
X

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CYCLE 1
28 days
CYCLE 2
28 days
CYCLES 3
(28 days per 
cycle)
END of TREATMENT (EOT)/FOLLOW-UP
Visit Identifiera
Screening1
(28 days prior 
to 
randomization)
Day 1
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal30
Post-Treatment 
Follow-Up31
(every 4 weeks until 
PD)
Survival
Follow-Up32 (every
4 months up to 
3 years, then every 
6 months thereafter)
Visit Time Window 
(days)
N/A
1
1
2
2
3
±7
7
For France and Germany 
only: Transthoracic 
echocardiogram (TTE) to 
assess PAP and right 
heart function.(refer to 
Section 7.4.6
X
X (pre-dose- not to 
be repeated if 
normal and 
performed 
<2 weeks prior to 
randomization)
X (at least 
every 
6 months 
during 
treatment)
X (to be performed 
only if patient received 
at least 3 months of 
study drug treatment 
and if the last previous
TTE assessment was
performed more than
4 weeks before)
Randomization and 
Treatment
Randomization17
X
Arm A: lorlatinib
orally on a continuous QD dosing schedule
Arm B: crizotinib 
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CYCLE 1
28 days
CYCLE 2
28 days
CYCLES ≥3
(28 days per 
cycle)
END of TREATMENT (EOT)/FOLLOW-UP
Visit Identifiera
Screening1
(≤28 days prior 
to 
randomization)
Day 1
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal30
Post-Treatment 
Follow-Up31
(every 4 weeks until 
PD)
Survival
Follow-Up32 (every
4 months up to 
3 years, then every 
6 months thereafter)
Visit Time Window 
(days)
N/A
±1
±1
±2
±2
±3
±7
±7
Tumor Assessments
CT (Computed 
Tomography) or MRI 
(Magnetic Resonance 
Imaging) scan18
X
• every 8 weeks (±1 week) since 
randomization for CT or MRI scan. 
• every 16 weeks (+1 week) for Bone 
Scan/MRI only if evidence of bone 
metastases is observed at baseline.
X
X (every 8 weeks, 
±1 week, until PD; for 
bone scan/MRI every 
16 weeks ±1 week, 
until PD only if 
evidence of bone 
metastases is observed 
at baseline.
Diagnostic Cerebrospinal 
Fluid 
 
19
X
To be repeated as clinically indicated and if clinically safe and feasible
Other Clinical 
Assessments
Serious and non-serious 
adverse event 
monitoring20
X
→
→
→
→
→
→
Concomitant medications 
and non-drug supportive 
interventions21
X
X
→
→
→
→
→
X (subsequent 
anticancer treatment)
PRO Assessment22
X
X
X
X
X (only if patient visits 
the clinic)
Mood Assessment23
X
X
X (up to Cycle 
6 and then 
Day 1 of 
every other 
cycle)
X
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CYCLE 1
28 days
CYCLE 2
28 days
CYCLES ≥3
(28 days per 
cycle)
END of TREATMENT (EOT)/FOLLOW-UP
Visit Identifiera
Screening1
(≤28 days prior 
to 
randomization)
Day 1
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal30
Post-Treatment 
Follow-Up31
(every 4 weeks until 
PD)
Survival
Follow-Up32 (every
4 months up to 
3 years, then every 
6 months thereafter)
Visit Time Window 
(days)
N/A
±1
±1
±2
±2
±3
±7
±7
Suicidal Ideation and 
Behavior24
X
X
X (up to Cycle 
6 and then 
Day 1 of 
every other 
cycle)
X
Survival status31
X
Other Samples
Archival tumor tissue 
specimen25
X
De Novo tumor 
specimens26
(X)
(X)
 
 
 
 
 
 
a.
Day relative to start of study treatment (Day 1 of Cycle 1).
Abbreviations: → = ongoing/continuous event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; LVEF = left ventricular ejection 
fraction; MUGA = Multigate acquisition; TTE = Transthoracic echocardiogram; CT = computed tomography; MRI = Magnetic Resonance Imaging; 
EORTC = European Organisation for Research and Treatment of Cancer; PD = Progression of Disease; ALK = anaplastic lymphoma kinase; PE = Physical 
examination; CTCAE = Common Terminology Criteria for Adverse Events; HBV = Hepatitis B Virus; HCV = Hepatitis C Virus; PRO = Patient-reported 
Outcome; QD = Quaque Die (every day); BID = Bis in Die (twice daily); 
; N/A = Not Applicable; PAP =Pulmonary arterial 
pressure 
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Footnotes:
(X) refer to specific footnote when the assessment may be optional/repeat assessment might not be required.
Acceptable time windows for performing each assessment are described in the column headers.
1.
Screening: To be obtained within 28 days prior to randomization.  Available results for assessements that have been performed prior to informed consent being obtained as 
part of routine standard of care (laboratory tests or tumor imaging scans ) may be used to determine patient eligibility, provided they have been performed within the required 
timing (that is 7 days prior randomization for laboratory tests or 28 days prior randomization for tumor imaging).
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.  Informed consent for use of tissue for other 
research or diagnostic 
development must also be obtained.  Molecular Presceening Informed Consent must also be obtained in case the ALK status determination is not already available or has been 
performed through a test different from the required Ventana ALK (D5F3).  IHC test performed on the ULTRA or XT platforms are acceptable, while tests performed on the 
GX platform cannot be accepted.
3.
Prescreening activities to determine ALK status will be performed as needed:
a.
Patients who have historical results available showing ALK-positivity through Ventana ALK D5F3 CDx(Companion Diagnostics) test can proceed with the screening 
assessments.  Available pathological reports must be prospectively collected and sent to Pfizer for confirmation of patient eligibility.
b.
Patients who have historical results available showing ALK-positivity through a non-Ventana ALK D5F3 CDx test can start the screening assessments while waiting for 
the Ventana ALK D5F3 CDx assay to be performed.  Re -testing time should be in the 28 days time window.
c.
Patients who do not have historical results available must undergo a pre-screening Ventana ALK D5F3 CDx test and, if positive, can start the screening assessments.
Please refer to Section 6.1.1.1 for additional details.
4.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced and present pre-dose on Day 1 of Cycle 1.
5.
Ophthalmologic Examination (right and left eye): Includes best corrected visual acuity, and refractive error slit lamp biomicroscopy and fundoscopy, and should be performed 
by an ophthalmologist.  Testing will be performed at screening and should be repeated during the study whenever a vision disorder AE is observed or CTCAE grade change 
occurs from the previous visit (more frequent examinations may be performed based on local requirement).
6.
Vital Signs: Blood pressure and pulse rate to be recorded in sitting position after 5 min rest.  Body weight to be recorded on Day 1 of each cycle.
7.
Performance Status: According to Eastern Cooperative Oncology Group (ECOG) classification (see Appendix 2). 
8.
Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to follow the contraception guidelines in 
Section 4.3.1.
9.
Hematology: Required tests are listed in the Appendix 4 of the protocol.  Not to be repeated at C1D1 if performed within 7 days before.  May also be performed when 
clinically indicated (results to be entered in CRF as unplanned visit).
10. Blood Chemistry: Required tests are listed in Appendix 4 of the protocol.  Not to be repeated at C1D1 if performed within 7 days before.  May also be performed when 
clinically indicated (results to be entered in CRF as unplanned visit).
11. Lipids: Required tests are listed in the Appendix 4 of the protocol.  Not to be repeated at C1D1 if performed within 7 days before.  May also be performed when clinically 
indicated. (results to be entered in CRF as unplanned visit).
12. Coagulation: Required tests are listed in the Appendix 4 of the protocol.  Not to be repeated at C1D1 if performed within 7 days before.  May also be performed when 
clinically indicated (results to be entered in CRF as unplanned visit). 
13. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal and/or if this is the local standard.  To be repeated as clinically indicated, for example upon 
diagnosis of renal cysts (more frequent assessment may be performed based on local requirement).  Not to be repeated at C1D1 if performed within 7 days before.
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14. Serum or Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, to be performed on two occasions prior to starting study 
therapy, once at the start of screening (serum) and once at the baseline visit (serum or urine), whose results must be available before investigational product administration.  
Pregnancy tests also routinely repeated at every cycle during the active treatment period, at the end of treatment and additionally whenever one menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  Additional pregnancy tests if requested by IRB/IECs or by local regulations.
15. Triplicate 12-Lead ECGs: At each time point, 3 consecutive 12-lead ECGs are to be performed approximately 2 minutes apart (or within 10 minutes, whichever is applicable).  
The ECG must occur prior to any blood sample collections or venipuncturing.  Whenever it is not feasible, blood chemistry and hematology lab tests may be collected prior to 
the pre-dose ECG provided at least 30 minutes has elapsed between the venipunturing and the collection of the ECG.  
 
 
  For Arm A 
(lorlatinib), ECGs are to be collected at pre-dose and 1-4 hours post-dose on Cycle 1 Day 1.  ECGs will also be collected at 1-4 hours post-dose on Cycle 1 Day 8 and Day 
15, and on Cycle 2 Day 1. Additional ECGs may be collected as clinically indicated.  For Arm B (crizotinib), ECGs are to be collected at pre-dose on Cycle 1 Day 1.  For 
Cycle 2 Day 1, the ECGs must be collected 2-6 hours after the morning dose.  Additional ECGs at may be collected as clinically indicated.  At End of Treatment/Withdrawal, 
triplicate ECGs are to be collected for both treatment arms.  Additional ECG time points may be performed based on the emerging data.  Single reading ECG are to be 
collected pre-dose on Day 1 of Cycle 3 and every other cycle thereafter.
16. LVEF Assessment: Echocardiogram or MUGA to be performed at Screening, at pre-dose (0 hour), on Cycle 1 Day 1 and on Day 1 of every other cycle thereafter, and at the 
EOT visit.  The same method should be used at each time point.  If the screening ECHO or MUGA is normal and has been performed within 2 weeks prior to randomization, 
there is no need to repeat this assessment at Day1 of Cycle 1.  At subsequent visits a time window of 1 week prior to Day 1 of subsequent cycles will be permitted for the 
ECHO/MUGA assessment.
17. Randomization: Patient number and treatment arm allocation will be operated through an automated system.  Study treatments to be initiated preferably on the randomization 
day but no later than 7 days after randomization.
Arm A: lorlatinib administered orally, on a continuous QD dosing schedule, as described in Section 5.4.1.
Arm B: crizotinib administered orally, on a continuous BID dosing schedule, as described in Section 5.4.2.
18. Tumor Assessments: To include all known or suspected disease sites.  Baseline and on study imaging to include as mandatory exams: chest, abdomen, and pelvis CT or MRI 
scans; Brain MRI; Bone scan or MRI.  Brain MRI (Gadolinium contrast enhanced) to be used for assessment of CNS lesions (even if brain metastases not suspected), with 
contingent slices of 1 mm for lesions with a minimum size of 5 mm – 10 mm in size, 5 mm for lesions greater than 10 mm.  Bone scans (or bone MRI if preferred by 
investigator) to be performed at baseline for all patients and repeated every 16 weeks (+1 week) on study only if evidence of bone metastases is observed at baseline.  For all 
tumor assessments, the method of assessment that was used at baseline should be the same method used throughout the study.  CT or MRI scans to be done at every 8 weeks 
±1 week (every 16 weeks for bone scans/MRI) starting from randomization while on treatment or post-treatment follow-up (until PD).  Responses will be confirmed ≥4 weeks 
later.  Tumor assessment should be repeated at the EOT visit if more than 8 weeks have passed since the last evaluation.  Tumor assessments must continue until documented 
progression of disease by BICR.  If a patient continues study treatment beyond disease progression confirmed by BICR, based on investigator judgement of clinical benefit, 
(eg, in case the intracranial lesions are not in progression) tumor assessment must continue to be performed every 8 weeks ±1 week (16 weeks ±1 week for Bone Scan/MRI if 
applicable).  Patients who discontinue treatment without PD should be followed radiologically until PD is confirmed by BICR regardless of subsequent anti-cancer treatments.  
Assessment of response will be made using RECIST v.1.1.  Assessment of response of measurable intracranial disease will be made using a modified version of RECIST 
v.1.1.33
19. Diagnostic Cerebrospinal Fluid (CSF) analysis is mandatory for patients with suspected or confirmed leptomeningeal disease/carcinomatous meningitis (LMD/CM) not 
visualized on MRI (optional for the remaining patients).  To be performed at baseline, and if clinically safe and feasible, further CSF cytology will be performed as clinically 
indicated to assess anti-tumor response and to determine 
 crizotinib concentrations.  (Of note: if a patient is required to undergo a lumbar puncture while on study 
drug, an additional ~5 mL sample of CSF should be collected for determining 
 crizotinib and its metabolite (for 
Arm B) concentrations.  If a CSF sample is collected, 
  Detailed collection procedures will be 
provided in the Study Manual).
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20. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.03.  For AEs and Serious Adverse Events (SAEs), the active collection period to Pfizer or its designated representative begins from the time 
that the patient provides informed consent, through and including 28 calendar days after the last administration of the investigational product.  If a patient begins a new 
anticancer therapy, the recording period for non-serious 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.
21. Concomitant Medications and Non-Drug Supportive Interventions: All concomitant medications and non-drug supportive interventions will be recorded in the CRF from 
28 days prior to start of study treatment and up to 28 after the last dose of study treatment.
22. PRO Assessment: Patients must complete all EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L self-assessment questionnaires in the clinic as these cannot be taken 
home.  All scheduled assessments of the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L must be completed in the clinic prior to any other study or medical 
procedures.
23. Mood Assessment: An assessment of mood via the Beck Depression Inventory II (BDI II) scale will be administered to patients prior to the first day of investigational drugs 
dosing (ie, Cycle 1 Day1) and then prior to dosing on Day 1 of Cycle 2 through –Cycle 6.  After Cycle 6 Day 1, this test will be administered prior to dosing on Day 1 of 
every other cycle (ie, Cycle 8 Day 1, Cycle 10 Day 1, etc.) and at EOT.
24. Suicidal Ideation and Behavior: An assessment of suicidal ideation and behavior via the Columbia Suicide Severity Rating Scale (C- SSRS) will be administered to patients 
prior to the first day of investigational drugs dosing (ie, Cycle 1 Day1) and then prior to dosing on Day 1 of Cycle 2 through Cycle 6.  After Cycle 6 Day 1, this test will be 
administered prior to dosing on Day 1 of every other cycle (ie, Cycle 8 Day 1, Cycle 10 Day 1, etc.) and at EOT.
25. Archival Tumor Tissue Specimens: All patients must provide a formalin-fixed paraffin-embedded (FFPE) archival tumor specimen, specifically a FFPE tissue block that 
contains sufficient tissue to generate at least 10 (preferably 15) unstained slides, each with tissue sections that are ~5-microns thick.  If a FFPE tissue block cannot be 
provided, at least 10 (preferably 15) unbaked glass slides, each containing an unstained ~5-micron FFPE tissue section must be submitted.  If archived FFPE tissue is not 
available, a de novo (fresh) tumor sample must be obtained in accordance with local institutional practice for tumor biopsies.  Acquisition of archival or de novo tumor tissue 
is mandatory for patient enrollment.  Archived or de novo tumor tissue from cytological sampling (eg, fine needle aspiration, pleural effusion, including FFPE block is 
acceptable at screening and can be submitted.  Archived or de novo tumor tissue from bone metastasis (eg, bone biopsy specimen), is not adequate at screening and should not 
be submitted.
26. De Novo Tumor Specimens: De novo tumor core needle biopsy collection will be mandatory at screening if archival tissue is not available. 
 
  Endobronchial 
Ultrasound Guided Transbronchial Core Needle biopsies are adequate.  Pleural effusions (PE) cell pellets may substitute for tumor core biopsy as appropriate.  Fine needle 
aspiration (FNA) samples (2-3 pass minimum prepared as FFPE cell block) should only be performed in the event a biopsy or pleural effusion cell pellet is not safe or 
feasible. Tumor tissue should be provided as a FFPE tumor tissue block containing sufficient tumor tissue to allow if possible for sectioning of at least 10 (preferably 15) 
slides each containing a ~5-micron tissue section.  If local country regulations do not allow for tissue block to be submitted or if a tissue block cannot be provided, sites 
should provide if possible at least 10 (preferably 15) unbaked glass slides each containing a ~5-micron tissue section cut serially from the same block.  Details for handling of 
these samples including processing, storage, and shipment will be provided in the Study Manual.
 
 
 
 
 
 
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30. End of Treatment (EOT) Visit: Obtain these assessments if not completed in the last week (Tumor assessment should be repeated a the EOT visit if more than 8 weeks have 
passed since the last evaluation.).  EOT visit is usually scheduled for 28 days after the last dose of investigational product or when decision taken to provide alternative 
anti-cancer therapy whichever is sooner.
31. Post-Treatment Follow-Up Visits: Patients will return to undergo review of concomitant medications, laboratory tests, vital signs, and assessment for resolution of any 
treatment-related toxicity until PD or until the time of initiation of new anticancer treatment.  At this point, patients continuing to experience treatment related toxicities will 
continue to be followed at least every 4 weeks (except for the tumor assessment which will be performed every 8 weeks 1 week (every 16 weeks week for bone scan/MRI 
if applicable), until resolution or determination, in the clinical judgment of the Investigator, that no further improvement is expected.  Patients discontinuing treatment for 
reasons other than progression of disease will continue to perform tumor assessments until PD documented by BICR, regardless of subsequent anti-cancer treatments.
32. Survival Follow-Up: After discontinuation of study treatment, information on post-study survival status and subsequent anti-cancer treatment (including administration start 
and stop dates, reason for treatment discontinuation and date of disease progression, if applicable) will be collected every 4 months up to 3 years, then every 6 months until 
death, or patient withdrawal of consent or study closure (after the required number of OS events have been reported), whichever occurs first.  Telephone contact is acceptable 
for patients refusing/unable to go back to the site.

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06463922 (lorlatinib) is an anaplastic lymphoma kinase (ALK) and c-ROS 
oncogene-1 (ROS1) receptor tyrosine kinase inhibitor that is currently being investigated in 
patients with previously untreated advanced ALK-positive non-small cell lung cancer 
(NSCLC).
The mechanism of actions of crizotinib and lorlatinib are described in Section 1.2.4 and
Section 1.2.5, respectively.
1.2. Background and Rationale
1.2.1. NSCLC
NSCLC is the most common cause of fatal malignancy globally, most often diagnosed in 
advanced stages, where surgery and local radiotherapy are no longer curative or 
indicated.1,2 Standard therapy in later stages of disease is primarily palliative in nature, 
involving the use of cytotoxic chemotherapy with or without radiation therapy and
immunotherapy.3,4,5
In spite of these treatments, 5-year survival is only about 17% for advanced-stage NSCLC 
patients, highlighting the need for novel therapies and treatment regimens.6,7
Targeted therapies such as tyrosine kinase inhibitors (TKIs) may be used in advanced 
NSCLC patients who have tumors that harbor various alterations, including the fusion 
protein EML4-ALK.  The first approved agent for anaplastic lymphoma kinase 
(ALK)-positive NSCLC was crizotinib.  Although most patients with ALK-positive NSCLC 
derive substantial clinical benefit from crizotinib, some ALK-positive NSCLC patients will 
not derive any benefit (intrinsic resistance), while other patients who initially derive benefit 
will develop resistance (acquired resistance).  In the case of crizotinib-resistant ALK-positive 
NSCLC, the rate of resistance due to mutations in the ALK kinase domain is typically 
reported in the range of 35-40%.31
1.2.2. ALK Alterations in NSCLC 
A rearrangement within chromosome 2p resulting in the formation of a fusion gene product 
comprising portions of the echinoderm microtubule-associated protein-like-4 (EML4) gene 
and the ALK gene was discovered in 2007 in NSCLC cell lines and archived clinical 
specimens.8 A subsequent series of studies have described 9 fusion variants of EML4-ALK 
plus additional but less common fusion partners with ALK.9 Currently, there are at least 
27 different ALK fusion variants reported in the literature, the majority of isoforms involve 
EML4-ALK.  ALK-positive NSCLC patients, who represent between 3% and 5% of all 
NSCLC cases, tend to be young (average age 50 years at diagnosis), and light or never 
smokers.10

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Oncogenic fusions of ALK and ROS1 define 2 distinct subsets of human lung
adenocarcinomas,8,11 and play essential roles in regulation of tumor cell survival, growth, and 
metastasis.  Targeting ALK or ROS1 in these cancers provides a novel opportunity to 
selectively target cancer cells bearing ALK or ROS1 fusions that are implicated as causative 
oncogenic driver events in these patients’ tumors.12,13
The first-generation ALK/ROS1/cMET inhibitor crizotinib (Xalkori®) has demonstrated 
impressive clinical benefit in ALK and ROS1 fusion-positive lung cancers12,13 leading to the 
approval of crizotinib for the treatment of advanced ALK-positive NSCLC patients.  The 
European Commission also approved a product label update to expand use of crizotinib to 
first-line treatment of adults with ALK-positive advanced NSCLC.13 Thus, crizotinib has 
become the global standard of care (SOC) for patients with ALK-positive NSCLC.
1.2.3. Resistance Mechanisms 
Although most patients with ALK-positive NSCLC derive substantial clinical benefit from 
crizotinib, some patients will not derive any benefit (intrinsic resistance), while most patients
who initially derived benefit will eventually develop resistance (acquired resistance) to 
crizotinib.14 Acquired ALK kinase domain mutations and/or brain metastases are two major 
relapse mechanisms to crizotinib therapy.14,15,16 In the case of crizotinib-resistant 
ALK-positive NSCLC, the rate of resistance due to mutations in the ALK kinase domain is 
typically reported in the range of 35-40%.16 Resistance to ALK TKIs may be related to 
gatekeeper mutations along with activation of bypass resistance mechanisms such as somatic
variations in tumor response pathways.  Multiple types of ALK kinase mutations have been 
identified in crizotinib-refractory or resistant patients.16-19
In response to these causes of crizotinib treatment failure, next-generation ALK/ROS1 TKIs 
are being developed.
The first of the second-generation ALK inhibitors to show a significant clinical activity has 
been ceritinib (ZYKADIATM).20 Results from a global Phase 1 study led to the drug’s 
accelerated approval for the treatment of NSCLC patients who progressed or were intolerant 
to crizotinib in US and Europe, based on tumor response and duration of response. 
Alectinib (ALECENSATM) is a selective ALK inhibitor, has CNS (central nervous system)
activity, and has shown clinical activity in both crizotinib-resistant and treatment-naïve 
patients.  Alectinib is approved in Japan and has received accelerated approval in the US for 
the treatment of patients with ALK-positive NSCLC who have progressed or are intolerant to 
crizotinib.23
The second-generation ALK inhibitors, which have demonstrated activity in a 
crizotinib-refractory or resistant treatment setting, may have the potential for even greater 
activity in treatment-naïve patients. Data from both alectinib1,21 and ceritinib25 have shown 
that using these more potent agents in the first-line advanced ALK-positive NSCLC 
treatment setting may exceed the median PFS time for crizotinib.

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The Phase 3 study J-ALEX of alectinib vs. crizotinib conducted in Japanese patients with 
ALK-positive NSCLC had been stopped early following a recommendation by an 
Independent Data Monitoring Committee, as the study met its primary endpoint at a 
pre-planned interim analysis.1,21
A separate Phase 3 study of alectinib compared with crizotinib in patients with 
treatment-naïve ALK-positive advanced NSCLC (ALEX) has just completed accrual with a 
total of 303 patients enrolled. The study Primary Completion Date that is the final data 
collection for the primary outcome measure is expected in March 2017.24
In the Phase 1/2 Study B7461001, lorlatinib demonstrated robust clinical activity in both 
ALK-positive and ROS1-positive NSCLC patients, most of whom had brain metastases and 
had received ≥1 prior ALK TKI.  An objective response rate (ORR) of 46% was observed in 
patients who received ≥2 prior ALK TKI treatments.  When considering the patients who 
received only 1 previous ALK TKI, the ORR was 57%.
 
 
 
 
Significant intracranial responses were also observed, showing that lorlatinib can cross the 
blood–brain barrier to achieve clinically meaningful anti-tumor activity in patients with brain 
metastases after treatment with ALK inhibitors including crizotinib.  Lorlatinib in fact 
showed an intracranial ORR of 31% when considering both target and non-target lesions and 
of 39% when considering the target lesions only.30 Further, lorlatinib appears to be the only 
ALK TKI active against certain mutations that are the most difficult to inhibit, such as the 
G1202R mutation. 
Lorlatinib, therefore, has the potential to improve PFS times in the treatment-naïve 
ALK-positive advanced NSCLC treatment setting based on its greater potency against ALK 
and its broader coverage against all known single point mutations that lead to resistance to 
crizotinib and second generation ALK inhibitors.29
1.2.4. Crizotinib (XALKORI®)
Crizotinib, which is used in this study as the comparator arm vs the experimental arms, is the 
SOC used to treat NSCLC that has spread to other parts of the body and is caused by a defect 
in the ALK gene.  To date, crizotinib has received traditional or conditional approval for the 
treatment of patients with ALK-positive advanced NSCLC in many countries including the 
United States (US), Europe (EU), and Japan.  Crizotinib has also received traditional
approval for the treatment of patients with ROS1-positive advanced NSCLC in the US.
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Crizotinib is a selective ATP-competitive small-molecule inhibitor of ALK, ROS1, RON 
(Recepteur d’Origine Nantais), and c-MET/Hepatocyte Growth Factor Receptor (HGFR) 
tyrosine kinases and their oncogenic variants (eg, ALK or ROS1 fusion proteins or 
c-MET/HGFR mutant variants).  Consistent with this mechanism of action, crizotinib 
inhibited phosphorylation of c-MET/HGFR and selected ALK fusion or mutant variants in 
tumor cells both in vitro and in vivo, and RON and ROS1 in vitro.  Crizotinib exhibited 
potent and selective growth inhibitory activity against tumor cells exhibiting 
translocation/inversion or selected mutations involving the ALK gene locus (EML4-ALK or 
nucleophosmin [NPM]-ALK fusion variants). 
Oral dosing of crizotinib 250 mg twice daily (BID) showed plasma concentrations reach 
steady state within 15 days and remain stable.  The mean apparent terminal half-life was 
42 hours in cancer patients after a single dose.  Crizotinib is absorbed with a peak plasma 
concentration occurring between 4 and 6 hours under fasted condition.  Crizotinib is a 
substrate of P- glycoprotein and is predominately metabolized by CYP3A4/5.  Elimination of 
crizotinib was related to its hepatic, and possibly gastrointestinal, metabolism with a mean of 
63.1% of [14C] crizotinib excreted in the feces and 22.2% in the urine (crizotinib 
Investigator’s Brochure [IB]).
Overall, the adverse events (AEs) reported for crizotinib in clinical studies were considered 
generally tolerable and manageable.  For single-agent crizotinib, the most common AEs 
(≥20% of patients) reported as of March 2015 from 1761 (95.7%) of the 1840 patients with 
advanced NSCLC as treatment-related were vision disorders (60.4%), nausea (49.1%), 
diarrhea (48.1%), vomiting (43.9%), edema (38.1%), constipation (32.4%), elevated 
transaminases (30.4%), fatigue (21%), and neutropenia (20.4%).  The majority of AEs were 
Grades 1 or 2 in severity, while treatment-related AEs of Grades 3, 4, or 5 in severity were 
observed among 701 (38.1%) advanced NSCLC patients who received at least 1 dose of 
single-agent crizotinib 250 mg BID.  The most common (≥2%) Grade 3 treatment-related 
AEs were neutropenia, elevated transaminases, hypophosphatemia, lymphopenia, leukopenia, 
and fatigue.  The most common (≥1%) Grade 4 treatment-related AEs were neutropenia, and 
elevated transaminases.  The Grade 5 treatment-related AEs were interstitial lung disease
(ILD) (0.4%), death (0.2%), and pneumonia, hepatotoxicity, lung infection, disseminated 
intravascular coagulation, arrhythmia, dyspnea, pulmonary embolism and deep vein 
thrombosis (0.1% each) (crizotinib IB). 
There are special warnings regarding crizotinib use that must be considered and are described 
in detail in the crizotinib IB.  Fatal drug-induced hepatotoxicity occurred in less than 1% of 
all patients treated with crizotinib in clinical trials and usually appeared within the first 
2 months of therapy.  Other warnings are pneumonitis/ILD and QTc prolongation, which 
both occurred in fewer than 2% of patients, and bradycardia which occurred in approximately 
6% of patients.  Specific management for these events is described in Table 5.
Clinical trials of crizotinib showed high rates of objective tumor response, and the responses 
were rapid and durable (Studies A8081001 and A8081005).  In Study A8081007 (PROFILE 
1007), second-line treatment of advanced ALK-positive NSCLC patients with crizotinib 
(after initial platinum-based chemotherapy) demonstrated a significant improvement in 

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median PFS when compared to chemotherapy (pemetrexed or docetaxel monotherapy) of 
7.7 months vs. 3.0 months, respectively (HR 0.487; 95% CI (confidence interval): 
0.371, 0.638; P <0.0001).  The ORRs were 65% (95% CI: 58, 72) with crizotinib, as 
compared with 20% (95% CI: 14, 26) with chemotherapy (p<0.001).  The median DR was 
32.1 weeks with crizotinib (95% CI: 2.1, 72.4), as compared to 24.4 weeks with 
chemotherapy (95% CI: 3.0, 43.6).14
Validated questionnaires (EORTC QLQ-C30 and QLQ-LC13) showed a significantly greater 
improvement in patient-reported lung cancer symptoms and global quality of life receiving 
crizotinib as compared with chemotherapy.14
The first-line use of crizotinib was evaluated in Study A8081014 (PROFILE 1014) as 
compared with chemotherapy.  The treatment of patients with ALK-positive NSCLC with 
crizotinib demonstrated significant improvement in median PFS and ORR when compared 
with pemetrexed plus platinum chemotherapy (median PFS: 10.9 months vs. 7.0 months, 
respectively; HR 0.454; 95% CI: 0.346, 0.596; p <0.001; ORR: 74% vs. 45%, respectively; 
p <0.001).  The DR was 11.3 months with crizotinib (95% CI: 8.1, 13.8) as compared with 
5.3 months (95% CI: 4.1, 5.8).27
Additional improvements were seen in the use of crizotinib over chemotherapy in patients 
with ROS1-positive advanced NSCLC.28
Complete information for crizotinib may be found in the single reference safety document 
(SRSD) which, for this drug, is the crizotinib core data sheet (CDS).
1.2.5. Lorlatinib (PF-06463922)  
The lorlatinib program was initiated with the aim to develop a next-generation ALK inhibitor 
that is more potent than crizotinib, capable of inhibiting the catalytic activity of 
ALK-resistant mutants, and able to cross the blood-brain barrier.29
Lorlatinib is a potent and selective, macrocyclic, ATP competitive small molecule inhibitor 
of ALK and ROS1 receptor tyrosine kinases.  It is orally available, brain penetrating, and 
able to inhibit all clinically reported ALK kinase domain mutations responsible for resistance 
to crizotinib.30
This drug is currently in clinical development and is being investigated for the treatment of 
ALK-positive or ROS1-positive advanced NSCLC.  Lorlatinib has so far had substantial 
efficacy results which are described in more detail in Section 1.2.5.3.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the lorlatinib IB.

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1.2.5.1. Preclinical Data
Lorlatinib has been studied in a variety of in vitro and in vivo model systems to determine 
potency for inhibition of ALK or ROS1 tyrosine kinase activity, kinase selectivity, antitumor 
efficacy, pharmacokinetic (PK)/pharmacodynamic (PD) relationships, and mechanism of 
action.
In vitro, lorlatinib demonstrated potent, concentration-dependent inhibition of catalytic 
activities of ALK, ALK mutants, and ROS1 kinases in recombinant enzyme and cell-based 
assays.  PF-06463922 also inhibited ALK and ROS1 dependent oncogenic functions in 
human NSCLC cell lines and demonstrated potent and selective growth inhibitory activity 
and induced apoptosis in tumor cell lines exhibiting either non-mutant ALK and 
ROS1 fusion variants or mutant ALK fusions that are resistant to crizotinib treatment. 
In vivo, lorlatinib demonstrated marked cytoreductive activity in mice bearing tumor 
xenografts that express ALK or ROS1 fusion variants, including the crizotinib-resistant 
EML4-ALKL1196M or EML4-ALKG1269A mutations. Lorlatinib treatment significantly 
reduced tumor size and prolonged animal survival in the orthotopic brain models 
(EML4-ALK and EML4-ALKL1196M) in mice.  The antitumor efficacy of lorlatinib was 
dose-dependent and demonstrated a strong correlation to inhibition of ALK or 
ROS1 phosphorylation. 
Detailed information on PK/PD modeling, ADME (Absorption, Distribution, Metabolism 
and Elimination), and CYP enzymes inhibition can be found in the lorlatinib IB.
As described in the lorlatinib IB, the nonclinical safety profile of PF-06463922 has been 
adequately characterized to support continued clinical trials in advanced cancer indications.
1.2.5.2. Teratogenicity
Preliminary developmental toxicity studies using lorlatinib have been completed in rats and 
rabbits.  Embryonic and fetal toxicity (including embryo lethality, fewer and smaller viable 
fetuses with some external and visceral malformations) was observed in both species at all 
doses, where the low dose was projected to yield similar exposure as the RP2D of 100 mg 
once daily.  Based on the study results, lorlatinib induces embryonic and fetal toxicity in 
animals, and the current safety measures in the clinical development program for lorlatinib to 
prevent pregnancy should remain in place.
Additional information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the IB. 
1.2.5.3. Clinical Data
The first-in-human Study B7461001 with lorlatinib is a Phase 1/2, dose escalation, safety, 
PK, PD, and anti-cancer efficacy exploration study of this investigational drug as a single 
agent in patients with advanced ALK-positive or ROS1-positive NSCLC.

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This clinical study consists of 2 parts: both parts - Phase 1 and Phase 2 portion - have 
completed the enrollment (329 patients have been enrolled, 54 in the Phase 1 portion and 
275 in the Phase 2).
As of the data cutoff date of 5 May 2016 a total of 165 patients have been treated with 
lorlatinib, 54 in the Phase 1 portion and 111 in the Phase 2 portion.
Maximum Tolerated Dose (MTD) Determination
The Phase 1 portion of the study was designed to estimate the maximum tolerated dose 
(MTD) for lorlatinib as a single agent in patients with advanced ALK-positive or advanced 
ROS1-positive NSCLC with or without asymptomatic CNS metastases.  As part of this 
study, the food effect was also tested in a limited subset of patients, as well as the midazolam 
(MDZ) drug-drug interaction (DDI), given at steady-state, to evaluate the effect of lorlatinib 
on CYP3A inhibition/induction. 
The MTD estimate was defined as the highest dose level associated with 33% of patients 
experiencing a dose-limiting toxicity (DLT).  Due to the discreteness of the dose levels and 
in the interest of patient safety, the estimated MTD was defined as the highest dose level with 
a DLT rate <0.33. The primary endpoint of first-cycle DLTs was defined with pre-specified 
severity based upon predicted target organ toxicity in hematologic and non-hematologic 
system organ classes.  Additionally, the inability to obtain sufficient drug administration due 
to treatment-related toxicities (but not of DLT severity) was also considered a DLT. 
Importantly, the neurocognitive AEs observed in the first portion of dose escalation were late 
appearing and considered undesirable, even though most did not meet the definition of a 
DLT.  Thus, the RP2D was determined based on the entirety of the safety, efficacy, and 
clinical pharmacology data instead of a formal DLT and MTD determination.
To date, lorlatinib has been administered across 7 different daily (QD) doses (10 mg, 25 mg, 
50 mg, 75 mg, 100 mg, 150 mg, and 200 mg) and 3 different BID doses (35 mg BID, 75 mg 
BID, and 100 mg BID). A continual reassessment method (CRM) model was used in the 
dose escalation portion of Phase 1 to determine which doses to test based on the 
dose-limiting toxicities (DLTs) observed during Cycle 1. 
A food effect cohort was tested at 100 mg QD (3 patients in fed/fasted state and 3 patients in 
fasted/fed state).  Finally, a cerebrospinal fluid (CSF) sampling cohort was tested at 100 mg 
QD to obtain preliminary information about lorlatinib penetration into the brain.
Taken together, the 100 mg QD dose was chosen as the RP2D based on the entirety of the 
safety, efficacy, and clinical pharmacology data. 
The Phase 2 portion was designed to evaluate the anti-cancer activity of single-agent 
lorlatinib administered at the dose of 100 mg QD in different cohorts of patients with 
advanced ALK-positive and with advanced ROS1-positive NSCLC.  This will also allow 
characterization of the safety, PK, and PD profiles of single-agent lorlatinib at the RP2D 
determined at the end of Phase 1. 

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Safety
Overall, lorlatinib was well tolerated in Phase 1.  As of the data cutoff date of 5 May 2016, 
the most commonly occurring treatment-related AEs across all of the doses tested were 
hypercholesterolemia (68.5%), CNS effects (44.4%), peripheral edema and 
hypertriglyceridemia (37% each), and peripheral neuropathy (35.2%).  The most frequently 
occurring treatment-related Grade ≥3 AEs were hypercholesterolemia (11.1%) and 
hypertriglyceridemia (5.6%), for which treatment with a statin is recommended at the first 
signs of elevated (Grade 1) cholesterol and/or triglycerides.30
The Phase 2 portion confirmed the safety profile of the Phase 1 portion, with the most 
commonly occurring treatment-related AEs including hypercholesterolemia in 75.7% of 
patients, hypertriglyceridemia reported in 57.7% of patients, and CNS effects reported in 
30.6% of patients.  The most commonly reported Grade ≥3 treatment-related AEs were 
hypercholesterolemia (15.3%) and hypertriglyceridemia (10.8%).  There were no 
Grade 5 treatment-related treatment-emergent AEs (TEAEs) reported.
Temporary dosing interruptions and dose reductions were reported in 18 (33.3%) and 
13 (24.1%) patients, respectively in the Phase 1 portion and in 13 (11.7%) and 11 (9.9%) of 
patients respectively in the Phase 2 portion.  Most of these delays and reductions occurred at 
doses higher than 100 mg QD and the most common reasons for dosing interruption and/or 
dose reduction at these higher doses were hypercholesterolemia and CNS effects.
Treatment-related CNS effects have been observed in 24 (44.4%) Phase 1 patients and 
34 (31%) Phase 2 patients.  The most common treatment-related CNS effects reported in the 
Phase 1 portion was Slow speech, occurring in 9.3% of patients.  The most common 
treatment-related CNS effects individual AEs reported in the Phase 2 portion have been 
Dizziness and Memory impairment, each occurring in 4.5% of patients.  The CNS effects 
reported in both Phase 1 and Phase 2 portions have been generally considered mild (Grade 
1 and Grade 2) in severity and transient and improved upon dose delay and/or dose reduction.  
No Grade 4 or 5 CNS effects have been reported in the Phase 1 or Phase 2 portions.
A more detailed evaluation of CNS effects is ongoing in the Phase 2 portion by routine 
assessment of cognition, mood, and suicidality through a computerized test (using laptops 
provided by Cogstate).  Based on the preliminary results observed, the assessments in this 
randomized Phase 3 study will be limited to mood and suicidality. 
Treatment-related peripheral neuropathy events have been observed in 19 (35.2%) 
Phase 1 patients and 14 (12.6%) Phase 2 patients.  The most commonly reported individual 
TEAE was Neuropathy peripheral, reported in 12 (22.2) Phase 1 patients and 6 (5.4%) 
Phase 2 patients.  Similar to CNS effects, the peripheral neuropathy TEAEs were generally 
mild in severity and improved upon dose delay and/or dose reduction.  No Grade 
≥3 peripheral neuropathy TEAEs have been reported.

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A total of 6 patients had treatment-related serious adverse events (SAEs) in the 
Phase 1 portion; 4 had CNS events that included Grade 2 hallucinations and seizure and 
Grade 3 delirium and mental status changes.  In addition, 1 patient had Grade 
3 dermatomyositis, and 1 patient had Grade 3 lipase increased.  No Grade 4 or Grade 
5 treatment-related SAEs were reported.  There were neither any AEs that were associated 
with permanent treatment discontinuation, nor any treatment-related deaths (lorlatinib IB).  
In the Phase 2 portion, 9 patients had treatment-related SAEs, including 2 cases of acute 
respiratory failure of Grade 3 and 4 severity, respectively; 1 case of Grade 
4 hypercholesterolemia; Grade 3 gastritis, pancreatitis, pneumonia, and mental status 
changes; 1 case of Grade 2 presyncope; and 1 case of Grade 1 worsening nausea.
As of the data cutoff date, a total of 20 deaths have been reported in Phase 1 and 5 deaths 
have been reported in Phase 2; none of these 25 events were attributed to lorlatinib.
Efficacy
In terms of preliminary efficacy in Phase 1, lorlatinib demonstrated promising clinical 
activity, although these patients represent a heterogeneous mix of driver mutations, prior 
treatments, and dose levels at which they were treated. 
There were 25 Phase 1 patients still receiving treatment as of the data cutoff date.  Among 
53 patients evaluable for efficacy as of the data cutoff date (05 May 2016), the ORR was 
47.2% and included 3 (5.7%) confirmed complete responses (CR), and 22 (41.5%) confirmed 
partial responses (PR).  In addition, 10 (18.9%) patients had stable disease (SD) as their best 
overall response.
Thirty-nine (72%) out of 54 patients enrolled in the Phase 1 portion had CNS metastases at 
study entry.  Of the 39 patients evaluable for intracranial response at the time of the data 
cutoff date, 10 (25.6%) patients had a confirmed CR and 4 (10.3%) patients had a confirmed 
PR, resulting in an intracranial ORR of 35.9%.  Further, 13 (33.3%) patients had SD as their 
best overall response.
Overall Results
Taken together, these preliminary efficacy results from Phase 1 suggest substantial 
anti-tumor activity and brain penetration which are being further characterized in Phase 2.
Although the AE profile of lorlatinib in Phase 1 consists mostly of laboratory abnormalities, 
none of which were dose limiting, there was concern over the appearance of CNS effects 
particularly at doses higher than 100 mg QD, which were considered intolerable to some 
patients and were a cause for dose modification (ie, dosing interruption and/or dose 
reduction).  Overall, 100 mg QD was a well-tolerated dose.  None of the Phase 1 patients at 
this dose required dose reduction.  Dose delays did occur in 44.4% of patients, in 33.3 % of 
them due to treatment-related AEs.  These dose delays were not attributed to CNS effects, 
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Additionally, based on the PK data observed, simulated patient exposure suggested that the 
100 mg QD dose was the lowest dose exceeding the lorlatinib Ceff of 150 ng/mL during the 
majority of the dosing cycle once steady state was reached.  The Ceff of 150 ng/mL was a 
concentration predicted to result in  80% tumor growth inhibition of the ALK G1202R 
resistance mutation.  Further, lorlatinib demonstrated response rates of 47% (including a 
36% intracranial response rate), which indicated that this compound is active both inside and
outside the brain.
Taken together, the 100 mg QD dose was chosen as the RP2D based on the entirety of the 
safety, efficacy, and clinical pharmacology data. 
Lorlatinib received food and Drug (FDA) orphan drug designation for the treatment of ALK
positive or ROS1 positive NSCLC in June 2015.
1.2.6. Study Rationale
In response to causes of crizotinib treatment failure, next-generation ALK/ROS1 TKIs are 
being developed.  Lorlatinib is a selective, brain penetrant ALK TKI with potent activity 
against ALK and ROS1 fusions, including those harboring resistance mutations.  Crizotinib 
is the current SOC in the treatment of patients with advanced ALK-positive NSCLC, who 
have not received any prior NSCLC treatment, including molecularly targeted agents, 
angiogenesis inhibitors, immunotherapy, or chemotherapy). 
Lorlatinib has the potential to improve PFS in this setting based on its greater potency against 
ALK and its broad coverage against all known resistance mutations to crizotinib and 
second-generation ALK inhibitors.29 Additionally, lorlatinib has the ability to cross the 
blood-brain barrier with demonstrated clinically meaningful anti-tumor activity in patients 
with brain metastases after treatment with ALK inhibitors including crizotinib.30
Lorlatinib is expected to have greater efficacy than the SOC, and thus will be tested against 
crizotinib in the previously untreated advanced ALK-positive NSCLC treatment setting.  
Additionally, competitor ALK TKI data suggest that use of more potent agents in the 
first-line treatment setting will lead to prolonged PFS.  Both alectinib21 and ceritinib,25 in 
fact, have shown longer median PFS times in the treatment-naïve advanced ALK-positive 
NSCLC population than that observed in patients with crizotinib-refractory or resistant 
disease. 
Data on resistance mutations and mechanisms are still emerging from the clinic; there may be 
other resistance mutations and mechanisms that will not be sensitive to ALK inhibition.  To 
further expand on biomarker data currently being collected in the ongoing Phase 2 study, this 
Phase 3 study will also evaluate candidate predictive biomarkers of sensitivity or resistance 
to single-agent crizotinib or lorlatinib in pretreatment tumor tissue and evaluate blood-based 
molecular markers of response and resistance to single-agent crizotinib or lorlatinib.

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1.2.7. Rationale for Starting Dosing Regimens

Arm A: Lorlatinib starting dosing regimen will be 100 mg QD which was chosen as 
the RP2D based on the entirety of the safety, efficacy, and clinical pharmacology data 
available.

Arm B: Crizotinib starting dosing regimen will be 250 mg BID.  This dose is the 
approved starting dose for treatment of ALK-positive metastatic NSCLC according to 
the crizotinib product label.
1.2.8. Summary of Benefit/Risk Assessment 
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
For single-agent lorlatinib, based on the non-clinical results and the clinical data available to 
date from the Phase 1/2 clinical trial, the conduct of this study with the proposed lorlatinib 
dosing regimen is considered justifiable.
Lorlatinib treatment significantly reduced the tumor size and prolonged animal survival in 
the orthotopic brain models (EML4-ALK and EML4-ALKL1196M) in mice.  The anti-tumor 
efficacy of lorlatinib was dose dependent and demonstrated strong correlations to inhibition 
of ALK or ROS1 phosphorylation.  The plasma levels associated with the anti-tumor efficacy 
in EML4-ALKL1196M dependent human NSCLC cell line models were utilized to project 
target human plasma concentrations for clinical studies. 
Among the 53 patients who were evaluable for efficacy in the Phase 1 part of the study as of 
the data cutoff date, the ORR was 47.2% and included 3 (5.75%) confirmed complete 
responses (CRs), and 22 (41.5%) confirmed partial responses (PRs).  Ten (10) patients 
(18.9%) had stable disease (SD) as their best overall response.
Thirty-nine (72%) Phase 1 patients had CNS metastases at study entry.  Of the 39 patients 
evaluable for intracranial response at the time of the data cutoff, 10 (25.6%) patients had a 
confirmed CR and 4 (10.3%) patients had a confirmed PR, resulting in an intracranial ORR 
of 35.9%.  Further, 13 (33.3%) patients had SD as their best overall response.
The clinical safety data available to date with single-agent lorlatinib in patients with 
advanced NSCLC who received ≥1 previous treatment(s) have suggested an acceptable 
safety profile of the compound.  Most of the observed events were in line with the underlying 
disease.  Anti-tumor activity with lorlatinib observed on both extracranial and intracranial 
lesions, has showed good BBB (blood brain barrier) penetration associated with clinically 
significant activity on brain metastases.  The resulting potential for CNS toxicity some of 
which were predicted using preclinical models, has been monitored in the clinic by studying 
the effect of different administration schedules (BID vs QD) and with the use of formal 
neurological assessment to better characterize the changes seen.  The selected administration 
schedules for Phase 2 and 3 study of 100 mg QD has been associated with reduction of CNS 
toxicity. 

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Hypertriglyceridemia and hypercholesterolemia have been identified as risks associated with 
the administration of lorlatinib.  Respective safety risk mitigation measures have been 
implemented in the ongoing studies and are also included in this clinical trial protocol. These 
include instructions for proper management of hyperlipidemia and a list of recommended 
statins (see Section 5.5.1.1).  Close safety monitoring will be performed throughout the study 
as outlined in the Schedule of Activities table.
Peripheral neuropathy, Mood Disorders, Cognitive Disorders, Speech Disorders, Vision 
Disorders, Diarrhoea, Constipation, Arthralgia, Oedema, Fatigue, Weight Increased are 
others identified risks associated with lorlatinib administration, for which dose delay/dose 
reduction has been effective.
For complete details of the in vitro /nonclinical/clinical studies, refer to lorlatinib current 
investigator’s brochure.
Crizotinib is approved multinationally as the SOC for the treatment of ALK-positive 
NSCLC, both treatment-naïve or after failure of prior systemic therapy.  Overall, the adverse 
events reported for crizotinib in clinical studies are considered tolerable and manageable, and 
the safety profile of crizotinib is well characterized and described in the XALKORI package 
insert. 
Overall, the anticipated benefit-risk profile supports the investigation of lorlatinib 
head-to-head against the SOC crizotinib in the patient population chosen for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:

To demonstrate that lorlatinib as a single agent 
(Arm A) is superior to crizotinib alone (Arm B) 
in prolonging Progression-Free Survival (PFS) 
in advanced ALK-positive NSCLC patients who 
are treatment naïve.

PFS based on blinded independent central 
review (BICR) assessment (RECIST v.1.1).
Secondary Objectives:
Secondary Endpoints:

To compare Arm A and Arm B in 
treatment-naïve advanced ALK-positive NSCLC 
patients with respect to Overall Survival (OS);

To evaluate the antitumor activity in each 
treatment arm;

To evaluate the safety and tolerability in each 
treatment arm;

To evaluate patient-reported outcomes (PROs) 
of health-related quality of life, 
disease/treatment-related symptoms of lung 
cancer, and general health status for each 
treatment arm;

To evaluate candidate biomarkers of sensitivity 
or resistance to single-agent crizotinib or 
lorlatinib in pre-treatment tumor tissue;

To evaluate candidate biomarkers of sensitivity 
or resistance to single-agent crizotinib or 
lorlatinib in peripheral blood.

Efficacy: OS, PFS based on Investigator’s 
assessment, OR based on BICR and on 
Investigator’s assessment; intracranial OR 
(IC-OR), IC-TTP, DR and IC-DR, TTR and IC-
TTR all by BICR (RECIST v. 1.1) and PFS2;

Safety: AEs (as graded by NCI CTCAE v.4.03); 
laboratory abnormalities (as graded by NCI 
CTCAE v.4.03); vital signs (blood pressure, 
pulse rate) and body weight; electrocardiograms
(ECGs); echocardiogram or MUGA scan; 
ophthalmologic data;

PROs as assessed by EORTC QLC-C30, 
EORTC QLQ-LC13, EQ-5D-5L;

Tumor tissue biomarkers including, but not 
limited to, ALK gene rearrangement and/or 
mutation as measured by next-generation 
sequencing (NGS) and/or 
immunohistochemistry (IHC);

Peripheral blood cfDNA (circulating free 
Deoxyribonucleic acid) biomarkers including, 
but not limited to, ALK gene rearrangement 
and/or ALK kinase domain mutations.

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Exploratory Objectives:
Exploratory Endpoints:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol will use an independent endpoint adjudication committee (BICR) to determine 
whether certain investigator-reported events meet the definition of disease-related efficacy 
endpoints, using predefined endpoint criteria.
3. STUDY DESIGN
This is a Phase 3, multinational, multicenter (at approximately 160 sites) , randomized, 
open-label, parallel 2-arm study in which approximately 280 patients with previously 
untreated advanced ALK-positive NSCLC were to be randomized 1:1 to receive lorlatinib 
monotherapy or crizotinib monotherapy according to the study design shown in Figure 1
(296 patients were actually randomized).
Patients will be stratified according to (also see Section 5.1.1):
•
Presence of brain metastases (Yes vs No);
•
Ethnic origin (Asian vs Non-Asian).
Crossover between treatment arms will not be permitted.
3.1. Study Treatment
This study was to randomize approximately 280 patients in a 1:1 ratio to receive:
•
Arm A: Lorlatinib single agent;
•
Arm B: Crizotinib single agent.
A cycle duration will be 4 weeks (28 days) and will always be considered 4 weeks 
irrespective of any dose delays/dosing interruptions or missed doses which may affect 
nominal days of each cycle.
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Study treatment may continue until confirmed disease progression assessed by BICR, patient 
refusal, patient lost to follow-up, unacceptable toxicity, or the study is terminated by the 
sponsor, whichever comes first (see Section 6.4 Patient Withdrawal).
Patients who develop radiological disease progression confirmed by BICR assessment but 
are otherwise continuing to derive clinical benefit from study treatment will be eligible to 
continue with the treatment they have been assigned to, provided that the treating physician 
has determined that the benefit/risk for doing so is favorable.  See Section 7.2 for details on 
expedited BICR assessment of disease progression.
Details of the study treatment forms and packaging and recommendations for dose 
modifications are included in the Study Treatment Section 5 of the protocol.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis:
a.
Study Population: Patients with histologically or cytologically confirmed 
diagnosis of locally advanced [(Stage IIIB not amenable for multimodality 
treatment) or metastatic (Stage IV) by American Joint Committee on Cancer 
(AJCC) v 7.0] ALK-positive NSCLC where ALK status is determined by the 
FDA-approved (for use in US), CE (Conformité Européene) marked (for EU and 
other countries that accept CE marking), and PMDA(Pharmaceuticals and 
Medical Devices Agency)-approved (for use in Japan) Ventana ALK (D5F3) 
Companion Diagnostic (CDx) IHC test performed on the Ventana ULTRA or XT 
platforms (refer to Section 6.1.1.1 for any prescreening activity related to ALK 
determination);
b. Tumor Requirements: At least 1 extracranial measurable target lesion per 
RECIST v. 1.1 that has not been previously irradiated.  CNS metastases are 
allowed if asymptomatic and:
1. Either untreated and not currently requiring corticosteroid treatment, or on a
stable or decreasing dose of ≤10 mg QD prednisone or equivalent; or

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2. Local treatment has been completed with full recovery from the acute effects 
of radiation therapy or surgery prior to randomization, and if corticosteroid 
treatment for these metastases has been withdrawn for at least 4 weeks with 
neurological stability; or
3. In case of leptomeningeal disease (LMD) or carcinomatous meningitis (CM) 
if visualized on magnetic resonance imaging (MRI), or if baseline CSF 
positive cytology is available.
c.
Tissue Requirements: All patients must have an archival formalin fixed, paraffin 
embedded (FFPE) tissue specimen available and collected prior to randomization.  
If archived tissue is unavailable, then a mandatory de novo biopsy must be 
performed.
2. No prior systemic NSCLC treatment for advanced (Stage IIIB not amenable for 
multimodality treatment) or metastatic (Stage IV) disease, including molecularly 
targeted agents (eg, ALK TKIs), angiogenesis inhibitors, immunotherapy, or 
chemotherapy.  Prior treatment for earlier Stages of the NSCLC only allowed if 
completed more than 12 months prior to randomization.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2.
4. Age ≥18 years (or ≥20 years as required by local regulation).
5. Adequate Bone Marrow Function, including:
a.
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥1.5 x 109/L;
b. Platelets ≥100,000/mm3 or ≥100 x 109/L;
c.
Hemoglobin ≥9 g/dL.
6. Adequate Pancreatic Function, including:
a.
Serum total amylase ≤1.5 x upper limit of normal (ULN)*;
b. Serum lipase ≤1.5 x ULN.
*if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then patient may be 
enrolled.
7. Adequate Renal Function, including:
a.
Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution.
8. Adequate Liver Function, including:

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a.
Total serum bilirubin ≤1.5 x ULN; 
b. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x 
ULN (≤5.0 x ULN in case of liver metastases).
9. Acute effects of prior radiotherapy 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 patient.
10. Serum pregnancy test (for females of childbearing potential) negative at screening.  
Female patients of non-childbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause (which may be confirmed with a serum follicle-stimulating 
hormone [FSH] level confirming the postmenopausal state if appropriate);

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
11. Evidence of a personally signed and dated informed consent document indicating 
that the patient (or a legally acceptable representative) has been informed of all 
pertinent aspects of the study.
12. Willing and able to comply with scheduled visits, treatment plans, laboratory tests 
and other procedures.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Spinal cord compression unless the patient has good pain control attained through 
therapy, and there is stabilization or recovery of neurological function for the 
4 weeks prior to randomization.
2. Major surgery within 4 weeks prior to randomization.  Minor surgical procedures 
(eg, port insertion) are not excluded, but sufficient time should have passed for 
adequate wound healing.
3. Radiation therapy within 2 weeks prior to randomization, including stereotactic or 
partial brain irradiation.  Patients who complete whole brain irradiation within
4 weeks prior to randomization or palliative radiation therapy outside of the CNS 
within 48 hours prior to randomization will also not be included in the study.

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4. Gastrointestinal abnormalities, including inability to take oral medication; 
requirement for intravenous alimentation; prior surgical procedures affecting 
absorption including total gastric resection or lap band; active inflammatory 
gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; 
treatment for active peptic ulcer disease in the past 6 months; malabsorption 
syndromes.
5. Known prior or suspected severe hypersensitivity to study drugs or any component 
in their formulations.
6. Active and clinically significant bacterial, fungal, or viral infection including 
hepatitis B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known HBsAg 
or HCV antibody positivity), known human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS)-related illness.
7. 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:

Arterial disease such as cerebral vascular accident/stroke (including Transient 
Ischemic Attack -TIA), myocardial infarction, unstable angina;

Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary 
embolism;

Non-vascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥ II), second-degree or third-degree AV block 
(unless paced) or any AV block with PR >220 msec; or ongoing cardiac 
dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any 
grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such 
as long-distance runners, etc.), machine-read Electrocardiogram (ECG) with QTc 
>470 msec, or congenital long QT syndrome.
8. Patients with predisposing characteristics for acute pancreatitis according to 
investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) 
in the last month prior to randomization.
9. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, and pulmonary fibrosis.
10. Evidence of active malignancy (other than NSCLC, non-melanoma skin cancer, or 
localized prostate cancer or any in situ cancer which does not currently require 
treatment) within the last 3 years prior to randomization. 

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11. 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 above categories) within 
12 days prior to the first dose of lorlatinib or crizotinib. 
a.
Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or 
grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], 
boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, 
ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir or 
paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir, 
troleandomycin, and voriconazole. The topical use of these medications (if 
applicable), such as 2% ketoconazole cream, is allowed.
b. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, 
terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, 
alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, 
dihydroergotamine) (*withdrawn from US market).
c.
Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort).
d. Known P-gp substrates with a narrow therapeutic index (eg, digoxin).
12. 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 patient 
inappropriate for entry into this study.
13. Patients 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 patients who are Pfizer employees, including their family 
members, directly involved in the conduct of the study.
14. Participation in other studies involving investigational drug(s) within 2 weeks prior 
to study entry and/or during study participation.
15. Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential who are unwilling or unable to use 
a highly effective method of contraception as outlined in this protocol for the 
duration of the study and for at least 97 days, if male or 35 days if female, after the 
last dose of investigational product if under lorlatinib or 90 days if under crizotinib.

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4.3. Lifestyle Requirements
4.3.1. Contraception 
Lorlatinib is teratogenic and an aneugen and can therefore cause harm when administered to 
a pregnant woman.  Crizotinib can also cause fetal harm when administered to a pregnant 
woman.  Therefore, use of an appropriate method of contraception during treatment with
these study drugs is mandatory.
The investigator or his or her designee, in consultation with the participant, will confirm that
the participant has selected a highly effective method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
below, Section 4.3.1.2) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use a highly effective 
method of contraception consistently and correctly and document the conversation and the 
participant’s affirmation in the participant’s chart (participants need to affirm their consistent 
and correct use of at least one of the appropriate methods of contraception listed below, 
Section 4.3.1.2).  
Patients receiving lorlatinib:
Women of childbearing potential (WOCBP, definition provided below, Section 4.3.1.1) must 
agree to use a highly effective nonhormonal method of contraception, because lorlatinib can 
render hormonal contraceptives ineffective. If a hormonal method of contraception is 
unavoidable, then a condom must be used in combination with the hormonal method.
Contraception must be continued for at least 35 days after completing therapy.
During treatment with lorlatinib and for at least 97 days after the final dose, male patients 
with WOCBP partners must agree to use a highly effective method of contraception, 
including a condom, and male patients with pregnant partners must be agreed to use condoms
(see Section 4.3.1.2).
Patients receiving crizotinib: 
WOCBP and male patients with WOCBP partners must agree to use an highly effective 
method of contraception (see Section 4.3.1.2) throughout the study and continue to do so for 
at least 90 days after last dose of crizotinib.
Patients receiving either lorlatinib or crizotinib:
All sexually active male patients must agree to prevent potential transfer to and exposure of 
pregnant partner(s) and fetus to drug through ejaculate by using a condom consistently and 
correctly, beginning with the first dose of lorlatinib or crizotinib and continuing for at least 
97 days after the last dose of lorlatinib, or 90 days after the last dose of crizotinib.

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In addition, the investigator or designee will instruct the patient to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.
4.3.1.1. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. 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 categories 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.
2. Postmenopausal female:
A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal appropriate 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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4.3.1.2. Methods of Contraception
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided a condom is used in combination with the 
hormonal method.  The patient must have been using that hormonal contraceptive for 
an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4. Male condom must be used in association with a female highly effective method of 
contraception.
5. Male sterilization with absence of sperm in the postvasectomy ejaculate.
NOTE: For subjects not sexually active, sexual abstinence, defined as completely and 
persistently refraining from all heterosexual intercourse (during the entire period of risk 
associated with the study treatments) may obviate the need for contraception ONLY if 
this is the preferred and usual lifestyle of the subject. Investigator should assess at each 
visit if a change of patient lifestyle occurred and in case reconsider, in consultation with 
the patient, to select an appropriate method of contraception for the individual patient and 
his/her partner(s) from the list of permitted contraception methods.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.

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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational products are lorlatinib (PF-06463922) and crizotinib 
(Xalkori), which is the reference comparator.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular patient or affect the order in which patients are enrolled.
A patient must sign an informed consent form (ICF) before being evaluated for study entry.  
Once a patient who has met inclusion and exclusion criteria has provided a signed ICF, 
allocation of patients to the treatment arms will proceed through the use of an interactive 
response technology (IRT) system (interactive web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the patient number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number assigned.  The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.
Note: The IRT is the source of the patient number.  The IRT system will provide the patient 
number at the end of the first IRT patient transaction.  Study treatment must be initiated 
preferably on the randomization day but no later than 7 days after randomization.
Qualified patients will be randomized in a 1:1 ratio to receive:

Arm A: Lorlatinib monotherapy at the RP2D of 100 mg QD, administered as 4 x 
25 mg oral tablets, continuously.

Arm B: Crizotinib monotherapy at the registered starting dose of 250 mg BID, 
administered as 1 x 250 oral capsules/twice daily, continuously.
5.1.1. Stratification Factors 
Allocation of patients will be stratified according to:

Presence of brain metastases.

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
Yes* vs No.
* Yes: means that the brain lesions can be either present and observed at patient entry or 
known from the patient medical history to have been present in the past even if no 
longer visible (eg, irradiated or surgically removed lesions, etc).  The brain lesions can 
be either measurable or non- measurable lesions, and can be classified as either target 
or non-target lesions.

Ethnic origin**

Asian vs non-Asian.
**This refers to the actual patient race, not the place where he/she lives or is treated.  If 
the patient’s parents are 50% Asian and 50% non-Asian, the patient must be treated as 
non-Asian; in case 75% Asian and 25% non-Asian, patient is treated as Asian; in case 
75% non-Asian and 25% Asian patient is treated as non-Asian.
This stratified randomization will be centrally allocated across all centers via the IRT system.  
A central randomization will be adopted due to the high number of participating centers in 
contrast to the anticipated small number of patients randomized at each center.
5.2. Patient Compliance
For self-administration of lorlatinib or crizotinib at home, compliance will be captured and 
completed by the patient.
A patient diary will be provided to the patients to aid in lorlatinib (Arm A) and crizotinib 
(Arm B) compliance.  The diary will be maintained by the patient to include unchanged, 
missed, or changed lorlatinib (Arm A) or crizotinib doses (Arm B).
In Arm A, patients will be required to return to the investigational site all bottles of lorlatinib
at the end of each 28-day cycle during the planned visit at the site.  The number of lorlatinib 
tablets remaining will be documented and recorded at each clinic visit. 
In Arm B, patients will be required to return to the investigational site all bottles of crizotinib 
at the end of each 28-day cycle during the planned visit at the site.  The number of crizotinib 
capsules remaining will be documented and recorded at each clinic visit. 
The study site must follow up (for example, via a telephone call) with each patient on 
Cycle 1 Day 5 (±3 days) to confirm that the patient understands and is in compliance with 
lorlatinib or crizotinib dosing instructions.  If needed, the patient will be re-trained.  The 
same follow- up process will be applied in case the dose of lorlatinib or crizotinib is modified 
during the treatment period. 
5.3. Investigational Product Supplies
Lorlatinib and crizotinib will be supplied for the study by Pfizer Global Clinical Supply.
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 

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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.
5.3.1. Dosage Forms and Packaging
5.3.1.1. Lorlatinib (PF-06463922)
Lorlatinib will be supplied for oral administration as 25 mg tablets in High-Density 
Polyethylene (HDPE) bottles with desiccant and labeled according to local regulatory 
requirements. 
5.3.1.2. Crizotinib
Crizotinib will be supplied for oral administration as capsules containing 200 mg or 250 mg 
of investigational product and will be packaged in -High-Density Polyethylene (HDPE) 
bottles and labeled according to local regulatory requirements.
5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of investigational agents. Investigational product should be prepared and dispensed 
by an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) 
as allowed by local, state, and institutional guidance.
5.3.2.1. Lorlatinib (PF-06463922)
Lorlatinib will be dispensed at the beginning of every 28-day cycle (or as otherwise 
indicated) using an IRT drug management system.  Patients should be instructed to keep their 
medication in the bottles provided and not transfer it to any other container.  Lorlatinib will 
be provided in bottles containing 25 mg tablets.  Site personnel must ensure that patients 
clearly understand the directions for self-medication.  Patients should be given sufficient 
supply to last until their next study visit.  Patients will be provided with Drug Administration 
Cards and Patient Diaries.  In addition, administration instructions will be detailed for site 
personnel in the Investigational Product (IP) Manual.
5.3.2.2. Crizotinib
Crizotinib will be dispensed at the beginning of every 28-day cycle (or as otherwise 
indicated) using an IRT drug management system.  Patients should be instructed to keep their 
medication in the bottles provided and not transfer it to any other container.  Crizotinib will 
be provided in bottles containing 200 mg or 250 mg capsules.  Site personnel must ensure 
that patients clearly understand the directions for self-medication.  Patients should be given 
sufficient supply to last until their next study visit.  Patients will be provided with Drug 
Administration Cards and Patient Diaries.  In addition, administration instructions will be 
detailed for site personnel in the IP Manual.

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5.4. Administration
All trial treatments will be administered on an outpatient basis.
A cycle is defined as 28 days, irrespective of any dose delays/dosing interruptions or missed 
doses which may affect nominal days of each cycle.
5.4.1. Lorlatinib (PF-06463922)
Lorlatinib will be administered orally QD at approximately the same time of the day on a 
continuous daily dosing schedule, ie, without a break in dosing in the absence of drug-related 
toxicity.  Patients must swallow the study medication whole and must not manipulate or 
chew the medication prior to swallowing.  A dosing card will be provided to the patients to 
provide guidance for the correct use of lorlatinib.  Patients must be instructed that should 
they miss a dose or vomit any time after taking a dose, they must not “make it up” with an 
extra dose.  Instead, resume the subsequent doses as originally prescribed.  Any missed dose 
may be taken up to 6 hours prior to the next scheduled dose, otherwise it should be skipped 
and dosing resumed with subsequent doses as prescribed.  The patient must be instructed to 
record all doses (including missed or vomited) in a dosing diary supplied by the site.  If doses 
are missed or vomited, this must be indicated in the source documents and Case Record 
Forms (CRFs).
 
 
  On ECG assessment days, the lorlatinib dose 
should be taken in the clinic under the supervision of the study site personnel so that timing 
of assessments is appropriately synchronized.
Since no clinically meaningful effect of food on the PK of lorlatinib has been observed, 
lorlatinib can be administered with or without food.
5.4.2. Crizotinib 
Crizotinib will be administered orally BID at approximately the same time in the morning 
and evening 12 hours apart on a continuous daily dosing schedule, ie, without a break in 
dosing in the absence of drug-related toxicity.  Patients must swallow the study medication 
whole and must not manipulate or chew the medication prior to swallowing.
A dosing card will be provided to the patients to provide guidance for the correct use of 
crizotinib.  Patients must be instructed that should they miss a dose or vomit any time after 
taking a dose, they must not “make it up” with an extra dose.  Instead, resume the subsequent 
doses as originally prescribed.  Any missed dose may be taken up to 6 hours prior to the next 
scheduled dose, otherwise it should be skipped and dosing resumed with subsequent doses as 
prescribed.  If a patient inadvertently takes 1 extra dose during a day, the patient should not 
take the next dose.  The patient must be instructed to record all doses (including missed or 
vomited) in a dosing diary supplied by the site.  If doses are missed or vomited, this must be 
indicated in the source documents and CRFs.
CCI

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On ECG triplicate assessment day, the crizotinib doses should be taken in the clinic under the
supervision of the study site personnel so timing of assessments is appropriately 
synchronized.
Oral crizotinib will be administered with at least 8 oz (240 mL) of water with or without 
food.
5.4.3. Treatment Duration
Treatment will continue until confirmation of disease progression, patient refusal, or 
unacceptable toxicity, whichever occurs first.  Once the patient has documented PD by 
BICR, patients should be discontinued from study treatment.
However, if according to the Investigator’s clinical judgment, a patient with evidence of PD 
is still experiencing clinical benefit, the patient may be eligible for continued treatment with 
the assigned study drug after discussion between the Investigator and Pfizer.  The 
Investigator’s judgment should be based on the overall benefit/risk assessment (eg,
intracranial response), and the patient’s clinical condition, including performance status, 
clinical symptoms, adverse events and laboratory data. In that case, the patient must undergo 
the same assessments foreseen during the active treatment period. As far as tumor 
assessments: 

If only extracranial progression was documented, with intracranial lesions stable or in 
response, intracranial assessments should be performed until intracranial PD;

Once intracranial PD is documented no further tumor assessments are required.
At completion of the study (ie, after the required number of OS events have been reported), 
drug supply for patients benefiting from therapy may continue beyond closure of the study
without further data collection.  At that time, patients not progressed or still experiencing 
clinical benefit may be candidates for continued treatment, provided that the treating 
physician has determined that the benefit/risk assessment for continuing study treatment is 
favourable.  A number of options will be considered for patients to continue to receive the 
study drug outside of the trial without any financial obligation to the patient.  These options 
may include, but are not be limited to, locally reimbursed commercial drug, or donated drug 
or other options available at that time.  A local country Pfizer representative will work with 
the Investigator to determine which will be the best option for each individual patient. 
5.5. Recommended Dose Modifications
Every effort should be made to administer investigational products on the planned dose and 
schedule.  In the event of significant toxicity, dosing may be delayed and/or reduced as 
described below.  In the event of multiple toxicities, dose modification should be based on 
the worst toxicity observed.  Patients are to be instructed to notify their investigators at the 
first occurrence of any adverse event.

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If a dosing interruption longer than 6 weeks due to ongoing treatment-related toxicity is
necessary, study treatment should be permanently discontinued, unless there is a discussion 
of the clinical circumstance with the sponsor’s medical monitor and agreement that the 
patient may resume treatment after a lapse of greater than 6 weeks.
Dose levels for lorlatinib and crizotinib dose modifications are provided in Section 5.5.1 and
Section 5.5.2.  All dose modifications will be reported in the Case Report Form (CRF).
5.5.1. Lorlatinib Dose Modifications 
In case of adverse events, Investigators are encouraged to employ best supportive care 
according to local institutional clinical practices or follow the guidance for selected adverse 
events provided in Table 2.
Patients will be monitored closely for toxicity, and the dose of lorlatinib may be adjusted as 
indicated in Table 1 below.
Table 1.
Lorlatinib Dose Levels for Intra-patient Dose Modifications
Dose Levels
Lorlatinib Dose
0
100 mg QD
-1
75 mg QD
-2
50 mg QD
Dose reductions below dose level -2 are not allowed.
Intra-patient dose reduction by 1 and, if needed, 2 dose levels will be allowed depending on 
the type and severity of toxicity encountered (Dose Level -1 is 75 mg QD; Dose Level -2 is 
50 mg QD).*
If a patient has a significant toxicity from lorlatinib treatment which fails to recover within 
42 days (6 weeks) or, in the opinion of the investigator, requires permanent discontinuation 
of the treatment based on the severity of the adverse event, then this patient should not be 
further treated with lorlatinib but should remain in the trial with ongoing tumor assessments 
until RECIST-defined disease progression by the BICR.
Recommendations for lorlatinib dose modification for treatment-related non-hematological 
and hematological toxicity, as well as for treatment-related toxicity of special interest, are 
provided in Table 2 below.
Re-escalation is not allowed except if discussed with and approved by the sponsor’s medical 
contact.
*it is recommended that in case of lorlatinib dose decrease, the patient is assigned new drug 
rather than using less tablets from the bottle assigned at previous visit.

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Table 2.
Arm A Patients: Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Non-Hematologic Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
Pancreatitis 
NA
If elevated enzymes (both amylase and lipase are Grade ≤2) are 
observed in the absence of radiological findings of pancreatitis: 
continue lorlatinib at the same dose level without dose hold.  
Repeat lipase and amylase and obtain pancreatic isoenzyme if 
possible. 
If radiologically confirmed pancreatitis: withhold lorlatinib dose.  
Repeat radiology and lipase and amylase weekly and obtain 
pancreatic isoenzyme.  If appropriate, resume lorlatinib treatment at 
one dose level lower if radiology has returned to baseline and lipase 
and amylase are Grade ≤2. 
Permanently discontinue 
lorlatinib.
Permanently 
discontinue 
lorlatinib.
Pneumonitis (in the 
absence of disease 
progression, 
pulmonary 
embolism, positive 
cultures or radiation 
effect)§.
Asymptomatic, 
radiographic findings 
only: No need for 
lorlatinib dose 
adjustment.  Initiate 
appropriate monitoring. 
Withhold current lorlatinib dose until toxicity has returned to 
baseline.  Rule out infection and consider initiating treatment with 
corticosteroids.  Then resume lorlatinib treatment at one dose level 
lower.  Discontinue lorlatinib permanently if pneumonitis recurs or 
if failure to recover after 6 weeks of study treatment hold and 
steroid treatment.
Permanently discontinue 
lorlatinib.
Permanently 
discontinue 
lorlatinib.
Electrocardiogram 
QTc prolongation 
(see 
Section 5.5.1.2).
Assess electrolytes and 
concomitant medications.
Correct any electrolyte 
abnormalities, or 
hypoxia.
Continue lorlatinib at the 
same dose level.
Assess electrolytes and concomitant medications.
Correct any electrolyte abnormalities, or hypoxia. 
Continue lorlatinib at the same dose level.
Withhold lorlatinib dose.
Assess electrolytes and 
concomitant medications.
Correct any electrolyte 
abnormalities, or hypoxia. 
Upon recovery to 
Grade 1 resume lorlatinib 
treatment at one dose level 
lower. 
Permanently 
discontinue 
lorlatinib.
LV Dysfunction
CTCAE v4.03 does not 
report Grade 1. 
CTCAE v 4.03 does not report Grade 2.
Permanently discontinue 
lorlatinib.
Permanently 
discontinue 
lorlatinib.
Non-Hematologic 
General
Continue lorlatinib at the 
same dose level.
Continue lorlatinib at the same dose level. 
Withhold lorlatinib dose 
until toxicity is 
Grade 1(or has returned 
to baseline) then reduce 
the dose by 1 level or 
rechallenge at the same 
dose.*
Withhold dose 
until toxicity is 
Grade 1 (or 
has returned to 
baseline), then 
reduce the dose 
by 1 level* or 

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discontinue at 
the discretion 
of the 
investigator.
* Patients who develop asymptomatic Grade 4 hyperuricemia or Grade 3 hypophosphatemia may continue lorlatinib without dose modification at 
the discretion of the investigator.  Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy to require lorlatinib 
dose modification (for more detailed guidelines, see Section 5.5.2.1 and 5.5.2.2).
** In cases where no specific dose adjustments for Grade 1 or Grade 2 treatment-related toxicity are provided, investigators should always 
manage their patients according to their medical judgment which may include dose reduction or interruption based on the particular clinical 
circumstances.
§ If a patient has a potential diagnosis of pneumonitis or drug-related lung injury the same evaluations/procedures provided in 
Section 5.5.2.4 should be considered to assist or exclude the diagnosis of pneumonitis during this period.
Hematologic Toxicities
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Hematologic 
General
Continue lorlatinib at 
the same dose level.
Continue lorlatinib at the same dose level.
Withhold lorlatinib dose 
until toxicity is 
Grade 1 (or has returned 
to baseline), then 
rechallenge at the same 
dose or reduce the dose by 
1 dose level.
Withhold lorlatinib dose until 
toxicity is Grade 1 (or has 
returned to baseline) then 
rechallenge at the same dose or 
reduce the dose by 1 dose level.
Lymphopenia
Continue lorlatinib at 
the same dose level.
Continue lorlatinib at the same dose level.
If no evidence of infection 
or other clinically 
significant toxicity, 
continue lorlatinib at the 
same dose; otherwise, 
withhold dose until toxicity 
is Grade 1 (or baseline) 
then rechallenge at the 
same dose or reduce by 
1 level.
If no evidence of infection or 
other clinically significant 
toxicity, continue lorlatinib at 
same dose; otherwise, withhold 
dose until toxicity is 
Grade 1 (or baseline), then 
rechallenge at the same dose or 
reduce the dose by 1 dose level.
Lipid Elevation Toxicitiesα
Cholesterol
Continue lorlatinib at 
the same dose.  
Consider introducing 
use of a statin or other 
lipid lowering agent as 
Introduce the use of a statin or other lipid 
lowering agent as appropriate, and continue 
lorlatinib at the same dose.
Introduce the use of a statin 
or other lipid-lowering 
agent as appropriate, or 
increase the dose of the 
statin/lipid lowering agent 
Increase the dose of the statin or 
other lipid-lowering agents, or 
change to a new statin/lipid 
lowering agent.  Withhold 
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appropriate based on 
investigator’s medical 
judgment.
or change to a new agent.  
Either continue lorlatinib at 
the same dose without 
interruption or withhold 
dose until toxicity is 
Grade ≤2 and then 
continue at the same dose.
Grade ≤2 and then reduce the 
dose by 1 dose level or 
rechallenge at the same dose.
Triglycerides
Continue lorlatinib at 
the same dose.  
Consider introducing 
use of a statin or other 
lipid-lowering agent as 
appropriate based on 
investigator’s medical 
judgment.
Introduce the use of a statin or other 
lipid-lowering agent as appropriate, and 
continue lorlatinib at the same dose.
Introduce the use of a statin 
or other lipid-lowering 
agent as appropriate, or 
increase the dose of the 
statin/lipid-lowering agent 
or change to a new agent.  
Either continue lorlatinib at 
the same dose without 
interruption or withhold 
dose until toxicity is Grade 
≤2 and then continue at the 
same dose.
Increase the dose of the statin or 
other lipid-lowering agents, or 
change to a new 
statin/lipid-lowering agents.  
Withhold lorlatinib dose until 
toxicity is Grade ≤2 and then 
reduce the dose by 1 dose level 
or rechallenge at the same dose.
α See also instructions provided in Section 5.5.1.1 Hyperlipidemia.
CNS Toxicities 
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
CNS effectsβ
Continue lorlatinib at 
the same dose or 
withhold dose until 
recovery to baseline.
Continue lorlatinib at same dose or withhold 
dose until recovery to Grade ≤1.  Consider 
dose reduction or rechallenge at the same dose.
Withhold lorlatinib dose 
until toxicity is Grade ≤1.  
Reduce dose to the next 
lower dose.
Permanently discontinue 
lorlatinib.
β Examples of CNS effects could include changes in speech, memory, sleep, cognition, or vision.

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5.5.1.1. Hyperlipidemia 
In the lorlatinib Phase 1 Study B7461001, hypercholesterolemia was the most common AE 
reported.  Elevations in lipids usually begin in the first few cycles and, if statins are not 
introduced, can rise to Grade 3 levels by the next treatment cycle.  Therefore, the suggested 
management is to begin a statin for Grade 1 elevations in either cholesterol or triglycerides 
and to increase the statin dose if adequate control is not obtained, as outlined in Table 2.
Members of the statin class of agents are differentially sensitive to CYP3A4, and caution 
should be exercised when selecting statin for management of elevated lipid levels.
Pitavastatin and rosuvastatin can be used during lorlatinib treatment without dose adjustment 
since there is no CYP3A4 involvement in their elimination.  Pravastatin, fluvastatin and 
atorvastatin should be used with caution during lorlatinib treatment, and a dose adjustment of 
these statins may be necessary (increasing dose may be considered).  Lovastatin and 
simvastatin are not recommended for use during lorlatinib treatment.
5.5.1.2. PR Interval Prolongation
Analysis of ECG data from ongoing and completed human studies with lorlatinib has 
identified a subset of patients who exhibited ECG evidence of PR interval prolongation.  The 
ECG changes appear limited to the PR interval with no impact on QRS or QT intervals.  This 
impact on the PR interval is supported by preclinical animal studies as described in the 
current lorlatinib IB.
Guidance for management of PR interval prolongation is provided in Table 3 below and 
examples of drug with potential PR interval prolongation effect can be found in Appendix 5.
Table 3.
PR Interval Prolongation Management
Toxicity
Not Symptomatic
Symptomatic
1st-Degree Heart Block (PR 
interval >200 msec)
No dose hold or reduction needed.  Assess 
concomitant medications.  Monitor closely by 
obtaining pre-dose ECG at next visit, even if 
unscheduled.  Instruct patient to call if 
symptoms develop that may be related to heart 
block.
Withhold dose.  Assess concomitant 
medications.  Obtain ECG in 
approximately 48 hours and re-assess 
symptoms and PR-interval.  Restart at 
same dose or consider dose reduction 
when symptoms resolve.
2nd-Degree Heart Block  
Withhold dose.  Assess concomitant 
medications.  Repeat ECG in approximately 
48 hours.  Instruct patient to call if symptoms 
develop that may be related to heart block.  
Restart at same dose or consider dose 
reduction if subsequent ECG does not show 
2nd degree block.
Withhold dose.  Refer for cardiac 
observation and monitoring.  Consider 
pacemaker placement if symptomatic 
heart block persists.  Resume at 
reduced dose only when symptoms 
resolve AND 2nd degree block 
resolves.  If patients revert to 1st 
degree block with no symptoms, 
resume at reduced dose.
Complete Heart Block
Withhold dose.  Refer for cardiac observation and monitoring.  Temporary pacemaker 
placement may be indicated for severe symptoms associated with heart block.  If heart 
block does not resolve, placement of a permanent pacemaker may be considered. 
If pacemaker placed, may resume at full dose. 
If no pacemaker placed, permanently discontinue lorlatinib.

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5.5.2. Crizotinib Dose Modifications 
In case of adverse events, Investigators are encouraged to employ best supportive care 
according to local institutional clinical practices and follow the guidance for selected adverse 
events provided below.
Patients will be monitored closely for toxicity, and the dose of crizotinib may be adjusted as 
indicated in Table 4 below. 
Table 4.
Crizotinib Dose Levels for Intra-patient Dose Modifications
Dose Levels
Crizotinib Dose
0
250 mg BID
-1
200 mg BID
-2
250 mg QD
Dose reductions below dose level -2 level are not allowed.
Intra-patient dose reduction by 1 and, if needed, 2 dose levels will be allowed depending on 
the type and severity of toxicity encountered (Dose Level -1 is 200 mg BID; Dose Level -2 is 
250 mg QD).  Treatment continuation for patients requiring more than 2 dose reductions due 
to treatment-related toxicity is not allowed.
If a patient has a significant toxicity from crizotinib treatment which fails to recover within 
42 days (6 weeks) or, in the opinion of the investigator, requires permanent discontinuation 
of the treatment based on the severity of the adverse event, then this patient should not be 
further treated with crizotinib but should remain in the trial with ongoing tumor assessments 
until RECIST-defined disease progression by the BICR.
Recommendations for crizotinib dose modifications for treatment-related toxicities are 
provided in Table 5 below.
Re-escalation is not allowed except for the cases specified in Table 5.

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Table 5.
Arm B Patients: Crizotinib Dose Modifications for Crizotinib-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
ALT elevation possibly related to 
crizotinib with total bilirubin 
<2 X ULN.
Continue 
crizotinib at the 
same dose level.
Continue crizotinib at the 
same dose level. Obtain 
repeat ALT and total 
bilirubin when 
symptomatic or within
7 days. 
§Country-specific 
guidelines may also 
apply.
Withhold crizotinib dose until toxicity is 
Grade 1, or has returned to baseline, 
then resume treatment by reducing by one 
dose level.  If Grade 3 ALT elevation 
recurs reduce further (at most by 2 dose 
levels from the initial dose level).  If 
recurrence at dose level -2, then discuss 
with sponsor whether or not to
discontinue permanently.  If ALT 
elevation does not recur after at least
4 weeks, the dose may be escalated by 
single dose level increments up to the 
initial dose level.  §Country-specific 
guidelines may also apply.
See Grade 3
§Country-specific 
guidelines may also 
apply.
ALT elevation and total bilirubin 
elevation ≥2X ULN (in absence of 
cholestasis or hemolysis).
Continue 
crizotinib at the 
same dose level.  
Obtain repeat 
ALT and total 
bilirubin within 
48 hours.
Discontinue crizotinib 
treatment and do not 
retreat.
Discontinue crizotinib treatment and do 
not retreat.
Discontinue crizotinib 
treatment and do not 
retreat.

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Table 5.
Arm B Patients: Crizotinib Dose Modifications for Crizotinib-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Bradycardia (heart rate less than 
60 beats per minute).
See also instructions in 
Section 5.5.2.3.
Continue 
crizotinib at the 
same dose level.
Withhold crizotinib until 
recovery to Grade ≤1 or 
to heart rate
≥60.
Evaluate concomitant 
medications known to 
cause bradycardia, as 
well as anti-hypertensive 
medications.
If contributing 
concomitant medication 
is identified and 
discontinued, or its dose 
is adjusted, resume 
crizotinib at previous 
dose upon recovery to 
Grade ≤1 or to heart rate 
≥60.
If no contributing 
concomitant medication 
is identified, or if 
contributing concomitant 
medications are not 
discontinued or dose 
modified, resume 
crizotinib at reduced dose 
upon recovery to 
Grade ≤1 or to heart rate 
≥60.
Same as for Grade 2 bradycardia.
Permanently discontinue 
crizotinib if no 
contributing 
concomitant medication 
is identified.
If contributing 
concomitant medication 
is identified and 
discontinued, or its dose 
is adjusted, resume 
crizotinib at 250 mg 
once daily upon 
recovery to Grade ≤1 or 
to heart rate ≥60, with 
frequent monitoring
Permanently discontinue 
crizotinib for 
recurrence.

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Table 5.
Arm B Patients: Crizotinib Dose Modifications for Crizotinib-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Pneumonitis (not attributable to 
NSCLC progression, other 
pulmonary disease, infection, or 
radiation effect).
See also instructions in 
Section 5.5.2.4.
Discontinue 
crizotinib 
treatment and do 
not retreat.
Discontinue crizotinib 
treatment and do not 
retreat.
Discontinue crizotinib treatment and do 
not retreat.
Discontinue crizotinib 
treatment and do not 
retreat.
Left ventricular systolic 
dysfunction.
Continue 
crizotinib at the 
same dose level.
Continue crizotinib at the 
same dose level.
Discontinue crizotinib treatment and do 
not retreat.
Discontinue crizotinib 
treatment and do not 
retreat.
Electrocardiogram QTc 
prolongation.
Continue 
crizotinib at the 
same dose level.
Assess electrolytes and 
concomitant medications
Correct any electrolyte or 
magnesium abnormalities
Continue crizotinib at the 
same dose level.
Interrupt crizotinib until recovery to 
Grade ≤1.
Assess and correct electrolytes and 
concomitant medications. 
Upon recovery to Grade ≤1, resume 
crizotinib treatment by reducing the dose 
by one dose level if no other cause for 
QTc prolongation is found otherwise 
resume crizotinib at the same dose level.
Discontinue crizotinib 
treatment and do not 
retreat.
Vision disorders‡
Continue 
crizotinib at the 
same dose level
Repeat 
ophthalmologic 
consultation.
Continue crizotinib at the 
same dose level
Repeat ophthalmologic 
consultation.
Interrupt crizotinib until recovery to 
Grade ≤1.
Repeat ophthalmologic consultation‡
Resume crizotinib treatment by reducing 
the dose by one dose level upon recovery 
to Grade ≤1.
Discontinue crizotinib 
and do not retreat. 
Repeat ophthalmologic 
consultation.
Non-Hematologic 
General (excluding those mentioned 
above).
Continue 
crizotinib at the 
same dose level.
Continue crizotinib at the 
same dose level. 
Withhold crizotinib dose until toxicity is 
grade 1, or has returned to baseline, then 
resume crizotinib treatment at the same 
dose or reduce the dose by 1 level at the 
discretion of the investigator.*
Withhold crizotinib 
dose until toxicity is 
grade 1, or has 
returned to baseline, 
then reduce crizotinib 
dose by 1 level and 
resume treatment, or 
discontinue at the 
discretion of the 
investigator.*

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Table 5.
Arm B Patients: Crizotinib Dose Modifications for Crizotinib-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Hematologic (excluding 
lymphopenia†).
Continue 
crizotinib at the 
same dose level.
Continue crizotinib at the 
same dose level.
Withhold crizotinib dose until toxicity is 
grade 2, or has returned to baseline, then 
resume crizotinib treatment at the same 
dose level or reduce the dose by 
1 dose level after discussion with the 
sponsor.†
Withhold crizotinib 
dose until toxicity is 
grade 2, or has 
returned to baseline, 
then reduce the 
crizotinib dose by 
1 level and resume 
treatment†
*Patients who develop Grade 4 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms may continue study treatment without interruption at the 
discretion of the investigator.  Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, to require dose modification.
†Patients who develop Grade 3 or 4 lymphopenia without other dose-limiting events (eg, opportunistic infection) may continue study treatment without 
interruption. 
‡ Ophthalmologic examination includes visual acuity, fundoscopy, and slit lamp, biomicroscopy and should be performed by an ophthalmologist. 
Ophthalmologic examinations should be repeated during the study whenever a vision disorder AE is observed or NCI -CTCAE v4.0 grade change occurs from 
the previous visit.
§ If required per country-specific guidelines (eg, France): Patient management of increased ALT >3 - ≤5 x ULN (Grade 2) with a total bilirubin <2 x ULN will 
be discussed on a case-by-case basis between the principal investigator and an internal sponsor clinical committee (including Medical Monitor and Safety Risk 
Lead) and determine whether to: a. Continue treatment at the same dose level of crizotinib; b. Withhold crizotinib until ALT is Grade ≤1 or has returned to 
baseline, then resume treatment at the same dose level; or c. Withhold crizotinib until ALT is Grade ≤1 or has returned to baseline, then reduce the dose by 
1 dose level.  For patient enrolling in France, discontinue crizotinib therapy if Grade 3 and 4 ALT elevation possibly related to crizotinib with total bilirubin 
<2 X ULN.

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5.5.2.1. Nausea and Emesis
For nausea and emesis with crizotinib, treat with standard antiemetics as per institutional 
standard practice.  Taking the medication with food may reduce nausea.  The use of 
prophylactic antiemetics should be considered.
5.5.2.2. Diarrhea
Grade 1: Symptomatic care with anti-diarrheal medication (such as loperamide), or no 
intervention as per investigator judgment. 
Grade 2: Loperamide (4 mg at first onset, then 2 mg every 2 to 4 hours until symptom-free 
for 12 hours).  Other anti-diarrheal medications can be used per local standard-of-care.  No 
dose modification unless patient is intolerant or symptom is recurrent. 
Grade 3-4 (despite use of anti-diarrheal medication such as loperamide): Withhold crizotinib 
(or lorlatinib) treatment until recovery to Grade ≥1. 
5.5.2.3. Bradycardia
Avoid using crizotinib in combination with other bradycardic agents (eg, beta blockers, 
non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, 
digoxin) due to the increased risk of symptomatic bradycardia (syncope, dizziness, 
hypotension).  Heart rate and blood pressure should be monitored regularly.  Dose 
modification is not required in case of asymptomatic bradycardia.  See Table 5.
5.5.2.4. Pneumonitis/Pneumonia
Investigators must evaluate thoroughly patients who demonstrate potential signs/symptoms 
of pneumonitis/pneumonia. If a patient has a potential diagnosis of pneumonitis or 
drug-related lung injury, then the following evaluations/procedures should be considered to 
confirm or exclude the diagnosis of pneumonitis during this period in the absence of disease 
progression, other pulmonary disease, infection, or radiation effects:

A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and mycobacteria;

Blood culture should be performed in febrile patients.  Consider appropriate 
serologies (mycoplasma, legionella, cytomegalovirus, other viruses, etc.);

Thoracentesis if pleural fluid is present (culture, microbiology, cytology);

Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate.  The BAL fluid 
should be sent for culture, microbiology, and cytology (same pathogens as above);

Lung biopsy (eg, open or thorascopic preferable, bronchoscopy with transbronchial 
biopsy) if appropriate;

A plasma sample for BNP (B-type natriuretic peptide) to evaluate for evidence of 
congestive heart failure (CHF);

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
For Asian countries based patients, a blood sample for β-D glucan to evaluate for the 
presence of fungal pneumonia (eg, Pneumocystis jirovecii).
If clinically appropriate, high-dose corticosteroid treatment should be initiated.  Should the 
event be fatal an autopsy is highly recommended to confirm/exclude the diagnosis.
For any case of drug-related pneumonitis, discontinue crizotinib and contact the sponsor.  
See Table 5.
5.5.2.5. Renal Cysts 
The development of complex renal cysts has been reported in some patients with NSCLC 
treated with crizotinib.  These cysts may be symptomatic or asymptomatic, and have 
developed from 2 and 6 months after starting crizotinib.  The precise nature and significance 
of these cysts is unclear; however, while no evidence of malignancy has been found based on 
aspiration of cyst fluid and biopsy in the reported cases, complex renal cysts may be 
associated with renal malignancy, and thus consultation with a urologist or suitable alternate 
medical expert is recommended. 
Active surveillance with appropriate imaging (contrast-enhanced CT scanning or magnetic 
resonance imaging) should be performed at the time of the renal cysts diagnosis.  
Investigators should also review retrospectively all CT/MRIs for any prior occurrence of 
complex renal cysts. 
In addition, multitest dipstick urinalysis (should include test for protein and blood) should be 
performed at the time of the renal cysts diagnosis and on Day 1 of each cycle thereafter.*
Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or 
protein and/or if this is the local standard.
*Additional analysis per local requirement may be performed.
5.5.2.6. Severe Visual Loss
Discontinue crizotinib in patients with severe visual loss (best corrected vision less than 
20/200 in one or both eyes).
Any adverse event of Grade ≥2 of potential sight threatening (PST) or severe vision loss 
(SVL) that occurs in crizotinib treated patient should be treated as SAEs (Serious Adverse 
Events) regardless of relatedness to study drug (except for visual field defect, for which only 
Grade ≥3 should be treated as SAE).
Additional efforts will be made to obtain relevant clinical and diagnostic information related 
to all cases of Grade 4 vision loss and including an ophthalmological evaluation that should 
consist of best corrected visual acuity, retinal photographs, visual fields, optical coherence 
tomography (OCT), and other evaluations as appropriate for new onset of severe visual loss. 

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In addition to collecting this information as requested for Study B7461006, investigators 
must also be reminded of a separate data collection for crizotinib-related visual loss which is 
currently ongoing under the non-interventional Study A8081062.
5.6. Management of Overdose 
An overdose is defined as any dose of lorlatinib >100 mg QD or any dose of crizotinib
>250 mg BID. Any overdose must be recorded in the trial drug section of the CRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE 
(serious or not), must be reported to the sponsor (see Section 8.2.1).
Investigators should use their clinical judgment and treat potential cases of overdose with the 
appropriate general supportive measures.
5.7. Investigational Product Storage 
The investigator, or an approved representative, (eg, pharmacist), will ensure that all 
investigational products, including any comparator, are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  Any storage conditions stated in the single reference safety document (SRSD) (ie, the 
IBs for lorlatinib and the CDS for crizotinib) will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report

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for each excursion will be provided to the site. Receipt of materials, door opening and 
closing, and other routine handling operations where the products are briefly out of the 
temperature range described in the labeling are not considered excursions.
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 
5.8. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
All bottles of the investigational product (lorlatinib and crizotinib) are taken home by the 
patient, and must be returned to the investigator by the patient at the end of each cycle and at 
the end of the trial. The sponsor will provide instructions as to the process for drug 
accountability in the monitoring plan.
5.8.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study 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.
5.9. Concomitant Treatments
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
Concomitant medications and treatments will be recorded from 28 days prior to the start of 
study treatment and up to 28 days after the last dose of study treatment.  All concomitant
medications should be recorded in the CRF including supportive care drugs (eg, antiemetic 
treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, 
and non-drug supportive interventions (eg, transfusions).
Medications intended solely for supportive care (eg, antiemetics, analgesics, megestrol 
acetate for anorexia, bisphosphonates or RANK-ligands for metastatic bone disease or 
osteoporosis) are allowed.  In case the patient is already on treatment with RANK-ligands 
(like denosumab) before study entry, the therapy should be at a stable dose prior to 
randomization.
There are no prohibited therapies during the Post-Treatment Follow-Up Phase.
5.9.1. Inhibitors and Inducers of CYP Enzymes
The list of food and drugs to be avoided provided below may not be fully exhaustive.  
Consult the sponsor when in doubt whether a food or a drug falls into any of the categories 
below.

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5.9.1.1. Arm A Lorlatinib
The in vitro studies have demonstrated that CYP3A, and UGT1A4 are primarily involved in 
the metabolism of lorlatinib, with additional minor contributions from CYP2C19 and 
CYP2C8.  Inhibition or induction of the above enzymes may result in potential alteration of 
lorlatinib systemic exposure.
Initial in vitro assessment for inhibition and induction drug-drug interaction potential 
indicated that lorlatinib is a time-dependent inhibitor of CYP 3A and also an inducer of 
CYP3A and CYP2B6.  At substantially higher concentrations than those observed clinically, 
lorlatinib also inhibited CYP2C9 in in vitro studies.
To protect patient safety, the following cautions are provided:

Lorlatinib metabolism may be inhibited by strong CYP3A inhibitors leading to a 
potential increase in lorlatinib toxicities. Coadministration of strong CYP3A 
inhibitors (eg, boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, and 
posaconazole, ritonavir alone and with danoprevir or elvitegravir or indinavir or 
lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, 
telaprevir, troleandomycin, and voriconazole, grapefruit juice or grapefruit/grapefruit-
related citrus fruits [eg, Seville oranges, pomelos]) is not recommended and alternate 
medications should be considered. If the concomitant use of the strong CYP3A 
inhibitor cannot be avoided, reduce the starting dose of lorlatinib from 100 mg orally 
once daily to 75 mg orally once daily.  In patients who have had a dose reduction to 
75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A 
inhibitor, reduce the lorlatinib dose to 50 mg orally once daily.  The patient should be 
closely monitored for safety and reduction of the lorlatinib dose if necessary.  If 
concomitant use of a strong CYP3A inhibitor is discontinued, increase the lorlatinib 
dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to the dose that was 
used before starting the strong inhibitor. 

Use of strong CYP3A inducers with lorlatinib is contraindicated.  
Lorlatinib metabolism may be induced when taking strong CYP3A inducers 
(eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort)
resulting in reduced plasma concentrations.  Furthermore, when lorlatinib was 
coadministered with rifampin, 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 (eg, bosentan, efavirenz, etravirine, modafinil) should be 
avoided due to the potential reduction in lorlatinib exposure.

Lorlatinib induces CYP2B6 (in vitro) so concurrent use of drugs that are 
CYP2B6 substrates, such as bupropion and efavirenz, may have less effect.  
Concomitant CYP2B6 substrates should be used with caution, as the net clinical 
effect of lorlatinib on CYP2B6 is currently being investigated. 

Lorlatinib induces CYP3A (in vivo) which may lead to a decreased effect of 
concurrently used CYP3A substrates (eg. hormonal contraceptives etc.).  

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Coadministration of lorlatinib with CYP3A substrates with a narrow therapeutic 
index (NTI) such as alfentanil, fentanyl (including transdermal patch), astemizole*, 
cisapride*, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine* (*withdrawn from US market) is not permitted at 
study entry.  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 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 inhibits P-glycoprotein (P-gp) (in vitro) so concurrent use of drugs which 
are P-gp substrates with a narrow therapeutic index may have increased effect.  The 
concurrent use of drugs which are P-gp substrates with narrow therapeutic index, 
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.  The net clinical effect of lorlatinib on P-gp 
is currently being investigated.
Any questions regarding the use of alternative medications should be directed to the sponsor 
for guidance.
5.9.1.2. Arm B Crizotinib
If there is a clinical indication for one of these or other medications specifically prohibited 
during the trial, discontinuation from study therapy or medication may be required.  The final 
decision on any supportive therapy rests with the Investigator and/or the patient’s primary 
physician.  However, the decision to continue the patient on study therapy or medication 
schedule requires the mutual agreement of the Investigator, the sponsor, and the patient. 

The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in 
human liver microsomes and hepatocytes. Coadministration with drugs that are 
CYP3A inhibitors and inducers may change the plasma concentrations of crizotinib in 
humans.  The concurrent use of potent CYP3A inhibitors, including but not limited to 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, troleandomycin, saquinavir, voriconazole, and grapefruit or grapefruit juice, 
are not allowed in the study.  The topical use of these medications (if applicable), 
such as 2% ketoconazole cream, may be allowed.  The concurrent use of potent 
CYP3A inducers, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort, are not allowed in the study.

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
In vitro data indicate that the most pronounced inhibitory potential of crizotinib was 
observed toward CYP3A4 (testosterone)-mediated drug metabolism.  Crizotinib has 
minimal potential to inhibit other human CYP isoforms such as CYP1A2, 2C8, 2C9, 
2C19 and 2D6.  Crizotinib also showed time-dependent inhibition of CYP3A 
isozymes in human liver microsomes.  In cancer patients, a mean 3.6-fold (90% CI: 
2.7-4.9) increase in the oral midazolam AUC was observed following 28 days of 
crizotinib dosing at 250 mg BID, suggesting that crizotinib is a moderate inhibitor of 
CYP3A.  Caution (excluding those restricted medications mentioned above) must be 
exercised in patients receiving crizotinib in combination with drugs that are 
predominantly metabolized by CYP3A such as alfentanil, cyclosporine, fentanyl, 
quinidine, sirolimus, and tacrolimus. In particular, coadministration of crizotinib with 
CYP3A4 substrates with narrow therapeutic indices including, but not limited to 
dihydroergotamine, ergotamine, pimozide, astemizole,* cisapride,* and terfenadine* 
(*withdrawn from U.S. market) must be avoided from the time of the first dose of 
crizotinib until treatment discontinuation
5.9.2. Other Anti-Tumor/Anti-Cancer or Experimental Drugs
No additional concurrent anti-tumor treatment will be permitted while patients are receiving 
study treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is 
not permitted.
5.9.3. Other Prohibited Concomitant Medications and Therapies 
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy.

Investigational agents other than lorlatinib.

Radiation therapy (with the exception noted in the Concomitant Radiotherapy
Section).

Other experimental pharmaceutical products.

Herbal remedies with anticancer properties or known to potentially interfere with 
major organ function or study drug metabolism (eg, hypericin).
5.9.4. Hematopoietic Growth Factors
Use of granulocyte colony stimulating factors should follow the current American Society of 
Clinical Oncology (ASCO) guidelines.32 Patients who enter the study on stable doses of 
erythropoietin or darbepoetin may continue this treatment, and patients may start either drug 
during the study at the discretion of the investigator.

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5.10. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study. 
The appropriate interval of time between surgery and crizotinib or lorlatinib administration 
required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  Stopping crizotinib or lorlatinib is recommended at least 2 days prior to surgery.  
Postoperatively, the decision to reinitiate crizotinib or lorlatinib treatment should be based on 
a clinical assessment of satisfactory wound healing and recovery from surgery, but resumed 
no sooner than 48 hours after surgery. 
5.11. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline, otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression. 
Crizotinib must be stopped 24 hours before and at least 24 hours after completion of 
radiation therapy.  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.
6. STUDY PROCEDURES 
As applicable, all visits must occur within the pre-defined windows outlined in this protocol. 
6.1. Screening
Informed Consent must be obtained prior to undergoing any study specific procedures.  
Informed consent for use of tissue for other 
research or diagnostic development 
must also be obtained. In addition, Molecular Prescreening Informed Consent must be 
obtained in case the ALK status determination is not already available or has been obtained
through a test other than the required Ventana ALK (D5F3) IHC test performed on the 
Ventana ULTRA or XT platforms, are acceptable, while tests performed on the GX platform 
cannot be accepted.
For screening procedures see the Schedule of Activities (SOA) and ASSESSMENTS section.
6.1.1. Tumor Biospecimens
Provision of an archival formalin fixed and paraffin embedded (FFPE) tumor tissue sample is 
required from all patients prior to registration.  The archival tumor tissue specimen may be 
from either a primary or metastatic lesion, and may represent tissue obtained at the time of, 
or subsequent to, the initial diagnosis.  It would be preferable if the tumor tissue was 
collected within 6 months of the enrollment onto the trial to provide the most up-to-date 
information regarding the tumor and its microenvironment.  Archived tumor tissue should be 
CCI

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provided as a FFPE tumor tissue block containing sufficient tumor tissue to allow if possible 
for sectioning of at least 10 (preferably 15) slides each containing a ~5-micron tissue section.
If local country regulations do not allow for tissue block to be submitted or if a tissue block 
cannot be provided, sites should provide if possible at least 10 (preferably 15) unbaked glass 
slides each containing a ~5-micron tissue section cut serially from the same block.  If 
archived FFPE tissue is not available, a de novo (ie, fresh) core needle tumor biopsy sample 
must be obtained in accord with local institutional practice for tumor biopsies.  Archived or 
de novo tumor tissue from cytological sampling (eg, fine needle aspiration, pleural effusion, 
processed as FFPE block) is acceptable at screening and can be submitted. Archived or de 
novo tumor tissue from bone metastasis is not adequate and should not be submitted.
 
 
 
 
Tumor core needle biopsies (2-3 cores) are preferred; pleural effusions (PE) cell pellets may 
substitute for tumor core biopsy as appropriate.  Fine needle aspiration (FNA) samples 
(2-3 passes minimum prepared as FFPE cell block) should only be performed in the event a 
biopsy or pleural effusion cell pellet is not safe or feasible. The de novo biopsy samples 
should be formalin fixed and paraffin embedded as per routine (see Study Manual), and the 
resulting FFPE tissue block(s) should be submitted to the Central Laboratory. If the FFPE 
tissue block cannot be provided, a minimum of 15 unstained slides each containing a 
5-micron tissue section cut serially from the block can substitute. Additional information on 
tumor biospecimen collection procedures is included in the Study Manual.
6.1.1.1. Determination of ALK Status
ALK status determination will be performed at screening using the FDA-approved (in US) 
and the CE (Conformité Européene) marked (for EU and other countries that accept CE 
marking), or PMDA-approved (in Japan) Ventana ALK (D5F3) CDx IHC test performed on 
the Ventana ULTRA or XT platforms, performed by either local or central laboratory testing.  
Ventana ALK (DF53) test data performed on the GX platform cannot be accepted.
Determination of ALK Status
•
Patients who have historical results available showing ALK-positivity through 
Ventana ALK D5F3 CDx test can proceed with the screening assessments. The 
pathology reports to verify that the approved Ventana ALK (D5F3) CDx test was 
performed must be prospectively collected and sent to Pfizer for patient eligibility 
confirmation before proceeding to randomization.
Where available, Ventana ALK results are only defined as “Positive” or “Negative.”
ALK reports should be provided in English and the translation must be certified.
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If the correct test verbiage (Ventana ALK (D5F3) CDx assay, or the platform 
(Ventana Benchmark ULTRA or XT platform) need to be added to the original ALK 
report, the amended report must include the signature and date of entry to confirm the 
information included is correct and accurate. 
•
Patients who have historical results available showing ALK-positivity through a 
non-Ventana ALK D5F3 CDx test can start the screening assessments while waiting 
for the Ventana ALK D5F3 CDx assay to be performed. If ALK-positivity is not 
confirmed, the patient is a screen failure. Re-testing time should be within the 
28 days screening time
•
Patients who do not have historical results available must undergo a pre-screening 
Ventana ALK D5F3 CDx test and, if positive, can start the screening assessments.
 
 
 
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
6.3. End of Treatment/Withdrawal and Post-Treatment Follow-Up 
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
6.4. Patient Withdrawal 
Patients 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 or sponsor for safety (see also the 
Withdrawl From the Study Due to Adverse Events Section 8.1.3) or behavioral reasons, or 
the inability of the patient to comply with the protocol required schedule of study visits or 
procedures at a given study site.
Reasons for withdrawal of study treatment may include:
•
Objective disease progression (either by BICR or by Investigator).  However, patients 
with disease progression who are continuing to derive clinical benefit from the study 
treatment per the Investigator will be eligible to continue with lorlatinib or with 
crizotinib as single agent, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable and discussed with the sponsor;
•
Global deterioration of health status requiring discontinuation;
•
Unacceptable toxicity;
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
Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment (follow up permitted by patient);

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow up may include:

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
6.5. Survival Follow up Visits
For survival follow up procedures see Schedule of Activities table and ASSESSMENTS
section.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
products, request that the patient return for a final visit, if applicable, and follow up with the 
patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival.  If 
the patient 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
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging will include 
chest, abdomen, and pelvis CT or MRI scans and brain MRI.  CNS imaging using MRI 
(unless contraindicated) is required at baseline in all patients and at every tumor assessment.  
The response of measurable intracranial disease (ie, lesions ≥5 mm) will be assessed by a 
modified version of RECIST v1.1,33 see Appendix 3.  Tumor assessments are to be done at 
screening, then repeated every 8 weeks (±1 week) starting from randomization while on 
treatment and during follow-up until PD.  Bone scans will be performed (or bone MRI if 
preferred by Investigator) at baseline and on study only if bony metastases are suspected.  
Patients with positive results on the bone scans (or bone MRI) will have these repeated every 
16 weeks (±1 week). 
Tumor assessments must continue until documented disease progression has been determined 
by BICR.  If a patient continues treatment based on the investigator’s judgement of clinical 
benefit in spite of disease progression- confimed by BICR- (eg, intracranial lesions are not in 
progression) tumor assessment must continue to be performed every 8 weeks 1 week 
(16 weeks 1 week for Bone Scan/MRI if applicable).
For patients discontinuing treatment for reasons other than progression of disease, tumor 
assessments must be evaluated for tumor response until PD, regardless of new anti-cancer 
therapy. 
Both target and non-target lesions are to be followed using the same modality used at 
baseline and interval unless clinically indicated.  Tumor assessments should be repeated after 
at least 4 weeks to confirm response, and at the End of Treatment visit if more than 8 weeks 
have passed since the last evaluation. 
7.2. Expedited Blinded Independent Central Review for Disease Progression
An expedited BICR review will be performed for investigator-assessed disease progression.  
Upon investigator-assessed disease progression, all radiographic images collected for a 
patient from baseline onwards will be submitted to the BICR for expedited review (see the 
Study Manual for process details and maximum allowable time).  Every effort should be 
made to keep the patient on study treatment and have all the assessments performed as per 
Schedule of Activities until the BICR has completed the radiographic image review, unless 
contraindicated by the investigator.  Once the patient has documented PD by BICR, patients 
should be discontinued from study treatment. 
However, if according to the Investigator’s clinical judgment, a patient with evidence of PD 
is still experiencing clinical benefit, the patient may be eligible for continued treatment with 
the assigned drug after discussion between the Investigator and Pfizer.  The Investigator’s 
judgment should be based on the overall benefit/risk assessment, like the intracranial effect, 
and the patient’s clinical condition, including performance status, clinical symptoms, adverse 
events and laboratory data.  In this specific circumstance (eg, intracranial lesions are not in 

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progression), the tumor assessments will continue to be performed every 8 weeks (every 
16 weeks for bone) (±1 week) until treatment stop or as clinically indicated.
A request for an expedited BICR review may also be triggered by Pfizer upon notification of 
cases that have been reported as PD by Parexel during their timepoint review, but not 
submitted for global expedited review yet since not identified as PD cases by the 
investigator. 
7.3. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL will be performed on 2 occasions prior to starting 
administration of study treatment, once at the start of screening and once at the baseline visit 
immediately before starting the investigational product administration.  Following a negative 
serum pregnancy test result at screening, appropriate contraception must be commenced and 
another negative serum or urine pregnancy test result will then be required at the baseline 
visit before the patient may receive the investigational product.  Urine pregnancy tests will 
also be routinely repeated at every treatment cycle during the active treatment period, at the 
end of study treatment, and additionally whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  In the case of a positive confirmed pregnancy, 
the patient will be withdrawn from administration of investigational product but may remain 
in the study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board (IRBs)/ECs or if required by local regulations.
7.4. Safety Assessments 
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, 12 lead ECGs, echocardiogram/MUGA, laboratory assessments, including 
pregnancy tests and verification of concomitant treatments.  Ophthalmologic examinations 
will be performed in all patients. Assessment for mood and suicidal ideation and behavior 
will also be performed (see Schedule of Activities).
7.4.1. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03) 
timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the AE CRF page.
7.4.2. Laboratory Safety Assessment
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the Schedule of Activities table and analyzed at local laboratories.  They may also be 
performed when clinically indicated and relevant results reported in the CRF as ‘unplanned 
visits’.  The required laboratory tests are listed in Appendix 4.  Local laboratory 
certification(s) and reference ranges should be provided to the sponsor prior to study patient 
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7.4.3. Vital Signs and Physical Examinations
Patients will have a physical examination to include major body systems, body weight, blood 
pressure, pulse rate, assessment of ECOG performance status, and height (height will be 
measured at screening only) at the time points described in the Schedule of Activities.  Blood 
pressure and pulse rate should be taken with the patient in the seated position after the patient 
has been sitting quietly for at least 5 minutes.
7.4.4. (12-Lead) Electrocardiograms 
A triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all ECG 
assessments, except for ECG at Day 1 of Cycle ≥3, which will be single readings according 
to Schedule of Activities.
All patients require a triplicate ECG measurement at screening.  On treatment ECGs will be 
performed as outlined in the SOA table.  At each time point which requires a triplicate 
reading per SoA, 3 consecutive 12 lead ECGs will be performed approximately 2 minutes 
apart (or within 10 minutes, whichever is appropriate) to determine mean QTc (average of 
triplicates).  
 
 Clinically significant findings seen on 
subsequent ECGs should be recorded as adverse events.  In case of QTc >500 msec (ie,
CTCAE Grade >2), ECG must be reviewed by qualified personnel at the site as soon as the 
finding is made, including verifying that the machine reading is accurate and that the 
Fridericia correction formula is applied.  If the manual reading verifies a rate corrected QTc 
of >500 msec, repeat ECG should be immediately performed at least two times 
approximately 2 to 4 minutes apart. 
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc is due to study drug, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by a specialist.  If QTc reverts to less than 500 msec, and in the judgment of investigator and 
sponsor is determined to be due to a cause other than study drug, treatment may be continued 
with regular ECG monitoring.
If a patient experiences PR interval prolongation >200 msec or second-degree or third-degree 
AV block, while on treatment with lorlatinib, refer to Section 5.5.1.2. If a patient 
experiences bradycardia while on crizotinib, refer to the general recommendations for 
crizotinib dose modification in Section 5.5.2.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), triplicate ECGs should be obtained at time of the event.  If the mean QTc is 
prolonged (>500 msec), or new or worsened AV block is noted, then ECGs should be 
re- evaluated by a qualified person at the institution for confirmation and repeated as 
clinically indicated. 
 
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  Additional triplicate ECGs may be performed as clinically indicated and 
relevant results reported in the CRF as ‘unplanned visits’. 
7.4.5. Echocardiograms/MUGA Scans
In order to monitor left ventricular ejection fraction (LVEF), an echocardiogram or MUGA 
will be performed at the time point described in the Schedule of Activities. The same 
method should be used at each time point.
7.4.6. Transthoracic echocardiogram (France and Germany only)
Two (2) patients receiving lorlatinib under compassionate use programme in France have 
been reported to have Pulmonary Arterial Hypertension (PAH), which have been diagnosed 
in absence of right heart catheterization. However, in one of these patients, PAH was a 
pre-existing condition and confounding factors were present in the other patient.  In addition, 
3 cases of Pulmonary Hypertension (PH) (1 not-related SAE, 1 not-related non-SAE, and 
1 related non-SAE) were reported in study B7461001. No other cases were reported in 
approximately 900 patients treated with lorlatinib and no findings associated with pulmonary 
hypertension have been observed in lorlatinib nonclinical studies. 
Although the current evidence does not indicate PH is a risk associated with lorlatinib 
treatment, investigators in Germany and France have been required, as requested by French 
(Agence National de Sécurité du Medicament et des produits de santé- ANSM) and German 
(Bundesinstitut für Arzneimittel und Medizinprodukte-BfArM) health authorities, to 
implement appropriate risk-reduction measures, including a trans thoracic echocardiogram 
(TTE) along the study treatment period for patients enrolled in these two countries.
In order to monitor pulmonary blood pressure, the condition of the heart valves, and 
ventricular motion, transthoracic echocardiogram (TTE) will be performed at the time points 
described in the Schedule of Activities.  In this respect, the benefits/risks of including 
patients with cardiopulmonary disorders/comorbidities or risk factors should be carefully 
considered.  In addition:
•
A prompt TTE must be performed in the event of symptoms or signs suggesting PH, 
and all other explorations pursuant to PH diagnosis guidelines.
•
Should PH occur during treatment, following multidisciplinary discussions involving 
a PH specialist (cardiologist or pulmonologist), consider dose reductions or even 
permanently discontinuing lorlatinib in the absence of haemodynamic and clinical 
recovery.
•
Information must be provided to patients treated with lorlatinib on the new safety 
finding, with the recommendation to seek immediate medical attention in the event of 
signs suggesting PH (particularly dyspnoea and fatigue).
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7.6. CSF Collection for Lorlatinib and Crizotinib Concentration Measurements 
Diagnostic CSF analysis is mandatory for patients with suspected or confirmed 
leptomeningeal disease/carcinomatous meningitis (LMD/CM) not visualized on MRI 
(optional for the remaining patients).  To be performed at baseline, and if clinically safe and 
feasible, further CSF cytology will be performed as clinically indicated to assess anti-tumor 
response and to determine lorlatinib or crizotinib concentrations.
If a patient is required to undergo a lumbar puncture while on trial, an additional ~5 mL 
sample of CSF should be collected for determining 
 
 Crizotinib and its metabolite (Arm B) concentrations.  If a CSF 
sample is collected, 
 at approximately the same 
time. The CSF concentrations of crizotinib, 
 other potential metabolites may be 
determined using a validated or non-validated method.  Detailed collection and shipment 
procedures will be provided in the Study Manual.
 
 
  
 
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7.9. Patient-Reported Outcome Assessments
PROs will be assessed using the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-C30)34 and its corresponding module 
for lung cancer (QLQ-LC13)35 and the EuroQol 5 dimension 5 level (EQ-5D-5L) 
questionnaire.36,37 See PRO instruments included in Appendix 6.
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Patients must complete all EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L 
self-assessment questionnaires in the clinic and these cannot be taken home.  All scheduled 
assessments of the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L must be 
completed in the clinic prior to any other study or medical procedures. 
EORTC QLQ-C30 and QLQ-LC13:
The EORTC QLQ-C30 (Version 3.0) is a published, validated, and self-administered PRO
questionnaire.34 The EORTC QLQ-C30 consists of 30 questions and includes 5 functional 
scales (physical, role, cognitive, emotional, and social); a global health status/global quality 
of life scale; 3 symptom scales (fatigue, pain, nausea and vomiting); and 6 single items that 
assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and 
diarrhea) and financial impact.  All scales and single item measures range in score from 0 to 
100.  Higher scores on the functional scales represent higher levels of functioning.  Higher 
scores on the global health status/quality of life scale represent higher health status/quality of 
life.  Higher scores on symptom scales/items represent a greater presence of symptoms.
The EORTC QLQ-LC13 is the lung cancer-specific module of the EORTC Quality of Life 
Questionnaire.35 The EORTC QLQ-LC13 consists of 13 questions and includes 1 multi-item 
scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific 
pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain 
medication use.  Similar to the EORTC QLQ-C30, higher scores are reflective of a greater 
presence of symptoms.
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be administered as noted on the SOA
table.  Both the EORTC QLQ-C30 and QLQ-LC13 modules require about 15 minutes to 
complete.
EQ-5D-5L:
The EuroQol EQ-5D-5L is a patient-completed questionnaire designed to assess health status 
in terms of a single index value or utility score.36,37 There are 2 components to the EuroQol 
EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, 
slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) in which 
patients rate their overall health status from 0 (worst imaginable) to 100 (best imaginable).  
Published weights are available that allow for the creation of a single summary score. 
The EuroQol EQ-5D-5L questionnaire will be administered as noted on the SOA table.  The 
amount of time for a patient to complete the EQ-5D-5L is estimated to be about 2 minutes.
7.10. Assessment of Mood
An assessment of mood will be administered to patients via the Beck Depression Inventory-II 
scale at the time points described in the Schedule of Activities table.  This is a 21- item 
self-report scale, with each item rated by patients on a 4 point scale (ranging from 0-3).  The 
scale includes items capturing mood (loss of pleasure, sadness, irritability), suicidal ideation, 
and cognitive signs (punitive thoughts, self- criticism, self-dislike, pessimism poor 
concentration) as well as somatic signs (appetite, sleep, fatigue, libido).

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7.11. Assessment of Suicidal Ideation and Behavior
To assess suicidal ideation behaviors, the Columbia Suicide Severity Rating Scale 
(C-SSRS)37 will be administered to patients at the time points described in the Schedule of 
Activities table.  The C-SSRS is a unique, simple and short method of assessing both 
behavior and ideation that tracks all suicidal events and provides a summary of suicidality.  It 
assesses the lethality of attempts and other features of ideation (frequency, duration, 
controllability, reasons for ideation, and deterrents), all of which are significantly predictive 
of completed suicide. 
7.12. Ophthalmologic Examinations 
Ophthalmologic examinations for both right and left eyes will be performed at screening for 
all patients enrolled and should be performed by an ophthalmologist.
Ophthalmologic examinations should be repeated during the course of the study whenever a 
vision disorder AE is observed or CTCAE grade change occurs from a previous visit. 
Best Corrected Visual Acuity and Refraction 
Best corrected visual acuity will be assessed by using a standard wall or projection chart 
(Snellen, or another validated scale, provided that the result is converted to Snellen value) 
before implementing any procedures that can affect vision (eg, pupil dilation).  The same 
chart will be used throughout the study for a specific patient, and the right eye should be 
tested first.  The refractive error also will be determined.  The ophthalmologist should ensure 
that patients are seated comfortably and that they do not move their head forward or 
backward during testing.  Patients will be told that the chart contains only letters. 
Biomicroscopy
Slit-lamp biomicroscopy will be performed without dilation of the pupil and should precede 
the administration of any pupil-dilating agent for ophthalmoscopy.
Any abnormalities (including severity) of the eyelids, conjunctivae, sclerae, corneas, anterior 
chambers, irises, or lens will be recorded. 
Fundoscopy
Fundoscopy will be performed after pupillary dilation to examine the vitreous body, retina 
macula, retina non-macula (peripheral), optic nerve head, fundus and optic disc notching. 
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
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 
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8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/legally acceptable representative.  In addition, each study 
patient/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (Also See Section 6.4 Patient 
Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety 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 investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
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If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. 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 on the CRF, 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.  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, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject 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 signs and symptoms;

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
Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and 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 recorded 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.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

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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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event 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.
Or that is considered to be:

An important medical event.
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.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
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.
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 active collection 
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 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of 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 is assessed for medical importance.

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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 a persistent pretreatment laboratory abnormality);

Social admission (eg, subject 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);

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 subject;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.

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8.3. Severity Assessment
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed below.
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
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
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study with exception of those mentioned at 
Section 5.5.2.6 Severe Visual Loss for Crizotinib Patients. All SAEs will be reported to 
Pfizer Safety by the investigator as described in previous sections, and will be handled as 
SAEs in the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 

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considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

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).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × 
ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The subject should return to the investigator 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 and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 

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collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function tests (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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).

A male 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. 

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
If a subject or subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an 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 subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety 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 Safety 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 baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety 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 the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.

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8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject 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 subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.

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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
In order to provide overall estimates of treatment effect, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subset analyses due to 
the high number of participating centers in contrast to the anticipated small number of 
patients randomized/treated at each center.
9.1. Sample Size Determination
The primary objective of the study is to demonstrate that lorlatinib (Arm A) is superior to 
crizotinib (Arm B) in prolonging PFS by BICR assessment per RECIST v1.1. A key 
secondary objective of the study is to demonstrate that lorlatinib is superior to crizotinib in 
prolonging OS. 
The study is designed to test H0: HRPFS ≥1 vs. HA: HRPFS <1, where HRPFS is the hazard ratio 
(Arm A/Arm B) of PFS.
Approximately 280 patients (140 in each arm) were to be randomized using a 1:1 ratio 
stratified by presence of brain metastases and ethnic origin. As of 28 February, 2019 
enrollment was closed with 296 patients randomized. One hundred seventy seven (177) PFS 
events will be required to have at least 90% power to detect a HR of 0.611 using a one-sided 
stratified log-rank test at a significance level of 0.025 (one-sided), and a 2-look 
group-sequential design with a Lan-DeMets (O’Brien-Fleming) α-spending function to 
determine the efficacy boundaries,
The planned sample size was determined based on the assumption of a HR of 0.611 under the 
alternative hypothesis (under an exponential model, assumes median PFS of 11 months in the 
crizotinib arm and 18 months in the lorlatinib arm).  The sample size further assumed a 15% 
drop-out rate within each treatment arm at 30 months, a non-uniform patient accrual over 
approximately 15 months and follow-up after the last patient is randomized of approximately 
18 months.

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This sample size will also allow comparison of OS between the 2 treatment arms, provided 
that superiority of lorlatinib over crizotinib with respect to PFS has been demonstrated.  If the 
true HR is 0.70 under the alternative hypothesis (under an exponential model, assumes 
median OS of 48 months on the crizotinib arm and 68.6 months on the lorlatinib arm), a total 
of 198 deaths will be required to have 70% power using a one-sided stratified log-rank test at 
a significance level of 0.025 (one-sided), and  3-look group-sequential design with a 
Lan-DeMets (O’Brien-Fleming) α-spending function to determine the efficacy boundaries.
These calculations further assumed a 15% drop-out rate for OS on either treatment arm at 
120 months, and a follow-up of approximately 110 months after the last patient is 
randomized.
The study will be considered positive if the primary objective is met as assessed by the 
stratified log-rank test for the primary PFS endpoint.
9.2. Analysis Sets
9.2.1. Full Analysis Set
The full analysis (FA) set will include all patients who are randomized.  Patients will be 
classified according to the treatment assigned at randomization.  The FA set will be the 
primary population for evaluating all efficacy endpoints and patient characteristics.
9.2.2. Safety Analysis Set
The safety analysis (SA) set will include all patients who receive at least 1 dose of study 
drug.  Patients will be classified according to the treatment assigned at randomization unless 
the incorrect treatment(s) are received throughout the dosing period, in which case patients 
will be classified according to the first study treatment received.  The SA set will be the 
primary population for evaluating treatment administration/compliance and safety. Efficacy 
endpoints may be assessed in this population as well.
 
9.2.4. PRO Analysis Set
The PRO analysis set is defined as patients from the FA set who completed a baseline (last 
PRO assessment prior to randomization day) and at least 1 post-baseline PRO assessment.
The PRO analysis set will be the primary population for the analysis of change from baseline 
scores and time to deterioration (TTD) in patient-reported pain, dyspnea, or cough.
CCI

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9.2.5. Biomarker Analysis Set
The biomarker analysis set will include all patients in the SA set that have at least 
1 screening biomarker assessment.  Analysis sets will be defined separately for blood-based 
and tumor tissue-based biomarkers and will also be defined separately for non-paired and 
paired biomarkers. 
9.3. Efficacy Analysis
All efficacy analyses will be performed on the FA set unless otherwise specified. 
All analyses will be performed by using SAS® Version 9.1.3 or higher. 
Radiographic images and clinical information collected on study will be reviewed by a 
BICR.  BICR assessment will be used for the primary analysis of PFS and for all secondary 
endpoints based on radiological assessments of tumor burden (ie, OR, DR, TTR, IC-OR, 
IC-DR, IC-TTR and IC-TTP).  PFS and OR will also be derived using the local 
radiologist’s/investigator’s assessment.
All planned sensitivity analyses will be described in the SAP.
9.3.1. Analysis of the Primary Endpoint
The primary endpoint is PFS which is defined as the time from randomization to the date of 
the first documentation of objective progression of disease or death due to any cause, 
whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment (prior to any 
new anti-cancer treatment) for patients who do not have an event (PD or death), for patients 
who start new anti-cancer treatment prior to an event, or for patients with an event after two 
or more missing tumor assessments.  Patients who do not have a baseline tumor assessment, 
or who do not have any post-baseline tumor assessments will be censored on the day of 
randomization, with a duration of 1 day, unless death occurred on or before the time of the 
second planned tumor assessment, in which case the death will be considered an event.
The primary analysis of PFS will be performed on the FA set, based on BICR assessment.  A 
stratified log-rank test (one-sided) will be used to compare PFS time between the 2 treatment 
arms at the interim and/or final analyses with the overall significance level preserved at
0.025 (one-sided).  The stratification factors used to conduct the stratified log-rank test for
the primary analysis will include the two randomization stratification factors and 
additionally, as a sensitivity analysis, may include other factors, such as baseline ECOG PS, 
that will be specified in the SAP.  PFS times associated with each treatment arm will be 
summarized using the Kaplan-Meier method and displayed graphically where appropriate.  
Confidence intervals (CIs) for the 25th, 50th, and 75th percentiles will be reported.  The Cox 
proportional hazards model will be fitted to compute the treatment HRs and the 
corresponding 95% CIs. 

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Sensitivity analyses of PFS by BICR assessment will also be performed as described in the 
statistical analysis plan.  Additionally, a Cox regression model, stratified for baseline
stratification factors, will be used to explore the potential influences of the other factors on
the primary PFS endpoint. 
9.3.2. Analysis of Secondary Endpoints
All analyses will be performed using the FA set.  The analysis of PFS will be repeated based 
on the Investigator’s assessment.
The analyses of other tumor-related endpoints will be based on the BICR assessment, with 
the exception of OR that will be based both on BICR and on the investigator’s assessment.
9.3.2.1. Overall Survival
Overall Survival (OS) is defined as the time from date of randomization to date of death due 
to any cause.  Patients last known to be alive will be censored at date of last contact.
OS will be hierarchically tested for significance at the time of PFS interim/final analysis, 
provided the primary endpoint, PFS, is statistically significant at that analysis.  In this case, 
OS will also be tested at 70% of the OS events (provided the first interim analysis of OS is 
not statistically significant) and at the OS final analysis (provided both interim analyses of 
OS are not statistically significant).  A stratified log-rank test (one sided; using the same 
stratification factors used for PFS analysis) will be used at the interim and/or final analyses 
with the overall significance level preserved at 0.025 (one sided).  OS time associated with 
each treatment arm will be summarized using the Kaplan- Meier method and displayed 
graphically where appropriate.  CIs for the 25th, 50th, and 75th percentiles will be reported.  
The Cox proportional hazards model will be fitted to compute the treatment HRs and the 
corresponding 95% CIs.
Sensitivity analyses to adjust for the influence of subsequent therapy on the OS may be 
conducted, and further details will be specified in the statistical analysis plan. 
9.3.2.2. Objective Response 
Objective Response (OR) is defined as a complete response (CR) or partial response (PR) per 
RECIST version 1.1 (see Appendix 3) recorded from randomization until disease progression 
or start of new anti-cancer therapy.  Both CR and PR must be confirmed by repeat 
assessments performed no less than 4 weeks after the criteria for response are first met.  A 
patient will be considered to have achieved an OR if the patient has a sustained CR or PR 
according to RECIST version 1.1 definitions.  Otherwise, the patient will be considered as a 
non-responder in the ORR analysis.  Additionally, patients with inadequate data for tumor 
assessment (eg, no baseline assessment or no follow-up assessments) will be considered as 
non-responders in the ORR analysis.

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The ORR on each treatment arm will be estimated by dividing the number of patients with 
OR (CR or PR) by the number of patients randomized to the respective treatment arm.  The 
corresponding exact 2-sided 95% CIs will be provided.  OR comparison between the 
2 treatment arms will be assessed using Cochran-Mantel-Haenszel (CMH) test using the 
same stratification factors as for the PFS analysis.
In addition, the Best Overall Response (BOR) for each patient will be summarized by 
treatment arm.
9.3.2.3. Intracranial Objective Response
Intracranial Objective Response (IC-OR) is defined as above for OR but it is only based on 
intracranial disease in the subset of patients with at least 1 intracranial lesion. 
The IC-OR will be summarized similar to how OR will be summarized as described above. 
If data permits, IC-OR will also be summarized in the subset of patients with at least 
1 measurable intracranial lesion.
9.3.2.4. Intracranial Time to Progression
Intracranial Time to Progression (TTP) is defined as the time from randomization to the date 
of the first documentation of objective progression of intracranial disease, based on either 
new brain metastases or progression of existing brain metastases. 
IC-TTP will be calculated for the FA set and for subgroups of patients with and without brain 
metastases at baseline. For the subgroup of patients without brain metastases at baseline only 
the new brain metastases will be considered events.
Differences between treatment arms will be assessed by the stratified log-rank test.  IC-TTP 
associated with each treatment arm will be summarized using the Kaplan -Meier method and 
displayed graphically where appropriate.  CIs for the 25th, 50th, and 75th percentiles will be 
reported.  The Cox proportional hazards model will be fitted to compute the treatment HRs 
and the corresponding 95% CIs.  Intracranial progression events may also be analyzed by 
cumulative incidence functions.
9.3.2.5. Duration of Response 
Duration of Response (DR) is defined, for patients with an OR per RECIST version 1.1, as 
the time from the first documentation of objective tumor response (CR or PR) to the first 
documentation of objective tumor progression or death due to any cause, whichever occurs 
first.  Censoring rules for DR will follow those described above for PFS. 
DR will be summarized by treatment arm using Kaplan-Meier methods and displayed 
graphically, where appropriate.  The median DR and 95% CI for the median will be provided
for each treatment arm.

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9.3.2.6. Intracranial Duration of Response 
The IC-DR, based on BICR, will be summarized similar to DR as described above in the 
subset of the FA population with an IC-BOR of CR or PR, as the time from the first 
documentation of intracranial objective response (CR or PR) per RECIST 1.1 based on BICR 
to the date of first documentation of intracranial objective progression of disease (PD) or 
death due to any cause. If IC-OR will be summarized in the subset of patients with at least 
1 measurable intracranial lesion, a corresponding IC-DR will be provided. 
9.3.2.7. Time to Tumor Response
Time to Tumor Response (TTR) is defined, for patients with a confirmed OR, as the time 
from the date of randomization to the first documentation of objective response (CR or PR) 
which is subsequently confirmed.
TTR will be summarized using simple descriptive statistics (mean, SD (standard deviation), 
min, max, 25th, 50th, and 75th percentiles).
9.3.2.8. Intracranial Time to Tumor Response 
Intracranial TTR based on BICR is defined, for patients with a confirmed IC-OR, as the time 
from the date of randomization to the first documentation of intracranial objective response 
(CR or PR) which is subsequently confirmed.
IC-TTR will be summarized using simple descriptive statistics (mean, SD, median, min, 
max, Q1, Q3).
9.3.2.9. Progression-Free Survival 2
PFS2 is defined as the time from randomization to the date of progression of disease on first
subsequent systemic anti-cancer therapy, or death from any cause, whichever occurs first. If 
no date of disease progression on first subsequent systemic anti-cancer therapy is available, 
patients will be censored at date of last contact.  A sensitivity analysis will be conducted 
including the date of discontinuation from first subsequent systemic anti-cancer therapy as an 
event. 
Differences between treatment arms will be assessed by the stratified log-rank test. 
PFS2 time associated with each treatment arm will be summarized using the Kaplan-Meier 
method and displayed graphically where appropriate.  CIs for the 25th, 50th, and 75th 
percentiles will be reported.  The Cox proportional hazards model will be fitted to compute 
the treatment HRs and the corresponding 95% CIs.
9.3.2.10. Patient-Reported Outcomes
The EORTC QLQ-C30, EORTC QLQ LC13, and EQ-5D-5L will be scored according to 
their respective user guides/scoring manuals.42,39
For each treatment arm and at each time point, the number and percentage of patients who 
complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L will be summarized in 
a table, as will the reasons for non-completion of these measures.

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Patient-reported HRQoL, disease/treatment-related symptoms of lung cancer, and health 
status will be assessed.  Summary statistics (mean (and SD), median, range, and 95% CI) of 
absolute scores will be reported for the items and subscales of the EORTC QLQ C30, the 
items and subscales of the EORTC QLQ-LC13, and the EQ-5D-5L VAS scale.  The mean 
change of absolute scores from baseline (and 95% CI) will also be assessed.  Line charts 
depicting the means and mean changes of items and subscales over time will be provided for 
each treatment arm.
The number and proportion of patients who improved, worsened, or remained stable for the 
symptom and functional domains, global QOL and single items of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 will be summarized for each treatment arm. 
Improvement, worsening, and stable categories will be determined over each cycle and 
summarized as an average by patient in the symptom scales, functioning scales, and in the 
global QOL scale.  In the symptom scales, improvement is defined as a decrease of at least 
10 points.  In the functioning and global QOL scales improvement is defined as an increase 
of at least 10 points.  In the symptom scales worsening is defined as an increase of at least 
10 points.  In the functioning scale and global QOL scales, worsening is defined as a 
decrease of at least 10 points.  Global QOL, functioning scales, and symptom scales that have 
not improved nor worsened will be considered stable Osoba et al, established that a ≥10 point 
minimally important difference from baseline (ie, the first PRO measurement prior to initial 
treatment) on the scales of the EORTC QLQ-C30 would correlate with significant (moderate) 
change in disease symptoms and functioning.41
For the EQ-5D-5L health state profiles, the proportions of patients reporting “no”, “slight”, 
“moderate”, “severe”, or “extreme” problems will be reported at each time point.
Scales assessing pain in chest, dyspnea, and cough from the EORTC-QLQ-LC13 will be 
used to evaluate TTD of these symptoms.  TTD in pain in chest, dyspnea, or cough 
individually and as a composite endpoint will be defined as the time from randomization to 
the first time the patient’s score shows a 10 point or greater increase after baseline in any of 
the 3 symptoms.  Patients will be censored at the last time they completed a subscale 
assessment if they have not deteriorated.
TTD of the symptom subscales will be summarized using Kaplan-Meier methods.  The 
estimated Kaplan-Meier plots will be provided, and the 1-sided log-rank test stratified by 
randomization stratification factors will be the primary method to compare the time to first 
deterioration between lorlatinib and crizotinib.  The median TTD and 2-sided 95% CI for the 
median will also be provided based on the Brookmeyer-Crowley method.
Treatment arms will be evaluated based on the mean scores of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 and the EQ-5D-5L utility and VAS scores obtained from longitudinal 
mixed-effects regression models that contain the baseline score as a covariate.  Other 
exploratory PRO analyses may be performed subsequently as needed.

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9.4. Analysis of Other Endpoints
 
 
 
 
 
9.4.3. Biomarker Analysis for Secondary 
 Endpoints
Biomarkers will be assessed separately for whole blood, serum, plasma, archival tumor 
tissue, and de novo tumor tissue biospecimens.  In each case, summaries of baseline levels, 
changes from baseline (where appropriate), expression or genetic alterations will be reported.  
For continuous variables, summary statistics may include the mean, ratio to baseline, 
standard deviation, 25th, median, and 75th percentile, %CV and minimum/maximum levels 
of biomarker measures; for categorical variables, summary may include number and 
percentage, odds ratio, frequency statistics, as appropriate. 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Wilcoxon Signed Rank, Wilcoxon Rank Sum Test, Kaplan-Meier estimates 
of efficacy parameters (eg, PFS, OS) with biomarkers as a covariate, or Box plots (this list is 
not exhaustive.)  The statistical approach will examine correlations of biomarker results with 
pharmacokinetic parameters and measures of anti-tumor efficacy.
 
  
9.5. Safety Analysis
The SA set will be the primary population for safety evaluations.  Summaries of AEs and 
other safety parameters will be provided, by treatment arm, as appropriate.
9.5.1. Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).
CCI
CCI
CCI

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The frequency of patients experiencing TEAEs corresponding to system organ class and 
MedDRA preferred term will be reported.  Adverse events will be summarized by worst NCI 
CTCAE v4.03 severity grade and relatedness to study treatment within each treatment arm.
In all summaries, emphasis will be on TEAEs, namely, those with initial onset or that worsen 
in severity after the first dose of study medication.
Adverse events leading to death or discontinuation of study treatment, events classified as 
NCI CTCAE v4.03 Grade ≥3, trial drug-related events, and serious adverse events will be 
considered with special attention.  As appropriate, the difference in risk between treatment 
arms for adverse events of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each adverse event will include a description of the event, 
duration, whether the adverse event was serious, intensity, relationship to study treatment, 
action taken, and clinical outcome.
9.5.2. Laboratory Abnormalities
Laboratory test results will be graded according to NCI CTCAE v4.03.  The frequency of 
patients with laboratory test abnormalities will be summarized according to the worst grade 
for each laboratory test result. 
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.
9.5.3. Electrocardiograms
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged, and all summary statistics and data presentations will use the triplicate averaged 
data.  Any data obtained from ECGs repeated for safety reasons after the nominal time points 
will not be averaged along with the preceding triplicates.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s [default correction], Bazett’s, and possibly a study-specific factor, as 
appropriate).  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) of 
corrected QT interval 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.
9.5.4. Left Ventricular Ejection Fraction
For patients with MUGA scans or echocardiograms, individual LVEF proportion (%) and its 
changes from baseline will be summarized by time point.  The number of patients and the 

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percentage whose maximum relative decrease from baseline in LVEF is greater than 20% 
will be calculated. 
9.5.5. Ophthalmologic Data
For the ophthalmologic data, baseline is defined as the ophthalmologic exam performed at 
screening.
Best-corrected visual acuity examination results: changes from baseline will be 
summarized/listed for all patients from the SA set with a baseline and at least one 
post-baseline assessment.
Biomicroscopy (Slit Lamp) and Ophthalmoscopy (Fundoscopy) Exam Results: For baseline 
results, percentage of patients falling into each category of the examination status (normal, 
abnormal: mild, abnormal: moderate, abnormal: severe, not done) will be summarized for 
each structure by eye.  For post-baseline results, percentage of patients falling into each 
category of the examination status (new findings/worsening of findings, no change, 
improvement of findings, not done, etc.) will be summarized for each structure by eye, for all 
patients with a baseline and at least 1 post-baseline assessment.
Additional summaries of ophthalmologic data will be considered as appropriate and 
described in the SAP.
9.5.6. Mood and Suicidal Ideation and Behavior Analyses
Changes across treatment will be described according to the Statistical Analysis Plan.
9.6. Interim Analysis 
The interim analysis (IA) will be performed based on the FA set.  Any safety evaluation at 
the time of the IA will be based on the SA set.
The goals of the IA are to allow early stopping of the study for efficacy and to assess the 
safety of lorlatinib. The IA will be performed with all patients randomized in the study.
The study is designed to have 1 IA and the final analysis based on the primary PFS endpoint 
as assessed by BICR.  A Lan-DeMets (O’Brien-Fleming) α-spending function is used to 
determine the efficacy boundaries for PFS as shown in table below (Table 6).
Table 6.
Stopping Boundaries for PFS
Analysis
Number of events 
(Information fraction)
Z scale
p-value (1-sided)
Interim
133 (75%)
Z <-2.337
P<0.01
Final
177 (100%)
Z <-2.012
P<0.022
The IA will be performed after approximately 133 PFS events (75% of the 177 events 
planned at the end of the study) If the value of the test statistic exceeds the efficacy boundary 
(z <-2.337, p <0.01, if the interim analysis is performed after exactly 133 events), then the 
study is considered to have met its primary objective. If the results of the IA indicate serious 

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safety concerns, the sponsor will communicate with the Health Authorities regarding 
stopping the clinical trial.
The secondary OS endpoint will be analyzed using a hierarchical testing procedure, provided 
the primary PFS endpoint is statistically significant favoring lorlatinib.  A maximum of 
3 analyses are planned for OS: at the time of the interim/final PFS analysis (the one that 
exceeded the efficacy boundary), at 70% and 100% (final OS analysis) of the 198 OS events. 
An α-spending function according to Lan-DeMets (O’Brien-Fleming) independent of the one 
used for the primary efficacy analysis will be used to preserve the 0.025 overall level of 
significance across the repeated testing of the OS hypotheses in the interim and final 
analyses. The exact nominal p-values that will need to be observed to declare statistical 
significance at the time of these analyses for OS will depend on the number of OS events that 
have been observed at the time of these analyses and the α for OS already spent at the time of 
earlier analyses.  The trial allows for the stopping of the study for a superior OS result, 
provided the primary PFS endpoint has already been shown to be statistically significant 
favoring lorlatinib.
9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC) comprised of at least 
3 members with at least one having appropriate medical qualifications and one statistician.
The E-DMC will be responsible for ongoing monitoring of the safety of patients in the study 
and the evaluation of efficacy at the IAs according to the charter.  The recommendations 
made by the E-DMC to alter the conduct of the study will be forwarded to Pfizer Oncology 
Management for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data that are not endpoints, 
to regulatory authorities, as appropriate. 
The expected frequency of the E-DMC meetings and what will be presented or decided at the 
meetings will be detailed in the DMC charter. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct 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 are 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.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/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.

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The investigators will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigators 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 patient.  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 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 are 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 hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(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 

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correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
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 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/Ethics Committee
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 patients.  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 the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
In addition, the study will be conducted in accordance with the protocol, and any applicable 
local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 

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When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH Good Clinical Practice (GCP), local regulatory requirements, and legal 
requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study patient, 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 patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’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 patient or the patient's legally acceptable representative, before any 
study-specific activity is performed.  The investigator will retain the original of each patient's 
signed consent document.
12.4. 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 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 

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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects 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 TRIAL
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
lorlatinib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  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), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the pre-specified protocol or was terminated.

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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is 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 before disclosure, except for any study-or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  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, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the 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.

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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control. If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

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Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:829-38.
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Alecensa US package insert at 
http://www.google.it/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&cad=rja
&uact=8&ved=0ahUKEwjbxKufn_3NAhUJNhoKHbGgBh8QFggfMAA&url=http%3
A%2F%2Fwww.accessdata.fda.gov%2Fdrugsatfda_docs%2Flabel%2F2015%2F20843
4s000lbl.pdf&usg=AFQjCNE8ZHU2xdzp7BqM3yz0S1zsN7hKKg.
24.
ALEX study (A Randomized, Phase III Study Comparing Alectinib With Crizotinib in 
Treatment-Naïve Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell 
Lung Cancer Participants) at https://clinicaltrials.gov/ct2/show/NCT02075840.
25.
Kim DW et al. Activity and safety of ceritinib in patients with ALK-rearranged non-
small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, 
phase 1 trial.  Lancet Oncology 2016; 17:452-63.
26.
Shaw AT et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung 
Cancer. NEJM 2013; 365:2385-94.

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27.
Solomon BJ et al. First Line Crizotinib versus Chemotherapy in ALK Positive Lung 
Cancer. NEJM 2014; 371;23, 2167-77.
28.
Shaw AT et al. Crizotinib in ROS1 Rearranged Non–Small Cell Lung Cancer. NEJM 
2014; 371:1963-71.
29.
Zou, H et al. PF 06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and 
second generation ALK inhibitors in preclinical models. Cancer Cell 28: 70 81, 2015.
30.
Bauer, TM, Clinical Activity and Safety of the ALK /ROS1 TK Inhibitor PF 06463922 
in Advanced NSCLC Oral Presentation 33.07, World Conference on Lung Cancer, 
Denver, Colorado, September 2015.
31.
Camidge DR, Pao W and Sequist LV. Acquired resistance to TKIs in solid tumours: 
learning from lung cancer. Nat Rev Clin Onc. 2014; 11: 473-481.
32.
Smith,TJ et al. Recommendations for the Use of WBC Growth Factors: American 
Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol, 2015; 
33.
33.
Long G et al. Dabrafenib in patients with Val600GLu or Val600Lys BRAF-mutant 
melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, Phase 2 
trial.  Lancet Oncology 2012; 13:1087-1095.
34.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research 
and Treatment of Cancer QLQ C30: a quality of life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 1993; 85:365-76.
35.
Bergman B et al. The EORTC QLQ LC13: a modular supplement to the EORTC Core 
Quality of Life Questionnaire (QLQ C30) for use in lung cancer clinical trials. EORTC 
Study Group on Quality of Life. Eur J Cancer 1994, 30A:635 42.
36.
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. 
2011. Development and preliminary testing of the new five level version of EQ 5D (EQ 
5D 5L). Quality of Life Research. 20:1727-1736.
37.
Posner K, Brown GK, et al.  The Columbia–Suicide Severity Rating Scale: Initial 
Validity and Internal Consistency Findings from Three Multisite Studies with 
Adolescents and Adults.  Am J Psychiatry 2011; 168: 1266-1277.
38.
Janssen et al 2013. Measurement properties of the EQ 5D 5L compared to the EQ 5D 
3L across eight patient groups: a multi country study. Qual Life Res. 22:1717- 1727.
39.
The EuroQol Group.  EQ-5D-5L: User Guide. V 2.1, April 2015. EuroQol Research 
Foundation, Rotterdam.

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40.
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med. 2001 Jul; 33 (5): 337-43. Review.
41.
Osoba D et al, Interpreting the significance of changes in health-related quality of life 
scores. 3. Cin Oncology. 1998. 16:139-144.
42.
Fayers P et al. EORTC QLQ-C30 Scoring Manual. 2001. EORTC, Brussels.
43.
Brookmeyer R, Crowley 33. A confidence interval for the median survival time. 
Biometrics 1982; 38:29-41.
44.
Nada A et al. The evaluation and management of drug effects on cardiac conduction 
(PR and QRS Intervals) in clinical development. Am Heart J 2013;165:489-500).

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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ADME
Absorption, Distribution, Metabolism and 
Elimiation
AE
adverse event
AIDS
Acquired Immune Deficiency Syndrome
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
Absolute neutrophils count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time 
curve
BAL
bronchoalveolar lavage
BBB
blood brain barrier
BfArM
Bundesinstitut für Arzneimittel und 
Medizinprodukte
BICR
Blinded Independent Central Review 
BID
bis in die (twice daily)
BNP
B-type natriuretic peptide
BOR
Best Overall Response
CDx
Companion Diagnostics
Cmax
maximum plasma concentration
Ctrough
trough plasma concentration
CDS
Core data sheet
CE
Conformité Européene
CI
Confidence Interval
CK
Creatine kinase
CM
carcinomatous meningitis
CNS
central nervous system
CR
Complete response
CRF
case report form
CRM
continual reassessment method
CSA
clinical study agreement
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse 
CCI

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Abbreviation
Term
Events
CV
Coefficient of variation
DDI
Drug-drug interaction
DILI
Drug-Induced Liver Injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
Duration of Response
DU
dispensing unit
EC
ethics committee
ECG
electrocardiogram
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EDP
exposure during pregnancy
EudraCT
European Clinical Trials Database
FA
Full Analysis 
FDA
Food and Drug Administration (United 
States)
FFPE
formalin fixed paraffin embedded
FNA
fine needle aspiration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
High density lipoprotein
HDPE
High Density Polyethylene
HGFR
Hepatocyte Growth Factor Receptor 
HIV
human immunodeficiency virus
HR
hazard ratio
HRQL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analyses
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IC-OR
Intracranial Objective Response
IC-DR
Intracranial Duration of Response
IC-TTR
Intracranial Time to Tumor Response
ID
identification
IHC
Immunohistochemistry
ILD
interstitial lung disease
IND
investigational new drug application
INR
international normalized ratio
IP
Investigational product

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Abbreviation
Term
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IVR
interactive voice response
IWR
interactive web response
LDL
Low density protein
LVEF
left ventricular ejection fraction
LFT
liver function test
LMD
leptomeningeal disease
LPLV
last patient last visit 
MRI
Magnetic Resonance Imaging
MDZ
midazolam
MUGA
multigated acquisition
N/A
not applicable
NGS
next generation sequencing
NSCLC
non-small cell lung cancer
NTI
Narrow therapeutic index
OCT
optical coherence tomography
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PAH
Pulmonary Arterial Hypertension
PAP
Pulmonary Arterial Pressure
PCD
primary completion date
PD
Pharmacodynamics
PFS
Progression-Free Survival
P-gp
Permeability glycoprotein
PMDA
Pharmaceuticals and Medical Devices 
Agency
PK
Pharmacokinetics
PH
Pulmonary Hypertension
PI
Principal Investigator
PR
Partial response
PRO
Patient-Reported Outcome
PST
Potential Sight Threatening 
PT
prothrombin time
QD
quaque die (every day)
RECIST
Response Evaluation Criteria In Solid Tumor
RNA
ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
serious adverse event
SAP
statistical analysis plan
SCL
Supply Chain Lead
SD
Stable disease

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Abbreviation
Term
SD
Standard deviation
SIB
suicidal ideation and behavior
SoA
Schedule of Assessment
SOC
Standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SVL
Severe Vision Loss 
TEAE
treatment-emergent adverse event
Tmax
time to reach Cmax
TKI
Tyrosine Kinase Inhibitor
TTE
Trans Thoracic Echocardiogram
TTP
Time to Tumor Progression
TTR
Time to Tumor Response
ULN
upper limit of normal
US
United States
VAS
Visual Analogue Scale
WOCBP
Women of Childbearing Potential

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Appendix 2. Eastern Cooperative Oncology Group (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 3. RECIST Version 1.1 - Modified to Include Assessment of CNS Metastases
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation. 
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable:
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

5 mm for CNS lesions provided gadolinium contrast enhanced MRI is performed with 
contingent slices of 1 mm;

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable: All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin, or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques. 
NOTE: If 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 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Exception to this rule 
is in the presence of CNS metastases ≥5 mm in diameter assessed by gadolinium 
contrasted MRI with slices of 1 mm; up to 5 CNS lesions will be permitted in addition 
to 5 extracranial lesions previously noted.33 Target lesions should be selected on the basis 
of their size (lesion with the longest diameters) and their suitability for accurate repetitive 
measurements (either by imaging techniques or clinically). 

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The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 
diameter to be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters.
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” or “absent.”
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Definitions of Tumor Response
Target Lesions

Complete response (CR) is defined as the disappearance of all target lesions.  Any
pathological lymph nodes (whether target or non-target) must have reduction in short 
axis to <10 mm.

Partial response (PR) is defined as a 30% decrease in the sum of the longest 
dimensions of the target lesions taking as a reference the baseline sum longest 
dimensions.

Progressive disease (PD) is defined as a 20% increase in the sum of the longest 
dimensions of the target lesions taking as a reference the smallest sum of the longest 
dimensions recorded since the treatment started, or the appearance of one or more 
new lesions.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.

Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as a reference the smallest sum of the 
longest dimensions since the treatment started.
Non-Target Lesions

Complete response (CR) is defined as the disappearance of all non-target lesions.  
All lymph nodes must be non-pathological in size (<10 mm short axis).

Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.

Progressive disease (PD) is defined as unequivocal progression of existing 
non-target lesions, or the appearance of 1 new lesion.

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
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease and 
progressive disease.
Confirmation of Tumor Response
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.
Response Evaluation Criteria in Solid Tumors
Target Lesions1
Non-Target Lesions2
New Lesions3
Tumor 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
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
1 Measurable lesions only.
2 May include measurable lesions not followed as target lesions or non-measurable lesions.
3 Measurable or non-measurable lesions.

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Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  For CR and PR, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 6 weeks.
NOTE: 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 the objective 
progression even after discontinuation of treatment.  It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation to 
document whether or not objective tumor progression has occurred. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy before 
confirming the complete response status. 

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Appendix 4. Required Laboratory Tests
The following laboratory tests must be performed in fasted condition.
Hematology
Chemistry Panel
Urinalysis§
Coagulation Tests
Hemoglobin
ALT
Protein, glucose and 
blood, albumin
Urine dipstick for urine 
protein: If positive, and 
clinically indicated, 
collect 24-hour and 
microscopic urinalyses 
(Reflex Testing)
Urine dipstick for urine 
blood: If positive, 
collect microscopic 
urinalysis (Reflex 
Testing)
PT or INR
Platelets
AST
aPTT
WBC
Alkaline Phosphatase
Absolute Neutrophils*
Sodium
Absolute 
Lymphocytes*
Potassium
Absolute Monocytes*
Magnesium
Absolute Eosinophils*
Chloride
Absolute Basophils*
Calcium
Total Bilirubin 
BUN or Urea
Creatinine
Glucose 
Phosphorus or Phosphate
Albumin
Lipids
Total Protein
Pregnancy Tests
Total Cholesterol
Uric Acid
For female patients of 
childbearing potential, 
serum or urine 
LDL**
Amylase^
HDL  
Gamma glutamyl 
transferase (GGT)
Triglycerides
Infections 
Creatine kinase
HBV, HCV (Screening 
only and if clinically 
indicated in case 
infection status is 
unknonwn)
C-reactive protein (CRP) 
Lactate dehydrogenase 
(LDH)
Lipase
°Potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time 
(PT)/INR, alkaline phosphatase, and acetaminophen levels.

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^ Serum total amylase (pancreatic isoenzyme required if serum total amylase >1.5x ULN per local institutional 
ranges (ie, CTCAE Grade >1)).
§ Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal and/or if this is the local 
standard.  To be repeated as clinically indicated, for example upon diagnosis of renal cysts (more frequent 
assessment may be performed based on local requirement). In Korea, dipstick urinalysis should be performed 
in all patients at screening and on Day 1 of each cycle thereafter.
* If absolute values are not reported as per local laboratory standard practice, percentages (%) are acceptable.
**A measured LDL value is preferable instead of the calculated LDL. If LDL value is calculated from 
Friedewald equation, this can be considered only in absence of the following circumstances: plasma triglyceride 
concentration exceeds 400 mg/dL (4.52 mmol/L) and in patients with dysbetalipoproteinemia 
(type III hyperlipoproteinemia). 
ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CRP=C-reactive protein, GGT=gamma-glutamyltransferase, HDL = High density 
protein, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international normalized ratio, LDH=lactate 
dehydrogenase, LDL =Low density lipoprotein, WBC=white blood cell.

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Appendix 5. Medications with Potential PR Interval Prolongation Effect
Note that the drugs listed below are examples and this is not intended to be an all-inclusive 
listing (from Nada A, et al. Am Heart J 2013;165:489-500)44
Electrophysiologic Effects of Select Drugs on PR Interval Based on Product Labeling
Drug
Action
Indications
Affecting AV nodal conduction (PR interval
Adenosine
Adenosine receptor
PSVT
Amiodarone
Cardiac ion channels
Antiarrhythmics
Disopyarmide
Encainide
Flecainide
Moricizine
Propafenone
Verapamil
Arsenic trioxide
Multiple actions
Acute promyelocytic Leukemia
Atazanavir
HIV-protease inhibitors
Antiretroviral inhibitor
Lopinavir/Ritonavir
Saquinavir
Digoxin
Multiple actions
Congestive heart failure
Dolasetron
5HT3 receptor antagonist
Antiemetic
Fingolimod
S1P receptor modulator
Multiple sclerosis
Lacosamide
Not fully characterized
Partial-onset seizures
Pregabalin
Not fully characterized
Neuropathic pain
Mefloquine
Plasmodicidal effects
Antimalarial
Drugs were initially screened using the PDR3D database for PR interval prolongation using terms “PR 
interval prolongation”, “AV block”, “AV conduction delay”, or “heart block”.  Drugs were subsequently 
selected for inclusion on the basis on descriptions of PR interval prolongation/AVB contained with Warning 
or Precautions sections of drug labels. 
PSVT, Paroxysmal supraventricular tachycardia.

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Appendix 6. PRO Instruments

EORTC QLQ-C30 (version 3).

EORTC QLQ - LC13.

EQ-5D-5L.

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EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the 
questions yourself by circling the number that best applies to you.  There are no "right" or 
"wrong" answers. The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year):
________________________________________________________________________________
Not at 
A
Quite
Very
All
Little
a Bit
Much
1. Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2. Do you have any trouble taking a long walk?
1
2
3
4
3. Do you have any trouble taking a short walk 
outside of the house?
1
2
3
4
4. Do you need to stay in bed or a chair during the day?1
2
3
4
5. Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at 
A
Quite
Very
All
Little
a Bit
Much
6. Were you limited in doing either your
work or other daily activities?
1
2
3
4
7. Were you limited in pursuing your hobbies or 
other leisure time activities?
1
2
3
4
8. Were you short of breath?
1
2
3
4
9. Have you had pain?
1
2
3
4
10.Did you need to rest?
1
2
3
4
11.Have you had trouble sleeping?
1
2
3
4
12.Have you felt weak?
1
2
3
4

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13.Have you lacked appetite?
1
2
3
4
14.Have you felt nauseated?
1
2
3
4
15.Have you vomited?
1
2
3
4
16.Have you been constipated?
1
2
3
4
Please go on to the next page

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During the past week:
Not at 
A
Quite
Very
All
Little
a Bit
Much
17.Have you had diarrhea?
1
2
3
4
18.Were you tired?
1
2
3
4
19.Did pain interfere with your daily activities?
1
2
3
4
20.Have you had difficulty in concentrating on things,
like reading a newspaper or watching television? 1
2
3
4
21.Did you feel tense?
1
2
3
4
22.Did you worry?
1
2
3
4
23.Did you feel irritable?
1
2
3
4
24.Did you feel depressed?
1
2
3
4
25.Have you had difficulty remembering things? 1
2
3
4
26.Has your physical condition or medical
treatment interfered with your family life?
1
2
3
4
27.Has your physical condition or medical 
treatment interfered with your social activities?
1
2
3
4
28.Has your physical condition or medical 
treatment caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0

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EORTC QLQ - LC13
Patients sometimes report that they have the following symptoms. Please indicate the extent 
to which you have experienced these symptoms or problems during the past week.
____________________________________________________________________
During the past week:
Not at 
A
Quite
Very
All
Little
a Bit
Much
31.
How much did you cough?
1
2
3
4
32.
Did you cough up blood?
1
2
3
4
33.
Were you short of breath when 
you rested?
1
2
3
4
34.
Were you short of breath when 
you walked?
1
2
3
4
35.
Were you short of breath when you 
climbed stairs?
1
2
3
4
36.
Have you had a sore mouth or 
tongue?
1
2
3
4
37.
Have you had trouble swallowing?
1
2
3
4
38.
Have you had tingling hands or feet? 1
2
3
4
39.
Have you had hair loss?
1
2
3
4
40.
Have you had pain in your chest?
1
2
3
4
41.
Have you had pain in your arm or 
shoulder?
1
2
3
4
42.
Have you had pain in other parts 
of your body?
1
2
3
4
If yes, where 
43.
Did you take any medicine for pain? 
1
No
2
Yes
If yes, how much did it help? 
1
2
3
4
QLQ-C30-LC13 Copyright 1994 EORTC Study Group on Quality of life.  All rights reserved

Lorlatinib (PF 06463922)
B7461006
Final Protocol Amendment 4, 4 October 2019
PFIZER CONFIDENTIAL
Page 138
EQ-5D-5L
Health Questionnaire
English version for the USA
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (eg, work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities


Lorlatinib (PF 06463922)
B7461006
Final Protocol Amendment 4, 4 October 2019
PFIZER CONFIDENTIAL
Page 139
PAIN/DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY/DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed


Lorlatinib (PF 06463922)
B7461006
Final Protocol Amendment 4, 4 Oc

We would like to kno
how good or bad your
health is TODAY.

This scale is numbere
from 0 to 100.

100 means the best he
you can imagine.
0 means the worst hea
you can imagine.

Mark an X on the sca
indicate how your hea
TODAY.

Now, please write the
number you marked o
scale in the box below
ctober 2019
PFIZER CONFIDENTIAL
Page 140
The best health you can imagine
The worst health you can imagine
ow 
r 
ed 
ealth 
alth 
ale to 
alth is 
e 
on the 
w.
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95

Lorlatinib (PF 06463922)
B7461006
Final Protocol Amendment 4, 4 October 2019
PFIZER CONFIDENTIAL
Page 141
Appendix 7. Specific for France
This appendix applies to study sites located in France.
1. GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer.  Any investigators who later join 
the study will complete the Pfizer GCP Training or equivalent before performing 
study-related duties.  For studies of applicable duration, the investigator and 
sub-investigators will complete Pfizer GCP Training or equivalent every three years 
during the term of the study, or more often if there are significant changes to the ICH 
GCP guidelines or course materials.
2. Investigational Product
No subjects or third-party payers will be charged for investigational product.